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Niraparib for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer
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Niraparib for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer
Evidence-based recommendations on niraparib (Zejula) for treating relapsed, platinum-sensitive high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer in adults.
# Recommendations
Niraparib is recommended as an option for treating relapsed, platinum-sensitive high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to the most recent course of platinum-based chemotherapy in adults. It is recommended only if:
they have a BRCA mutation and have had 2 courses of platinum-based chemotherapy, or
they do not have a BRCA mutation and have had 2 or more courses of platinum-based chemotherapy, and
the company provides it according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for niraparib for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer (NICE technology appraisal guidance 528).
Niraparib improves how long people with relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer live before their disease progresses. New evidence collected while niraparib was available through the Cancer Drugs Fund suggests it may also extend how long these people live. But, it is uncertain if niraparib extends how long people without a BRCA mutation may live.
Cost-effectiveness estimates for niraparib in people with a BRCA mutation whose disease has responded to 2 courses of platinum-based chemotherapy and for people without a BRCA mutation whose disease has responded to 2 or more courses of platinum-based chemotherapy are in the range usually considered a cost-effective use of NHS resources. Therefore, niraparib is recommended.# Information about niraparib
# Marketing authorisation indication
Niraparib (Zejula, GSK) has a marketing authorisation for 'the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for niraparib.
# Price
The list price for niraparib is £4,500 for a 56‑tablet pack of 100 mg tablets; £6,750 for an 84‑tablet pack of 100 mg tablets (excluding VAT; BNF online, accessed August 2021).
The company has a commercial arrangement. This makes niraparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by GSK, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway and clinical need
## There is an unmet clinical need for maintenance treatments in clinical practice, especially for people without a BRCA mutation
Relapsed ovarian, fallopian tube or peritoneal cancer is a devastating condition with limited treatment options. For people with a BRCA mutation who have had fewer than 3 courses of platinum-based chemotherapy, there are no maintenance treatments available. For people without a BRCA mutation, there are no maintenance treatments available. People have multiple cycles of chemotherapy as the disease responds and relapses. The patient expert explained that chemotherapy side effects can substantially reduce a patient's quality of life, and concerns about relapse and the need for repeated courses of treatment are physically and psychologically challenging. NICE recommends olaparib for maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer for people with a BRCA1 or BRCA2 mutation who have had 3 or more courses of platinum-based chemotherapy. Niraparib and olaparib are both poly‑ADP‑ribose polymerase (PARP) inhibitors. The clinical expert explained that maintenance therapy with PARP inhibitors can delay disease progression and extend the time between platinum-based chemotherapies. Delaying disease progression may therefore delay the onset of platinum drug resistance. People with ovarian cancer that becomes platinum resistant have fewer chemotherapy regimen options available when the disease relapses and therefore have a poor prognosis. So, treatments that avoid the need for chemotherapy are highly valued by patients and their families. Extending survival, even by only a few months, can give people valuable extra time with family and friends. The clinical experts explained that several PARP inhibitors are currently available for first-line use through the Cancer Drugs Fund (see NICE's technology appraisal guidance on olaparib for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy, olaparib plus bevacizumab for maintenance treatment of advanced ovarian, fallopian tube or primary peritoneal cancer and niraparib for maintenance treatment of advanced ovarian, fallopian tube and peritoneal cancer after response to first-line platinum-based chemotherapy) for people with and without a BRCA mutation, but are limited to only niraparib in people without a BRCA mutation. The committee acknowledged that 80% of people with ovarian cancer do not have a BRCA mutation and that there is a particularly high unmet need in this group because no PARP inhibitors are recommended in routine commissioning after second-line treatment. The clinical expert also explained that because PARP inhibitors would not be used more than once in the treatment pathway, the number of people who would have treatment in a relapsed disease setting may be smaller in future clinical practice (depending on future Cancer Drugs Fund reviews). The committee concluded that there is an unmet need for maintenance treatments in clinical practice, especially for people without a BRCA mutation.
# Clinical evidence
## Niraparib improves progression-free survival compared with placebo regardless of how it is assessed
The clinical-effectiveness evidence came from NOVA, a double-blind, randomised, placebo-controlled trial. NOVA assessed the clinical effectiveness of niraparib in people with relapsed, platinum-sensitive ovarian cancer, with and without a BRCA mutation. Patients had previously had 2 or more platinum-based chemotherapy regimens and their cancer had responded to the last regimen. In the original appraisal, niraparib showed statistically significantly improved progression-free survival compared with placebo for both subgroups (with and without a BRCA mutation). However, the effect of niraparib on overall survival was uncertain. It was concluded that more mature data from NOVA could resolve this uncertainty and provide more evidence on the relative treatment effect. More data from NOVA has now been collected, and was analysed in October 2020. This analysis included an additional 49 months of data compared with the original appraisal. There was no updated data on progression-free survival because it was not assessed after the primary analysis. The committee recalled:
The median progression-free survival in people without a BRCA mutation was 9.3 months with niraparib and 3.9 months with placebo. The difference in median progression-free survival between niraparib and placebo was 5.4 months (hazard ratio 0.45; 95% confidence interval 0.34 to 0.61; p<0.001).
For people with a BRCA mutation, median progression-free survival was 21 months with niraparib and 5.5 months with placebo. The difference in median progression-free survival was 15.5 months (HR 0.27; 95% CI 0.17 to 0.41; p<0.001).The committee noted that progression-free survival results differed based on how they were assessed. The committee was aware that the company model used progression-free survival results assessed by an Independent Review Committee (IRC). The committee noted that any difference in benefit accrued could have a significant impact on the cost-effectiveness results because time on treatment (and so the related cost) was based on investigator assessment (IA), the preferred assumption from the original appraisal of niraparib. The ERG explained that this could result in costs and benefits not being aligned in the economic modelling. The committee considered the results of the 2 alternative methods of assessing progression-free survival (IA or IRC). Results are considered confidential and cannot be reported here. The committee noted niraparib increased progression-free survival compared with placebo in both treatment groups using both assessments. Both assessments showed greater clinical benefit in people with a BRCA mutation although the size of benefit was smaller for progression-free survival assessed by IA. The clinical expert and Cancer Drugs Fund clinical lead cautioned focusing only on the median results and explained that the hazard ratios of both IA and IRC assessed progression-free survival were similar. The committee agreed that, because hazards were similar regardless of who assessed, the method of assessment was unlikely to be critical to decision making. In response to the appraisal consultation document, the company prepared scenario analyses exploring the effect of using progression-free survival assessed by IA. These showed that results were not substantially different from results using IRC. The difference in median progression-free survival with the 2 assessment methods was less pronounced for people without a BRCA mutation and the committee concluded that the progression-free survival assessed by IA was not critical for decision making in this subgroup. Therefore, niraparib improves progression-free survival compared with placebo, regardless of how it is assessed.
## Niraparib may improve overall survival compared with placebo for people with a BRCA mutation but survival benefit with niraparib for people without a BRCA mutation is highly uncertain
The committee recalled that median overall survival had not been reached in the original appraisal of niraparib and that survival benefit with niraparib was the main clinical uncertainty. Updated data from NOVA showed:
Median overall survival in people without a BRCA mutation after 2 or more lines of platinum-based chemotherapy was 31.1 months with niraparib and 36.5 months with placebo. The difference in median overall survival between niraparib and placebo was 5.4 months (HR 1.1; 95% CI 0.83 to 1.46).
Results for people with a BRCA mutation after 2 lines of platinum-based chemotherapy are confidential and cannot be reported.The committee noted that NOVA was not powered to test for statistical significance for overall survival, and the company and ERG explained that the results for the placebo arm are confounded by a high rate of subsequent PARP inhibitor use and missing data. Discontinuation from the trial was more than 80% in both niraparib and placebo arms with at least 14% missing data. As a result, only updated survival data from the niraparib arm of NOVA was used for assessing relative effectiveness. The committee noted that, despite high levels of subsequent PARP inhibitor use in NOVA, the company had not attempted to adjust for this in their submission using methods such as the inverse probability of censoring weighting (IPCW) adjustment. The committee was aware that a recent commentary from a presentation at the Society of Gynecologic Oncology conference showed this result was available for a previous analysis from the NOVA trial. The clinical expert and the Cancer Drugs Fund clinical lead both agreed that the progression-free survival benefit shown for niraparib is likely to translate into an overall survival benefit for people with a BRCA mutation. The evidence was less certain for those without a BRCA mutation. In response to the appraisal consultation document, the company presented results adjusting for subsequent PARP inhibitor use in both people with and without a BRCA mutation. It highlighted the high discontinuation rate from both trial arms (see section 3.2) and considered that the IPCW results were not suitable for decision making because the amount of missing data meant subsequent PARP inhibitor treatment status was unknown for many people in the trial (25% incomplete) and there was also incomplete survival follow up. The ERG noted that, where data was available, crossover appeared to be limited (13%) for people in the placebo group who did not have a BRCA mutation and that the IPCW‑adjusted results were similar to unadjusted results. However, they cautioned that the analyses needed assumptions about the imputation of missing data. The committee concluded that niraparib may improve overall survival for people with a BRCA mutation but survival benefit with niraparib for people without a BRCA mutation is highly uncertain. Further analyses adjusting for crossover to subsequent treatments are inconclusive and are not able to resolve the uncertainty.
## Estimating relative effectiveness of niraparib compared with routine surveillance should be based on analyses adjusted for differences in baseline characteristics between NOVA and Study 19
Because of limitations in the survival data from the placebo arm of NOVA, the company used alternative data sources to estimate the relative effectiveness of niraparib compared with routine surveillance. In their original Cancer Drugs Fund review submission, the company used an assumption of a progression-free survival to overall survival benefit ratio of 1:1 to estimate overall survival for people on routine surveillance as their base case. For this appraisal, they also presented 2 alternative scenario analyses, one using placebo data from the olaparib trial, Study 19, and a second using routine surveillance data from UK real-world evidence published by Lord et al. (2020). The ERG preference was to use a naive comparison of niraparib data from NOVA with data from Study 19 for the routine surveillance arm. Study 19 is a double-blind, placebo-controlled, international multicentre randomised controlled trial (RCT) designed to assess the safety and efficacy of olaparib in people with platinum-sensitive recurrent ovarian or fallopian tube cancer or primary peritoneal cancer with high-grade serous features or a serous component. After technical engagement, the company revised its base case to use Study 19 data in alignment with the ERG. The committee noted there were differences in the patient characteristics between the subgroups in NOVA and Study 19 and that no adjustments had been attempted by the company to account for these differences. To account for the high uncertainty in the results of the naive comparison with Study 19 to estimate relative effectiveness of niraparib compared with routine surveillance, the company did an anchored matching-adjusted indirect treatment (MAIC) comparison for people without a BRCA mutation. Adjusted data from NOVA compared with Study 19 using weighted statistical analyses showed limited differences in results between MAIC-adjusted niraparib overall survival data from NOVA and naive comparison of niraparib data from NOVA with Study 19 routine surveillance arm. The committee concluded that using the MAIC analysis to estimate the relative effectiveness of niraparib compared with routine surveillance had limitations but was the best source of data available.
## The overall trial population in NOVA is not suitable for decision making
The ERG noted that the company reported results for the overall trial population, that is, they presented combined data for people with and without a BRCA mutation from NOVA. The company highlighted that the pooled population is aligned with the marketing authorisation for niraparib and that it allows survival outcomes of people who have had niraparib to be compared with the UK‑based, real-world evidence. Lord et al. (2020) published survival outcomes of people who had standard care across 13 NHS trusts. This study included people who had completed at least 2 lines of platinum-based chemotherapy with evidence of an objective disease response (complete or partial response), similar to people enrolled in NOVA. BRCA mutation status was unknown for most people in the study (84.5%), so results were not available by BRCA status. The clinical expert explained that although both people with and without a BRCA mutation could have niraparib, clinical trial evidence suggests considering these groups separately because prognosis is different for each subgroup. The committee concluded that the overall trial population is not suitable for decision making and that the subgroups of interest in this appraisal are people with a BRCA mutation who have had 2 lines of platinum-based chemotherapy or people without a BRCA mutation who have had 2 or more lines of platinum-based chemotherapy.
## Data from the SACT dataset is less relevant than updated data from NOVA
Observational data for people having niraparib through the Cancer Drugs Fund from the Systemic Anti-Cancer Therapy (SACT) dataset was presented by the company but was not originally included in its economic analysis. SACT data was collected for people with a BRCA mutation whose disease had responded to 2 courses of platinum-based chemotherapy and people without a BRCA mutation whose disease had responded to 2 or more courses of platinum-based chemotherapy. In the December 2019 data cut, 43% (n=68) of people with a BRCA mutation and 59% (n=509) of people without a BRCA mutation had completed treatment, that is, people had stopped treatment because of progression, acute toxicity, personal choice, or death, or because the patient did not have a treatment record entered in SACT for at least 3 months. Median follow up for overall survival was 20.3 months and 17.5 months for people with a BRCA mutation and people without a BRCA mutation, respectively. Median overall survival was not reached for people with a BRCA mutation, but the survival rates show that 87% were alive at 12 months, and 64% at 24 months. For people without a BRCA mutation, median overall survival was 22.6 months. The ERG highlighted that differences seen between SACT and NOVA results are likely to be because of differences between patient populations. The committee was aware that no comparator data is available from the SACT dataset. It considered alternative data sources for the comparator treatment arm such as the Study 19 placebo arm and Lord et al. (2020). The committee recalled that the observational data from Lord et al. are not split by BRCA status (see section 3.5) and so did not consider it suitable for decision making. The ERG explained that using Study 19 placebo arm data would be comparing RCT data with non-randomised data, which may underestimate the relative efficacy of niraparib because of the high heterogeneity in the patient populations. In response to the appraisal consultation document, the company reiterated that overall survival data for niraparib from SACT compared with overall survival data for the routine surveillance arm of Lord et al. (2020) provides an important real-world evidence comparative analysis to reduce uncertainty in the overall survival benefit with niraparib. Results from SACT and the Lord et al. (2020) scenario analyses show that cost-effectiveness estimates using a variety of data sources are within a similar range or less than the company's updated base case. The ERG did not consider the analyses were robust because of limitations in a naive comparison between non-randomised real-world sources and randomised data. They noted that prognosis is often better in a clinical trial setting than in clinical practice and the scenario comparing Lord et al. (2020) with the SACT intention-to-treat population is not relevant because it does not provide clinical- or cost-effectiveness estimates for people with or without a BRCA mutation separately (the populations of interest in this appraisal, see section 3.5). The committee agreed that although subgroup data from NOVA may not be fully reflective of NHS clinical practice, it is still the source of the most mature and robust data for niraparib. The committee concluded that data from the SACT database is less useful for decision making than updated data from NOVA.
# Cost effectiveness
## The company's updated model is suitable for decision making
The committee considered the preferred committee assumptions from the original appraisal of niraparib. It recalled that variation in the cost-effectiveness estimates was largely dependent on choice of survival curves to model progression-free survival and ratio of the progression-free survival to overall survival benefit used to estimate overall survival. The committee in the original appraisal of niraparib had concluded that there was a plausible potential for niraparib to be cost effective, and that updated survival data from NOVA could reduce the uncertainty and produce more reliable cost-effectiveness estimates using the original economic model. It had accepted the company's means‑based model, noting that the choice of model structure was not critical to decision making, because the company had explored other model structures such as the partitioned survival model and stated that results did not differ by much. The ERG considered the company's means‑based model structure to be inappropriate now that mature survival data from NOVA is available and considered that a partitioned survival model should be used to validate results of the company model. The committee agreed that a partitioned survival model would be more suitable considering mature overall survival data is available. It would have preferred that the company's original partitioned survival model was validated by the ERG and the impact of model structure on the updated results explored. However, on balance the committee concluded that that the company's updated means-based model was suitable for decision making.
## The company's approach to modelling survival is suitable for people with a BRCA mutation
The committee recalled that the progression-free survival data was unchanged for this Cancer Drugs Fund review but that the terms of engagement outline that survival modelling should consider both statistical and visual fit of parametric and flexible spline models for modelling progression-free survival data and for the company to fully investigate the most appropriate overall survival modelling using updated clinical trial data. After technical engagement, for people with a BRCA mutation the ERG and company agreed on using the same survival curves to extrapolate progression-free (a flexible hazard k=1 curve) and overall survival (log-normal distributions) to extrapolate data from Study 19 for the routine surveillance arm and updated overall survival data from NOVA for the niraparib arm. The committee recalled their conclusion that there was a progression-free survival benefit with niraparib in this subgroup (see section 3.2) and a possible benefit in overall survival (see section 3.3). It agreed that the approach used by the ERG and company to model survival was suitable. The committee noted it would have preferred to see adjustments for crossover and baseline characteristics for people with a BRCA mutation but that these analyses were unlikely to affect the cost-effectiveness results significantly. The committee concluded that the company's approach to modelling survival is suitable for people with a BRCA mutation whose disease has responded to 2 courses of platinum-based chemotherapy.
## The extrapolation of progression-free survival for people without a BRCA mutation is not critical to decision making
The company used a flexible normal k=1 curve to estimate progression-free survival beyond the trial period for people without a BRCA mutation. The ERG preferred a more conservative curve (flexible hazard k=1) which was considered more clinically plausible. The committee noted that the estimates from the 2 curves were almost identical but that the company's normal k=1 had a better statistical fit. The committee also noted that the long-term estimates from the hazard k=1 curve were more aligned with the subgroup of people with a BRCA mutation from 15 years onwards. The committee concluded that the choice between these extrapolations of progression-free survival for people without a BRCA mutation is not critical to decision making.
## Estimating overall survival for people without a BRCA mutation using data from Study 19 for routine surveillance is reasonable
The company had agreed with the ERG's preferred approach to estimate overall survival for routine surveillance after technical engagement. They agreed to use overall survival data from Study 19 for the routine surveillance arm and updated overall survival data from NOVA for the niraparib arm (see section 3.4). Analyses provided in response to the appraisal consultation document accounting for crossover to PARP inhibitors (see section 3.3) and adjusting for differences in baseline characteristics (see section 3.4) showed that adjusted overall survival results were similar to the unadjusted results. The committee accepted that estimating overall survival for people without a BRCA mutation using data from Study 19 for the routine surveillance arm presented the most robust source for comparative data. In response to the committee's request for a conservative scenario assuming no overall survival benefit for people without a BRCA mutation, the company highlighted that the assumption of a gain in progression-free survival resulting in zero overall survival gain is not clinically plausible. It noted that this was supported by trial evidence for maintenance therapies in advanced relapsed ovarian cancer and that a 1:1 progression-free survival to overall survival ratio should be the minimum survival benefit with niraparib compared with routine surveillance. The committee concluded that estimating overall survival for people without a BRCA mutation using data from Study 19 for routine surveillance which results in a survival benefit for people without a BRCA mutation is reasonable.
## The extrapolation of time to treatment discontinuation is not critical to decision making and the company's estimates are reasonable
The company and the ERG had different approaches to modelling time to treatment discontinuation. The company applied a log-logistic distribution for people without a BRCA mutation and applied a cap to the modelling so it could not exceed progression-free survival. The company noted this was the best-fitting distribution based on AIC and BIC statistics as well as visual inspection and better reflected the long-term SACT data. The ERG explained that the log-logistic curve underestimates the tail of the Kaplan–Meier curve, which could underestimate the costs of niraparib. It considered that the Gompertz curve provided a more conservative assumption for costs of niraparib. The committee concluded that the company's estimation of time to treatment discontinuation was more reflective of clinical practice and therefore the most appropriate.
## Treatment-specific utility values are appropriate for decision making
The company used treatment-specific and progression-based utility values based on mapped EQ‑5D‑3L data from NOVA in its original submission for niraparib. For the Cancer Drugs Fund submission, the company updated the treatment-specific and progression-based utility values using the later 2020 data cut from NOVA. The company noted that these utilities reflected a higher quality of life on niraparib compared with routine surveillance. The higher utility values may reflect lower symptom burden from previous chemotherapy. The ERG preferred health-state utilities based on progression status because it did not think that niraparib would be associated with better health-related quality of life because the adverse event rate was higher for niraparib compared with placebo. The clinical expert and Cancer Drugs Fund clinical lead noted that utilities may improve on niraparib as it may improve clinical response for people with partial response to treatment. The company explained that having an active treatment that delays progression of disease such as niraparib has a positive effect on a person's mental health instead of a "wait and watch" approach. They noted that this benefit was not captured in the trial data because of the double-blind nature of NOVA and was not incorporated in the utilities and economic model. A linear mixed effects regression showed a statistically significant difference between treatment arms in the mean utility scores after controlling for health state. The committee noted that using progression-based utility values caused the cost-effectiveness estimates to increase but concluded that treatment-specific utility values are appropriate for decision making.
## The dose of niraparib may be lower in clinical practice and this is reflected using the company's treatment dose estimates
The company amended the mean cost for niraparib based on updated dose data from the latest NOVA data cut (the company used the prescribed dose in the original appraisal of niraparib). The dose used by the company in the Cancer Drugs Fund review was based on actual dose consumed (dispensed dose minus returned dose per cycle) and reflected treatment doses returned by people to the investigator during the trial. In its original appraisal, the committee agreed to use the prescribed dose as a weighted average. The committee considered that prescribed niraparib doses are unlikely to be returned to the NHS and reused. In response to the appraisal consultation document, the company agreed that prescribed doses are unlikely to be returned in clinical practice but considered that unused doses can be used in subsequent cycles with minimal wastage. It also highlighted that the niraparib dose used in the economic model reflects actual dosage used in NOVA. All people in NOVA started treatment on 300 mg of niraparib daily as per the summary of product characteristics. The clinical expert explained that clinicians favour starting treatment with a lower 200 mg daily dose of niraparib in clinical practice because it is associated with reduced toxicity and treatment stopping rates. The company explained that the NORA clinical trial which used lower doses showed equal efficacy to the NOVA study and results are therefore expected to be sustained and similar to the 300 mg daily higher dose in clinical practice. The committee noted that the company produces 100 mg tablets to account for this change in clinical practice and concluded that actual dose data for niraparib from NOVA is appropriate to use in the economic model.
# Cost-effectiveness results
## The ICERs are within the range considered a cost-effective use of NHS resources
The committee recalled that the company's model was suitable for decision making (see section 3.7) and the company's base-case assumptions were reasonable for decision making. The company's incremental cost-effectiveness ratios (ICERs) for people with a BRCA mutation was £22,185 per quality-adjusted life year (QALY) gained. After the second appraisal committee, the company updated its commercial arrangement for people without a BRCA mutation. The ICER for this population was then within the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee concluded that niraparib could be recommended for routine commissioning for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer for people with a BRCA mutation whose disease has responded to 2 courses of platinum-based chemotherapy and for people without a BRCA mutation whose disease has responded to 2 or more courses of platinum-based chemotherapy.
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{'Recommendations': 'Niraparib is recommended as an option for treating relapsed, platinum-sensitive high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer that has responded to the most recent course of platinum-based chemotherapy in adults. It is recommended only if:\n\nthey have a BRCA mutation and have had 2\xa0courses of platinum-based chemotherapy, or\n\nthey do not have a BRCA mutation and have had 2 or more courses of platinum-based chemotherapy, and\n\nthe company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for niraparib for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer (NICE technology appraisal guidance 528).\n\nNiraparib improves how long people with relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer live before their disease progresses. New evidence collected while niraparib was available through the Cancer Drugs Fund suggests it may also extend how long these people live. But, it is uncertain if niraparib extends how long people without a BRCA mutation may live.\n\nCost-effectiveness estimates for niraparib in people with a BRCA mutation whose disease has responded to 2\xa0courses of platinum-based chemotherapy and for people without a BRCA mutation whose disease has responded to 2 or more courses of platinum-based chemotherapy are in the range usually considered a cost-effective use of NHS resources. Therefore, niraparib is recommended.', 'Information about niraparib': "# Marketing authorisation indication\n\nNiraparib (Zejula, GSK) has a marketing authorisation for 'the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for niraparib.\n\n# Price\n\nThe list price for niraparib is £4,500 for a 56‑tablet pack of 100\xa0mg tablets; £6,750 for an 84‑tablet pack of 100\xa0mg tablets (excluding VAT; BNF online, accessed August\xa02021).\n\nThe company has a commercial arrangement. This makes niraparib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': 'The appraisal committee considered evidence submitted by GSK, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway and clinical need\n\n## There is an unmet clinical need for maintenance treatments in clinical practice, especially for people without a BRCA mutation\n\nRelapsed ovarian, fallopian tube or peritoneal cancer is a devastating condition with limited treatment options. For people with a BRCA mutation who have had fewer than 3\xa0courses of platinum-based chemotherapy, there are no maintenance treatments available. For people without a BRCA mutation, there are no maintenance treatments available. People have multiple cycles of chemotherapy as the disease responds and relapses. The patient expert explained that chemotherapy side effects can substantially reduce a patient\'s quality of life, and concerns about relapse and the need for repeated courses of treatment are physically and psychologically challenging. NICE recommends olaparib for maintenance treatment of relapsed platinum-sensitive ovarian, fallopian tube or peritoneal cancer for people with a BRCA1 or BRCA2 mutation who have had 3\xa0or more courses of platinum-based chemotherapy. Niraparib and olaparib are both poly‑ADP‑ribose polymerase (PARP) inhibitors. The clinical expert explained that maintenance therapy with PARP inhibitors can delay disease progression and extend the time between platinum-based chemotherapies. Delaying disease progression may therefore delay the onset of platinum drug resistance. People with ovarian cancer that becomes platinum resistant have fewer chemotherapy regimen options available when the disease relapses and therefore have a poor prognosis. So, treatments that avoid the need for chemotherapy are highly valued by patients and their families. Extending survival, even by only a few months, can give people valuable extra time with family and friends. The clinical experts explained that several PARP inhibitors are currently available for first-line use through the Cancer Drugs Fund (see NICE\'s technology appraisal guidance on olaparib for maintenance treatment of BRCA mutation-positive advanced ovarian, fallopian tube or peritoneal cancer after response to first-line platinum-based chemotherapy, olaparib plus bevacizumab for maintenance treatment of advanced ovarian, fallopian tube or primary peritoneal cancer and niraparib for maintenance treatment of advanced ovarian, fallopian tube and peritoneal cancer after response to first-line platinum-based chemotherapy) for people with and without a BRCA mutation, but are limited to only niraparib in people without a BRCA mutation. The committee acknowledged that 80% of people with ovarian cancer do not have a BRCA mutation and that there is a particularly high unmet need in this group because no PARP inhibitors are recommended in routine commissioning after second-line treatment. The clinical expert also explained that because PARP inhibitors would not be used more than once in the treatment pathway, the number of people who would have treatment in a relapsed disease setting may be smaller in future clinical practice (depending on future Cancer Drugs Fund reviews). The committee concluded that there is an unmet need for maintenance treatments in clinical practice, especially for people without a BRCA mutation.\n\n# Clinical evidence\n\n## Niraparib improves progression-free survival compared with placebo regardless of how it is assessed\n\nThe clinical-effectiveness evidence came from NOVA, a double-blind, randomised, placebo-controlled trial. NOVA assessed the clinical effectiveness of niraparib in people with relapsed, platinum-sensitive ovarian cancer, with and without a BRCA mutation. Patients had previously had 2\xa0or more platinum-based chemotherapy regimens and their cancer had responded to the last regimen. In the original appraisal, niraparib showed statistically significantly improved progression-free survival compared with placebo for both subgroups (with and without a BRCA mutation). However, the effect of niraparib on overall survival was uncertain. It was concluded that more mature data from NOVA could resolve this uncertainty and provide more evidence on the relative treatment effect. More data from NOVA has now been collected, and was analysed in October\xa02020. This analysis included an additional 49\xa0months of data compared with the original appraisal. There was no updated data on progression-free survival because it was not assessed after the primary analysis. The committee recalled:\n\nThe median progression-free survival in people without a BRCA mutation was 9.3\xa0months with niraparib and 3.9\xa0months with placebo. The difference in median progression-free survival between niraparib and placebo was 5.4\xa0months (hazard ratio [HR]\xa00.45; 95% confidence interval [CI] 0.34\xa0to\xa00.61; p<0.001).\n\nFor people with a BRCA mutation, median progression-free survival was 21\xa0months with niraparib and 5.5\xa0months with placebo. The difference in median progression-free survival was 15.5\xa0months (HR\xa00.27; 95%\xa0CI 0.17\xa0to\xa00.41; p<0.001).The committee noted that progression-free survival results differed based on how they were assessed. The committee was aware that the company model used progression-free survival results assessed by an Independent Review Committee (IRC). The committee noted that any difference in benefit accrued could have a significant impact on the cost-effectiveness results because time on treatment (and so the related cost) was based on investigator assessment (IA), the preferred assumption from the original appraisal of niraparib. The ERG explained that this could result in costs and benefits not being aligned in the economic modelling. The committee considered the results of the 2\xa0alternative methods of assessing progression-free survival (IA or IRC). Results are considered confidential and cannot be reported here. The committee noted niraparib increased progression-free survival compared with placebo in both treatment groups using both assessments. Both assessments showed greater clinical benefit in people with a BRCA mutation although the size of benefit was smaller for progression-free survival assessed by IA. The clinical expert and Cancer Drugs Fund clinical lead cautioned focusing only on the median results and explained that the hazard ratios of both IA and IRC assessed progression-free survival were similar. The committee agreed that, because hazards were similar regardless of who assessed, the method of assessment was unlikely to be critical to decision making. In response to the appraisal consultation document, the company prepared scenario analyses exploring the effect of using progression-free survival assessed by IA. These showed that results were not substantially different from results using IRC. The difference in median progression-free survival with the 2\xa0assessment methods was less pronounced for people without a BRCA mutation and the committee concluded that the progression-free survival assessed by IA was not critical for decision making in this subgroup. Therefore, niraparib improves progression-free survival compared with placebo, regardless of how it is assessed.\n\n## Niraparib may improve overall survival compared with placebo for people with a BRCA mutation but survival benefit with niraparib for people without a BRCA mutation is highly uncertain\n\nThe committee recalled that median overall survival had not been reached in the original appraisal of niraparib and that survival benefit with niraparib was the main clinical uncertainty. Updated data from NOVA showed:\n\nMedian overall survival in people without a BRCA mutation after 2 or more lines of platinum-based chemotherapy was 31.1\xa0months with niraparib and 36.5\xa0months with placebo. The difference in median overall survival between niraparib and placebo was 5.4\xa0months (HR 1.1; 95% CI 0.83 to 1.46).\n\nResults for people with a BRCA mutation after 2\xa0lines of platinum-based chemotherapy are confidential and cannot be reported.The committee noted that NOVA was not powered to test for statistical significance for overall survival, and the company and ERG explained that the results for the placebo arm are confounded by a high rate of subsequent PARP inhibitor use and missing data. Discontinuation from the trial was more than 80% in both niraparib and placebo arms with at least 14% missing data. As a result, only updated survival data from the niraparib arm of NOVA was used for assessing relative effectiveness. The committee noted that, despite high levels of subsequent PARP inhibitor use in NOVA, the company had not attempted to adjust for this in their submission using methods such as the inverse probability of censoring weighting (IPCW) adjustment. The committee was aware that a recent commentary from a presentation at the Society of Gynecologic Oncology conference showed this result was available for a previous analysis from the NOVA trial. The clinical expert and the Cancer Drugs Fund clinical lead both agreed that the progression-free survival benefit shown for niraparib is likely to translate into an overall survival benefit for people with a BRCA mutation. The evidence was less certain for those without a BRCA mutation. In response to the appraisal consultation document, the company presented results adjusting for subsequent PARP inhibitor use in both people with and without a BRCA mutation. It highlighted the high discontinuation rate from both trial arms (see section\xa03.2) and considered that the IPCW results were not suitable for decision making because the amount of missing data meant subsequent PARP inhibitor treatment status was unknown for many people in the trial (25% incomplete) and there was also incomplete survival follow up. The ERG noted that, where data was available, crossover appeared to be limited (13%) for people in the placebo group who did not have a BRCA mutation and that the IPCW‑adjusted results were similar to unadjusted results. However, they cautioned that the analyses needed assumptions about the imputation of missing data. The committee concluded that niraparib may improve overall survival for people with a BRCA mutation but survival benefit with niraparib for people without a BRCA mutation is highly uncertain. Further analyses adjusting for crossover to subsequent treatments are inconclusive and are not able to resolve the uncertainty.\n\n## Estimating relative effectiveness of niraparib compared with routine surveillance should be based on analyses adjusted for differences in baseline characteristics between NOVA and Study\xa019\n\nBecause of limitations in the survival data from the placebo arm of NOVA, the company used alternative data sources to estimate the relative effectiveness of niraparib compared with routine surveillance. In their original Cancer Drugs Fund review submission, the company used an assumption of a progression-free survival to overall survival benefit ratio of 1:1 to estimate overall survival for people on routine surveillance as their base case. For this appraisal, they also presented 2\xa0alternative scenario analyses, one using placebo data from the olaparib trial, Study\xa019, and a second using routine surveillance data from UK real-world evidence published by Lord et al. (2020). The ERG preference was to use a naive comparison of niraparib data from NOVA with data from Study\xa019 for the routine surveillance arm. Study\xa019 is a double-blind, placebo-controlled, international multicentre randomised controlled trial (RCT) designed to assess the safety and efficacy of olaparib in people with platinum-sensitive recurrent ovarian or fallopian tube cancer or primary peritoneal cancer with high-grade serous features or a serous component. After technical engagement, the company revised its base case to use Study\xa019 data in alignment with the ERG. The committee noted there were differences in the patient characteristics between the subgroups in NOVA and Study\xa019 and that no adjustments had been attempted by the company to account for these differences. To account for the high uncertainty in the results of the naive comparison with Study\xa019 to estimate relative effectiveness of niraparib compared with routine surveillance, the company did an anchored matching-adjusted indirect treatment (MAIC) comparison for people without a BRCA mutation. Adjusted data from NOVA compared with Study\xa019 using weighted statistical analyses showed limited differences in results between MAIC-adjusted niraparib overall survival data from NOVA and naive comparison of niraparib data from NOVA with Study\xa019 routine surveillance arm. The committee concluded that using the MAIC analysis to estimate the relative effectiveness of niraparib compared with routine surveillance had limitations but was the best source of data available.\n\n## The overall trial population in NOVA is not suitable for decision making\n\nThe ERG noted that the company reported results for the overall trial population, that is, they presented combined data for people with and without a BRCA mutation from NOVA. The company highlighted that the pooled population is aligned with the marketing authorisation for niraparib and that it allows survival outcomes of people who have had niraparib to be compared with the UK‑based, real-world evidence. Lord et al. (2020) published survival outcomes of people who had standard care across 13\xa0NHS trusts. This study included people who had completed at least 2\xa0lines of platinum-based chemotherapy with evidence of an objective disease response (complete or partial response), similar to people enrolled in NOVA. BRCA mutation status was unknown for most people in the study (84.5%), so results were not available by BRCA status. The clinical expert explained that although both people with and without a BRCA mutation could have niraparib, clinical trial evidence suggests considering these groups separately because prognosis is different for each subgroup. The committee concluded that the overall trial population is not suitable for decision making and that the subgroups of interest in this appraisal are people with a BRCA mutation who have had 2\xa0lines of platinum-based chemotherapy or people without a BRCA mutation who have had 2 or more lines of platinum-based chemotherapy.\n\n## Data from the SACT dataset is less relevant than updated data from NOVA\n\nObservational data for people having niraparib through the Cancer Drugs Fund from the Systemic Anti-Cancer Therapy (SACT) dataset was presented by the company but was not originally included in its economic analysis. SACT data was collected for people with a BRCA mutation whose disease had responded to 2\xa0courses of platinum-based chemotherapy and people without a BRCA mutation whose disease had responded to 2 or more courses of platinum-based chemotherapy. In the December\xa02019 data cut, 43% (n=68) of people with a BRCA mutation and 59% (n=509) of people without a BRCA mutation had completed treatment, that is, people had stopped treatment because of progression, acute toxicity, personal choice, or death, or because the patient did not have a treatment record entered in SACT for at least 3\xa0months. Median follow up for overall survival was 20.3\xa0months and 17.5\xa0months for people with a BRCA mutation and people without a BRCA mutation, respectively. Median overall survival was not reached for people with a BRCA mutation, but the survival rates show that 87% were alive at 12\xa0months, and 64% at 24\xa0months. For people without a BRCA mutation, median overall survival was 22.6\xa0months. The ERG highlighted that differences seen between SACT and NOVA results are likely to be because of differences between patient populations. The committee was aware that no comparator data is available from the SACT dataset. It considered alternative data sources for the comparator treatment arm such as the Study\xa019 placebo arm and Lord et al. (2020). The committee recalled that the observational data from Lord et al. are not split by BRCA status (see section\xa03.5) and so did not consider it suitable for decision making. The ERG explained that using Study\xa019 placebo arm data would be comparing RCT data with non-randomised data, which may underestimate the relative efficacy of niraparib because of the high heterogeneity in the patient populations. In response to the appraisal consultation document, the company reiterated that overall survival data for niraparib from SACT compared with overall survival data for the routine surveillance arm of Lord et al. (2020) provides an important real-world evidence comparative analysis to reduce uncertainty in the overall survival benefit with niraparib. Results from SACT and the Lord et al. (2020) scenario analyses show that cost-effectiveness estimates using a variety of data sources are within a similar range or less than the company\'s updated base case. The ERG did not consider the analyses were robust because of limitations in a naive comparison between non-randomised real-world sources and randomised data. They noted that prognosis is often better in a clinical trial setting than in clinical practice and the scenario comparing Lord et al. (2020) with the SACT intention-to-treat population is not relevant because it does not provide clinical- or cost-effectiveness estimates for people with or without a BRCA mutation separately (the populations of interest in this appraisal, see section\xa03.5). The committee agreed that although subgroup data from NOVA may not be fully reflective of NHS clinical practice, it is still the source of the most mature and robust data for niraparib. The committee concluded that data from the SACT database is less useful for decision making than updated data from NOVA.\n\n# Cost effectiveness\n\n## The company\'s updated model is suitable for decision making\n\nThe committee considered the preferred committee assumptions from the original appraisal of niraparib. It recalled that variation in the cost-effectiveness estimates was largely dependent on choice of survival curves to model progression-free survival and ratio of the progression-free survival to overall survival benefit used to estimate overall survival. The committee in the original appraisal of niraparib had concluded that there was a plausible potential for niraparib to be cost effective, and that updated survival data from NOVA could reduce the uncertainty and produce more reliable cost-effectiveness estimates using the original economic model. It had accepted the company\'s means‑based model, noting that the choice of model structure was not critical to decision making, because the company had explored other model structures such as the partitioned survival model and stated that results did not differ by much. The ERG considered the company\'s means‑based model structure to be inappropriate now that mature survival data from NOVA is available and considered that a partitioned survival model should be used to validate results of the company model. The committee agreed that a partitioned survival model would be more suitable considering mature overall survival data is available. It would have preferred that the company\'s original partitioned survival model was validated by the ERG and the impact of model structure on the updated results explored. However, on balance the committee concluded that that the company\'s updated means-based model was suitable for decision making.\n\n## The company\'s approach to modelling survival is suitable for people with a BRCA mutation\n\nThe committee recalled that the progression-free survival data was unchanged for this Cancer Drugs Fund review but that the terms of engagement outline that survival modelling should consider both statistical and visual fit of parametric and flexible spline models for modelling progression-free survival data and for the company to fully investigate the most appropriate overall survival modelling using updated clinical trial data. After technical engagement, for people with a BRCA mutation the ERG and company agreed on using the same survival curves to extrapolate progression-free (a flexible hazard k=1 curve) and overall survival (log-normal distributions) to extrapolate data from Study\xa019 for the routine surveillance arm and updated overall survival data from NOVA for the niraparib arm. The committee recalled their conclusion that there was a progression-free survival benefit with niraparib in this subgroup (see section\xa03.2) and a possible benefit in overall survival (see section\xa03.3). It agreed that the approach used by the ERG and company to model survival was suitable. The committee noted it would have preferred to see adjustments for crossover and baseline characteristics for people with a BRCA mutation but that these analyses were unlikely to affect the cost-effectiveness results significantly. The committee concluded that the company\'s approach to modelling survival is suitable for people with a BRCA mutation whose disease has responded to 2\xa0courses of platinum-based chemotherapy.\n\n## The extrapolation of progression-free survival for people without a BRCA mutation is not critical to decision making\n\nThe company used a flexible normal k=1 curve to estimate progression-free survival beyond the trial period for people without a BRCA mutation. The ERG preferred a more conservative curve (flexible hazard k=1) which was considered more clinically plausible. The committee noted that the estimates from the 2\xa0curves were almost identical but that the company\'s normal k=1 had a better statistical fit. The committee also noted that the long-term estimates from the hazard k=1 curve were more aligned with the subgroup of people with a BRCA mutation from 15\xa0years onwards. The committee concluded that the choice between these extrapolations of progression-free survival for people without a BRCA mutation is not critical to decision making.\n\n## Estimating overall survival for people without a BRCA mutation using data from Study\xa019 for routine surveillance is reasonable\n\nThe company had agreed with the ERG\'s preferred approach to estimate overall survival for routine surveillance after technical engagement. They agreed to use overall survival data from Study\xa019 for the routine surveillance arm and updated overall survival data from NOVA for the niraparib arm (see section\xa03.4). Analyses provided in response to the appraisal consultation document accounting for crossover to PARP inhibitors (see section\xa03.3) and adjusting for differences in baseline characteristics (see section\xa03.4) showed that adjusted overall survival results were similar to the unadjusted results. The committee accepted that estimating overall survival for people without a BRCA mutation using data from Study\xa019 for the routine surveillance arm presented the most robust source for comparative data. In response to the committee\'s request for a conservative scenario assuming no overall survival benefit for people without a BRCA mutation, the company highlighted that the assumption of a gain in progression-free survival resulting in zero overall survival gain is not clinically plausible. It noted that this was supported by trial evidence for maintenance therapies in advanced relapsed ovarian cancer and that a 1:1 progression-free survival to overall survival ratio should be the minimum survival benefit with niraparib compared with routine surveillance. The committee concluded that estimating overall survival for people without a BRCA mutation using data from Study\xa019 for routine surveillance which results in a survival benefit for people without a BRCA mutation is reasonable.\n\n## The extrapolation of time to treatment discontinuation is not critical to decision making and the company\'s estimates are reasonable\n\nThe company and the ERG had different approaches to modelling time to treatment discontinuation. The company applied a log-logistic distribution for people without a BRCA mutation and applied a cap to the modelling so it could not exceed progression-free survival. The company noted this was the best-fitting distribution based on AIC and BIC statistics as well as visual inspection and better reflected the long-term SACT data. The ERG explained that the log-logistic curve underestimates the tail of the Kaplan–Meier curve, which could underestimate the costs of niraparib. It considered that the Gompertz curve provided a more conservative assumption for costs of niraparib. The committee concluded that the company\'s estimation of time to treatment discontinuation was more reflective of clinical practice and therefore the most appropriate.\n\n## Treatment-specific utility values are appropriate for decision making\n\nThe company used treatment-specific and progression-based utility values based on mapped EQ‑5D‑3L data from NOVA in its original submission for niraparib. For the Cancer Drugs Fund submission, the company updated the treatment-specific and progression-based utility values using the later 2020 data cut from NOVA. The company noted that these utilities reflected a higher quality of life on niraparib compared with routine surveillance. The higher utility values may reflect lower symptom burden from previous chemotherapy. The ERG preferred health-state utilities based on progression status because it did not think that niraparib would be associated with better health-related quality of life because the adverse event rate was higher for niraparib compared with placebo. The clinical expert and Cancer Drugs Fund clinical lead noted that utilities may improve on niraparib as it may improve clinical response for people with partial response to treatment. The company explained that having an active treatment that delays progression of disease such as niraparib has a positive effect on a person\'s mental health instead of a "wait and watch" approach. They noted that this benefit was not captured in the trial data because of the double-blind nature of NOVA and was not incorporated in the utilities and economic model. A linear mixed effects regression showed a statistically significant difference between treatment arms in the mean utility scores after controlling for health state. The committee noted that using progression-based utility values caused the cost-effectiveness estimates to increase but concluded that treatment-specific utility values are appropriate for decision making.\n\n## The dose of niraparib may be lower in clinical practice and this is reflected using the company\'s treatment dose estimates\n\nThe company amended the mean cost for niraparib based on updated dose data from the latest NOVA data cut (the company used the prescribed dose in the original appraisal of niraparib). The dose used by the company in the Cancer Drugs Fund review was based on actual dose consumed (dispensed dose minus returned dose per cycle) and reflected treatment doses returned by people to the investigator during the trial. In its original appraisal, the committee agreed to use the prescribed dose as a weighted average. The committee considered that prescribed niraparib doses are unlikely to be returned to the NHS and reused. In response to the appraisal consultation document, the company agreed that prescribed doses are unlikely to be returned in clinical practice but considered that unused doses can be used in subsequent cycles with minimal wastage. It also highlighted that the niraparib dose used in the economic model reflects actual dosage used in NOVA. All people in NOVA started treatment on 300\xa0mg of niraparib daily as per the summary of product characteristics. The clinical expert explained that clinicians favour starting treatment with a lower 200\xa0mg daily dose of niraparib in clinical practice because it is associated with reduced toxicity and treatment stopping rates. The company explained that the NORA clinical trial which used lower doses showed equal efficacy to the NOVA study and results are therefore expected to be sustained and similar to the 300\xa0mg daily higher dose in clinical practice. The committee noted that the company produces 100\xa0mg tablets to account for this change in clinical practice and concluded that actual dose data for niraparib from NOVA is appropriate to use in the economic model.\n\n# Cost-effectiveness results\n\n## The ICERs are within the range considered a cost-effective use of NHS resources\n\nThe committee recalled that the company\'s model was suitable for decision making (see section\xa03.7) and the company\'s base-case assumptions were reasonable for decision making. The company\'s incremental cost-effectiveness ratios (ICERs) for people with a BRCA mutation was £22,185 per quality-adjusted life year (QALY) gained. After the second appraisal committee, the company updated its commercial arrangement for people without a BRCA mutation. The ICER for this population was then within the range normally considered to be a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). The committee concluded that niraparib could be recommended for routine commissioning for maintenance treatment of relapsed, platinum-sensitive ovarian, fallopian tube and peritoneal cancer for people with a BRCA mutation whose disease has responded to 2\xa0courses of platinum-based chemotherapy and for people without a BRCA mutation whose disease has responded to 2 or more courses of platinum-based chemotherapy.'}
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https://www.nice.org.uk/guidance/ta784
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Evidence-based recommendations on niraparib (Zejula) for treating relapsed, platinum-sensitive high-grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer in adults.
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74827d010665b18f9a25f32ee1d8148f86390f55
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nice
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Stroke and transient ischaemic attack in over 16s: diagnosis and initial management
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Stroke and transient ischaemic attack in over 16s: diagnosis and initial management
This guideline covers interventions in the acute stage of a stroke or transient ischaemic attack (TIA). It offers the best clinical advice on the diagnosis and acute management of stroke and TIA in the 48 hours after onset of symptoms.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
NICE has also produced patient decision aids on decompressive hemicraniectomy.
# Rapid recognition of symptoms and diagnosis
## Prompt recognition of symptoms of stroke and transient ischaemic attack
Use a validated tool, such as FAST (Face Arm Speech Test), outside hospital to screen people with sudden onset of neurological symptoms for a diagnosis of stroke or transient ischaemic attack (TIA).
Exclude hypoglycaemia in people with sudden onset of neurological symptoms as the cause of these symptoms.
For people who are admitted to the emergency department with a suspected stroke or TIA, establish the diagnosis rapidly using a validated tool, such as ROSIER (Recognition of Stroke in the Emergency Room).
## Initial management of suspected and confirmed TIA
Offer aspirin (300 mg daily), unless contraindicated, to people who have had a suspected TIA, to be started immediately.
For a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on initial management of suspected and confirmed transient ischaemic attack (aspirin) .
Full details of the evidence and the committee's discussion are in evidence review A: aspirin.
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Refer immediately people who have had a suspected TIA for specialist assessment and investigation, to be seen within 24 hours of onset of symptoms.
Do not use scoring systems, such as ABCD2, to assess risk of subsequent stroke or to inform urgency of referral for people who have had a suspected or confirmed TIA.
Offer secondary prevention, in addition to aspirin, as soon as possible after the diagnosis of TIA is confirmed.
For a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on initial management of suspected and confirmed transient ischaemic attack .
Full details of the evidence and the committee's discussion are in evidence review B: TIA prediction rules.
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# Imaging for people who have had a suspected TIA or acute non-disabling stroke
## Suspected TIA
Do not offer CT brain scanning to people with a suspected TIA unless there is clinical suspicion of an alternative diagnosis that CT could detect.
After specialist assessment in the TIA clinic, consider MRI (including diffusion-weighted and blood-sensitive sequences) to determine the territory of ischaemia, or to detect haemorrhage or alternative pathologies. If MRI is done, perform it on the same day as the assessment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on imaging for people who have had a suspected TIA or acute non-disabling stroke .
Full details of the evidence and the committee's discussion are in evidence review C: TIA imaging.
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## Carotid imaging
Everyone with TIA who after specialist assessment is considered as a candidate for carotid endarterectomy should have urgent carotid imaging.
## Urgent carotid endarterectomy
Ensure that people with stable neurological symptoms from acute non-disabling stroke or TIA who have symptomatic carotid stenosis of 50% to 99% according to the NASCET (North American Symptomatic Carotid Endarterectomy Trial) criteria, or 70% to 99% according to the ECST (European Carotid Surgery Trial) criteria:
are assessed and referred urgently for carotid endarterectomy to a service following current national standards (see the NHS England and NHS Improvement National Stroke Service Model)
receive best medical treatment (control of blood pressure, antiplatelet agents, cholesterol lowering through diet and drugs, lifestyle advice).
Ensure that people with stable neurological symptoms from acute non-disabling stroke or TIA who have symptomatic carotid stenosis of less than 50% according to the NASCET criteria, or less than 70% according to the ECST criteria:
do not have surgery
receive best medical treatment (control of blood pressure, antiplatelet agents, cholesterol lowering through diet and drugs, lifestyle advice).
Ensure that carotid imaging reports clearly state which criteria (ECST or NASCET) were used when measuring the extent of carotid stenosis.
# Specialist care for people with acute stroke
## Specialist stroke units
Admit everyone with suspected stroke directly to a specialist acute stroke unit after initial assessment, from either the community, the emergency department, or outpatient clinics. (An acute stroke unit is a discrete area in the hospital that is staffed by a specialist stroke multidisciplinary team. It has access to equipment for monitoring and rehabilitating patients. Regular multidisciplinary team meetings occur for goal setting.).
## Brain imaging for the early assessment of people with suspected acute stroke
Perform brain imaging immediately with a non-enhanced CT for people with suspected acute stroke if any of the following apply (see additional information):
indications for thrombolysis or thrombectomy
-n anticoagulant treatment
a known bleeding tendency
a depressed level of consciousness (Glasgow Coma Score below 13)
unexplained progressive or fluctuating symptoms
papilloedema, neck stiffness or fever
severe headache at onset of stroke symptoms.If thrombectomy might be indicated, perform imaging with CT contrast angiography following initial non-enhanced CT. Add CT perfusion imaging (or MR equivalent) if thrombectomy might be indicated beyond 6 hours of symptom onset.
Perform scanning as soon as possible and within 24 hours of symptom onset in everyone with suspected acute stroke without indications for immediate brain imaging. The NHS England and NHS Improvement National Stroke Service Model contains a patient-centred national optimal stroke imaging pathway.
# Pharmacological treatments and thrombectomy for people with acute stroke
## Thrombolysis with alteplase for people with acute ischaemic stroke
Alteplase is recommended within its marketing authorisation for treating acute ischaemic stroke in adults if:
treatment is started as soon as possible within 4.5 hours of onset of stroke symptoms and
intracranial haemorrhage has been excluded by appropriate imaging techniques. This recommendation is from NICE's technology appraisal guidance on alteplase for treating acute ischaemic stroke.
Administer alteplase only within a well-organised stroke service with:
staff trained in delivering thrombolysis and in monitoring for any complications associated with thrombolysis
nursing staff trained in acute stroke and thrombolysis to provide level 1 and level 2 care (seen the NHS Data Model and Dictionary on critical care level)
immediate access to imaging and re‑imaging, and staff trained to interpret the images.
Staff in emergency departments, if appropriately trained and supported, can administer alteplase for the treatment of ischaemic stroke provided that patients can be managed within an acute stroke service with appropriate neuroradiological and stroke physician support.
Ensure that protocols are in place for delivering and managing intravenous thrombolysis, including post-thrombolysis complications.
## Thrombectomy for people with acute ischaemic stroke
Offer thrombectomy as soon as possible and within 6 hours of symptom onset, together with intravenous thrombolysis (if not contraindicated and within the licensed time window), to people who have:
acute ischaemic stroke and
confirmed occlusion of the proximal anterior circulation demonstrated by computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) taking into account the factors in recommendation 1.4.8 (see additional information).
Offer thrombectomy as soon as possible to people who were last known to be well between 6 hours and 24 hours previously (including wake‑up strokes):
who have acute ischaemic stroke and confirmed occlusion of the proximal anterior circulation demonstrated by CTA or MRA and
if there is the potential to salvage brain tissue, as shown by imaging such as CT perfusion or diffusion-weighted MRI sequences showing limited infarct core volumetaking into account the factors in recommendation 1.4.8 (see additional information).
Consider thrombectomy together with intravenous thrombolysis (where not contraindicated and within the licensed time window) as soon as possible for people last known to be well up to 24 hours previously (including wake‑up strokes):
who have acute ischaemic stroke and confirmed occlusion of the proximal posterior circulation (that is, basilar or posterior cerebral artery) demonstrated by CTA or MRA and
if there is the potential to salvage brain tissue, as shown by imaging such as CT perfusion or diffusion-weighted MRI sequences showing limited infarct core volumetaking into account the factors in recommendation 1.4.8 (see additional information).
Take into account the person's overall clinical status and the extent of established infarction on initial brain imaging to inform decisions about thrombectomy. Select people who have (in addition to the factors in recommendations 1.4.5 to 1.4.7):
a pre-stroke functional status of less than 3 on the modified Rankin scale and
a score of more than 5 on the National Institutes of Health Stroke Scale (NIHSS).
For a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on thrombectomy for people with acute ischaemic stroke .
Full details of the evidence and the committee's discussion are in evidence review D: thrombectomy.
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## Aspirin and anticoagulant treatment
Offer the following as soon as possible, but certainly within 24 hours, to everyone presenting with acute stroke who has had a diagnosis of intracerebral haemorrhage excluded by brain imaging:
aspirin 300 mg orally if they do not have dysphagia or
aspirin 300 mg rectally or by enteral tube if they do have dysphagia. Continue aspirin daily 300 mg until 2 weeks after the onset of stroke symptoms, at which time start definitive long-term antithrombotic treatment. Start people on long-term treatment earlier if they are being discharged before 2 weeks.
Offer a proton pump inhibitor, in addition to aspirin, to anyone with acute ischaemic stroke for whom previous dyspepsia associated with aspirin is reported.
Offer an alternative antiplatelet agent to anyone with acute ischaemic stroke who is allergic to or genuinely intolerant of aspirin. (Aspirin intolerance is defined as either of the following: proven hypersensitivity to aspirin-containing medicines, or history of severe dyspepsia induced by low-dose aspirin.)
Do not use anticoagulation treatment routinely for the treatment of acute stroke (see additional information).
Offer people diagnosed with cerebral venous sinus thrombosis (including those with secondary cerebral haemorrhage) full-dose anticoagulation treatment (initially full-dose heparin and then warfarin ) unless there are comorbidities that preclude its use.
Offer either anticoagulants or antiplatelet agents to people who have stroke secondary to acute arterial dissection.
Manage acute ischaemic stroke associated with antiphospholipid syndrome in the same way as acute ischaemic stroke without antiphospholipid syndrome (see additional information).
Return clotting levels to normal as soon as possible in people with a primary intracerebral haemorrhage who were receiving warfarin before their stroke (and have elevated international normalised ratio). Do this by reversing the effects of the warfarin using a combination of prothrombin complex concentrate and intravenous vitamin K.
Ensure that people with disabling ischaemic stroke who are in atrial fibrillation are treated with aspirin 300 mg for the first 2 weeks before anticoagulation treatment is considered.
For people with prosthetic valves who have disabling cerebral infarction and who are at significant risk of haemorrhagic transformation, stop anticoagulation treatment for 1 week and substitute aspirin 300 mg.
Ensure that people with ischaemic stroke and symptomatic proximal deep vein thrombosis or pulmonary embolism receive anticoagulation treatment in preference to treatment with aspirin unless there are other contraindications to anticoagulation.
Treat people who have haemorrhagic stroke and symptomatic deep vein thrombosis or pulmonary embolism to prevent the development of further pulmonary emboli using either anticoagulation or a caval filter.
## Statin treatment
Immediate initiation of statin treatment is not recommended in people with acute stroke (see additional information).
Continue statin treatment in people with acute stroke who are already receiving statins.
# Maintenance or restoration of homeostasis
## Supplemental oxygen therapy
Give supplemental oxygen to people who have had a stroke only if their oxygen saturation drops below 95%. The routine use of supplemental oxygen is not recommended in people with acute stroke who are not hypoxic. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
## Blood sugar control
Maintain a blood glucose concentration between 4 and 11 mmol/litre in people with acute stroke.
Provide optimal insulin therapy, which can be achieved by the use of intravenous insulin and glucose, to all adults with type 1 diabetes with threatened or actual stroke. Critical care and emergency departments should have a protocol for such management.
## Blood pressure control for people with acute intracerebral haemorrhage
Consider rapid blood pressure lowering for people with acute intracerebral haemorrhage who do not have any of the exclusions listed in recommendation 1.5.7 and who:
present within 6 hours of symptom onset and
have a systolic blood pressure of between 150 and 220 mmHg.
Taking into account the risk of harm, consider rapid blood pressure lowering on a case-by-case basis for people with acute intracerebral haemorrhage who do not have any of the exclusions listed in recommendation 1.5.7 and who:
present beyond 6 hours of symptom onset or
have a systolic blood pressure greater than 220 mmHg.
When rapidly lowering blood pressure in people with acute intracerebral haemorrhage, aim to reach a systolic blood pressure of 140 mmHg or lower while ensuring that the magnitude drop does not exceed 60 mmHg within 1 hour of starting treatment.
Do not offer rapid blood pressure lowering to people who:
have an underlying structural cause (for example, tumour, arteriovenous malformation or aneurysm)
have a score on the Glasgow Coma Scale of below 6
are going to have early neurosurgery to evacuate the haematoma
have a massive haematoma with a poor expected prognosis.
When considering blood pressure lowering in young people aged 16 or 17 with acute intracerebral haemorrhage who do not have any of the exclusions listed in recommendation 1.5.7, seek advice from a paediatric specialist.
For a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on blood pressure control for people with acute intracerebral haemorrhage .
Full details of the evidence and the committee's discussion are in evidence review E: intensive interventions to lower blood pressure in people with acute intracerebral haemorrhage.
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## Blood pressure control for people with acute ischaemic stroke
Anti-hypertensive treatment in people with acute ischaemic stroke is recommended only if there is a hypertensive emergency with one or more of the following serious concomitant medical issues:
hypertensive encephalopathy
hypertensive nephropathy
hypertensive cardiac failure/myocardial infarction
aortic dissection
pre-eclampsia/eclampsia.
Blood pressure reduction to 185/110 mmHg or lower should be considered in people who are candidates for intravenous thrombolysis.
# Nutrition and hydration
## Assessment of swallowing function
On admission, ensure that people with acute stroke have their swallowing screened by an appropriately trained healthcare professional before being given any oral food, fluid or medication.
If the admission screen indicates problems with swallowing, ensure that the person has a specialist assessment of swallowing, preferably within 24 hours of admission and not more than 72 hours afterwards.
People with suspected aspiration on specialist assessment, or who require tube feeding or dietary modification for 3 days, should be:
re-assessed and considered for instrumental examination
referred for dietary advice.
People with acute stroke who are unable to take adequate nutrition, fluids and medication orally should:
receive tube feeding with a nasogastric tube within 24 hours of admission unless they have had thrombolysis
be considered for a nasal bridle tube or gastrostomy if they are unable to tolerate a nasogastric tube
be referred to an appropriately trained healthcare professional for detailed nutritional assessment, individualised advice and monitoring
have their oral medication reviewed to amend either the formulation or the route of administration.
## Oral nutritional supplementation
Screen all hospital inpatients on admission for malnutrition and the risk of malnutrition. Repeat screening weekly for inpatients.
Screening should assess body mass index (BMI) and percentage unintentional weight loss. It should also consider the time over which a nutrient intake has been unintentionally reduced and/or the likelihood of future impaired nutrient intake. The Malnutrition Universal Screening Tool (MUST), for example, may be used to do this.
When screening for malnutrition and the risk of malnutrition, be aware that dysphagia, poor oral health and reduced ability to self-feed will affect nutrition in people with stroke.
Screening for malnutrition and the risk of malnutrition should be carried out by healthcare professionals with appropriate skills and training.
Routine nutritional supplementation is not recommended for people with acute stroke who are adequately nourished on admission.
Start nutrition support for people with stroke who are at risk of malnutrition. This may include oral nutritional supplements, specialist dietary advice and/or tube feeding.
## Hydration
Assess, on admission, the hydration of everyone with acute stroke. Review hydration regularly and manage it so that normal hydration is maintained.
# Optimal positioning and early mobilisation for people with acute stroke
## Optimal positioning
Assess the individual clinical needs and personal preferences of people with acute stroke to determine their optimal head position. Take into account factors such as their comfort, physical and cognitive abilities and postural control.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on optimal positioning for people with acute stroke .
Full details of the evidence and the committee's discussion are in evidence review G: head positioning.
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## Early mobilisation
Help people with acute stroke to sit out of bed, stand or walk as soon as their clinical condition permits as part of an active management programme in a specialist stroke unit.
If people need help to sit out of bed, stand or walk, do not offer high-intensity mobilisation in the first 24 hours after symptom onset.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on early mobilisation for people with acute stroke .
Full details of the evidence and the committee's discussion are in evidence review F: very early mobilisation.
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# Avoiding aspiration pneumonia
To avoid aspiration pneumonia, give food, fluids and medication to people with dysphagia in a form that can be swallowed without aspiration, after specialist assessment of swallowing (see recommendation 1.6.2).
# Surgery for people with acute stroke
## Acute intracerebral haemorrhage
Stroke services should agree protocols for monitoring, referring and transferring people to regional neurosurgical centres for the management of symptomatic hydrocephalus.
People with intracerebral haemorrhage should be monitored by specialists in neurosurgical or stroke care for deterioration in function and referred immediately for brain imaging when necessary.
Previously fit people should be considered for surgical intervention following primary intracerebral haemorrhage if they have hydrocephalus.
People with any of the following rarely require surgical intervention and should receive medical treatment initially:
small deep haemorrhages
lobar haemorrhage without either hydrocephalus or rapid neurological deterioration
a large haemorrhage and significant comorbidities before the stroke
a score on the Glasgow Coma Scale of below 8 unless this is because of hydrocephalus
posterior fossa haemorrhage.
## Decompressive hemicraniectomy
Consider decompressive hemicraniectomy (which should be performed within 48 hours of symptom onset) for people with acute stroke who meet all of the following criteria:
clinical deficits that suggest infarction in the territory of the middle cerebral artery, with a score above 15 on the NIHSS
decreased level of consciousness, with a score of 1 or more on item 1a of the NIHSS
signs on CT of an infarct of at least 50% of the middle cerebral artery territory:
with or without additional infarction in the territory of the anterior or posterior cerebral artery on the same side or
with infarct volume greater than 145 cm3, as shown on diffusion-weighted MRI scan.
Discuss the risks and benefits of decompressive hemicraniectomy with people or their family members or carers (as appropriate), taking into account their functional status before the stroke, and their wishes and preferences. NICE has produced patient decision aids to support discussions about decompressive hemicraniectomy.
People who are referred for decompressive hemicraniectomy should be monitored by appropriately trained professionals skilled in neurological assessment.
For a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on decompressive hemicraniectomy for people with acute stroke .
Full details of the evidence and the committee's discussion are in evidence review H: surgery (decompressive hemicraniectomy).
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary.
## High-intensity mobilisation
High-intensity mobilisation refers to the very early mobilisation intervention from the AVERT trial. (Further details of the intervention performed in the trial can be found in NICE's evidence review F: very early mobilisation.) It includes mobilisation that:
begins within the first 24 hours of stroke onset
includes at least 3 additional out-of-bed sessions compared with usual care
focuses on sitting, standing and walking (that is, out of bed) activity.# Additional information
# Recommendation 1.3.2
The committee felt that 'immediately' is defined as 'ideally the next slot and definitely within 1 hour, whichever is sooner'.
# Recommendations 1.4.5 to 1.4.7
In May 2019, not all devices with a CE mark for thrombectomy were intended by the manufacturer for use as recommended here. The healthcare professional should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. Medicines and Healthcare products Regulatory Agency (MHRA) advice remains to use CE‑marked devices for their intended purpose where possible. See MHRA's guidance on off-label use of a medical device for further information.
# Recommendation 1.4.12
There may be a subgroup of people for whom the risk of venous thromboembolism outweighs the risk of haemorrhagic transformation. People considered to be at particularly high risk of venous thromboembolism include anyone with complete paralysis of the leg, a previous history of venous thromboembolism, dehydration or comorbidities (such as malignant disease), or who is a current or recent smoker. Such people should be kept under regular review if they are given prophylactic anticoagulation.
# Recommendation 1.4.15
There was insufficient evidence to support any recommendation on the safety and efficacy of anticoagulants versus antiplatelets for the treatment of people with acute ischaemic stroke associated with antiphospholipid syndrome.
# Recommendation 1.4.21
The consensus of the committee is that it would be safe to start statins after 48 hours.# Recommendations for research
As part of the 2022 update, the guideline committee made an additional 2 research recommendations.
As part of the 2019 update, the guideline committee retained the research recommendations on avoidance of aspiration pneumonia, aspirin and anticoagulant treatment for acute ischaemic stroke, aspirin treatment in acute ischaemic stroke, early mobilisation and optimum positioning of people with acute stroke, blood pressure control, and safety and efficacy of carotid stenting. The committee made an additional research recommendation on MRI brain scanning.
# Key recommendations for research
## Impact of intensive blood pressure lowering on people who are frail
What is the efficacy and safety of intensive interventions to lower blood pressure compared with less intensive interventions for people with acute intracerebral haemorrhage who are frail at presentation?
For a short explanation of why the committee made this recommendation for research, see the rationale section on blood pressure control for people with acute intracerebral haemorrhage .
Full details of the evidence and the committee's discussion are in evidence review E: intensive interventions to lower blood pressure in people with acute intracerebral haemorrhage.
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## Impact of intensive interventions to lower blood pressure on cognitive function, functional ability and quality of life
What are the long-term effects of intensive interventions to lower blood pressure on cognitive function, functional ability and quality of life compared with standard interventions in people with acute intracerebral haemorrhage?
For a short explanation of why the committee made this recommendation for research, see the rationale section on blood pressure control for people with acute intracerebral haemorrhage .
Full details of the evidence and the committee's discussion are in evidence review E: intensive interventions to lower blood pressure in people with acute intracerebral haemorrhage.
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## MRI brain scanning
Does early MRI brain scanning improve outcomes after suspected transient ischaemic attack (TIA)?
For a short explanation of why the committee made this recommendation for research, see the rationale section on imaging for people who have had a suspected TIA or acute non-disabling stroke .
Full details of the evidence and the committee's discussion are in evidence review C: TIA imaging.
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## Avoidance of aspiration pneumonia
Does the withdrawal of oral liquids or the use of modified (thickened) oral fluids prevent the development of aspiration pneumonia after an acute stroke?
People with dysphagia after an acute stroke are at higher risk of aspiration pneumonia. The guideline development group considered how best to reduce the likelihood of people with acute stroke developing aspiration pneumonia, but there was insufficient evidence on which to base a recommendation. Current clinical practice dictates that those people with clinical evidence of aspiration are given 'nil by mouth' or are given modified (thickened) oral fluids. However, there is little evidence to suggest that withdrawal or modification of fluids reduces the incidence of pneumonia. Oral hygiene is impaired by the withdrawal of oral fluids, and aspirated saliva (up to 2 litres/day) may be infected as a result. Medications are not given orally, and patients may be distressed by the withholding of oral fluids. The research question is whether allowing people with evidence of aspiration free access to water predisposes them to the development of aspiration pneumonia compared with withdrawal of oral liquids or the use of modified (thickened) oral fluids.
## Aspirin and anticoagulant treatment for acute ischaemic stroke
Does modified-release dipyridamole or clopidogrel with aspirin improve outcome compared with aspirin alone when administered early after acute ischaemic stroke?
Aspirin administered within 48 hours of acute ischaemic stroke improves outcome compared with no treatment or early anticoagulation. In the secondary prevention of stroke, the combination of modified-release dipyridamole with aspirin improves outcome compared with aspirin alone. Clopidogrel, administered with aspirin, improves outcome after myocardial infarction. It is not known whether antiplatelet agents other than aspirin (alone or in combination) may be more effective than aspirin alone in the acute phase of ischaemic stroke. The research question to be addressed is whether modified-release dipyridamole or clopidogrel with aspirin improves outcome compared with aspirin alone when administered early after acute ischaemic stroke.
## Aspirin treatment in acute ischaemic stroke
Should a person who has a stroke or a TIA and is already taking aspirin be prescribed the same or an increased dose of aspirin after the stroke?
Many people take aspirin routinely for the secondary or primary prevention of vascular disease. When a person who is taking 75 mg aspirin daily has a stroke or TIA, there is no evidence to guide clinicians on whether to maintain or increase the dose. The research question to be addressed is whether a person already on aspirin who has a stroke or TIA should be offered the same or an increased dose of aspirin.
## Early mobilisation and optimum positioning of people with acute stroke
How safe and effective is very early mobilisation delivered by appropriately trained healthcare professionals after stroke?
Most people with stroke are nursed in bed for at least the first day after their admission to the stroke unit. The severity of limb weakness or incoordination and reduced awareness or an impaired level of consciousness may make mobilisation potentially hazardous. There are concerns about the effect of very early mobilisation on blood pressure and cerebral perfusion pressure. However, early mobilisation may have beneficial effects on oxygenation and lead to a reduction in complications such as venous thromboembolism and hypostatic pneumonia. There could be benefits for motor and sensory recovery, and patient motivation. The research question to be addressed is whether very early mobilisation with the aid of appropriately trained professionals is safe and improves outcome compared with standard care.
## Safety and efficacy of carotid stenting
What is the safety and efficacy of carotid stenting compared with carotid endarterectomy when these procedures are carried out within 2 weeks of TIA or recovered stroke?
Carotid stenting is less invasive than carotid endarterectomy and might be safer, particularly for patients very soon after a TIA or stroke, for whom the risks of general anaesthetic might be high. However, neither the risk of stroke nor long-term outcomes after early carotid stenting are known. A randomised controlled trial comparing these interventions early after stroke would determine which of them is associated with the best outcome, as well as comparing their relative safety and cost effectiveness. # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Initial management of suspected and confirmed transient ischaemic attack (aspirin)
Recommendation 1.1.4
## Why the committee made the recommendation
There was some evidence for a benefit of aspirin in the early management of confirmed transient ischaemic attack (TIA) or minor stroke in reducing the risk of stroke or recurrent stroke in secondary care in stroke services units. This is not directly applicable to the area of review, which was about TIA at first contact with a healthcare professional. However, in the committee's experience, the earlier that aspirin can be administered, the better this will also be for patient outcomes in this group. The risk of haemorrhage in this group, and of other risks associated with administering aspirin (aspirin allergy or gastrointestinal bleed), is low. The recommendation was based largely on the knowledge and experience of the committee supported by the indirect evidence.
## How the recommendation might affect practice
The recommendation represents a change from current practice. However, because of the low unit cost of aspirin, the committee did not expect the recommendation to result in a significant resource impact. General practices will need to ensure they have adequate supplies of aspirin to enable immediate administration.
Return to recommendation
# Initial management of suspected and confirmed transient ischaemic attack
Recommendations 1.1.5 to 1.1.7
## Why the committee made the recommendations
Evidence showed that risk prediction scores (ABCD2 and ABCD3) used in isolation are poor at discriminating low and high risk of stroke after TIA. Adding imaging of the brain and carotid arteries to the risk scores (as is done in the ABCD2‑I and ABCD3‑I tools) modestly improves discrimination. However, appropriate imaging (including MRI) is not available in general practice or for paramedics, 2 of the key situations when these tools would be used. Arranging specialist assessment less urgently for some people based on a tool with poor discriminative ability for stroke risk has the potential for harm. Therefore, the committee agreed that risk scores should not be used.
The committee agreed, based on their clinical experience and the limited predictive performance of risk scores, that all cases of suspected TIA should be considered as potentially high risk for stroke. Also, because there is no reliable diagnostic test for TIA (the risk stratification tools are not diagnostic tests), it is important to urgently confirm or refute the diagnosis of a suspected TIA with specialist opinion. This is particularly so because in practice, a significant proportion of suspected TIA (30% to 50%) will have an alternative diagnosis (that is, TIA-mimic). Therefore, it was agreed that everyone who has had a suspected TIA should have specialist assessment and investigation within 24 hours of the onset of symptoms. The committee noted the results of an original cost–utility analysis, which was undertaken for this review question in the 2008 version of the stroke guideline (CG68). The analysis concluded that 'immediate assessment' had both better health outcomes and lower costs than 'assessment within a week' for the entire population of suspected TIA, without the use of a risk stratification tool.
The committee acknowledged that having a TIA (or suspected TIA) is a worrying time and most people would prefer to be assessed as soon as possible. Urgent specialist assessment should ensure that people at high risk of stroke are identified early. This would allow preventative treatment to begin, which should be introduced as soon as the diagnosis of TIA is confirmed.
## How the recommendations might affect practice
The recommendations reflect current best practice of expert assessment in a TIA clinic within 24 hours, irrespective of risk stratification using clinical scoring systems. Although everyone with a suspected TIA should be seen within 24 hours, provision of daily TIA clinics is not universal. Therefore, some areas will need to set up daily TIA clinics to provide this best practice service.
The recommendations should not influence the absolute number of people who need to be subsequently assessed in a TIA clinic, but will result in all suspected TIAs being assessed with an equal degree of urgency. There are likely to be implementation challenges for some areas in providing an adequately responsive 7‑days-a-week TIA clinic (or a suitable alternative 7‑day service) where they currently do not exist. However, services are already being encouraged to implement TIA clinics 7 days a week. The committee acknowledged that setting up responsive (7 days a week) services in trusts that do not currently offer daily clinics could require significant additional resource and this may result in a substantial resource impact for the NHS in England. However, preventing stroke is likely to result in cost savings later on.
The recommendation on offering measures for secondary prevention reflects current practice so no change is expected.
Return to recommendations
# Imaging for people who have had a suspected TIA or acute non-disabling stroke
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendations
No evidence was identified from test-and-treat trials (which the committee considered would have been the most useful form of evidence to inform decision making). In these studies, different imaging strategies are performed on randomised groups followed by management on the basis of the results, to compare patient outcomes after different imaging strategies. Therefore, the committee used their knowledge and experience to conclude that clinical assessment is the best form of diagnosis at this point. The committee agreed that CT is most useful when there is a clinical suspicion of an alternative diagnosis that CT could detect. It should not be routinely performed for everyone with a suspected TIA because it rarely confirms a diagnosis in these patients.
Routine CT imaging is common in current practice and the committee agreed that this could waste resources, extend the length of stay in the emergency department, and expose people to unnecessary radiation.
The committee discussed the possible risks of not offering CT brain imaging to everyone with a suspected TIA. They agreed that, in the absence of clinical 'red flag' indicators (for example, headache, anticoagulation, head injury, repetitive stereotyped events), it is rare for a CT scan to reveal an alternative diagnosis needing a different referral pathway. Therefore, the number of referrals to TIA clinics should not increase greatly.
In a TIA clinic, not all people will need an MRI. Therefore, clinical assessment by a specialist in a TIA clinic is important for identifying people who may need MRI to determine the vascular territory of ischaemia (the region of the brain with loss of blood flow, supplied by either the anterior or posterior circulation). For example, this could be before a decision is made to refer for a carotid endarterectomy, or to detect alternative pathologies such as tumours, demyelinating disorders or convexity subarachnoid haemorrhage. There was uncertainty about whether urgent, routine MRI screening improves the outcomes for people with suspected TIA, and so the committee made a research recommendation on early MRI brain scanning.
## How the recommendations might affect practice
Not routinely offering CT brain imaging will be a change in practice for some providers (especially in the emergency department), whereas MRI use in the TIA clinic aligns broadly with current practice.
The committee was uncertain whether these recommendations will be cost saving overall. It will be a trade‑off between a reduction in CT requests against a potential increase in MRI requests. The committee also highlighted that any increase in MRI requests may be small because the decision to perform an MRI will not generally be affected by the results of a previous CT scan.
The committee recognised that if there was an increase in MRI requests, this could be a challenge because access to high-quality MRI scanners is limited in some trusts. In addition, there are limits on the number of MRI slots per day, so there may be a need for dedicated MRI slots for people with suspected TIA.
Return to recommendations
# Thrombectomy for people with acute ischaemic stroke
Recommendations 1.4.5 to 1.4.8
## Why the committee made the recommendations
Overall, the evidence across timeframes showed that thrombectomy, with or without thrombolysis, improved functional outcome as measured by the modified Rankin Scale (mRS) in people last known to be well up to 24 hours previously, compared with usual care. There was also a potential benefit for improved quality of life. However, there was no clinical difference in mortality and there were low rates of symptomatic intracerebral haemorrhage. The committee noted there had been some procedural complications associated with thrombectomy, but agreed that these were outweighed by the benefits of improvement in functional outcome.
The committee looked at the results of 2 published cost–utility analyses with a UK NHS perspective. The first estimated that thrombectomy alongside intravenous thrombolysis (when appropriate) is cost effective compared with intravenous thrombolysis alone, when performed within 6 hours of stroke onset (that is, from when a person was last known to be well). The second demonstrated the cost effectiveness of thrombectomy therapy and best medical therapy compared with best medical therapy alone, when performed 6 to 24 hours after stroke onset. Therefore, the committee agreed to recommend thrombectomy up to 24 hours after stroke onset, together with intravenous thrombolysis if within the licensed time window, for people with appropriate clinical and radiological characteristics. Few people presenting between 6 and 24 hours after stroke onset received thrombolysis because this is outside the licensed time window. Therefore, the recommendation for those presenting beyond 6 hours is for thrombectomy alone.
The evidence for thrombectomy within 6 hours of symptom onset was from populations selected using computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) to identify proximal anterior circulation occlusions. For thrombectomy undertaken between 6 and 24 hours after stroke onset, the evidence was based on more highly selected populations using CT perfusion, MRI diffusion and MRI perfusion imaging, in addition to identifying a proximal anterior circulation arterial occlusion. Because the effectiveness of thrombectomy is likely to be lower in a less selected population, the committee recommended that, in line with the evidence, imaging such as CT perfusion or diffusion-weighted MRI sequences is performed if presentation is 6 to 24 hours after stroke onset in people being considered for thrombectomy. This would ensure that there is vulnerable but salvageable brain tissue to be targeted for thrombectomy. Although benefit is still seen up to 24 hours after stroke, time is still critical. Therefore, the committee agreed that thrombectomy should be performed as soon as possible.
To help determine what clinical characteristics make this intervention suitable, it is important to consider the National Institutes of Health Stroke Scale (NIHSS) score and the person's overall functional capacity before the stroke. The committee agreed that it was not possible on the basis of the evidence reviewed to specify strict threshold criteria for eligibility based on pre-stroke functional status, clinical severity of stroke or the extent of established infarction on initial brain imaging. This is because there was variation in the trial entry criteria used in the studies and the committee agreed that these factors should be considered as part of the clinical judgement on an individual basis. However, because it was important to make a recommendation that can be implemented in practice, mRS and NIHSS eligibility thresholds were included to be consistent with the NHS England clinical commissioning policy on mechanical thrombectomy for acute ischaemic stroke.
No clinical- or cost-effectiveness evidence was identified for the population with posterior circulation stroke. The committee discussed that prognosis is usually very poor in basilar artery occlusion, with around an 80% mortality. As few as 2% to 5% of people with basilar artery occlusion make a full neurological recovery in the absence of interventions to achieve recanalisation or reperfusion. The committee agreed that the prevalent current practice is to consider intravenous thrombolysis and mechanical thrombectomy. Good outcomes can be achieved even up to 24 hours after stroke onset, which is important because diagnosis can be delayed in this population by a non-focal presentation, a reduced conscious level, or both.
The main risk of thrombectomy and thrombolysis in this population is intervening when there is established disabling ischaemic brain injury. For example, if a person with basilar artery occlusion has irreversible bilateral damage to the pons, they may be left with locked-in-syndrome with complete face and body paralysis but clear consciousness, even if the basilar artery is opened. The committee agreed that it is standard practice to perform brain imaging and look for established tissue damage in the brain regions affected by the arterial occlusion, particularly in the brainstem, before intervening. This reduces the number of people surviving with severe neurological disability. Appropriate CT perfusion imaging or diffusion-weighted MRI sequences should be performed to demonstrate that there is salvageable brain tissue and to seek evidence of established injury to functionally critical areas of the posterior circulation.
The outlook for this population without intervention is poor, but good outcomes can be achieved with intervention and there is supportive evidence from treating anterior stroke. Therefore, the committee agreed that thrombectomy, and thrombolysis within its licensed indications, should be considered for people with posterior circulation proximal occlusions and without evidence of irreversible infarction who were last known well up to 24 hours previously. This should be done as soon as possible after presentation because better outcomes are likely with earlier intervention.
## How the recommendations might affect practice
The committee noted that in current practice, around 10% of people presenting with all strokes in the UK are eligible for endovascular therapy. More people are likely to be offered endovascular therapy as a result of these recommendations. The recommendation on thrombectomy together with thrombolysis within 6 hours of symptom onset is aligned with current best practice and the NHS England clinical commissioning policy on mechanical thrombectomy for acute ischaemic stroke. The recommendation for thrombectomy between 6 and 24 hours requires a change from current practice by most providers. Currently, the NHS England clinical commissioning policy states that mechanical thrombectomy will be commissioned when substantial salvageable brain tissue is identified up to 12 hours. However, this extension of the eligibility period up to 24 hours was supported by clinical- and cost-effectiveness evidence as discussed above. The recommendation to consider endovascular therapy for posterior circulation stroke reflects current best practice.
Overall, the new recommendations are likely to have a substantial resource impact on the NHS. Thrombectomy is already performed in most neuroscience centres, but the recommendations will mean 24‑hour access to appropriate staffing and imaging.
The committee discussed the possibility that the new recommendations could initially result in a large increase in referrals to centres that already have thrombectomy services. It also noted that there are likely to be additional costs incurred in transferring people to these centres. This will have implications for the spoke site for arranging transfers, for the ambulance service and at the hub site, where more people will be received. There may need to be networked arrangements for spoke sites around a thrombectomy 'hub' with fast image transfer, referral, eligibility assessment and responsive repatriation systems.
The positive implications for other aspects of stroke care help to address the balance in demand for resources. For example, it is expected that there will be a decrease in demand for decompressive hemicraniectomies and inpatient rehabilitation. There may also be a reduction in the need for long-term social care.
Return to recommendations
# Blood pressure control for people with acute intracerebral haemorrhage
Recommendations 1.5.4 to 1.5.8
## Why the committee made the recommendations
For the groups covered, moderate-quality evidence from a large clinical trial showed a modest benefit treatment effect on haematoma expansion and quality of life (EQ‑5D utility index) in rapidly lowering blood pressure to a target systolic blood pressure of 140 mmHg or lower compared with less intensive blood pressure lowering treatment.
The committee acknowledged the uncertainty over the evidence. They discussed the additional potential harms relating to rapid blood pressure lowering in people who present after 6 hours or who have a systolic blood pressure greater than 220 mmHg, and agreed that these factors should be taken into account when considering rapid blood pressure lowering for these groups.
The committee decided to remove the aim of reaching the target within 1 hour because only a minority (33.4%) of participants in the INTERACT2 trial achieved the target of 140 mmHg within 1 hour and, more importantly, to avoid the potential harm of reducing systolic blood pressure by more than 60 mmHg in the first hour.
There was evidence that rapidly lowering blood pressure does not increase the risk of neurological deterioration caused by reduced blood flow to the brain and has the potential to improve quality of life.
In contrast, the committee noted that in another clinical trial, there was no benefit to rapidly lowering blood pressure and there was an increase in adverse renal events. The committee noted the treatment regimens were more aggressive in this trial compared with the other trials included in the review.
The committee agreed that while there is some evidence that rapid blood pressure lowering treatment is beneficial, there may be an increase in adverse renal events, and they were concerned about the lack of evidence in people who are frail. Taking this into account, the committee agreed that rapid blood pressure lowering treatment should be considered as a treatment option except for the groups highlighted in recommendation 1.5.7.
There was evidence that a moderate reduction of up to 60 mmHg within the first hour was associated with better outcomes such as functional independence. A reduction of more than 60 mmHg within 1 hour was associated with significantly worse outcomes such as renal failure, early neurological deterioration, and death, compared with standard treatment. Therefore, the committee agreed that a large reduction of 60 mmHg or more within 1 hour should be avoided.
The 2019 guideline included a 130 mmHg lower target limit. However, the committee were concerned that a narrow range would be too restrictive, and the variation in the class of drugs used in practice means it is difficult to predict the blood pressure reduction. The committee decided to remove the 130 mmHg lower target limit. The committee considered the potential risk of systolic blood pressure dropping too low but noted that this potential concern is addressed by the avoidance of a large reduction of 60 mmHg or more within 1 hour. The committee also agreed that the target systolic blood pressure and the systolic blood pressure reduction should be made into a separate recommendation (1.5.6).
There was little evidence on people presenting beyond 6 hours or those with a systolic blood pressure over 220 mmHg. However, the committee agreed that some guidance is needed on treating hypertension in these groups and that it is appropriate to extrapolate from the available data to these groups, but that healthcare professionals should take into account the individual risk of harm when considering rapid blood pressure lowering using clinical judgement on a case-by-case basis.
The committee agreed that the evidence to support maintaining the target blood pressure for at least 7 days is weak. They were also concerned about the potential impact on patient flow, bed management and resources in the NHS, so removed the timeframe.
The committee discussed the uncertainty about how long to continue acute treatment. However, this evidence review is primarily concerned with treatment within the first 24 hours. The committee highlighted that blood pressure should still remain lowered after acute treatment in order to reduce the longer-term effect of the acute intracerebral haemorrhage. The committee agreed that people receiving intensive blood pressure treatment would not need to stay in hospital for acute management for 7 days. This can be managed through secondary prevention, which can be indicated when treatment is changed from intravenous to an oral route of administration. The committee also noted that longer-term management of blood pressure can be managed in primary care.
The committee did not change the existing practice of not offering rapid blood pressure lowering to specific groups that were excluded from the key clinical trial. This is because there is no evidence of whether this would be safe or beneficial.
The committee discussed rapid blood pressure lowering for young people aged 16 and 17. The evidence reviewed covers adults 18 and over, but the committee agreed that this can be extrapolated for young people after seeking advice from a paediatric specialist.
The committee wanted to consider the long-term effect of intensive blood pressure lowering on quality of life, but limited evidence was available to show how it affected quality of life at 6 and 12 months, and no evidence was available on cognitive function or functional ability. Given the lack of evidence for these important outcomes, the committee made a research recommendation about the impact of intensive interventions to lower blood pressure on cognitive function, functional ability and quality of life compared with less intensive interventions.
The committee identified a gap in the evidence on the impact of intensive blood pressure treatment on people who are frail. There is currently no guidance or treatment pathway for people who are frail, so the committee also made a research recommendation about the impact of intensive blood pressure lowering on people who are frail, and encouraged the use of frailty scores to evaluate the impact of frailty on outcomes and treatment prognoses.
## Other factors the committee took into account
The committee were aware of the European Stroke Organisation (ESO) guideline on blood pressure management in acute ischaemic stroke and intracerebral haemorrhage, which suggests 'In patients with hyperacute (presenting within 6 hours) intracerebral haemorrhage, lowering blood pressure to below 140 mmHg (and to keep it above 110 mmHg) to reduce haematoma expansion'. The committee agreed that this is broadly in line with NICE recommendations.
## How the recommendations might affect practice
The recommendations reflect a small change to current best practice. The difference in target blood pressure range and magnitude in drop from starting treatment up to the first hour in the 2022 update might need additional planning and closer management by the nursing team. Given that these people currently need close monitoring, any change is likely to be very small. There may be an increased cost of intravenous antihypertension medication, but the recommendations should save resources because of reduced harms. Overall, the recommendations should not have a resource impact to the NHS in England.
Return to recommendations
# Optimal positioning for people with acute stroke
Recommendation 1.7.1
## Why the committee made the recommendation
The evidence did not indicate any difference in outcomes between lying flat or with the head elevated. No cost-effectiveness evidence was identified and no cost difference between the 2 strategies is expected. Therefore, the committee used their knowledge and experience to recommend positioning people according to their preferences and individual requirements.
## How the recommendation might affect practice
Optimal positioning is an important part of early acute stroke management and rehabilitation. In current practice, people are assessed in bed and optimal head positioning is determined based on clinical presentation, medical needs and patient comfort. The recommendation therefore reflects current practice in most hospitals and so the committee agreed that there should be little or no change.
Return to recommendation
# Early mobilisation for people with acute stroke
Recommendations 1.7.2 and 1.7.3
## Why the committee made the recommendations
Regarding the recommendation to mobilise people after having a stroke when their clinical condition permits, there was no clear evidence of benefit or harm for early mobilisation within the first 48 hours after symptom onset compared with standard care. Therefore, the committee made a recommendation based on their knowledge and experience. The committee agreed that early mobilisation may be appropriate in some cases where people need minimal assistance to mobilise, such as in those who have suffered a mild stroke, or are experiencing language and/or upper limb dysfunction alone.
Regarding the recommendation not to offer high-intensity mobilisation within the first 24 hours of symptom onset, a published within-trial cost-effectiveness analysis from the Australian hospital perspective was identified. However, the treatment effect for the health outcome mRS 0 to 2 used in the study differed from the treatment effect calculated in the clinical review. Because the cost-effectiveness evidence was incompatible with the results of the clinical review, the committee chose to make a recommendation based on the clinical evidence for mortality. The evidence suggested clinical harm associated with high-intensity mobilisation within the first 24 hours after acute stroke. However, based on their clinical experience they discussed that this harm was most relevant to those who need help to sit out of bed, stand or walk. Therefore, they limited the recommendation to this group because they did not want to prevent appropriate early mobilisation in people who are independently mobile after having a stroke.
## How the recommendations might affect practice
The committee was confident that making these recommendations would not have a resource impact, because there was no indication that mobilising later and with a lower intensity leads to a longer length of stay. The committee noted that people will still be assessed and mobilised and there are unlikely to be differences in staff costs. In current practice, mobilisation strategies differ according to stroke severity and the clinical condition of the person with stroke. The strategy may also be impacted by the availability of different types of specialist seating. The recommendations may change current practice in stroke units where there is an 'as soon as possible' focus on mobilisation. They will encourage healthcare professionals to consider the intensity of very early mobilisation and advice on intensity of activities to people discharged from hospital early after a stroke.
Return to recommendations
# Decompressive hemicraniectomy for people with acute stroke
Recommendations 1.9.5 and 1.9.7
## Why the committee made the recommendations
The evidence showed that surgery improved mortality rates and, to a lesser extent, functional outcomes as measured by the mRS. The benefit on mortality was seen in all age groups considered, although the benefit for functional outcome was smaller in people aged over 60 years than in people under 60 years. Based on this, and to ensure that people over 60 have similar opportunities for the surgery as younger people, the committee removed the previous age cut‑off for considering surgery. The committee also acknowledged that although surgery results in more people surviving and better functional outcome than without surgery, many still have overall poor functional outcome and their quality of life may be low. The acceptability of this trade‑off was agreed to be a very individual judgement. Some people may choose not to have surgery if there is a risk of severe disability, whereas others may wish to go ahead based on mortality benefit alone. Therefore, the committee highlighted the need for careful discussion about risks and benefits between clinicians and family members or carers. They noted that patients would not be able to be involved at the time because of the severity of the stroke, so the family or carers would be responsible for making the decision. In deciding whether to opt for surgery, considerations should include pre-stroke functional status, because surgery would not be appropriate for people with severe disability before stroke.
The committee noted that although some of the trials included people who had surgery as long as 96 hours after symptom onset, the benefits in terms of reduced mortality and improved functional outcome were largely driven by studies that only allowed surgery up to a maximum of 48 hours after onset. Therefore, it agreed to retain the reference to surgery being performed within 48 hours of onset from the original recommendations. The committee also reviewed the criteria used to determine eligibility for hemicraniectomy from NICE's stroke guideline published in 2008. It was agreed that these were still appropriate and reflect the populations included in the studies used to inform the new recommendations.
The committee agreed that although the cost effectiveness of decompressive hemicraniectomy remains uncertain, it should be considered for some people because of the clear mortality benefit and the improved functional outcomes. Shared decision making between physicians, surgeons, families and carers is important given the high likelihood of residual moderate or severe disability after surgery.
## How the recommendations might affect practice
In current practice, around 5% of people on the stroke unit are referred for decompressive hemicraniectomy. Decompressive hemicraniectomy is currently considered for those aged under 60.
This recommendation will require a change from current practice by all providers. The guidance will also require healthcare professionals to take into account people's pre-stroke functional status and to have a discussion about the risks and benefits.
The committee believed that including people over 60 years would not necessarily lead to significantly more people undergoing surgery because informed discussion of the outcomes might reduce its uptake in this population. In addition, increasing the population eligible for endovascular therapy and its provision is likely to decrease the population referred for decompressive hemicraniectomy. The committee therefore did not anticipate a substantial resource impact to result from this recommendation.
Return to recommendations# Context
Since NICE published its guideline on stroke and transient ischaemic attack (TIA) in 2008, the management of stroke has changed. New evidence has emerged in areas such as thrombectomy (clot retrieval procedures) in ischaemic stroke, controlling high blood pressure in people with acute haemorrhagic stroke, the role of hemicraniectomy and early mobilisation and optimum positioning of people with acute stroke. In addition, there is some uncertainty about the use of aspirin when TIA is first suspected, the role of conventional risk stratification in TIA and the best approach to intracerebral imaging after TIA. This guideline update includes recommendations on these specific issues.
A stroke occurs when the blood supply to a part of the brain is acutely compromised. Most strokes (85%) are caused by a blockage in a blood vessel (artery) that supplies blood to the brain. A TIA or 'mini stroke' has the same clinical presentation as a stroke except that symptoms disappear within 24 hours.
The symptoms experienced depend on the part of the brain that is affected. They usually occur suddenly and without any warning. Common symptoms include loss of movement or sensation in an arm or leg, problems speaking, a drooping of one side of the face or problems with vision.
A stroke can occur at any age. The average age for stroke varies across the UK, with a median age of 77 years (interquartile range 67 to 85). A quarter of strokes occur in people of working age.
First-ever stroke affects 230 people per 100,000 each year, with over 80,000 people hospitalised per year in England. Although the death rate has been falling, figures from the Sentinel Stroke National Audit Programme show that 13.6% of people admitted to hospital with stroke in England and Wales died (either in hospital or after being discharged from inpatient care) within 30 days. There are approximately 1.2 million stroke survivors in the UK. The risk of recurrent stroke is 26% within 5 years of a first stroke and 39% by 10 years.
Stroke is the single biggest cause of disability in adults. The Stroke Association has estimated an annual cost to the NHS in England of £2.98 billion per year. In addition, annual social care costs have been estimated at £4.55 billion with almost half of that estimated to be from public funds. Of stroke survivors, 1 in 12 have to move into a care home because of the effects of their stroke. There is also a substantial burden to families of people who have had a stroke in terms of informal unpaid care. The importance of stroke care in the NHS is also highlighted in the NHS Long Term Plan, the National Stroke Programme, the Intercollegiate Stroke Working Party national clinical guideline for stroke, and the 2018 publication of NHS England's clinical commissioning policy for mechanical thrombectomy for acute ischaemic stroke in the NHS. Also, the Royal College of Paediatrics and Child Health published guidelines in 2017 on the treatment of stroke in those under 18 years old.
This guideline covers people over 16 with suspected or confirmed TIAs or completed strokes, that is, an acute neurological event presumed to be vascular in origin and causing cerebral ischaemia, cerebral infarction or cerebral haemorrhage. This includes first and recurrent events, thrombotic and embolic events and primary intracerebral haemorrhage of any cause, including venous thrombosis. Areas that are not covered include specific issues relating to the general management of underlying conditions and subarachnoid haemorrhage.# Finding more information and resources
To find NICE guidance on related topics, including guidance in development, see the NICE topic page on cardiovascular conditions.
For full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.
NICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off‑label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nNICE has also produced patient decision aids on decompressive hemicraniectomy.\n\n# Rapid recognition of symptoms and diagnosis\n\n## Prompt recognition of symptoms of stroke and transient ischaemic attack\n\nUse a validated tool, such as FAST (Face Arm Speech Test), outside hospital to screen people with sudden onset of neurological symptoms for a diagnosis of stroke or transient ischaemic attack (TIA). \n\nExclude hypoglycaemia in people with sudden onset of neurological symptoms as the cause of these symptoms. \n\nFor people who are admitted to the emergency department with a suspected stroke or TIA, establish the diagnosis rapidly using a validated tool, such as ROSIER (Recognition of Stroke in the Emergency Room). \n\n## Initial management of suspected and confirmed TIA\n\nOffer aspirin (300\xa0mg daily), unless contraindicated, to people who have had a suspected TIA, to be started immediately. \n\nFor a short explanation of why the committee made this 2019 recommendation and how it might affect practice, see the rationale and impact section on initial management of suspected and confirmed transient ischaemic attack (aspirin)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: aspirin.\n\nLoading. Please wait.\n\nRefer immediately people who have had a suspected TIA for specialist assessment and investigation, to be seen within 24\xa0hours of onset of symptoms. \n\nDo not use scoring systems, such as ABCD2, to assess risk of subsequent stroke or to inform urgency of referral for people who have had a suspected or confirmed TIA. \n\nOffer secondary prevention, in addition to aspirin, as soon as possible after the diagnosis of TIA is confirmed. [2008, amended 2019]\n\nFor a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on initial management of suspected and confirmed transient ischaemic attack\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: TIA prediction rules.\n\nLoading. Please wait.\n\n# Imaging for people who have had a suspected TIA or acute non-disabling stroke\n\n## Suspected TIA\n\nDo not offer CT brain scanning to people with a suspected TIA unless there is clinical suspicion of an alternative diagnosis that CT could detect. \n\nAfter specialist assessment in the TIA clinic, consider MRI (including diffusion-weighted and blood-sensitive sequences) to determine the territory of ischaemia, or to detect haemorrhage or alternative pathologies. If MRI is done, perform it on the same day as the assessment. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on imaging for people who have had a suspected TIA or acute non-disabling stroke\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: TIA imaging.\n\nLoading. Please wait.\n\n## Carotid imaging\n\nEveryone with TIA who after specialist assessment is considered as a candidate for carotid endarterectomy should have urgent carotid imaging. [2008, amended 2019]\n\n## Urgent carotid endarterectomy\n\nEnsure that people with stable neurological symptoms from acute non-disabling stroke or TIA who have symptomatic carotid stenosis of 50%\xa0to\xa099% according to the NASCET (North American Symptomatic Carotid Endarterectomy Trial) criteria, or 70%\xa0to\xa099% according to the ECST (European Carotid Surgery Trial) criteria:\n\nare assessed and referred urgently for carotid endarterectomy to a service following current national standards (see the NHS England and NHS Improvement National Stroke Service Model)\n\nreceive best medical treatment (control of blood pressure, antiplatelet agents, cholesterol lowering through diet and drugs, lifestyle advice). [2008, amended 2019]\n\nEnsure that people with stable neurological symptoms from acute non-disabling stroke or TIA who have symptomatic carotid stenosis of less than 50% according to the NASCET criteria, or less than 70% according to the ECST criteria:\n\ndo not have surgery\n\nreceive best medical treatment (control of blood pressure, antiplatelet agents, cholesterol lowering through diet and drugs, lifestyle advice). \n\nEnsure that carotid imaging reports clearly state which criteria (ECST or NASCET) were used when measuring the extent of carotid stenosis. \n\n# Specialist care for people with acute stroke\n\n## Specialist stroke units\n\nAdmit everyone with suspected stroke directly to a specialist acute stroke unit after initial assessment, from either the community, the emergency department, or outpatient clinics. (An acute stroke unit is a discrete area in the hospital that is staffed by a specialist stroke multidisciplinary team. It has access to equipment for monitoring and rehabilitating patients. Regular multidisciplinary team meetings occur for goal setting.). \n\n## Brain imaging for the early assessment of people with suspected acute stroke\n\nPerform brain imaging immediately with a non-enhanced CT for people with suspected acute stroke if any of the following apply (see additional information):\n\nindications for thrombolysis or thrombectomy\n\non anticoagulant treatment\n\na known bleeding tendency\n\na depressed level of consciousness (Glasgow Coma Score below\xa013)\n\nunexplained progressive or fluctuating symptoms\n\npapilloedema, neck stiffness or fever\n\nsevere headache at onset of stroke symptoms.If thrombectomy might be indicated, perform imaging with CT contrast angiography following initial non-enhanced CT. Add CT perfusion imaging (or MR equivalent) if thrombectomy might be indicated beyond 6\xa0hours of symptom onset. [2008, amended 2019]\n\nPerform scanning as soon as possible and within 24\xa0hours of symptom onset in everyone with suspected acute stroke without indications for immediate brain imaging. The NHS England and NHS Improvement National Stroke Service Model contains a patient-centred national optimal stroke imaging pathway.\n\n# Pharmacological treatments and thrombectomy for people with acute stroke\n\n## Thrombolysis with alteplase for people with acute ischaemic stroke\n\nAlteplase is recommended within its marketing authorisation for treating acute ischaemic stroke in adults if:\n\ntreatment is started as soon as possible within 4.5\xa0hours of onset of stroke symptoms and\n\nintracranial haemorrhage has been excluded by appropriate imaging techniques. This recommendation is from NICE's technology appraisal guidance on alteplase for treating acute ischaemic stroke.\n\nAdminister alteplase only within a well-organised stroke service with:\n\nstaff trained in delivering thrombolysis and in monitoring for any complications associated with thrombolysis\n\nnursing staff trained in acute stroke and thrombolysis to provide level\xa01 and level\xa02 care (seen the NHS Data Model and Dictionary on critical care level)\n\nimmediate access to imaging and re‑imaging, and staff trained to interpret the images. [2008, amended 2019]\n\nStaff in emergency departments, if appropriately trained and supported, can administer alteplase for the treatment of ischaemic stroke provided that patients can be managed within an acute stroke service with appropriate neuroradiological and stroke physician support. \n\nEnsure that protocols are in place for delivering and managing intravenous thrombolysis, including post-thrombolysis complications. \n\n## Thrombectomy for people with acute ischaemic stroke\n\nOffer thrombectomy as soon as possible and within 6\xa0hours of symptom onset, together with intravenous thrombolysis (if not contraindicated and within the licensed time window), to people who have:\n\nacute ischaemic stroke and\n\nconfirmed occlusion of the proximal anterior circulation demonstrated by computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) taking into account the factors in recommendation 1.4.8 (see additional information). \n\nOffer thrombectomy as soon as possible to people who were last known to be well between 6\xa0hours and 24\xa0hours previously (including wake‑up strokes):\n\nwho have acute ischaemic stroke and confirmed occlusion of the proximal anterior circulation demonstrated by CTA or MRA and\n\nif there is the potential to salvage brain tissue, as shown by imaging such as CT perfusion or diffusion-weighted MRI sequences showing limited infarct core volumetaking into account the factors in recommendation 1.4.8 (see additional information). \n\nConsider thrombectomy together with intravenous thrombolysis (where not contraindicated and within the licensed time window) as soon as possible for people last known to be well up to 24\xa0hours previously (including wake‑up strokes):\n\nwho have acute ischaemic stroke and confirmed occlusion of the proximal posterior circulation (that is, basilar or posterior cerebral artery) demonstrated by CTA or MRA and\n\nif there is the potential to salvage brain tissue, as shown by imaging such as CT perfusion or diffusion-weighted MRI sequences showing limited infarct core volumetaking into account the factors in recommendation 1.4.8 (see additional information). \n\nTake into account the person's overall clinical status and the extent of established infarction on initial brain imaging to inform decisions about thrombectomy. Select people who have (in addition to the factors in recommendations 1.4.5\xa0to\xa01.4.7):\n\na pre-stroke functional status of less than\xa03 on the modified Rankin scale and\n\na score of more than\xa05 on the National Institutes of Health Stroke Scale (NIHSS). \n\nFor a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on thrombectomy for people with acute ischaemic stroke\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: thrombectomy.\n\nLoading. Please wait.\n\n## Aspirin and anticoagulant treatment\n\nOffer the following as soon as possible, but certainly within 24\xa0hours, to everyone presenting with acute stroke who has had a diagnosis of intracerebral haemorrhage excluded by brain imaging:\n\naspirin 300\xa0mg orally if they do not have dysphagia or\n\naspirin 300\xa0mg rectally or by enteral tube if they do have dysphagia. Continue aspirin daily 300\xa0mg until 2\xa0weeks after the onset of stroke symptoms, at which time start definitive long-term antithrombotic treatment. Start people on long-term treatment earlier if they are being discharged before 2\xa0weeks. \n\nOffer a proton pump inhibitor, in addition to aspirin, to anyone with acute ischaemic stroke for whom previous dyspepsia associated with aspirin is reported. \n\nOffer an alternative antiplatelet agent to anyone with acute ischaemic stroke who is allergic to or genuinely intolerant of aspirin. (Aspirin intolerance is defined as either of the following: proven hypersensitivity to aspirin-containing medicines, or history of severe dyspepsia induced by low-dose aspirin.) \n\nDo not use anticoagulation treatment routinely for the treatment of acute stroke (see additional information). \n\nOffer people diagnosed with cerebral venous sinus thrombosis (including those with secondary cerebral haemorrhage) full-dose anticoagulation treatment (initially full-dose heparin and then warfarin [international normalised ratio 2\xa0to\xa03]) unless there are comorbidities that preclude its use. \n\nOffer either anticoagulants or antiplatelet agents to people who have stroke secondary to acute arterial dissection. [2008, amended 2019]\n\nManage acute ischaemic stroke associated with antiphospholipid syndrome in the same way as acute ischaemic stroke without antiphospholipid syndrome (see additional information). \n\nReturn clotting levels to normal as soon as possible in people with a primary intracerebral haemorrhage who were receiving warfarin before their stroke (and have elevated international normalised ratio). Do this by reversing the effects of the warfarin using a combination of prothrombin complex concentrate and intravenous vitamin\xa0K. [2008, amended 2019]\n\nEnsure that people with disabling ischaemic stroke who are in atrial fibrillation are treated with aspirin 300\xa0mg for the first 2\xa0weeks before anticoagulation treatment is considered. \n\nFor people with prosthetic valves who have disabling cerebral infarction and who are at significant risk of haemorrhagic transformation, stop anticoagulation treatment for 1\xa0week and substitute aspirin 300\xa0mg. \n\nEnsure that people with ischaemic stroke and symptomatic proximal deep vein thrombosis or pulmonary embolism receive anticoagulation treatment in preference to treatment with aspirin unless there are other contraindications to anticoagulation. \n\nTreat people who have haemorrhagic stroke and symptomatic deep vein thrombosis or pulmonary embolism to prevent the development of further pulmonary emboli using either anticoagulation or a caval filter. \n\n## Statin treatment\n\nImmediate initiation of statin treatment is not recommended in people with acute stroke (see additional information). \n\nContinue statin treatment in people with acute stroke who are already receiving statins. \n\n# Maintenance or restoration of homeostasis\n\n## Supplemental oxygen therapy\n\nGive supplemental oxygen to people who have had a stroke only if their oxygen saturation drops below 95%. The routine use of supplemental oxygen is not recommended in people with acute stroke who are not hypoxic. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\n## Blood sugar control\n\nMaintain a blood glucose concentration between 4\xa0and 11\xa0mmol/litre in people with acute stroke. \n\nProvide optimal insulin therapy, which can be achieved by the use of intravenous insulin and glucose, to all adults with type\xa01 diabetes with threatened or actual stroke. Critical care and emergency departments should have a protocol for such management. \n\n## Blood pressure control for people with acute intracerebral haemorrhage\n\nConsider rapid blood pressure lowering for people with acute intracerebral haemorrhage who do not have any of the exclusions listed in recommendation 1.5.7 and who:\n\npresent within 6\xa0hours of symptom onset and\n\nhave a systolic blood pressure of between 150\xa0and 220\xa0mmHg. \n\nTaking into account the risk of harm, consider rapid blood pressure lowering on a case-by-case basis for people with acute intracerebral haemorrhage who do not have any of the exclusions listed in recommendation 1.5.7 and who:\n\npresent beyond 6\xa0hours of symptom onset or\n\nhave a systolic blood pressure greater than 220\xa0mmHg. \n\nWhen rapidly lowering blood pressure in people with acute intracerebral haemorrhage, aim to reach a systolic blood pressure of 140\xa0mmHg or lower while ensuring that the magnitude drop does not exceed 60\xa0mmHg within 1\xa0hour of starting treatment. \n\nDo not offer rapid blood pressure lowering to people who:\n\nhave an underlying structural cause (for example, tumour, arteriovenous malformation or aneurysm)\n\nhave a score on the Glasgow Coma Scale of below\xa06\n\nare going to have early neurosurgery to evacuate the haematoma\n\nhave a massive haematoma with a poor expected prognosis. \n\nWhen considering blood pressure lowering in young people aged 16\xa0or\xa017 with acute intracerebral haemorrhage who do not have any of the exclusions listed in recommendation 1.5.7, seek advice from a paediatric specialist. \n\nFor a short explanation of why the committee made the 2022 recommendations and how they might affect practice, see the rationale and impact section on blood pressure control for people with acute intracerebral haemorrhage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: intensive interventions to lower blood pressure in people with acute intracerebral haemorrhage.\n\nLoading. Please wait.\n\n## Blood pressure control for people with acute ischaemic stroke\n\nAnti-hypertensive treatment in people with acute ischaemic stroke is recommended only if there is a hypertensive emergency with one\xa0or more of the following serious concomitant medical issues:\n\nhypertensive encephalopathy\n\nhypertensive nephropathy\n\nhypertensive cardiac failure/myocardial infarction\n\naortic dissection\n\npre-eclampsia/eclampsia. [2008, amended 2019]\n\nBlood pressure reduction to 185/110\xa0mmHg or lower should be considered in people who are candidates for intravenous thrombolysis. \n\n# Nutrition and hydration\n\n## Assessment of swallowing function\n\nOn admission, ensure that people with acute stroke have their swallowing screened by an appropriately trained healthcare professional before being given any oral food, fluid or medication. \n\nIf the admission screen indicates problems with swallowing, ensure that the person has a specialist assessment of swallowing, preferably within 24\xa0hours of admission and not more than 72\xa0hours afterwards. \n\nPeople with suspected aspiration on specialist assessment, or who require tube feeding or dietary modification for 3\xa0days, should be:\n\nre-assessed and considered for instrumental examination\n\nreferred for dietary advice. \n\nPeople with acute stroke who are unable to take adequate nutrition, fluids and medication orally should:\n\nreceive tube feeding with a nasogastric tube within 24\xa0hours of admission unless they have had thrombolysis\n\nbe considered for a nasal bridle tube or gastrostomy if they are unable to tolerate a nasogastric tube\n\nbe referred to an appropriately trained healthcare professional for detailed nutritional assessment, individualised advice and monitoring\n\nhave their oral medication reviewed to amend either the formulation or the route of administration. [2008, amended 2019]\n\n## Oral nutritional supplementation\n\nScreen all hospital inpatients on admission for malnutrition and the risk of malnutrition. Repeat screening weekly for inpatients. \n\nScreening should assess body mass index (BMI) and percentage unintentional weight loss. It should also consider the time over which a nutrient intake has been unintentionally reduced and/or the likelihood of future impaired nutrient intake. The Malnutrition Universal Screening Tool (MUST), for example, may be used to do this. \n\nWhen screening for malnutrition and the risk of malnutrition, be aware that dysphagia, poor oral health and reduced ability to self-feed will affect nutrition in people with stroke. \n\nScreening for malnutrition and the risk of malnutrition should be carried out by healthcare professionals with appropriate skills and training. \n\nRoutine nutritional supplementation is not recommended for people with acute stroke who are adequately nourished on admission. \n\nStart nutrition support for people with stroke who are at risk of malnutrition. This may include oral nutritional supplements, specialist dietary advice and/or tube feeding. \n\n## Hydration\n\nAssess, on admission, the hydration of everyone with acute stroke. Review hydration regularly and manage it so that normal hydration is maintained. \n\n# Optimal positioning and early mobilisation for people with acute stroke\n\n## Optimal positioning\n\nAssess the individual clinical needs and personal preferences of people with acute stroke to determine their optimal head position. Take into account factors such as their comfort, physical and cognitive abilities and postural control. \n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on optimal positioning for people with acute stroke\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: head positioning.\n\nLoading. Please wait.\n\n## Early mobilisation\n\nHelp people with acute stroke to sit out of bed, stand or walk as soon as their clinical condition permits as part of an active management programme in a specialist stroke unit. \n\nIf people need help to sit out of bed, stand or walk, do not offer high-intensity mobilisation in the first 24\xa0hours after symptom onset. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on early mobilisation for people with acute stroke\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: very early mobilisation.\n\nLoading. Please wait.\n\n# Avoiding aspiration pneumonia\n\nTo avoid aspiration pneumonia, give food, fluids and medication to people with dysphagia in a form that can be swallowed without aspiration, after specialist assessment of swallowing (see recommendation\xa01.6.2). \n\n# Surgery for people with acute stroke\n\n## Acute intracerebral haemorrhage\n\nStroke services should agree protocols for monitoring, referring and transferring people to regional neurosurgical centres for the management of symptomatic hydrocephalus. \n\nPeople with intracerebral haemorrhage should be monitored by specialists in neurosurgical or stroke care for deterioration in function and referred immediately for brain imaging when necessary. \n\nPreviously fit people should be considered for surgical intervention following primary intracerebral haemorrhage if they have hydrocephalus. \n\nPeople with any of the following rarely require surgical intervention and should receive medical treatment initially:\n\nsmall deep haemorrhages\n\nlobar haemorrhage without either hydrocephalus or rapid neurological deterioration\n\na large haemorrhage and significant comorbidities before the stroke\n\na score on the Glasgow Coma Scale of below\xa08 unless this is because of hydrocephalus\n\nposterior fossa haemorrhage. \n\n## Decompressive hemicraniectomy\n\nConsider decompressive hemicraniectomy (which should be performed within 48\xa0hours of symptom onset) for people with acute stroke who meet all of the following criteria:\n\nclinical deficits that suggest infarction in the territory of the middle cerebral artery, with a score above\xa015 on the NIHSS\n\ndecreased level of consciousness, with a score of\xa01 or more on item\xa01a of the NIHSS\n\nsigns on CT of an infarct of at least 50% of the middle cerebral artery territory:\n\n\n\nwith or without additional infarction in the territory of the anterior or posterior cerebral artery on the same side or\n\nwith infarct volume greater than 145\xa0cm3, as shown on diffusion-weighted MRI scan. \n\n\n\nDiscuss the risks and benefits of decompressive hemicraniectomy with people or their family members or carers (as appropriate), taking into account their functional status before the stroke, and their wishes and preferences. NICE has produced patient decision aids to support discussions about decompressive hemicraniectomy.\n\nPeople who are referred for decompressive hemicraniectomy should be monitored by appropriately trained professionals skilled in neurological assessment. \n\nFor a short explanation of why the committee made these 2019 recommendations and how they might affect practice, see the rationale and impact section on decompressive hemicraniectomy for people with acute stroke\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: surgery (decompressive hemicraniectomy).\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary.\n\n## High-intensity mobilisation\n\nHigh-intensity mobilisation refers to the very early mobilisation intervention from the AVERT trial. (Further details of the intervention performed in the trial can be found in NICE's evidence review\xa0F: very early mobilisation.) It includes mobilisation that:\n\nbegins within the first 24\xa0hours of stroke onset\n\nincludes at least 3\xa0additional out-of-bed sessions compared with usual care\n\nfocuses on sitting, standing and walking (that is, out of bed) activity.", 'Additional information': "# Recommendation 1.3.2\n\nThe committee felt that 'immediately' is defined as 'ideally the next slot and definitely within 1\xa0hour, whichever is sooner'.\n\n# Recommendations 1.4.5 to 1.4.7\n\nIn May 2019, not all devices with a CE mark for thrombectomy were intended by the manufacturer for use as recommended here. The healthcare professional should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. Medicines and Healthcare products Regulatory Agency (MHRA) advice remains to use CE‑marked devices for their intended purpose where possible. See MHRA's guidance on off-label use of a medical device for further information.\n\n# Recommendation 1.4.12\n\nThere may be a subgroup of people for whom the risk of venous thromboembolism outweighs the risk of haemorrhagic transformation. People considered to be at particularly high risk of venous thromboembolism include anyone with complete paralysis of the leg, a previous history of venous thromboembolism, dehydration or comorbidities (such as malignant disease), or who is a current or recent smoker. Such people should be kept under regular review if they are given prophylactic anticoagulation.\n\n# Recommendation 1.4.15\n\nThere was insufficient evidence to support any recommendation on the safety and efficacy of anticoagulants versus antiplatelets for the treatment of people with acute ischaemic stroke associated with antiphospholipid syndrome.\n\n# Recommendation 1.4.21\n\nThe consensus of the committee is that it would be safe to start statins after 48\xa0hours.", 'Recommendations for research': "As part of the 2022 update, the guideline committee made an additional 2\xa0research recommendations.\n\nAs part of the 2019 update, the guideline committee retained the research recommendations on avoidance of aspiration pneumonia, aspirin and anticoagulant treatment for acute ischaemic stroke, aspirin treatment in acute ischaemic stroke, early mobilisation and optimum positioning of people with acute stroke, blood pressure control, and safety and efficacy of carotid stenting. The committee made an additional research recommendation on MRI brain scanning.\n\n# Key recommendations for research\n\n## Impact of intensive blood pressure lowering on people who are frail\n\nWhat is the efficacy and safety of intensive interventions to lower blood pressure compared with less intensive interventions for people with acute intracerebral haemorrhage who are frail at presentation? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on blood pressure control for people with acute intracerebral haemorrhage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: intensive interventions to lower blood pressure in people with acute intracerebral haemorrhage.\n\nLoading. Please wait.\n\n## Impact of intensive interventions to lower blood pressure on cognitive function, functional ability and quality of life\n\nWhat are the long-term effects of intensive interventions to lower blood pressure on cognitive function, functional ability and quality of life compared with standard interventions in people with acute intracerebral haemorrhage? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on blood pressure control for people with acute intracerebral haemorrhage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: intensive interventions to lower blood pressure in people with acute intracerebral haemorrhage.\n\nLoading. Please wait.\n\n## MRI brain scanning\n\nDoes early MRI brain scanning improve outcomes after suspected transient ischaemic attack (TIA)? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on imaging for people who have had a suspected TIA or acute non-disabling stroke\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: TIA imaging.\n\nLoading. Please wait.\n\n## Avoidance of aspiration pneumonia\n\nDoes the withdrawal of oral liquids or the use of modified (thickened) oral fluids prevent the development of aspiration pneumonia after an acute stroke?\n\nPeople with dysphagia after an acute stroke are at higher risk of aspiration pneumonia. The guideline development group considered how best to reduce the likelihood of people with acute stroke developing aspiration pneumonia, but there was insufficient evidence on which to base a recommendation. Current clinical practice dictates that those people with clinical evidence of aspiration are given 'nil by mouth' or are given modified (thickened) oral fluids. However, there is little evidence to suggest that withdrawal or modification of fluids reduces the incidence of pneumonia. Oral hygiene is impaired by the withdrawal of oral fluids, and aspirated saliva (up to 2\xa0litres/day) may be infected as a result. Medications are not given orally, and patients may be distressed by the withholding of oral fluids. The research question is whether allowing people with evidence of aspiration free access to water predisposes them to the development of aspiration pneumonia compared with withdrawal of oral liquids or the use of modified (thickened) oral fluids. \n\n## Aspirin and anticoagulant treatment for acute ischaemic stroke\n\nDoes modified-release dipyridamole or clopidogrel with aspirin improve outcome compared with aspirin alone when administered early after acute ischaemic stroke?\n\nAspirin administered within 48\xa0hours of acute ischaemic stroke improves outcome compared with no treatment or early anticoagulation. In the secondary prevention of stroke, the combination of modified-release dipyridamole with aspirin improves outcome compared with aspirin alone. Clopidogrel, administered with aspirin, improves outcome after myocardial infarction. It is not known whether antiplatelet agents other than aspirin (alone or in combination) may be more effective than aspirin alone in the acute phase of ischaemic stroke. The research question to be addressed is whether modified-release dipyridamole or clopidogrel with aspirin improves outcome compared with aspirin alone when administered early after acute ischaemic stroke. \n\n## Aspirin treatment in acute ischaemic stroke\n\nShould a person who has a stroke or a TIA and is already taking aspirin be prescribed the same or an increased dose of aspirin after the stroke?\n\nMany people take aspirin routinely for the secondary or primary prevention of vascular disease. When a person who is taking 75\xa0mg aspirin daily has a stroke or TIA, there is no evidence to guide clinicians on whether to maintain or increase the dose. The research question to be addressed is whether a person already on aspirin who has a stroke or TIA should be offered the same or an increased dose of aspirin. \n\n## Early mobilisation and optimum positioning of people with acute stroke\n\nHow safe and effective is very early mobilisation delivered by appropriately trained healthcare professionals after stroke?\n\nMost people with stroke are nursed in bed for at least the first day after their admission to the stroke unit. The severity of limb weakness or incoordination and reduced awareness or an impaired level of consciousness may make mobilisation potentially hazardous. There are concerns about the effect of very early mobilisation on blood pressure and cerebral perfusion pressure. However, early mobilisation may have beneficial effects on oxygenation and lead to a reduction in complications such as venous thromboembolism and hypostatic pneumonia. There could be benefits for motor and sensory recovery, and patient motivation. The research question to be addressed is whether very early mobilisation with the aid of appropriately trained professionals is safe and improves outcome compared with standard care. \n\n## Safety and efficacy of carotid stenting\n\nWhat is the safety and efficacy of carotid stenting compared with carotid endarterectomy when these procedures are carried out within 2\xa0weeks of TIA or recovered stroke?\n\nCarotid stenting is less invasive than carotid endarterectomy and might be safer, particularly for patients very soon after a TIA or stroke, for whom the risks of general anaesthetic might be high. However, neither the risk of stroke nor long-term outcomes after early carotid stenting are known. A randomised controlled trial comparing these interventions early after stroke would determine which of them is associated with the best outcome, as well as comparing their relative safety and cost effectiveness. ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Initial management of suspected and confirmed transient ischaemic attack (aspirin)\n\nRecommendation 1.1.4\n\n## Why the committee made the recommendation\n\nThere was some evidence for a benefit of aspirin in the early management of confirmed transient ischaemic attack (TIA) or minor stroke in reducing the risk of stroke or recurrent stroke in secondary care in stroke services units. This is not directly applicable to the area of review, which was about TIA at first contact with a healthcare professional. However, in the committee's experience, the earlier that aspirin can be administered, the better this will also be for patient outcomes in this group. The risk of haemorrhage in this group, and of other risks associated with administering aspirin (aspirin allergy or gastrointestinal bleed), is low. The recommendation was based largely on the knowledge and experience of the committee supported by the indirect evidence.\n\n## How the recommendation might affect practice\n\nThe recommendation represents a change from current practice. However, because of the low unit cost of aspirin, the committee did not expect the recommendation to result in a significant resource impact. General practices will need to ensure they have adequate supplies of aspirin to enable immediate administration.\n\nReturn to recommendation\n\n# Initial management of suspected and confirmed transient ischaemic attack\n\nRecommendations 1.1.5 to 1.1.7\n\n## Why the committee made the recommendations\n\nEvidence showed that risk prediction scores (ABCD2 and ABCD3) used in isolation are poor at discriminating low and high risk of stroke after TIA. Adding imaging of the brain and carotid arteries to the risk scores (as is done in the ABCD2‑I and ABCD3‑I tools) modestly improves discrimination. However, appropriate imaging (including MRI) is not available in general practice or for paramedics, 2\xa0of the key situations when these tools would be used. Arranging specialist assessment less urgently for some people based on a tool with poor discriminative ability for stroke risk has the potential for harm. Therefore, the committee agreed that risk scores should not be used.\n\nThe committee agreed, based on their clinical experience and the limited predictive performance of risk scores, that all cases of suspected TIA should be considered as potentially high risk for stroke. Also, because there is no reliable diagnostic test for TIA (the risk stratification tools are not diagnostic tests), it is important to urgently confirm or refute the diagnosis of a suspected TIA with specialist opinion. This is particularly so because in practice, a significant proportion of suspected TIA (30%\xa0to\xa050%) will have an alternative diagnosis (that is, TIA-mimic). Therefore, it was agreed that everyone who has had a suspected TIA should have specialist assessment and investigation within 24\xa0hours of the onset of symptoms. The committee noted the results of an original cost–utility analysis, which was undertaken for this review question in the 2008 version of the stroke guideline (CG68). The analysis concluded that 'immediate assessment' had both better health outcomes and lower costs than 'assessment within a week' for the entire population of suspected TIA, without the use of a risk stratification tool.\n\nThe committee acknowledged that having a TIA (or suspected TIA) is a worrying time and most people would prefer to be assessed as soon as possible. Urgent specialist assessment should ensure that people at high risk of stroke are identified early. This would allow preventative treatment to begin, which should be introduced as soon as the diagnosis of TIA is confirmed.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current best practice of expert assessment in a TIA clinic within 24\xa0hours, irrespective of risk stratification using clinical scoring systems. Although everyone with a suspected TIA should be seen within 24\xa0hours, provision of daily TIA clinics is not universal. Therefore, some areas will need to set up daily TIA clinics to provide this best practice service.\n\nThe recommendations should not influence the absolute number of people who need to be subsequently assessed in a TIA clinic, but will result in all suspected TIAs being assessed with an equal degree of urgency. There are likely to be implementation challenges for some areas in providing an adequately responsive 7‑days-a-week TIA clinic (or a suitable alternative 7‑day service) where they currently do not exist. However, services are already being encouraged to implement TIA clinics 7\xa0days a week. The committee acknowledged that setting up responsive (7\xa0days a week) services in trusts that do not currently offer daily clinics could require significant additional resource and this may result in a substantial resource impact for the NHS in England. However, preventing stroke is likely to result in cost savings later on.\n\nThe recommendation on offering measures for secondary prevention reflects current practice so no change is expected.\n\nReturn to recommendations\n\n# Imaging for people who have had a suspected TIA or acute non-disabling stroke\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendations\n\nNo evidence was identified from test-and-treat trials (which the committee considered would have been the most useful form of evidence to inform decision making). In these studies, different imaging strategies are performed on randomised groups followed by management on the basis of the results, to compare patient outcomes after different imaging strategies. Therefore, the committee used their knowledge and experience to conclude that clinical assessment is the best form of diagnosis at this point. The committee agreed that CT is most useful when there is a clinical suspicion of an alternative diagnosis that CT could detect. It should not be routinely performed for everyone with a suspected TIA because it rarely confirms a diagnosis in these patients.\n\nRoutine CT imaging is common in current practice and the committee agreed that this could waste resources, extend the length of stay in the emergency department, and expose people to unnecessary radiation.\n\nThe committee discussed the possible risks of not offering CT brain imaging to everyone with a suspected TIA. They agreed that, in the absence of clinical 'red flag' indicators (for example, headache, anticoagulation, head injury, repetitive stereotyped events), it is rare for a CT scan to reveal an alternative diagnosis needing a different referral pathway. Therefore, the number of referrals to TIA clinics should not increase greatly.\n\nIn a TIA clinic, not all people will need an MRI. Therefore, clinical assessment by a specialist in a TIA clinic is important for identifying people who may need MRI to determine the vascular territory of ischaemia (the region of the brain with loss of blood flow, supplied by either the anterior or posterior circulation). For example, this could be before a decision is made to refer for a carotid endarterectomy, or to detect alternative pathologies such as tumours, demyelinating disorders or convexity subarachnoid haemorrhage. There was uncertainty about whether urgent, routine MRI screening improves the outcomes for people with suspected TIA, and so the committee made a research recommendation on early MRI brain scanning.\n\n## How the recommendations might affect practice\n\nNot routinely offering CT brain imaging will be a change in practice for some providers (especially in the emergency department), whereas MRI use in the TIA clinic aligns broadly with current practice.\n\nThe committee was uncertain whether these recommendations will be cost saving overall. It will be a trade‑off between a reduction in CT requests against a potential increase in MRI requests. The committee also highlighted that any increase in MRI requests may be small because the decision to perform an MRI will not generally be affected by the results of a previous CT scan.\n\nThe committee recognised that if there was an increase in MRI requests, this could be a challenge because access to high-quality MRI scanners is limited in some trusts. In addition, there are limits on the number of MRI slots per day, so there may be a need for dedicated MRI slots for people with suspected TIA.\n\nReturn to recommendations\n\n# Thrombectomy for people with acute ischaemic stroke\n\nRecommendations 1.4.5 to 1.4.8\n\n## Why the committee made the recommendations\n\nOverall, the evidence across timeframes showed that thrombectomy, with or without thrombolysis, improved functional outcome as measured by the modified Rankin Scale (mRS) in people last known to be well up to 24\xa0hours previously, compared with usual care. There was also a potential benefit for improved quality of life. However, there was no clinical difference in mortality and there were low rates of symptomatic intracerebral haemorrhage. The committee noted there had been some procedural complications associated with thrombectomy, but agreed that these were outweighed by the benefits of improvement in functional outcome.\n\nThe committee looked at the results of 2\xa0published cost–utility analyses with a UK NHS perspective. The first estimated that thrombectomy alongside intravenous thrombolysis (when appropriate) is cost effective compared with intravenous thrombolysis alone, when performed within 6\xa0hours of stroke onset (that is, from when a person was last known to be well). The second demonstrated the cost effectiveness of thrombectomy therapy and best medical therapy compared with best medical therapy alone, when performed 6\xa0to 24\xa0hours after stroke onset. Therefore, the committee agreed to recommend thrombectomy up to 24\xa0hours after stroke onset, together with intravenous thrombolysis if within the licensed time window, for people with appropriate clinical and radiological characteristics. Few people presenting between 6\xa0and 24\xa0hours after stroke onset received thrombolysis because this is outside the licensed time window. Therefore, the recommendation for those presenting beyond 6\xa0hours is for thrombectomy alone.\n\nThe evidence for thrombectomy within 6\xa0hours of symptom onset was from populations selected using computed tomographic angiography (CTA) or magnetic resonance angiography (MRA) to identify proximal anterior circulation occlusions. For thrombectomy undertaken between 6\xa0and 24\xa0hours after stroke onset, the evidence was based on more highly selected populations using CT perfusion, MRI diffusion and MRI perfusion imaging, in addition to identifying a proximal anterior circulation arterial occlusion. Because the effectiveness of thrombectomy is likely to be lower in a less selected population, the committee recommended that, in line with the evidence, imaging such as CT perfusion or diffusion-weighted MRI sequences is performed if presentation is 6\xa0to 24\xa0hours after stroke onset in people being considered for thrombectomy. This would ensure that there is vulnerable but salvageable brain tissue to be targeted for thrombectomy. Although benefit is still seen up to 24\xa0hours after stroke, time is still critical. Therefore, the committee agreed that thrombectomy should be performed as soon as possible.\n\nTo help determine what clinical characteristics make this intervention suitable, it is important to consider the National Institutes of Health Stroke Scale (NIHSS) score and the person's overall functional capacity before the stroke. The committee agreed that it was not possible on the basis of the evidence reviewed to specify strict threshold criteria for eligibility based on pre-stroke functional status, clinical severity of stroke or the extent of established infarction on initial brain imaging. This is because there was variation in the trial entry criteria used in the studies and the committee agreed that these factors should be considered as part of the clinical judgement on an individual basis. However, because it was important to make a recommendation that can be implemented in practice, mRS and NIHSS eligibility thresholds were included to be consistent with the NHS England clinical commissioning policy on mechanical thrombectomy for acute ischaemic stroke.\n\nNo clinical- or cost-effectiveness evidence was identified for the population with posterior circulation stroke. The committee discussed that prognosis is usually very poor in basilar artery occlusion, with around an 80% mortality. As few as 2%\xa0to\xa05% of people with basilar artery occlusion make a full neurological recovery in the absence of interventions to achieve recanalisation or reperfusion. The committee agreed that the prevalent current practice is to consider intravenous thrombolysis and mechanical thrombectomy. Good outcomes can be achieved even up to 24\xa0hours after stroke onset, which is important because diagnosis can be delayed in this population by a non-focal presentation, a reduced conscious level, or both.\n\nThe main risk of thrombectomy and thrombolysis in this population is intervening when there is established disabling ischaemic brain injury. For example, if a person with basilar artery occlusion has irreversible bilateral damage to the pons, they may be left with locked-in-syndrome with complete face and body paralysis but clear consciousness, even if the basilar artery is opened. The committee agreed that it is standard practice to perform brain imaging and look for established tissue damage in the brain regions affected by the arterial occlusion, particularly in the brainstem, before intervening. This reduces the number of people surviving with severe neurological disability. Appropriate CT perfusion imaging or diffusion-weighted MRI sequences should be performed to demonstrate that there is salvageable brain tissue and to seek evidence of established injury to functionally critical areas of the posterior circulation.\n\nThe outlook for this population without intervention is poor, but good outcomes can be achieved with intervention and there is supportive evidence from treating anterior stroke. Therefore, the committee agreed that thrombectomy, and thrombolysis within its licensed indications, should be considered for people with posterior circulation proximal occlusions and without evidence of irreversible infarction who were last known well up to 24\xa0hours previously. This should be done as soon as possible after presentation because better outcomes are likely with earlier intervention.\n\n## How the recommendations might affect practice\n\nThe committee noted that in current practice, around 10% of people presenting with all strokes in the UK are eligible for endovascular therapy. More people are likely to be offered endovascular therapy as a result of these recommendations. The recommendation on thrombectomy together with thrombolysis within 6\xa0hours of symptom onset is aligned with current best practice and the NHS England clinical commissioning policy on mechanical thrombectomy for acute ischaemic stroke. The recommendation for thrombectomy between 6\xa0and 24\xa0hours requires a change from current practice by most providers. Currently, the NHS England clinical commissioning policy states that mechanical thrombectomy will be commissioned when substantial salvageable brain tissue is identified up to 12\xa0hours. However, this extension of the eligibility period up to 24\xa0hours was supported by clinical- and cost-effectiveness evidence as discussed above. The recommendation to consider endovascular therapy for posterior circulation stroke reflects current best practice.\n\nOverall, the new recommendations are likely to have a substantial resource impact on the NHS. Thrombectomy is already performed in most neuroscience centres, but the recommendations will mean 24‑hour access to appropriate staffing and imaging.\n\nThe committee discussed the possibility that the new recommendations could initially result in a large increase in referrals to centres that already have thrombectomy services. It also noted that there are likely to be additional costs incurred in transferring people to these centres. This will have implications for the spoke site for arranging transfers, for the ambulance service and at the hub site, where more people will be received. There may need to be networked arrangements for spoke sites around a thrombectomy 'hub' with fast image transfer, referral, eligibility assessment and responsive repatriation systems.\n\nThe positive implications for other aspects of stroke care help to address the balance in demand for resources. For example, it is expected that there will be a decrease in demand for decompressive hemicraniectomies and inpatient rehabilitation. There may also be a reduction in the need for long-term social care.\n\nReturn to recommendations\n\n# Blood pressure control for people with acute intracerebral haemorrhage\n\nRecommendations 1.5.4 to 1.5.8\n\n## Why the committee made the recommendations\n\nFor the groups covered, moderate-quality evidence from a large clinical trial showed a modest benefit treatment effect on haematoma expansion and quality of life (EQ‑5D utility index) in rapidly lowering blood pressure to a target systolic blood pressure of 140\xa0mmHg or lower compared with less intensive blood pressure lowering treatment.\n\nThe committee acknowledged the uncertainty over the evidence. They discussed the additional potential harms relating to rapid blood pressure lowering in people who present after 6\xa0hours or who have a systolic blood pressure greater than 220\xa0mmHg, and agreed that these factors should be taken into account when considering rapid blood pressure lowering for these groups.\n\nThe committee decided to remove the aim of reaching the target within 1\xa0hour because only a minority (33.4%) of participants in the INTERACT2 trial achieved the target of 140\xa0mmHg within 1\xa0hour and, more importantly, to avoid the potential harm of reducing systolic blood pressure by more than 60\xa0mmHg in the first hour.\n\nThere was evidence that rapidly lowering blood pressure does not increase the risk of neurological deterioration caused by reduced blood flow to the brain and has the potential to improve quality of life.\n\nIn contrast, the committee noted that in another clinical trial, there was no benefit to rapidly lowering blood pressure and there was an increase in adverse renal events. The committee noted the treatment regimens were more aggressive in this trial compared with the other trials included in the review.\n\nThe committee agreed that while there is some evidence that rapid blood pressure lowering treatment is beneficial, there may be an increase in adverse renal events, and they were concerned about the lack of evidence in people who are frail. Taking this into account, the committee agreed that rapid blood pressure lowering treatment should be considered as a treatment option except for the groups highlighted in recommendation\xa01.5.7.\n\nThere was evidence that a moderate reduction of up to 60\xa0mmHg within the first hour was associated with better outcomes such as functional independence. A reduction of more than 60\xa0mmHg within 1\xa0hour was associated with significantly worse outcomes such as renal failure, early neurological deterioration, and death, compared with standard treatment. Therefore, the committee agreed that a large reduction of 60\xa0mmHg or more within 1\xa0hour should be avoided.\n\nThe 2019 guideline included a 130 mmHg lower target limit. However, the committee were concerned that a narrow range would be too restrictive, and the variation in the class of drugs used in practice means it is difficult to predict the blood pressure reduction. The committee decided to remove the 130 mmHg lower target limit. The committee considered the potential risk of systolic blood pressure dropping too low but noted that this potential concern is addressed by the avoidance of a large reduction of 60\xa0mmHg or more within 1\xa0hour. The committee also agreed that the target systolic blood pressure and the systolic blood pressure reduction should be made into a separate recommendation (1.5.6).\n\nThere was little evidence on people presenting beyond 6\xa0hours or those with a systolic blood pressure over 220\xa0mmHg. However, the committee agreed that some guidance is needed on treating hypertension in these groups and that it is appropriate to extrapolate from the available data to these groups, but that healthcare professionals should take into account the individual risk of harm when considering rapid blood pressure lowering using clinical judgement on a case-by-case basis.\n\nThe committee agreed that the evidence to support maintaining the target blood pressure for at least 7\xa0days is weak. They were also concerned about the potential impact on patient flow, bed management and resources in the NHS, so removed the timeframe.\n\nThe committee discussed the uncertainty about how long to continue acute treatment. However, this evidence review is primarily concerned with treatment within the first 24\xa0hours. The committee highlighted that blood pressure should still remain lowered after acute treatment in order to reduce the longer-term effect of the acute intracerebral haemorrhage. The committee agreed that people receiving intensive blood pressure treatment would not need to stay in hospital for acute management for 7\xa0days. This can be managed through secondary prevention, which can be indicated when treatment is changed from intravenous to an oral route of administration. The committee also noted that longer-term management of blood pressure can be managed in primary care.\n\nThe committee did not change the existing practice of not offering rapid blood pressure lowering to specific groups that were excluded from the key clinical trial. This is because there is no evidence of whether this would be safe or beneficial.\n\nThe committee discussed rapid blood pressure lowering for young people aged\xa016 and\xa017. The evidence reviewed covers adults 18\xa0and over, but the committee agreed that this can be extrapolated for young people after seeking advice from a paediatric specialist.\n\nThe committee wanted to consider the long-term effect of intensive blood pressure lowering on quality of life, but limited evidence was available to show how it affected quality of life at 6\xa0and 12\xa0months, and no evidence was available on cognitive function or functional ability. Given the lack of evidence for these important outcomes, the committee made a research recommendation about the impact of intensive interventions to lower blood pressure on cognitive function, functional ability and quality of life compared with less intensive interventions.\n\nThe committee identified a gap in the evidence on the impact of intensive blood pressure treatment on people who are frail. There is currently no guidance or treatment pathway for people who are frail, so the committee also made a research recommendation about the impact of intensive blood pressure lowering on people who are frail, and encouraged the use of frailty scores to evaluate the impact of frailty on outcomes and treatment prognoses.\n\n## Other factors the committee took into account\n\nThe committee were aware of the European Stroke Organisation (ESO) guideline on blood pressure management in acute ischaemic stroke and intracerebral haemorrhage, which suggests 'In patients with hyperacute (presenting within 6\xa0hours) intracerebral haemorrhage, lowering blood pressure to below 140\xa0mmHg (and to keep it above 110\xa0mmHg) to reduce haematoma expansion'. The committee agreed that this is broadly in line with NICE recommendations.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect a small change to current best practice. The difference in target blood pressure range and magnitude in drop from starting treatment up to the first hour in the 2022 update might need additional planning and closer management by the nursing team. Given that these people currently need close monitoring, any change is likely to be very small. There may be an increased cost of intravenous antihypertension medication, but the recommendations should save resources because of reduced harms. Overall, the recommendations should not have a resource impact to the NHS in England.\n\nReturn to recommendations\n\n# Optimal positioning for people with acute stroke\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nThe evidence did not indicate any difference in outcomes between lying flat or with the head elevated. No cost-effectiveness evidence was identified and no cost difference between the 2\xa0strategies is expected. Therefore, the committee used their knowledge and experience to recommend positioning people according to their preferences and individual requirements.\n\n## How the recommendation might affect practice\n\nOptimal positioning is an important part of early acute stroke management and rehabilitation. In current practice, people are assessed in bed and optimal head positioning is determined based on clinical presentation, medical needs and patient comfort. The recommendation therefore reflects current practice in most hospitals and so the committee agreed that there should be little or no change.\n\nReturn to recommendation\n\n# Early mobilisation for people with acute stroke\n\nRecommendations 1.7.2 and 1.7.3\n\n## Why the committee made the recommendations\n\nRegarding the recommendation to mobilise people after having a stroke when their clinical condition permits, there was no clear evidence of benefit or harm for early mobilisation within the first 48\xa0hours after symptom onset compared with standard care. Therefore, the committee made a recommendation based on their knowledge and experience. The committee agreed that early mobilisation may be appropriate in some cases where people need minimal assistance to mobilise, such as in those who have suffered a mild stroke, or are experiencing language and/or upper limb dysfunction alone.\n\nRegarding the recommendation not to offer high-intensity mobilisation within the first 24\xa0hours of symptom onset, a published within-trial cost-effectiveness analysis from the Australian hospital perspective was identified. However, the treatment effect for the health outcome mRS 0\xa0to\xa02 used in the study differed from the treatment effect calculated in the clinical review. Because the cost-effectiveness evidence was incompatible with the results of the clinical review, the committee chose to make a recommendation based on the clinical evidence for mortality. The evidence suggested clinical harm associated with high-intensity mobilisation within the first 24\xa0hours after acute stroke. However, based on their clinical experience they discussed that this harm was most relevant to those who need help to sit out of bed, stand or walk. Therefore, they limited the recommendation to this group because they did not want to prevent appropriate early mobilisation in people who are independently mobile after having a stroke.\n\n## How the recommendations might affect practice\n\nThe committee was confident that making these recommendations would not have a resource impact, because there was no indication that mobilising later and with a lower intensity leads to a longer length of stay. The committee noted that people will still be assessed and mobilised and there are unlikely to be differences in staff costs. In current practice, mobilisation strategies differ according to stroke severity and the clinical condition of the person with stroke. The strategy may also be impacted by the availability of different types of specialist seating. The recommendations may change current practice in stroke units where there is an 'as soon as possible' focus on mobilisation. They will encourage healthcare professionals to consider the intensity of very early mobilisation and advice on intensity of activities to people discharged from hospital early after a stroke.\n\nReturn to recommendations\n\n# Decompressive hemicraniectomy for people with acute stroke\n\nRecommendations 1.9.5 and 1.9.7\n\n## Why the committee made the recommendations\n\nThe evidence showed that surgery improved mortality rates and, to a lesser extent, functional outcomes as measured by the mRS. The benefit on mortality was seen in all age groups considered, although the benefit for functional outcome was smaller in people aged over 60\xa0years than in people under 60\xa0years. Based on this, and to ensure that people over\xa060 have similar opportunities for the surgery as younger people, the committee removed the previous age cut‑off for considering surgery. The committee also acknowledged that although surgery results in more people surviving and better functional outcome than without surgery, many still have overall poor functional outcome and their quality of life may be low. The acceptability of this trade‑off was agreed to be a very individual judgement. Some people may choose not to have surgery if there is a risk of severe disability, whereas others may wish to go ahead based on mortality benefit alone. Therefore, the committee highlighted the need for careful discussion about risks and benefits between clinicians and family members or carers. They noted that patients would not be able to be involved at the time because of the severity of the stroke, so the family or carers would be responsible for making the decision. In deciding whether to opt for surgery, considerations should include pre-stroke functional status, because surgery would not be appropriate for people with severe disability before stroke.\n\nThe committee noted that although some of the trials included people who had surgery as long as 96\xa0hours after symptom onset, the benefits in terms of reduced mortality and improved functional outcome were largely driven by studies that only allowed surgery up to a maximum of 48\xa0hours after onset. Therefore, it agreed to retain the reference to surgery being performed within 48\xa0hours of onset from the original recommendations. The committee also reviewed the criteria used to determine eligibility for hemicraniectomy from NICE's stroke guideline published in 2008. It was agreed that these were still appropriate and reflect the populations included in the studies used to inform the new recommendations.\n\nThe committee agreed that although the cost effectiveness of decompressive hemicraniectomy remains uncertain, it should be considered for some people because of the clear mortality benefit and the improved functional outcomes. Shared decision making between physicians, surgeons, families and carers is important given the high likelihood of residual moderate or severe disability after surgery.\n\n## How the recommendations might affect practice\n\nIn current practice, around 5% of people on the stroke unit are referred for decompressive hemicraniectomy. Decompressive hemicraniectomy is currently considered for those aged under\xa060.\n\nThis recommendation will require a change from current practice by all providers. The guidance will also require healthcare professionals to take into account people's pre-stroke functional status and to have a discussion about the risks and benefits.\n\nThe committee believed that including people over 60\xa0years would not necessarily lead to significantly more people undergoing surgery because informed discussion of the outcomes might reduce its uptake in this population. In addition, increasing the population eligible for endovascular therapy and its provision is likely to decrease the population referred for decompressive hemicraniectomy. The committee therefore did not anticipate a substantial resource impact to result from this recommendation.\n\nReturn to recommendations", 'Context': "Since NICE published its guideline on stroke and transient ischaemic attack (TIA) in 2008, the management of stroke has changed. New evidence has emerged in areas such as thrombectomy (clot retrieval procedures) in ischaemic stroke, controlling high blood pressure in people with acute haemorrhagic stroke, the role of hemicraniectomy and early mobilisation and optimum positioning of people with acute stroke. In addition, there is some uncertainty about the use of aspirin when TIA is first suspected, the role of conventional risk stratification in TIA and the best approach to intracerebral imaging after TIA. This guideline update includes recommendations on these specific issues.\n\nA stroke occurs when the blood supply to a part of the brain is acutely compromised. Most strokes (85%) are caused by a blockage in a blood vessel (artery) that supplies blood to the brain. A TIA or 'mini stroke' has the same clinical presentation as a stroke except that symptoms disappear within 24\xa0hours.\n\nThe symptoms experienced depend on the part of the brain that is affected. They usually occur suddenly and without any warning. Common symptoms include loss of movement or sensation in an arm or leg, problems speaking, a drooping of one side of the face or problems with vision.\n\nA stroke can occur at any age. The average age for stroke varies across the UK, with a median age of 77\xa0years (interquartile range 67\xa0to\xa085). A quarter of strokes occur in people of working age.\n\nFirst-ever stroke affects 230\xa0people per 100,000 each year, with over 80,000\xa0people hospitalised per year in England. Although the death rate has been falling, figures from the Sentinel Stroke National Audit Programme show that 13.6% of people admitted to hospital with stroke in England and Wales died (either in hospital or after being discharged from inpatient care) within 30\xa0days. There are approximately 1.2\xa0million stroke survivors in the UK. The risk of recurrent stroke is 26% within 5\xa0years of a first stroke and 39% by 10\xa0years.\n\nStroke is the single biggest cause of disability in adults. The Stroke Association has estimated an annual cost to the NHS in England of £2.98\xa0billion per year. In addition, annual social care costs have been estimated at £4.55\xa0billion with almost half of that estimated to be from public funds. Of stroke survivors, 1\xa0in\xa012 have to move into a care home because of the effects of their stroke. There is also a substantial burden to families of people who have had a stroke in terms of informal unpaid care. The importance of stroke care in the NHS is also highlighted in the NHS Long Term Plan, the National Stroke Programme, the Intercollegiate Stroke Working Party national clinical guideline for stroke, and the 2018 publication of NHS England's clinical commissioning policy for mechanical thrombectomy for acute ischaemic stroke in the NHS. Also, the Royal College of Paediatrics and Child Health published guidelines in 2017 on the treatment of stroke in those under 18\xa0years old.\n\nThis guideline covers people over\xa016 with suspected or confirmed TIAs or completed strokes, that is, an acute neurological event presumed to be vascular in origin and causing cerebral ischaemia, cerebral infarction or cerebral haemorrhage. This includes first and recurrent events, thrombotic and embolic events and primary intracerebral haemorrhage of any cause, including venous thrombosis. Areas that are not covered include specific issues relating to the general management of underlying conditions and subarachnoid haemorrhage.", 'Finding more information and resources': "To find NICE guidance on related topics, including guidance in development, see the NICE topic page on cardiovascular conditions.\n\nFor full details of the evidence and the guideline committee's discussions, see the evidence reviews. You can also find information about how the guideline was developed, including details of the committee.\n\nNICE has produced tools and resources to help you put this guideline into practice. For general help and advice on putting NICE guidelines into practice, see resources to help you put guidance into practice."}
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https://www.nice.org.uk/guidance/ng128
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This guideline covers interventions in the acute stage of a stroke or transient ischaemic attack (TIA). It offers the best clinical advice on the diagnosis and acute management of stroke and TIA in the 48 hours after onset of symptoms.
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c8c7e5845877cd04676eb0e393ed333614e3a766
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nice
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Daratumumab monotherapy for treating relapsed and refractory multiple myeloma
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Daratumumab monotherapy for treating relapsed and refractory multiple myeloma
Evidence-based recommendations on daratumumab (Darzalex) for relapsed and refractory multiple myeloma in adults.
# Recommendations
Daratumumab monotherapy is recommended as an option for treating relapsed and refractory multiple myeloma in adults who have had a proteasome inhibitor and an immunomodulator, and whose disease progressed on the last treatment, only if:
they have daratumumab after 3 treatments and
the company provides daratumumab according to the commercial arrangement.
Why the committee made this recommendation
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for daratumumab monotherapy for relapsed and refractory multiple myeloma in adults who have already had 3 treatments, including a proteasome inhibitor and an immunomodulator, and whose disease progressed on the last treatment.
Usual treatment for relapsed and refractory multiple myeloma in people who have already had 3 treatments is pomalidomide plus dexamethasone.
The new clinical evidence shows that daratumumab monotherapy increases how long people live compared with pomalidomide plus dexamethasone, but by how much is still uncertain.
Because of this uncertainty, the cost-effectiveness estimates vary. But the most likely estimates are within what NICE considers an acceptable use of NHS resources. Therefore, daratumumab is recommended for routine use.# Information about daratumumab
# Marketing authorisation indication
Daratumumab (Darzalex, Janssen) has a marketing authorisation as a monotherapy for 'the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy'.
# Dosage in the marketing authorisation
The dosage schedules for both injection and infusion are available in the summary of product characteristics for daratumumab.
# Price
The list prices of daratumumab (excluding VAT; BNF online, accessed January 2022) are:
£4,320 per 1,800 mg/15 ml solution for injection vial
£360 per 100 mg/5 ml concentrate for solution for infusion vial
£1,440 per 400 mg/20 ml concentrate for solution for infusion vial.
The company has a commercial arrangement. This makes daratumumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the MMY2002 study for people with relapsed and refractory multiple myeloma. In addition, data was collected on the use of daratumumab monotherapy in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.
# The condition
## Daratumumab is a highly valued treatment option for people with multiple myeloma
Multiple myeloma is a chronic condition that affects survival and quality of life. When deciding which treatments to use, response to previous treatments and toxicity are important, so having a range of treatment options is desirable. The Cancer Drugs Fund clinical lead reported that since daratumumab monotherapy was made available through the Cancer Drugs Fund, it has become a preferred fourth-line treatment. Patient experts explained that people with multiple myeloma are anxious about the possibility of their disease relapsing. However, they also reported that there are several new multiple myeloma drugs in development, and so any treatment that offered an extension to life offered hope, because it meant it may bridge getting onto a new trial, or perhaps make it possible to access a new treatment that would become available in the future. The patient and clinical experts stated that daratumumab has a favourable toxicity profile, which not only results in an increased quality of life, but also means that people are more likely to be well enough for more options later in the treatment pathway. They also stressed the importance of quality of life after multiple lines of therapy, because the adverse effects of treatments can build up over time. The committee recognised the need for effective, well-tolerated treatment options for people with multiple myeloma who have had previous therapies.
# Treatment pathway
## The treatment pathway for multiple myeloma is rapidly evolving
Treatment options for multiple myeloma depend on how many previous lines of treatment a person has had, the type of treatments they have had, the response to these treatments, and patient preferences.For someone with a new diagnosis of multiple myeloma, if a stem cell transplant is suitable, available options are:
Induction with bortezomib and dexamethasone with or without thalidomide (NICE's technology appraisal guidance on bortezomib for induction therapy) given before the stem cell transplant, followed by maintenance treatment with lenalidomide (lenalidomide maintenance treatment).
Induction with daratumumab plus bortezomib, thalidomide and dexamethasone (daratumumab in combination for untreated multiple myeloma when a stem cell transplant is suitable) before the stem cell transplant. If daratumumab plus bortezomib, thalidomide and dexamethasone is used as induction treatment, then it is also recommended as consolidation treatment after the transplant. Lenalidomide maintenance treatment is recommended after consolidation, or directly after the transplant if bortezomib and dexamethasone (with or without thalidomide) is used as induction treatment (lenalidomide maintenance treatment).If a stem cell transplant is not suitable:For untreated disease, treatments include thalidomide or bortezomib plus an alkylating agent, for example, melphalan or cyclophosphamide, and a corticosteroid, for example, dexamethasone (bortezomib and thalidomide for the first‑line treatment of multiple myeloma). Lenalidomide plus dexamethasone is also an option when thalidomide is not appropriate (lenalidomide plus dexamethasone for previously untreated multiple myeloma).After 1 previous line of treatment, the following options are available regardless of transplant eligibility:
Lenalidomide with dexamethasone (lenalidomide plus dexamethasone for multiple myeloma after 1 treatment with bortezomib), carfilzomib with dexamethasone (carfilzomib for previously treated multiple myeloma), carfilzomib with dexamethasone and lenalidomide if the person has had bortezomib before (carfilzomib with dexamethasone and lenalidomide for previously treated multiple myeloma) or bortezomib may be used again (bortezomib monotherapy for relapsed multiple myeloma); however, treatment is only continued in people whose condition has a complete or partial response. Also, daratumumab plus bortezomib and dexamethasone is available in the Cancer Drugs Fund (daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma).Treatment options at further relapse are influenced by the choice of initial treatment. The following options are available regardless of transplant eligibility:
After 2 previous lines of treatment, options include lenalidomide plus dexamethasone (lenalidomide for the treatment of multiple myeloma in people who have received at least 2 prior therapies) or panobinostat plus bortezomib and dexamethasone (panobinostat for treating multiple myeloma after at least 2 previous treatments). Also, ixazomib plus lenalidomide and dexamethasone is available in the Cancer Drugs Fund (ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma).
After 3 previous lines of treatment, options include pomalidomide plus dexamethasone (pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib), and panobinostat plus bortezomib and dexamethasone (panobinostat for treating multiple myeloma after at least 2 previous treatments). Also available through the Cancer Drugs Fund are ixazomib plus lenalidomide and dexamethasone (ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma) and isatuximab plus pomalidomide and dexamethasone (isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma).Daratumumab monotherapy can be used whether or not people have had a stem cell transplant. The Cancer Drugs Fund clinical lead explained that, following the publication of NICE's technology appraisal guidance on isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma, the use of fourth-line daratumumab monotherapy has decreased, but there is an important cohort of people still receiving this treatment. The recent NICE technology appraisal guidance on daratumumab plus bortezomib plus thalidomide and dexamethasone as first-line treatment when a stem cell transplant is suitable may further decrease the need for fourth-line daratumumab. The committee understood that the multiple myeloma pathway is rapidly evolving.
# Comparators
## After 3 previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator
The committee recalled that treatments recommended in the Cancer Drugs Fund (see section 3.2) are not considered to be comparators because they are not available in routine practice. NICE guidance recommends both pomalidomide plus dexamethasone and panobinostat plus bortezomib and dexamethasone after 3 previous lines of treatment for multiple myeloma. NICE's final scope for this appraisal lists these as the comparators. The company did provide analyses for both comparators to comply with the scope, but stated that it did not consider panobinostat plus bortezomib and dexamethasone to be a relevant comparator. It explained that this was because of toxic adverse effects and the lack of perceived efficacy noted by clinicians it consulted, which means it is usually used after 4 previous lines of treatment. The ERG's clinical advisers agreed with the company's position. The clinical expert at the meeting explained that daratumumab monotherapy or pomalidomide plus dexamethasone are the most commonly used options after 3 previous lines of treatment. They stated that panobinostat plus bortezomib and dexamethasone is rarely used after 3 previous lines of treatment because of toxicity and perceived poor clinical efficacy. The Cancer Drugs Fund clinical lead explained that clinicians can now offer bortezomib without having to use it with panobinostat, and that few clinicians offer panobinostat plus bortezomib and dexamethasone after 3 previous lines of treatment. The committee concluded that after 3 previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator.
# Clinical evidence
## The clinical trial evidence for daratumumab monotherapy does not include any head-to-head evidence
The key clinical study was MMY2002, a completed phase‑2 study investigating different doses of daratumumab (n=106). It included people with relapsed and refractory multiple myeloma who had had at least 3 previous lines of treatment (including proteasome inhibitors and immunomodulators) or whose condition was refractory to both a proteasome inhibitor and an immunomodulator. There was no comparator. The primary outcome was overall response rate. Overall survival and progression-free survival were among the secondary outcomes. In the original appraisal, people in MMY2002 had been followed up for a median of 20.7 months. At the time, median progression-free survival was 3.7 months (95% confidence interval 2.8 to 4.6) and median overall survival was 18.6 months (95% CI 13.7 to not reached). Since the original appraisal, people in MMY2002 have been followed up for a median of 36.7 months. The company considers the updated progression-free survival and overall survival data to be confidential, so it cannot be reported here. The committee concluded that the longer follow-up data was similar to that which it had seen previously, but that it would prefer to see head-to-head evidence for decision making.
## In the absence of comparative data, the SACT dataset provides useful evidence
Through the Cancer Drugs Fund, SACT data was collected from people having fourth-line daratumumab monotherapy for multiple myeloma. Between 17 January 2018 and 16 November 2020, 2,301 people had daratumumab, with a median age of 71 years. Most people had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 (20%) or 1 (41%). Less than half of people had previously had a stem cell transplant (44%). Compared with participants in MMY2002, people were older, and lower proportions had an ECOG score of 0, had a previous stem cell transplant, and went on to have subsequent therapy. People in MMY2002 were able to receive carfilzomib as a subsequent therapy, which did not reflect UK clinical practice or the SACT dataset. The committee considered that the SACT dataset provided useful information and represented people who would receive daratumumab in NHS clinical practice. The committee discussed the results from MMY2002 and the SACT dataset and concluded that they were similar, with any differences explained by the characteristics of the participants and subsequent therapies received.
## The company did a matching-adjusted indirect comparison to compare daratumumab with the comparators
To compare daratumumab with pomalidomide plus dexamethasone and with panobinostat plus bortezomib and dexamethasone in the absence of a common comparator (an 'anchor'), the company presented 'unanchored' matching-adjusted indirect comparisons (MAICs). Specifically, it adjusted individual patient-level characteristics in the MMY2002 population to match the published study-level summary characteristics of patients in the comparator trials (1 of 2 arms of the MM‑003 trial for pomalidomide plus dexamethasone, and the single-arm trial PANORAMA‑2 for panobinostat plus bortezomib and dexamethasone).
## The SACT trial data is preferred over the single-arm trial data
The committee discussed the company's approach to matching. It understood that the company presented a partially adjusted MAIC adjusting for the characteristics it considered important in predicting progression and death based on best practice, published evidence and expert opinion. For pomalidomide plus dexamethasone, 5 characteristics were chosen and adjusted. The company stated that this was necessary to maintain a large enough sample size to use for the analysis. The ERG disagreed with company's approach, referencing NICE technical support document 18 which states that, when only single-arm trial data is available, all the characteristics that could influence the outcomes of interest should be adjusted, that is, a fully adjusted MAIC should be done. Because of this, the ERG considered a fully adjusted MAIC to be methodologically superior to the company's partially adjusted MAIC. However, a fully adjusted MAIC gave implausible survival extrapolations for daratumumab, so the ERG also did a naive comparison of daratumumab against data from MM‑003 for pomalidomide with dexamethasone using the SACT data. The company disagreed with this approach, considering it fairer to compare trial data with trial data, rather than real-world evidence with trial data. The committee acknowledged that neither approach was methodologically sound. It discussed several alternatives that may have been useful. One would be an MAIC using a few key characteristics such as age and sex, using the SACT data for daratumumab; however, the Cancer Drugs Fund clinical lead explained this would be difficult because the SACT data is rather crude, so only a few characteristics would be available to be matched on. Another would be collecting real-world data on pomalidomide and dexamethasone from the SACT data from when daratumumab entered the Cancer Drugs Fund, but this was not available. Although the committee noted neither of the presented comparisons were ideal, it preferred to use the SACT data because the usual benefit of trial data is that it is comparative. However, in this instance, the data from MMY2002, which compared 2 different doses of daratumumab, provided no head-to-head evidence of the effectiveness of daratumumab with a relevant comparator. As such, the committee preferred the data from SACT, which had both a larger sample size and reflected UK clinical practice.
## Daratumumab likely increases overall survival, but not progression-free survival compared with pomalidomide and dexamethasone, but this is uncertain
In the fully adjusted and partially adjusted MAICs, daratumumab showed no difference in progression-free survival compared with pomalidomide with dexamethasone. In the partially adjusted MAIC preferred by the company, daratumumab provided an improvement in overall survival compared with pomalidomide with dexamethasone. In the naive comparison with SACT data preferred by the ERG, the point estimate indicated that daratumumab resulted in improved overall survival, but this was not statistically significant. The committee asked the clinical expert about the plausibility of seeing overall survival gains without progression-free survival gains. The clinical expert explained that in MMY2002, a significant proportion of people had no response to daratumumab, which in part explains why there was no difference in progression-free survival between daratumumab and pomalidomide plus dexamethasone. Additionally, as discussed in section 3.1, given the favourable tolerability and reduced toxicity of daratumumab, people may go on to receive further treatments later in the pathway, which may impact overall survival. The committee was satisfied with this explanation and agreed it was possible that daratumumab is associated with overall survival gains without providing progression-free survival gains.
## The overall survival benefit seen in the naive comparison is generalisable to NHS clinical practice
Several therapies are available if the cancer comes back after daratumumab (see NICE's technology appraisals on multiple myeloma). The company's submission included several data sources on subsequent treatments, including data from the MMY2002 and MM‑003 trials and the SACT dataset. The ERG expressed concerns about the overall survival data from MMY2002 because people in this trial could have several treatments not available in the NHS, including carfilzomib. The clinical expert agreed that several treatments given after daratumumab in MMY2002 did not reflect UK clinical practice. The evidence for subsequent treatments after daratumumab available from the SACT dataset not only reflects UK clinical practice, but is also a large sample. Because the SACT data is from the UK and is recent, the company, ERG and clinical expert all agreed it best reflects subsequent treatments given after daratumumab in UK clinical practice. The clinical expert explained that the choice of subsequent treatment depends on many factors, including how many previous lines of treatment a person has had, the specific treatments, the response to these treatments, and people's preferences (see section 3.1). They agreed that the subsequent treatments seen in the SACT cohort are consistent with what would be expected in clinical practice. Because MMY2002 included treatments not available in the NHS, they considered there was a greater degree of certainty in the SACT data. The committee concluded that subsequent treatment data from the SACT cohort best reflects clinical practice. The committee considered the treatments given after pomalidomide with dexamethasone in MM‑003. It heard from the clinical expert that these were generally aligned with NHS clinical practice. The committee was therefore satisfied that the overall survival benefit implied by the naive comparison (see section 3.7) is generalisable to NHS clinical practice, while recognising that this was a naive comparison that could be biased by imbalances in patient characteristics.
# Adverse events
## Daratumumab is well tolerated, improves quality of life, and allows people to receive other treatments further down the pathway
The clinical expert explained that daratumumab is well tolerated relative to other fourth-line treatments. The patient experts agreed with this, with one pointing out they have been taking daratumumab for some time, saying that it has been the best treatment they've ever had and is why they are still alive today. Additionally, the other patient expert explained that having a treatment that is so well tolerated gives people hope that they may be able to either go on to a clinical trial for a multiple myeloma treatment or that they will survive until they can have a new treatment once it becomes available. The clinical expert agreed with this and again pointed out that a likely reason why an overall survival gain is observed with daratumumab is because of the subsequent treatments people can receive. They also stated that in MMY2002, participants received intravenous daratumumab, which may be less well tolerated than the subcutaneous formulation available in NHS clinical practice. Additionally, people who take daratumumab subcutaneously often find it more convenient because it requires less time spent in a hospital because of the shorter administration time. The committee concluded that daratumumab is well tolerated, improves quality of life for people who take it, and allows them to receive other treatments further down the pathway.
## The company's model structure is acceptable for decision making
The company used a 4‑state, partitioned-survival economic model, including states representing pre-progressed disease on treatment, pre-progressed disease off treatment, progressed disease and death. The cycle length was 1 week, and the time horizon was 15 years. The committee noted that this model was similar to previous models used for multiple myeloma, and agreed that it was appropriate to capture the natural history of the disease. The ERG was satisfied that the model structure was suitable for estimating the cost effectiveness of daratumumab compared with pomalidomide plus dexamethasone. The committee concluded that the model structure is acceptable and closely matched its preferred assumptions from the original appraisal.
# Survival modelling in the economic model
## Estimates of overall survival are highly uncertain despite the additional analyses provided
As in the original appraisal, the model relied on estimates of relative treatment effects from the company's unanchored MAIC. The ERG raised concerns about the methodology of the partially adjusted MAIC, but recalled that the overall survival extrapolations from the fully adjusted MAIC were implausible. The ERG therefore did a naive comparison using daratumumab data from the SACT dataset (see section 3.7). The company accepted that its estimates were associated with uncertainty. It attempted to explore this uncertainty by performing scenario analyses in which different sources of the relative treatment effects were used, including the fully adjusted MAIC and an adjusted comparison with the SACT dataset. The ERG also explored this uncertainty, using the naive comparison with the SACT dataset as its preferred source of relative treatment effect. The committee considered all the scenarios presented by the company and the ERG and recognised that there were high levels of uncertainty in the estimates of overall survival used in the model.
# Costs of subsequent treatments in the economic model
## The cost of subsequent treatments should align with the source of clinical data
The company used data from SACT to inform both the proportion of people having further treatment and the treatments taken after daratumumab and after pomalidomide with dexamethasone. In the ERG's analysis, it aligned the cost of subsequent treatment with the source of clinical evidence. That is, for daratumumab, data from SACT on the proportion of people and type of subsequent therapy was used. But for pomalidomide with dexamethasone, data from MM‑003 informed the proportion of people and type of subsequent therapy used. A clinical expert stated that the subsequent therapies used are likely to be influenced by daratumumab, and that those in MM‑003 aligned well with NHS clinical practice after pomalidomide with dexamethasone. Taking this into account, the committee preferred the ERG's approach.
# End of life considerations
## Daratumumab meets the end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It considered life expectancy for people with relapsed and refractory multiple myeloma. In the ERG's analysis, the mean undiscounted total life years with pomalidomide with dexamethasone was 1.49 years. The committee was satisfied that the life expectancy in this population was less than 24 months. It was also satisfied that introducing daratumumab to the treatment pathway at this point offers at least a 3‑month life extension, because despite the uncertainty around the clinical efficacy of this treatment, there was no scenario by either the company or the ERG in which this criterion was not met. The minimum extension to life modelled in any scenario was 5.5 months. The committee concluded that daratumumab after 3 previous lines of treatment met the criteria to be considered a life-extending, end of life treatment.
# Cost-effectiveness results
## The cost-effectiveness estimates are uncertain, but the ERG's preferred ICER is likely the highest plausible ICER
The committee considered the company's and the ERG's cost-effectiveness results, including confidential discounts for daratumumab and all of the comparator technologies and subsequent treatments. The cost-effectiveness results are commercial in confidence and cannot be reported here. The committee noted that the incremental cost-effectiveness ratios (ICERs) for daratumumab compared with pomalidomide plus dexamethasone varied widely. This reflected the high degree of uncertainty in daratumumab's relative clinical effectiveness. Although the degree of uncertainty in the evidence was high, the committee noted that the naive comparison of clinical trial and real-world data would underestimate the benefits of daratumumab, so it believed that the ERG's preferred ICER likely represented the upper end of plausible values.
## The most likely ICER is within what NICE considers an acceptable use of NHS resources
Taking into account all the confidential patient access schemes for all of the comparator technologies and subsequent treatments, all the resulting ICERs were lower than £50,000 per quality-adjusted life year (QALY) gained. However, these were all associated with uncertainty. The committee would have preferred alternative methods to have been used to estimate the relative treatment efficacy of daratumumab compared with pomalidomide plus dexamethasone, specifically obtaining data on pomalidomide plus dexamethasone from the SACT database or an adjusted comparison of SACT data with trial data. The committee was aware that both of these methods would likely be challenging at this stage, but may be of value in future appraisals when considering what data to request when recommending a treatment for the Cancer Drugs Fund. However, because the committee viewed the ERG's preferred ICER as the very upper end of the plausible values, it considered that the true ICER likely fell below this. Taking all of this into account, the committee concluded that daratumumab was an acceptable use of NHS resources.
# Other factors
## Equalities
No equality issues were identified.
## Innovation
The company did not highlight any additional benefits that had not been captured in the QALY calculations.
# Conclusion
## Daratumumab is recommended for routine use
The committee concluded that the most plausible cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, daratumumab is recommended for treating relapsed and refractory multiple myeloma in adults whose previous therapy included a proteasome inhibitor and an immunomodulator, and whose disease progressed on the last therapy, if they have daratumumab after 3 previous therapies.
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{'Recommendations': 'Daratumumab monotherapy is recommended as an option for treating relapsed and refractory multiple myeloma in adults who have had a proteasome inhibitor and an immunomodulator, and whose disease progressed on the last treatment, only if:\n\nthey have daratumumab after 3\xa0treatments and\n\nthe company provides daratumumab according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for daratumumab monotherapy for relapsed and refractory multiple myeloma in adults who have already had 3\xa0treatments, including a proteasome inhibitor and an immunomodulator, and whose disease progressed on the last treatment.\n\nUsual treatment for relapsed and refractory multiple myeloma in people who have already had 3\xa0treatments is pomalidomide plus dexamethasone.\n\nThe new clinical evidence shows that daratumumab monotherapy increases how long people live compared with pomalidomide plus dexamethasone, but by how much is still uncertain.\n\nBecause of this uncertainty, the cost-effectiveness estimates vary. But the most likely estimates are within what NICE considers an acceptable use of NHS resources. Therefore, daratumumab is recommended for routine use.', 'Information about daratumumab': "# Marketing authorisation indication\n\nDaratumumab (Darzalex, Janssen) has a marketing authorisation as a monotherapy for 'the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on the last therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedules for both injection and infusion are available in the summary of product characteristics for daratumumab.\n\n# Price\n\nThe list prices of daratumumab (excluding VAT; BNF online, accessed January\xa02022) are:\n\n£4,320 per 1,800\xa0mg/15\xa0ml solution for injection vial\n\n£360 per 100\xa0mg/5\xa0ml concentrate for solution for infusion vial\n\n£1,440 per 400\xa0mg/20\xa0ml concentrate for solution for infusion vial.\n\nThe company has a commercial arrangement. This makes daratumumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the MMY2002 study for people with relapsed and refractory multiple myeloma. In addition, data was collected on the use of daratumumab monotherapy in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\n# The condition\n\n## Daratumumab is a highly valued treatment option for people with multiple myeloma\n\nMultiple myeloma is a chronic condition that affects survival and quality of life. When deciding which treatments to use, response to previous treatments and toxicity are important, so having a range of treatment options is desirable. The Cancer Drugs Fund clinical lead reported that since daratumumab monotherapy was made available through the Cancer Drugs Fund, it has become a preferred fourth-line treatment. Patient experts explained that people with multiple myeloma are anxious about the possibility of their disease relapsing. However, they also reported that there are several new multiple myeloma drugs in development, and so any treatment that offered an extension to life offered hope, because it meant it may bridge getting onto a new trial, or perhaps make it possible to access a new treatment that would become available in the future. The patient and clinical experts stated that daratumumab has a favourable toxicity profile, which not only results in an increased quality of life, but also means that people are more likely to be well enough for more options later in the treatment pathway. They also stressed the importance of quality of life after multiple lines of therapy, because the adverse effects of treatments can build up over time. The committee recognised the need for effective, well-tolerated treatment options for people with multiple myeloma who have had previous therapies.\n\n# Treatment pathway\n\n## The treatment pathway for multiple myeloma is rapidly evolving\n\nTreatment options for multiple myeloma depend on how many previous lines of treatment a person has had, the type of treatments they have had, the response to these treatments, and patient preferences.For someone with a new diagnosis of multiple myeloma, if a stem cell transplant is suitable, available options are:\n\nInduction with bortezomib and dexamethasone with or without thalidomide (NICE's technology appraisal guidance on bortezomib for induction therapy) given before the stem cell transplant, followed by maintenance treatment with lenalidomide (lenalidomide maintenance treatment).\n\nInduction with daratumumab plus bortezomib, thalidomide and dexamethasone (daratumumab in combination for untreated multiple myeloma when a stem cell transplant is suitable) before the stem cell transplant. If daratumumab plus bortezomib, thalidomide and dexamethasone is used as induction treatment, then it is also recommended as consolidation treatment after the transplant. Lenalidomide maintenance treatment is recommended after consolidation, or directly after the transplant if bortezomib and dexamethasone (with or without thalidomide) is used as induction treatment (lenalidomide maintenance treatment).If a stem cell transplant is not suitable:For untreated disease, treatments include thalidomide or bortezomib plus an alkylating agent, for example, melphalan or cyclophosphamide, and a corticosteroid, for example, dexamethasone (bortezomib and thalidomide for the first‑line treatment of multiple myeloma). Lenalidomide plus dexamethasone is also an option when thalidomide is not appropriate (lenalidomide plus dexamethasone for previously untreated multiple myeloma).After 1 previous line of treatment, the following options are available regardless of transplant eligibility:\n\nLenalidomide with dexamethasone (lenalidomide plus dexamethasone for multiple myeloma after 1 treatment with bortezomib), carfilzomib with dexamethasone (carfilzomib for previously treated multiple myeloma), carfilzomib with dexamethasone and lenalidomide if the person has had bortezomib before (carfilzomib with dexamethasone and lenalidomide for previously treated multiple myeloma) or bortezomib may be used again (bortezomib monotherapy for relapsed multiple myeloma); however, treatment is only continued in people whose condition has a complete or partial response. Also, daratumumab plus bortezomib and dexamethasone is available in the Cancer Drugs Fund (daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma).Treatment options at further relapse are influenced by the choice of initial treatment. The following options are available regardless of transplant eligibility:\n\nAfter 2 previous lines of treatment, options include lenalidomide plus dexamethasone (lenalidomide for the treatment of multiple myeloma in people who have received at least 2\xa0prior therapies) or panobinostat plus bortezomib and dexamethasone (panobinostat for treating multiple myeloma after at least 2\xa0previous treatments). Also, ixazomib plus lenalidomide and dexamethasone is available in the Cancer Drugs Fund (ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma).\n\nAfter 3\xa0previous lines of treatment, options include pomalidomide plus dexamethasone (pomalidomide for multiple myeloma previously treated with lenalidomide and bortezomib), and panobinostat plus bortezomib and dexamethasone (panobinostat for treating multiple myeloma after at least 2\xa0previous treatments). Also available through the Cancer Drugs Fund are ixazomib plus lenalidomide and dexamethasone (ixazomib with lenalidomide and dexamethasone for treating relapsed or refractory multiple myeloma) and isatuximab plus pomalidomide and dexamethasone (isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma).Daratumumab monotherapy can be used whether or not people have had a stem cell transplant. The Cancer Drugs Fund clinical lead explained that, following the publication of NICE's technology appraisal guidance on isatuximab with pomalidomide and dexamethasone for treating relapsed and refractory multiple myeloma, the use of fourth-line daratumumab monotherapy has decreased, but there is an important cohort of people still receiving this treatment. The recent NICE technology appraisal guidance on daratumumab plus bortezomib plus thalidomide and dexamethasone as first-line treatment when a stem cell transplant is suitable may further decrease the need for fourth-line daratumumab. The committee understood that the multiple myeloma pathway is rapidly evolving.\n\n# Comparators\n\n## After 3\xa0previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator\n\nThe committee recalled that treatments recommended in the Cancer Drugs Fund (see section\xa03.2) are not considered to be comparators because they are not available in routine practice. NICE guidance recommends both pomalidomide plus dexamethasone and panobinostat plus bortezomib and dexamethasone after 3\xa0previous lines of treatment for multiple myeloma. NICE's final scope for this appraisal lists these as the comparators. The company did provide analyses for both comparators to comply with the scope, but stated that it did not consider panobinostat plus bortezomib and dexamethasone to be a relevant comparator. It explained that this was because of toxic adverse effects and the lack of perceived efficacy noted by clinicians it consulted, which means it is usually used after 4\xa0previous lines of treatment. The ERG's clinical advisers agreed with the company's position. The clinical expert at the meeting explained that daratumumab monotherapy or pomalidomide plus dexamethasone are the most commonly used options after 3\xa0previous lines of treatment. They stated that panobinostat plus bortezomib and dexamethasone is rarely used after 3\xa0previous lines of treatment because of toxicity and perceived poor clinical efficacy. The Cancer Drugs Fund clinical lead explained that clinicians can now offer bortezomib without having to use it with panobinostat, and that few clinicians offer panobinostat plus bortezomib and dexamethasone after 3\xa0previous lines of treatment. The committee concluded that after 3\xa0previous lines of treatment, pomalidomide plus dexamethasone is the only relevant comparator.\n\n# Clinical evidence\n\n## The clinical trial evidence for daratumumab monotherapy does not include any head-to-head evidence\n\nThe key clinical study was MMY2002, a completed phase‑2 study investigating different doses of daratumumab (n=106). It included people with relapsed and refractory multiple myeloma who had had at least 3\xa0previous lines of treatment (including proteasome inhibitors and immunomodulators) or whose condition was refractory to both a proteasome inhibitor and an immunomodulator. There was no comparator. The primary outcome was overall response rate. Overall survival and progression-free survival were among the secondary outcomes. In the original appraisal, people in MMY2002 had been followed up for a median of 20.7\xa0months. At the time, median progression-free survival was 3.7\xa0months (95% confidence interval [CI] 2.8 to 4.6) and median overall survival was 18.6\xa0months (95% CI 13.7 to not reached). Since the original appraisal, people in MMY2002 have been followed up for a median of 36.7\xa0months. The company considers the updated progression-free survival and overall survival data to be confidential, so it cannot be reported here. The committee concluded that the longer follow-up data was similar to that which it had seen previously, but that it would prefer to see head-to-head evidence for decision making.\n\n## In the absence of comparative data, the SACT dataset provides useful evidence\n\nThrough the Cancer Drugs Fund, SACT data was collected from people having fourth-line daratumumab monotherapy for multiple myeloma. Between 17\xa0January\xa02018 and 16\xa0November\xa02020, 2,301\xa0people had daratumumab, with a median age of 71\xa0years. Most people had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 (20%) or 1 (41%). Less than half of people had previously had a stem cell transplant (44%). Compared with participants in MMY2002, people were older, and lower proportions had an ECOG score of 0, had a previous stem cell transplant, and went on to have subsequent therapy. People in MMY2002 were able to receive carfilzomib as a subsequent therapy, which did not reflect UK clinical practice or the SACT dataset. The committee considered that the SACT dataset provided useful information and represented people who would receive daratumumab in NHS clinical practice. The committee discussed the results from MMY2002 and the SACT dataset and concluded that they were similar, with any differences explained by the characteristics of the participants and subsequent therapies received.\n\n## The company did a matching-adjusted indirect comparison to compare daratumumab with the comparators\n\nTo compare daratumumab with pomalidomide plus dexamethasone and with panobinostat plus bortezomib and dexamethasone in the absence of a common comparator (an 'anchor'), the company presented 'unanchored' matching-adjusted indirect comparisons (MAICs). Specifically, it adjusted individual patient-level characteristics in the MMY2002 population to match the published study-level summary characteristics of patients in the comparator trials (1 of 2\xa0arms of the MM‑003 trial for pomalidomide plus dexamethasone, and the single-arm trial PANORAMA‑2 for panobinostat plus bortezomib and dexamethasone).\n\n## The SACT trial data is preferred over the single-arm trial data\n\nThe committee discussed the company's approach to matching. It understood that the company presented a partially adjusted MAIC adjusting for the characteristics it considered important in predicting progression and death based on best practice, published evidence and expert opinion. For pomalidomide plus dexamethasone, 5\xa0characteristics were chosen and adjusted. The company stated that this was necessary to maintain a large enough sample size to use for the analysis. The ERG disagreed with company's approach, referencing NICE technical support document 18 which states that, when only single-arm trial data is available, all the characteristics that could influence the outcomes of interest should be adjusted, that is, a fully adjusted MAIC should be done. Because of this, the ERG considered a fully adjusted MAIC to be methodologically superior to the company's partially adjusted MAIC. However, a fully adjusted MAIC gave implausible survival extrapolations for daratumumab, so the ERG also did a naive comparison of daratumumab against data from MM‑003 for pomalidomide with dexamethasone using the SACT data. The company disagreed with this approach, considering it fairer to compare trial data with trial data, rather than real-world evidence with trial data. The committee acknowledged that neither approach was methodologically sound. It discussed several alternatives that may have been useful. One would be an MAIC using a few key characteristics such as age and sex, using the SACT data for daratumumab; however, the Cancer Drugs Fund clinical lead explained this would be difficult because the SACT data is rather crude, so only a few characteristics would be available to be matched on. Another would be collecting real-world data on pomalidomide and dexamethasone from the SACT data from when daratumumab entered the Cancer Drugs Fund, but this was not available. Although the committee noted neither of the presented comparisons were ideal, it preferred to use the SACT data because the usual benefit of trial data is that it is comparative. However, in this instance, the data from MMY2002, which compared 2\xa0different doses of daratumumab, provided no head-to-head evidence of the effectiveness of daratumumab with a relevant comparator. As such, the committee preferred the data from SACT, which had both a larger sample size and reflected UK clinical practice.\n\n## Daratumumab likely increases overall survival, but not progression-free survival compared with pomalidomide and dexamethasone, but this is uncertain\n\nIn the fully adjusted and partially adjusted MAICs, daratumumab showed no difference in progression-free survival compared with pomalidomide with dexamethasone. In the partially adjusted MAIC preferred by the company, daratumumab provided an improvement in overall survival compared with pomalidomide with dexamethasone. In the naive comparison with SACT data preferred by the ERG, the point estimate indicated that daratumumab resulted in improved overall survival, but this was not statistically significant. The committee asked the clinical expert about the plausibility of seeing overall survival gains without progression-free survival gains. The clinical expert explained that in MMY2002, a significant proportion of people had no response to daratumumab, which in part explains why there was no difference in progression-free survival between daratumumab and pomalidomide plus dexamethasone. Additionally, as discussed in section\xa03.1, given the favourable tolerability and reduced toxicity of daratumumab, people may go on to receive further treatments later in the pathway, which may impact overall survival. The committee was satisfied with this explanation and agreed it was possible that daratumumab is associated with overall survival gains without providing progression-free survival gains.\n\n## The overall survival benefit seen in the naive comparison is generalisable to NHS clinical practice\n\nSeveral therapies are available if the cancer comes back after daratumumab (see NICE's technology appraisals on multiple myeloma). The company's submission included several data sources on subsequent treatments, including data from the MMY2002 and MM‑003 trials and the SACT dataset. The ERG expressed concerns about the overall survival data from MMY2002 because people in this trial could have several treatments not available in the NHS, including carfilzomib. The clinical expert agreed that several treatments given after daratumumab in MMY2002 did not reflect UK clinical practice. The evidence for subsequent treatments after daratumumab available from the SACT dataset not only reflects UK clinical practice, but is also a large sample. Because the SACT data is from the UK and is recent, the company, ERG and clinical expert all agreed it best reflects subsequent treatments given after daratumumab in UK clinical practice. The clinical expert explained that the choice of subsequent treatment depends on many factors, including how many previous lines of treatment a person has had, the specific treatments, the response to these treatments, and people's preferences (see section\xa03.1). They agreed that the subsequent treatments seen in the SACT cohort are consistent with what would be expected in clinical practice. Because MMY2002 included treatments not available in the NHS, they considered there was a greater degree of certainty in the SACT data. The committee concluded that subsequent treatment data from the SACT cohort best reflects clinical practice. The committee considered the treatments given after pomalidomide with dexamethasone in MM‑003. It heard from the clinical expert that these were generally aligned with NHS clinical practice. The committee was therefore satisfied that the overall survival benefit implied by the naive comparison (see section\xa03.7) is generalisable to NHS clinical practice, while recognising that this was a naive comparison that could be biased by imbalances in patient characteristics.\n\n# Adverse events\n\n## Daratumumab is well tolerated, improves quality of life, and allows people to receive other treatments further down the pathway\n\nThe clinical expert explained that daratumumab is well tolerated relative to other fourth-line treatments. The patient experts agreed with this, with one pointing out they have been taking daratumumab for some time, saying that it has been the best treatment they've ever had and is why they are still alive today. Additionally, the other patient expert explained that having a treatment that is so well tolerated gives people hope that they may be able to either go on to a clinical trial for a multiple myeloma treatment or that they will survive until they can have a new treatment once it becomes available. The clinical expert agreed with this and again pointed out that a likely reason why an overall survival gain is observed with daratumumab is because of the subsequent treatments people can receive. They also stated that in MMY2002, participants received intravenous daratumumab, which may be less well tolerated than the subcutaneous formulation available in NHS clinical practice. Additionally, people who take daratumumab subcutaneously often find it more convenient because it requires less time spent in a hospital because of the shorter administration time. The committee concluded that daratumumab is well tolerated, improves quality of life for people who take it, and allows them to receive other treatments further down the pathway.\n\n## The company's model structure is acceptable for decision making\n\nThe company used a 4‑state, partitioned-survival economic model, including states representing pre-progressed disease on treatment, pre-progressed disease off treatment, progressed disease and death. The cycle length was 1\xa0week, and the time horizon was 15\xa0years. The committee noted that this model was similar to previous models used for multiple myeloma, and agreed that it was appropriate to capture the natural history of the disease. The ERG was satisfied that the model structure was suitable for estimating the cost effectiveness of daratumumab compared with pomalidomide plus dexamethasone. The committee concluded that the model structure is acceptable and closely matched its preferred assumptions from the original appraisal.\n\n# Survival modelling in the economic model\n\n## Estimates of overall survival are highly uncertain despite the additional analyses provided\n\nAs in the original appraisal, the model relied on estimates of relative treatment effects from the company's unanchored MAIC. The ERG raised concerns about the methodology of the partially adjusted MAIC, but recalled that the overall survival extrapolations from the fully adjusted MAIC were implausible. The ERG therefore did a naive comparison using daratumumab data from the SACT dataset (see section\xa03.7). The company accepted that its estimates were associated with uncertainty. It attempted to explore this uncertainty by performing scenario analyses in which different sources of the relative treatment effects were used, including the fully adjusted MAIC and an adjusted comparison with the SACT dataset. The ERG also explored this uncertainty, using the naive comparison with the SACT dataset as its preferred source of relative treatment effect. The committee considered all the scenarios presented by the company and the ERG and recognised that there were high levels of uncertainty in the estimates of overall survival used in the model.\n\n# Costs of subsequent treatments in the economic model\n\n## The cost of subsequent treatments should align with the source of clinical data\n\nThe company used data from SACT to inform both the proportion of people having further treatment and the treatments taken after daratumumab and after pomalidomide with dexamethasone. In the ERG's analysis, it aligned the cost of subsequent treatment with the source of clinical evidence. That is, for daratumumab, data from SACT on the proportion of people and type of subsequent therapy was used. But for pomalidomide with dexamethasone, data from MM‑003 informed the proportion of people and type of subsequent therapy used. A clinical expert stated that the subsequent therapies used are likely to be influenced by daratumumab, and that those in MM‑003 aligned well with NHS clinical practice after pomalidomide with dexamethasone. Taking this into account, the committee preferred the ERG's approach.\n\n# End of life considerations\n\n## Daratumumab meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's final Cancer Drugs Fund technology appraisal process and methods. It considered life expectancy for people with relapsed and refractory multiple myeloma. In the ERG's analysis, the mean undiscounted total life years with pomalidomide with dexamethasone was 1.49\xa0years. The committee was satisfied that the life expectancy in this population was less than 24\xa0months. It was also satisfied that introducing daratumumab to the treatment pathway at this point offers at least a 3‑month life extension, because despite the uncertainty around the clinical efficacy of this treatment, there was no scenario by either the company or the ERG in which this criterion was not met. The minimum extension to life modelled in any scenario was 5.5\xa0months. The committee concluded that daratumumab after 3\xa0previous lines of treatment met the criteria to be considered a life-extending, end of life treatment.\n\n# Cost-effectiveness results\n\n## The cost-effectiveness estimates are uncertain, but the ERG's preferred ICER is likely the highest plausible ICER\n\nThe committee considered the company's and the ERG's cost-effectiveness results, including confidential discounts for daratumumab and all of the comparator technologies and subsequent treatments. The cost-effectiveness results are commercial in confidence and cannot be reported here. The committee noted that the incremental cost-effectiveness ratios (ICERs) for daratumumab compared with pomalidomide plus dexamethasone varied widely. This reflected the high degree of uncertainty in daratumumab's relative clinical effectiveness. Although the degree of uncertainty in the evidence was high, the committee noted that the naive comparison of clinical trial and real-world data would underestimate the benefits of daratumumab, so it believed that the ERG's preferred ICER likely represented the upper end of plausible values.\n\n## The most likely ICER is within what NICE considers an acceptable use of NHS resources\n\nTaking into account all the confidential patient access schemes for all of the comparator technologies and subsequent treatments, all the resulting ICERs were lower than £50,000 per quality-adjusted life year (QALY) gained. However, these were all associated with uncertainty. The committee would have preferred alternative methods to have been used to estimate the relative treatment efficacy of daratumumab compared with pomalidomide plus dexamethasone, specifically obtaining data on pomalidomide plus dexamethasone from the SACT database or an adjusted comparison of SACT data with trial data. The committee was aware that both of these methods would likely be challenging at this stage, but may be of value in future appraisals when considering what data to request when recommending a treatment for the Cancer Drugs Fund. However, because the committee viewed the ERG's preferred ICER as the very upper end of the plausible values, it considered that the true ICER likely fell below this. Taking all of this into account, the committee concluded that daratumumab was an acceptable use of NHS resources.\n\n# Other factors\n\n## Equalities\n\nNo equality issues were identified.\n\n## Innovation\n\nThe company did not highlight any additional benefits that had not been captured in the QALY calculations.\n\n# Conclusion\n\n## Daratumumab is recommended for routine use\n\nThe committee concluded that the most plausible cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, daratumumab is recommended for treating relapsed and refractory multiple myeloma in adults whose previous therapy included a proteasome inhibitor and an immunomodulator, and whose disease progressed on the last therapy, if they have daratumumab after 3\xa0previous therapies."}
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https://www.nice.org.uk/guidance/ta783
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Evidence-based recommendations on daratumumab (Darzalex) for relapsed and refractory multiple myeloma in adults.
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90947998e25639205e8e2c9aa60c56eb33bc4b04
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nice
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myCOPD for managing chronic obstructive pulmonary disease
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myCOPD for managing chronic obstructive pulmonary disease
Evidence-based recommendations on myCOPD for managing chronic obstructive pulmonary disease.
# Recommendations
More research is recommended on myCOPD for managing chronic obstructive pulmonary disease (COPD) in adults. Using it for self-managing COPD and remote pulmonary rehabilitation could provide significant patient and healthcare system benefits if uncertainties in the evidence are addressed.
Research should compare myCOPD with standard care for:
people who use it to self-manage COPD
people who are referred for pulmonary rehabilitation. Find out more in the further research section of this guidance.
Why the committee made these recommendations
Standard care for COPD includes a range of interventions such as self-management, pulmonary rehabilitation (a face-to-face programme of exercise and education) and inhalers. myCOPD is an app that helps people with COPD understand their condition and manage symptoms. It also has a pulmonary rehabilitation programme, so people can do this remotely.
Clinical trial evidence is uncertain because the trials were short and included few people. But it suggests that using myCOPD for self-management improved COPD symptoms, walking distance and inhaler technique compared with standard care. The evidence also suggests that pulmonary rehabilitation using myCOPD works as well as face-to-face sessions.
The cost savings are uncertain because of limitations in the clinical evidence. There is also a lack of information about how much myCOPD affects healthcare resource use, such as unscheduled hospital appointments. More evidence is needed to resolve these uncertainties, so further research is recommended.# The technology
# Technology and intended use
myCOPD is a digital tool for people with chronic obstructive pulmonary disease (COPD) and healthcare professionals. It is intended to support people to manage COPD. It can be used by people with any stage of COPD. Functions within the myCOPD app include:
education on how to use inhalers correctly
a self-management plan to help people understand what medicine to take and when
a prescription assessment function to cross-check prescribed medicine, and identify any conflicts
a COPD assessment for people to track their symptoms and learn how to control them
access to an online 6‑week pulmonary rehabilitation course including an incremental exercise programme and education sessions to help promote self-management.
People can use myCOPD with any digital device that connects to the internet, such as smartphones, tablets, televisions and computers. Users' data will be shared with clinical teams if people accept the terms and conditions when registering with myCOPD. Clinicians can review the person's data to remotely monitor their symptoms and if appropriate suggest a change to their medicines. These suggestions are automatically shared with the person through the app.
The technology was supported by NHS England's innovation and technology tariff in 2017. The company states that the technology is compliant with the NHS Digital Technology Assessment Criteria (DTAC).
# Care pathway
The NICE guideline on chronic obstructive pulmonary disease in over 16s: diagnosis and management provides recommendations on managing stable COPD, covering smoking cessation, inhaled therapy, oral therapy, oxygen therapy, pulmonary rehabilitation and managing pulmonary hypertension. A recent update of the guideline focuses on monitoring, education and self-management. The guideline notes that most people with COPD can develop adequate inhaler technique if they have training. The guideline also recommends making pulmonary rehabilitation available to all people with COPD if appropriate, including people who have had a recent hospitalisation for an acute exacerbation. Pulmonary rehabilitation programmes should include multicomponent, multidisciplinary interventions tailored to the individual's needs. The rehabilitation process should incorporate a programme of physical training, disease education, and nutritional, psychological and behavioural interventions.
NICE's COVID-19 rapid guideline on community-based care of patients with COPD recognises the need to reduce face-to-face contact and recommends people use online pulmonary rehabilitation resources.
# Innovative aspects
In the UK, face-to-face appointments are a standard approach when reviewing or monitoring COPD. myCOPD allows health service providers to offer a combination of remote care and face-to-face support. Using myCOPD could potentially minimise health service contacts and help with delivering care remotely.
# Costs
The company provides an unlimited licence plan to healthcare organisations such as clinical commissioning groups or integrated care systems who want to make the technology available across their regions. Based on a 3‑year contract, this unlimited licence plan has an annual cost of £0.25 per person registered with a GP in the region. Alternatively, pulmonary rehabilitation service providers who do not have regional access to the technology can obtain an unlimited licence plan at a cost of £10,000 per year.For more details, see the website for myCOPD.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The clinical evidence comprises 4 UK comparative studies
There were 4 peer-reviewed studies on myCOPD, including 3 randomised controlled trials (RCTs) and 1 observational study. All trials were done in the NHS with 6 weeks or 3 months of follow up. The sample sizes ranged from 41 to 90 people with mild, moderate or severe chronic obstructive pulmonary disease (COPD). Of the 3 RCTs, TROOPER used a non-inferiority design comparing myCOPD with a face-to-face pulmonary rehabilitation programme in people who were referred for rehabilitation (Bourne et al. 2017). The other 2 trials examined the use of myCOPD as a self-management tool: RESCUE, a feasibility trial, compared myCOPD with usual care including a written self-management plan in people who were discharged from hospital after an acute exacerbation (North et al. 2020). EARLY was a superiority RCT that compared myCOPD with standard care in people with mild to moderate COPD or recently diagnosed COPD (Crooks et al. 2020).
## Real-world evidence from 10 local evaluations is generalisable to the NHS
There was also real-world evidence on clinical benefits, health service use, patient experience and usage of the myCOPD app from 10 local evaluations. A service evaluation from Southend University Hospital explored using myCOPD to support a home-based pulmonary rehabilitation programme. Other local evaluations assessed the effect of myCOPD on self-managing COPD. Most evidence was from interim evaluations designed to inform commissioning decisions or service developments. The methodology, patient numbers or characteristics, clinical outcomes and follow-up periods were not fully reported in these evaluations. However, the EAC concluded that the real-world evidence reflected the use of myCOPD in clinical practice and the findings of these evaluations would be generalisable to local health services.
## Evidence on using myCOPD for self-managing COPD shows improvements in clinical outcomes
Evidence on using myCOPD for self-managing COPD showed improvements in clinical outcomes. There was evidence from trials and real-world evidence evaluating myCOPD for self-managing COPD in people with different COPD severity and exacerbation history. Results suggested improvements in clinical outcomes such as the COPD assessment test (CAT) score, 6‑minute walking test (6MWT) distances and inhaler techniques after using myCOPD. Of those who were admitted to hospital because of an acute exacerbation, RESCUE showed a significant CAT score mean difference of -4.49 (95% confidence interval -8.41 to -0.58, n=41) in all people in the study regardless of whether they completed the study. RESCUE also showed a non-significant CAT score mean difference of -2.94 (95% CI -6.92 to 1.05, n=35) with myCOPD in people who completed the study at 3‑month follow up (North et al. 2020). RESCUE showed a significant reduction in inhaler errors in people using myCOPD compared with people having standard care (relative risk, 0.38; 95% CI 0.18 to 0.80). Compared with people having standard care, people using myCOPD were less likely to have exacerbations (relative risk, 0.58; 95% CI 0.32 to 1.04).
## Pulmonary rehabilitation with myCOPD is comparable to face-to-face rehabilitation
TROOPER reported no statistically significant difference in CAT score and 6MWT between the intervention groups, indicating myCOPD was not inferior to face-to-face care for pulmonary rehabilitation (Bourne et al. 2017). Health-related quality of life was not worse in people using myCOPD for pulmonary rehabilitation compared with those having face-to-face rehabilitation. The EAC considered that the TROOPER trial was well designed, but the sample size was small. The company provided further information on the sample size calculation to show non-inferiority at consultation. The additional information did not address the EAC's methodological concerns, such as the choice of the non-inferiority limit, and the EAC considered a larger trial would probably be needed to confirm the results. Real-world evidence also reported improvements in CAT scores and 6‑minute walk test with myCOPD to support home-based pulmonary rehabilitation (NHS Southend clinical commissioning group evaluations).
## Trial evidence shows adherence to myCOPD declines over time
For self-managing COPD, usage data of myCOPD reported in the RESCUE and EARLY trials showed its use declined over time. TROOPER used myCOPD for pulmonary rehabilitation. It showed that although adherence declined over time it was comparable in both groups (Bourne et al. 2017). After 6 weeks, 66% of people using myCOPD had completed 2 or more sessions compared with 69% of people in the comparator group who attended 2 or more face-to-face sessions. Real-world evidence showed varying use of the app. There is no direct evidence on the relationship between adherence and clinical outcomes using myCOPD.
## myCOPD is easy to use and improves confidence in managing COPD
NICE's public involvement programme did a survey of people using myCOPD. In this, people reported that myCOPD was easy to use (n=297/359, 82.7%) and helped improve their understanding of the condition and manage symptoms. Three-quarters of people who responded (n=267/358, 74.6%) felt confident in managing COPD symptoms after using the app. Of those who used the app to control COPD symptoms, 66.1% (n=220/333) felt there had been a reduction in the number of exacerbations experienced after using the app. People thought that myCOPD was a helpful tool and provided useful information that improved their confidence in managing COPD.
# Cost evidence
## The company's cost models are in 2 populations
The company submitted cost models in 2 different populations:
people discharged from hospital after an acute exacerbation of COPD who used myCOPD for self-managing their condition (the AECOPD model)
people eligible for pulmonary rehabilitation who used myCOPD for pulmonary rehabilitation (the PR model).The company also presented results for 2 different pricing scenarios. For healthcare providers who purchased a population-based unlimited myCOPD licence package, the company's AECOPD model showed that myCOPD was cost saving by £204,641 per CCG over 1 year compared with standard care (not accounting for savings from pulmonary rehabilitation). The estimated savings in the PR model within the population licence package was £20,269 per CCG per year. Also, if the myCOPD licence package is purchased solely for pulmonary rehabilitation services, the estimated saving is £8,707 per pulmonary rehabilitation service per year.
## The EAC's changes to the cost models more accurately reflect the uptake rate of myCOPD for self-management and pulmonary rehabilitation
The EAC considered the company's 2 model structures to be appropriate. But it did not agree with the 100% uptake rate in the company's models. For the AECOPD model, the EAC used an uptake rate of 46% based on data from the RESCUE study (North et al. 2020). This rate is the proportion of people who chose to use myCOPD in the RESCUE trial.
For the PR model, the EAC changed the decision point from when people were referred to a pulmonary rehabilitation service to the point at which people have opted in or shown they would be willing to use myCOPD.
## myCOPD is cost saving in both cost models
In the AECOPD model, the EAC base-case results showed that myCOPD saved £86,297 per CCG per year. The saving was influenced by the myCOPD uptake rate and the 90‑day readmission rate. The EAC's threshold analysis suggested that using myCOPD becomes cost incurring if the uptake rate is below 26% or the 90‑day readmission rate is higher than 0.30 admissions per person. It judged that both these values were plausible. At consultation, the company noted that the national activation rate was 48%. The EAC did an additional analysis of the AECOPD model using this activation rate for the uptake, which resulted in a small increase in the cost savings.
For the PR model, the EAC's base case showed cost savings of £22,779 per CCG per year or £11,093 per pulmonary rehabilitation service per year depending on the licence package purchased. These savings were influenced by the number of people being referred and the uptake rate of pulmonary rehabilitation programmes. The EAC's threshold analysis suggested that using myCOPD becomes cost incurring if:
the referrals to the pulmonary rehabilitation service are below 249 people per year or
the uptake rate is below 9.8% for myCOPD alone or
the uptake rate for myCOPD alone is below 1.9% and the uptake rate for a hybrid option is below 12.2%. The EAC considered that there was uncertainty around the values used to inform the clinical inputs in the model. (For further details about the threshold analysis, see the EAC assessment report in the supporting documentation for this guidance.)# Committee discussion
# Clinical-effectiveness overview
## myCOPD shows promise for self-managing COPD but the clinical benefit is uncertain because of limitations in the evidence
The committee noted that evidence from 2 randomised controlled trials (the RESCUE and EARLY trials) and real-world evaluations showed that myCOPD had clinical benefits for self-managing chronic obstructive pulmonary disease (COPD). Populations included in the studies were heterogeneous in terms of the severity of COPD. The committee accepted that the evidence suggests clinical benefits showing improved inhaler technique, COPD assessment test (CAT) score and 6‑minute walk test. RESCUE showed encouraging results, but it was designed as a feasibility study. Evidence on the effect of using myCOPD for self-managing COPD on health service use was limited. RESCUE showed that there were fewer hospital readmissions for acute exacerbations of COPD in people using myCOPD compared with people having standard care. The difference was not statistically significant. The external assessment centre (EAC) explained that the small study sample size had limited power to show an effect on clinical outcomes. The committee agreed that more evidence is needed to clearly show the clinical and healthcare system benefits of myCOPD for self-managing COPD (see the section on further research).
## Evidence suggests that myCOPD is not worse than face-to-face pulmonary rehabilitation, but the clinical trial assessing this was small
The evidence presented on using myCOPD for pulmonary rehabilitation included 1 non-inferiority trial (TROOPER) and real-world evidence. In the trial, all clinical outcomes using myCOPD were not worse than conventional face-to-face pulmonary rehabilitation. The committee accepted that the trial was well designed but noted methodological concerns from the EAC about the power calculations, such as the selection of the non-inferiority limit (for further details, see the EAC assessment report addendum). It also considered that the trial was limited by being a single-site study. The TROOPER study authors acknowledged the small sample size and suggested that a larger randomised controlled trial would be needed to change clinical practice. The committee concluded that a larger randomised controlled trial was needed to be confident in the findings of the TROOPER study.
# Other patient benefits or issues
## Usability and patient experience are important considerations
A commissioning expert from NHS Dorset clinical commissioning group (CCG) explained that the evaluation of digital health technologies is complex. They noted that considerations should not only focus on the clinical benefits of the technology, but also the patient experience, the usability of the technology and the role of the health service team. A survey done by NICE's public involvement programme suggested that people found myCOPD easy to use. The committee concluded that the usability and patient experience of the technology for both patients and the healthcare system are important considerations.
# NHS considerations overview
## Support is needed to help patients to use myCOPD and the health service to implement it
The company confirmed that myCOPD has been used across health services for self-managing COPD and pulmonary rehabilitation. The clinical experts advised that the health service team, both clinical and non-clinical, plays an important role in keeping people engaged with myCOPD. The commissioning expert stated that their team provided support for people to register and set up the app for self-managing their symptoms. Ongoing support from non-clinical digital support workers is provided at different time points via text messaging, over the phone or by setting up face-to-face appointments to help maintain patient engagement. Similarly, the clinical expert said that people who used myCOPD for pulmonary rehabilitation in their service had a weekly call from the clinical team during the 6‑week pulmonary rehabilitation course to support their progress in the programme. The company also confirmed that digital health advisers have been included as part of a contract to support the implementation of the technology and to ensure that clinical and digital support teams are fully trained.
## Uptake data varies and more should be collected as real-world evidence
The committee understood that myCOPD uptake data varied widely across services. It acknowledged there are many factors influencing how much it was used, including the COVID‑19 pandemic. The commissioning expert said that real-time uptake data was available from Dorset CCG, where uptake for self-management increased from 43% to 65% in 2021. The committee questioned whether the uptake rates observed in Dorset were likely to be realised in other regions. A clinical expert advised that uptake of myCOPD for pulmonary rehabilitation in their service was around 26% in 2018; however, no recent uptake data was available. The committee agreed that understanding the uptake of myCOPD across different regions and settings, for both self-management and pulmonary rehabilitation, is important to ensure its value for money (see sections 3.10 and 3.11). It concluded that this information could easily be collected as real-world evidence.
## myCOPD could have an impact on health inequalities
Clinical experts explained that myCOPD has been implemented as an option alongside existing services in their practice. People have the option to choose whether or not to use it depending on preference. The experts noted that the populations in their regions using myCOPD were mainly older white British people living in areas with different levels of socioeconomic deprivation. The company confirmed that the average age of myCOPD users is 74 years old. The commissioning expert said that the implementation of myCOPD improved patients' access to health services in areas of deprivation. The committee also discussed the English language skills needed to use myCOPD. The average reading age needed to use myCOPD is between 8 and 12 years. The clinical experts noted that myCOPD may be difficult to use for people who are not able to use a smart device easily, such as those with a visual or cognitive impairment, limited manual dexterity, or with hearing loss. They added that in their experience, some people with COPD would prefer not to use the digital tool, while others found it helpful. The committee concluded that further evidence of myCOPD's use in a wide range of socioeconomic backgrounds, ethnicities and ages is needed to understand its effect on health inequalities.
# Cost modelling overview
## Uncertainties about the clinical benefits of myCOPD are reflected in the cost modelling
The committee understood that clinical parameters in the AECOPD model (see section 3.7 for details about the models) for self-management were based on RESCUE, a feasibility trial with fewer than 50 patients. It noted that the key drivers of cost saving in this model were the uptake of myCOPD and hospital readmissions, and both parameters were uncertain (see sections 3.10 and 3.11). The PR model has 3 treatment options, so people were able to choose myCOPD, face-to-face pulmonary rehabilitation or a hybrid format which consisted of face-to-face sessions and myCOPD. Results from TROOPER were used in the PR model. Key drivers for cost savings in this model were the uptake of myCOPD, both alone and in the hybrid format, and the number of people referred for pulmonary rehabilitation. The committee considered that the key uncertainty for the PR model related to the assumption of non-inferiority of pulmonary rehabilitation services delivered by the myCOPD app compared with face-to-face pulmonary rehabilitation (see section 4.2). It also considered that more information is needed on the uptake rate of myCOPD when it is used for pulmonary rehabilitation (see section 4.5).
# Further research
## Further good quality evidence is needed to address uncertainties about myCOPD's clinical benefits and its effect on healthcare resource use
myCOPD has potential for clinical benefits, but more evidence is needed to reduce uncertainties. The committee considered that comparative evidence is needed to show the clinical benefits of using myCOPD in 2 populations:
people using it to self-manage COPD
people referred to pulmonary rehabilitation.For self-management, a randomised controlled trial is preferred to show the clinical benefits of myCOPD. This could be powered based on the encouraging results in the RESCUE study. However, a high-quality comparative observational study designed to minimise bias in the results may provide acceptable evidence. Outcomes such as rates of exacerbations, hospital readmissions and unscheduled care appointments should be considered alongside patient-reported outcomes such as health-related quality of life. For pulmonary rehabilitation, further evidence is needed to show the clinical benefits of myCOPD. This could be a randomised controlled trial which is powered based on the encouraging results in the TROOPER study or a well-designed comparative observational study. Key outcomes will be the CAT score and 6‑minute walk test, ideally supported by additional longer-term outcomes such as rates of exacerbations and hospital admissions.
Real-world data could be used to inform the uptake rates in the economic modelling. It should also include qualitative data on patient experience using myCOPD such as patient preferences and adherence.
|
{'Recommendations': 'More research is recommended on myCOPD for managing chronic obstructive pulmonary disease (COPD) in adults. Using it for self-managing COPD and remote pulmonary rehabilitation could provide significant patient and healthcare system benefits if uncertainties in the evidence are addressed.\n\nResearch should compare myCOPD with standard care for:\n\npeople who use it to self-manage COPD\n\npeople who are referred for pulmonary rehabilitation. Find out more in the further research section of this guidance.\n\nWhy the committee made these recommendations\n\nStandard care for COPD includes a range of interventions such as self-management, pulmonary rehabilitation (a face-to-face programme of exercise and education) and inhalers. myCOPD is an app that helps people with COPD understand their condition and manage symptoms. It also has a pulmonary rehabilitation programme, so people can do this remotely.\n\nClinical trial evidence is uncertain because the trials were short and included few people. But it suggests that using myCOPD for self-management improved COPD symptoms, walking distance and inhaler technique compared with standard care. The evidence also suggests that pulmonary rehabilitation using myCOPD works as well as face-to-face sessions.\n\nThe cost savings are uncertain because of limitations in the clinical evidence. There is also a lack of information about how much myCOPD affects healthcare resource use, such as unscheduled hospital appointments. More evidence is needed to resolve these uncertainties, so further research is recommended.', 'The technology': "# Technology and intended use\n\nmyCOPD is a digital tool for people with chronic obstructive pulmonary disease (COPD) and healthcare professionals. It is intended to support people to manage COPD. It can be used by people with any stage of COPD. Functions within the myCOPD app include:\n\neducation on how to use inhalers correctly\n\na self-management plan to help people understand what medicine to take and when\n\na prescription assessment function to cross-check prescribed medicine, and identify any conflicts\n\na COPD assessment for people to track their symptoms and learn how to control them\n\naccess to an online 6‑week pulmonary rehabilitation course including an incremental exercise programme and education sessions to help promote self-management.\n\nPeople can use myCOPD with any digital device that connects to the internet, such as smartphones, tablets, televisions and computers. Users' data will be shared with clinical teams if people accept the terms and conditions when registering with myCOPD. Clinicians can review the person's data to remotely monitor their symptoms and if appropriate suggest a change to their medicines. These suggestions are automatically shared with the person through the app.\n\nThe technology was supported by NHS England's innovation and technology tariff in 2017. The company states that the technology is compliant with the NHS Digital Technology Assessment Criteria (DTAC).\n\n# Care pathway\n\nThe NICE guideline on chronic obstructive pulmonary disease in over 16s: diagnosis and management provides recommendations on managing stable COPD, covering smoking cessation, inhaled therapy, oral therapy, oxygen therapy, pulmonary rehabilitation and managing pulmonary hypertension. A recent update of the guideline focuses on monitoring, education and self-management. The guideline notes that most people with COPD can develop adequate inhaler technique if they have training. The guideline also recommends making pulmonary rehabilitation available to all people with COPD if appropriate, including people who have had a recent hospitalisation for an acute exacerbation. Pulmonary rehabilitation programmes should include multicomponent, multidisciplinary interventions tailored to the individual's needs. The rehabilitation process should incorporate a programme of physical training, disease education, and nutritional, psychological and behavioural interventions.\n\nNICE's COVID-19 rapid guideline on community-based care of patients with COPD recognises the need to reduce face-to-face contact and recommends people use online pulmonary rehabilitation resources.\n\n# Innovative aspects\n\nIn the UK, face-to-face appointments are a standard approach when reviewing or monitoring COPD. myCOPD allows health service providers to offer a combination of remote care and face-to-face support. Using myCOPD could potentially minimise health service contacts and help with delivering care remotely.\n\n# Costs\n\nThe company provides an unlimited licence plan to healthcare organisations such as clinical commissioning groups or integrated care systems who want to make the technology available across their regions. Based on a 3‑year contract, this unlimited licence plan has an annual cost of £0.25 per person registered with a GP in the region. Alternatively, pulmonary rehabilitation service providers who do not have regional access to the technology can obtain an unlimited licence plan at a cost of £10,000 per year.For more details, see the website for myCOPD.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The clinical evidence comprises 4\xa0UK comparative studies\n\nThere were 4\xa0peer-reviewed\xa0studies on myCOPD, including 3\xa0randomised controlled trials (RCTs) and 1\xa0observational study. All trials were done in the NHS with 6\xa0weeks or 3\xa0months of follow up. The sample sizes ranged from 41 to 90\xa0people with mild, moderate or severe chronic obstructive pulmonary disease (COPD). Of the 3\xa0RCTs, TROOPER used a non-inferiority design comparing myCOPD with a face-to-face pulmonary rehabilitation programme in people who were referred for rehabilitation (Bourne et al. 2017). The other 2\xa0trials examined the use of myCOPD as a self-management tool: RESCUE, a feasibility trial, compared myCOPD with usual care including a written self-management plan in people who were discharged from hospital after an acute exacerbation (North et al. 2020). EARLY was a superiority RCT that compared myCOPD with standard care in people with mild to moderate COPD or recently diagnosed COPD (Crooks et al. 2020).\n\n## Real-world evidence from 10\xa0local evaluations is generalisable to the NHS\n\nThere was also real-world evidence on clinical benefits, health service use, patient experience and usage of the myCOPD app from 10\xa0local evaluations. A service evaluation from Southend University Hospital explored using myCOPD to support a home-based pulmonary rehabilitation programme. Other local evaluations assessed the effect of myCOPD on self-managing COPD. Most evidence was from interim evaluations designed to inform commissioning decisions or service developments. The methodology, patient numbers or characteristics, clinical outcomes and follow-up periods were not fully reported in these evaluations. However, the EAC concluded that the real-world evidence reflected the use of myCOPD in clinical practice and the findings of these evaluations would be generalisable to local health services.\n\n## Evidence on using myCOPD for self-managing COPD shows improvements in clinical outcomes\n\nEvidence on using myCOPD for self-managing COPD showed improvements in clinical outcomes. There was evidence from trials and real-world evidence evaluating myCOPD for self-managing COPD in people with different COPD severity and exacerbation history. Results suggested improvements in clinical outcomes such as the COPD assessment test (CAT) score, 6‑minute walking test (6MWT) distances and inhaler techniques after using myCOPD. Of those who were admitted to hospital because of an acute exacerbation, RESCUE showed a significant CAT score mean difference of -4.49 (95% confidence interval [CI] -8.41 to -0.58, n=41) in all people in the study regardless of whether they completed the study. RESCUE also showed a non-significant CAT score mean difference of -2.94 (95% CI -6.92 to 1.05, n=35) with myCOPD in people who completed the study at 3‑month follow up (North et al. 2020). RESCUE showed a significant reduction in inhaler errors in people using myCOPD compared with people having standard care (relative risk, 0.38; 95% CI 0.18 to 0.80). Compared with people having standard care, people using myCOPD were less likely to have exacerbations (relative risk, 0.58; 95% CI 0.32 to 1.04).\n\n## Pulmonary rehabilitation with myCOPD is comparable to face-to-face rehabilitation\n\nTROOPER reported no statistically significant difference in CAT score and 6MWT between the intervention groups, indicating myCOPD was not inferior to face-to-face care for pulmonary rehabilitation (Bourne et al. 2017). Health-related quality of life was not worse in people using myCOPD for pulmonary rehabilitation compared with those having face-to-face rehabilitation. The EAC considered that the TROOPER trial was well designed, but the sample size was small. The company provided further information on the sample size calculation to show non-inferiority at consultation. The additional information did not address the EAC's methodological concerns, such as the choice of the non-inferiority limit, and the EAC considered a larger trial would probably be needed to confirm the results. Real-world evidence also reported improvements in CAT scores and 6‑minute walk test with myCOPD to support home-based pulmonary rehabilitation (NHS Southend clinical commissioning group [CCG] evaluations).\n\n## Trial evidence shows adherence to myCOPD declines over time\n\nFor self-managing COPD, usage data of myCOPD reported in the RESCUE and EARLY trials showed its use declined over time. TROOPER used myCOPD for pulmonary rehabilitation. It showed that although adherence declined over time it was comparable in both groups (Bourne et al. 2017). After 6\xa0weeks, 66% of people using myCOPD had completed 2 or more sessions compared with 69% of people in the comparator group who attended 2 or more face-to-face sessions. Real-world evidence showed varying use of the app. There is no direct evidence on the relationship between adherence and clinical outcomes using myCOPD.\n\n## myCOPD is easy to use and improves confidence in managing COPD\n\nNICE's public involvement programme did a survey of people using myCOPD. In this, people reported that myCOPD was easy to use (n=297/359, 82.7%) and helped improve their understanding of the condition and manage symptoms. Three-quarters of people who responded (n=267/358, 74.6%) felt confident in managing COPD symptoms after using the app. Of those who used the app to control COPD symptoms, 66.1% (n=220/333) felt there had been a reduction in the number of exacerbations experienced after using the app. People thought that myCOPD was a helpful tool and provided useful information that improved their confidence in managing COPD.\n\n# Cost evidence\n\n## The company's cost models are in 2\xa0populations\n\nThe company submitted cost models in 2\xa0different populations:\n\npeople discharged from hospital after an acute exacerbation of COPD who used myCOPD for self-managing their condition (the AECOPD model)\n\npeople eligible for pulmonary rehabilitation who used myCOPD for pulmonary rehabilitation (the PR model).The company also presented results for 2\xa0different pricing scenarios. For healthcare providers who purchased a population-based unlimited myCOPD licence package, the company's AECOPD model showed that myCOPD was cost saving by £204,641 per CCG over 1\xa0year compared with standard care (not accounting for savings from pulmonary rehabilitation). The estimated savings in the PR model within the population licence package was £20,269 per CCG per year. Also, if the myCOPD licence package is purchased solely for pulmonary rehabilitation services, the estimated saving is £8,707 per pulmonary rehabilitation service per year.\n\n## The EAC's changes to the cost models more accurately reflect the uptake rate of myCOPD for self-management and pulmonary rehabilitation\n\nThe EAC considered the company's 2\xa0model structures to be appropriate. But it did not agree with the 100% uptake rate in the company's models. For the AECOPD model, the EAC used an uptake rate of 46% based on data from the RESCUE study (North et al. 2020). This rate is the proportion of people who chose to use myCOPD in the RESCUE trial.\n\nFor the PR model, the EAC changed the decision point from when people were referred to a pulmonary rehabilitation service to the point at which people have opted in or shown they would be willing to use myCOPD.\n\n## myCOPD is cost saving in both cost models\n\nIn the AECOPD model, the EAC base-case results showed that myCOPD saved £86,297 per CCG per year. The saving was influenced by the myCOPD uptake rate and the 90‑day readmission rate. The EAC's threshold analysis suggested that using myCOPD becomes cost incurring if the uptake rate is below 26% or the 90‑day readmission rate is higher than 0.30\xa0admissions per person. It judged that both these values were plausible. At consultation, the company noted that the national activation rate was 48%. The EAC did an additional analysis of the AECOPD model using this activation rate for the uptake, which resulted in a small increase in the cost savings.\n\nFor the PR model, the EAC's base case showed cost savings of £22,779 per CCG per year or £11,093 per pulmonary rehabilitation service per year depending on the licence package purchased. These savings were influenced by the number of people being referred and the uptake rate of pulmonary rehabilitation programmes. The EAC's threshold analysis suggested that using myCOPD becomes cost incurring if:\n\nthe referrals to the pulmonary rehabilitation service are below 249\xa0people per year or\n\nthe uptake rate is below 9.8% for myCOPD alone or\n\nthe uptake rate for myCOPD alone is below 1.9% and the uptake rate for a hybrid option is below 12.2%. The EAC considered that there was uncertainty around the values used to inform the clinical inputs in the model. (For further details about the threshold analysis, see the EAC assessment report in the supporting documentation for this guidance.)", 'Committee discussion': "# Clinical-effectiveness overview\n\n## myCOPD shows promise for self-managing COPD but the clinical benefit is uncertain because of limitations in the evidence\n\nThe committee noted that evidence from 2\xa0randomised controlled trials (the RESCUE and EARLY trials) and real-world evaluations showed that myCOPD had clinical benefits for self-managing chronic obstructive pulmonary disease (COPD). Populations included in the studies were heterogeneous in terms of the severity of COPD. The committee accepted that the evidence suggests clinical benefits showing improved inhaler technique, COPD assessment test (CAT) score and 6‑minute walk test. RESCUE showed encouraging results, but it was designed as a feasibility study. Evidence on the effect of using myCOPD for self-managing COPD on health service use was limited. RESCUE showed that there were fewer hospital readmissions for acute exacerbations of COPD in people using myCOPD compared with people having standard care. The difference was not statistically significant. The external assessment centre (EAC) explained that the small study sample size had limited power to show an effect on clinical outcomes. The committee agreed that more evidence is needed to clearly show the clinical and healthcare system benefits of myCOPD for self-managing COPD (see the section on further research).\n\n## Evidence suggests that myCOPD is not worse than face-to-face pulmonary rehabilitation, but the clinical trial assessing this was small\n\nThe evidence presented on using myCOPD for pulmonary rehabilitation included 1\xa0non-inferiority trial (TROOPER) and real-world evidence. In the trial, all clinical outcomes using myCOPD were not worse than conventional face-to-face pulmonary rehabilitation. The committee accepted that the trial was well designed but noted methodological concerns from the EAC about the power calculations, such as the selection of the non-inferiority limit (for further details, see the EAC assessment report addendum). It also considered that the trial was limited by being a single-site study. The TROOPER study authors acknowledged the small sample size and suggested that a larger randomised controlled trial would be needed to change clinical practice. The committee concluded that a larger randomised controlled trial was needed to be confident in the findings of the TROOPER study.\n\n# Other patient benefits or issues\n\n## Usability and patient experience are important considerations\n\nA commissioning expert from NHS Dorset clinical commissioning group (CCG) explained that the evaluation of digital health technologies is complex. They noted that considerations should not only focus on the clinical benefits of the technology, but also the patient experience, the usability of the technology and the role of the health service team. A survey done by NICE's public involvement programme suggested that people found myCOPD easy to use. The committee concluded that the usability and patient experience of the technology for both patients and the healthcare system are important considerations.\n\n# NHS considerations overview\n\n## Support is needed to help patients to use myCOPD and the health service to implement it\n\nThe company confirmed that myCOPD has been used across health services for self-managing COPD and pulmonary rehabilitation. The clinical experts advised that the health service team, both clinical and non-clinical, plays an important role in keeping people engaged with myCOPD. The commissioning expert stated that their team provided support for people to register and set up the app for self-managing their symptoms. Ongoing support from non-clinical digital support workers is provided at different time points via text messaging, over the phone or by setting up face-to-face appointments to help maintain patient engagement. Similarly, the clinical expert said that people who used myCOPD for pulmonary rehabilitation in their service had a weekly call from the clinical team during the 6‑week pulmonary rehabilitation course to support their progress in the programme. The company also confirmed that digital health advisers have been included as part of a contract to support the implementation of the technology and to ensure that clinical and digital support teams are fully trained.\n\n## Uptake data varies and more should be collected as real-world evidence\n\nThe committee understood that myCOPD uptake data varied widely across services. It acknowledged there are many factors influencing how much it was used, including the COVID‑19 pandemic. The commissioning expert said that real-time uptake data was available from Dorset CCG, where uptake for self-management increased from 43% to 65% in 2021. The committee questioned whether the uptake rates observed in Dorset were likely to be realised in other regions. A clinical expert advised that uptake of myCOPD for pulmonary rehabilitation in their service was around 26% in 2018; however, no recent uptake data was available. The committee agreed that understanding the uptake of myCOPD across different regions and settings, for both self-management and pulmonary rehabilitation, is important to ensure its value for money (see sections\xa03.10 and 3.11). It concluded that this information could easily be collected as real-world evidence.\n\n## myCOPD could have an impact on health inequalities\n\nClinical experts explained that myCOPD has been implemented as an option alongside existing services in their practice. People have the option to choose whether or not to use it depending on preference. The experts noted that the populations in their regions using myCOPD were mainly older white British people living in areas with different levels of socioeconomic deprivation. The company confirmed that the average age of myCOPD users is 74\xa0years old. The commissioning expert said that the implementation of myCOPD improved patients' access to health services in areas of deprivation. The committee also discussed the English language skills needed to use myCOPD. The average reading age needed to use myCOPD is between 8 and 12\xa0years. The clinical experts noted that myCOPD may be difficult to use for people who are not able to use a smart device easily, such as those with a visual or cognitive impairment, limited manual dexterity, or with hearing loss. They added that in their experience, some people with COPD would prefer not to use the digital tool, while others found it helpful. The committee concluded that further evidence of myCOPD's use in a wide range of socioeconomic backgrounds, ethnicities and ages is needed to understand its effect on health inequalities.\n\n# Cost modelling overview\n\n## Uncertainties about the clinical benefits of myCOPD are reflected in the cost modelling\n\nThe committee understood that clinical parameters in the AECOPD model (see section\xa03.7 for details about the models) for self-management were based on RESCUE, a feasibility trial with fewer than 50\xa0patients. It noted that the key drivers of cost saving in this model were the uptake of myCOPD and hospital readmissions, and both parameters were uncertain (see sections\xa03.10 and 3.11). The PR model has 3\xa0treatment options, so people were able to choose myCOPD, face-to-face pulmonary rehabilitation or a hybrid format which consisted of face-to-face sessions and myCOPD. Results from TROOPER were used in the PR model. Key drivers for cost savings in this model were the uptake of myCOPD, both alone and in the hybrid format, and the number of people referred for pulmonary rehabilitation. The committee considered that the key uncertainty for the PR model related to the assumption of non-inferiority of pulmonary rehabilitation services delivered by the myCOPD app compared with face-to-face pulmonary rehabilitation (see section 4.2). It also considered that more information is needed on the uptake rate of myCOPD when it is used for pulmonary rehabilitation (see section 4.5).\n\n# Further research\n\n## Further good quality evidence is needed to address uncertainties about myCOPD's clinical benefits and its effect on healthcare resource use\n\nmyCOPD has potential for clinical benefits, but more evidence is needed to reduce uncertainties. The committee considered that comparative evidence is needed to show the clinical benefits of using myCOPD in 2\xa0populations:\n\npeople using it to self-manage COPD\n\npeople referred to pulmonary rehabilitation.For self-management, a randomised controlled trial is preferred to show the clinical benefits of myCOPD. This could be powered based on the encouraging results in the RESCUE study. However, a high-quality comparative observational study designed to minimise bias in the results may provide acceptable evidence. Outcomes such as rates of exacerbations, hospital readmissions and unscheduled care appointments should be considered alongside patient-reported outcomes such as health-related quality of life. For pulmonary rehabilitation, further evidence is needed to show the clinical benefits of myCOPD. This could be a randomised controlled trial which is powered based on the encouraging results in the TROOPER study or a well-designed comparative observational study. Key outcomes will be the CAT score and 6‑minute walk test, ideally supported by additional longer-term outcomes such as rates of exacerbations and hospital admissions.\n\nReal-world data could be used to inform the uptake rates in the economic modelling. It should also include qualitative data on patient experience using myCOPD such as patient preferences and adherence."}
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https://www.nice.org.uk/guidance/mtg68
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Evidence-based recommendations on myCOPD for managing chronic obstructive pulmonary disease.
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f0c8394ca39d4ee40d2ec9f50c1fa08e628e0a4a
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nice
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UroShield for preventing catheter-associated urinary tract infections
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UroShield for preventing catheter-associated urinary tract infections
Evidence-based recommendations on UroShield for preventing catheter-associated urinary tract infections.
# Recommendations
More research is recommended on UroShield for preventing catheter-associated urinary tract infections (UTIs). It has potential to provide significant patient and healthcare system benefits but uncertainties in the evidence need to be addressed.
Research should be comparative, and it should address uncertainties about the effectiveness of UroShield in preventing catheter-associated UTIs and other catheter-related complaints such as blockages. Find out more in the further research section of this guidance.
Why the committee made these recommendations
Standard care for preventing catheter-associated UTIs includes good hygiene, reviewing the frequency of planned catheter changes, increasing fluid intake, and documenting blockages. UroShield is an add-on to standard care.
The evidence on UroShield is limited but it suggests it may reduce bacteria in the urine (bacteriuria), infections, and catheter-related problems. Most of the studies measured bacteria in the urine. But it is not certain that this is the best way to detect changes in catheter-associated UTIs and the effectiveness of UroShield.
There is strong expert and patient support for UroShield. Patients and clinical experts anecdotally describe fewer infections, catheter blockages, and catheter-related problems when using UroShield. It may especially help people with long-term catheters in the community and may address a significant unmet clinical need.
Cost analyses suggest UroShield may be cost saving in hospital and in people with repeated UTIs or catheter blockages in community care. But because the clinical effectiveness of UroShield is uncertain and the published evidence very limited, the cost savings are also uncertain. More research is therefore recommended.# The technology
# Technology
UroShield is an ultrasound device designed to reduce the risk of catheter-associated urinary tract infection (UTI) by reducing bacterial colonisation and biofilm formation on indwelling urinary catheters. The technology works by generating low-intensity 90 kHz ultrasonic surface acoustic waves, which propagate throughout the catheter's length on its inner and outer lumens. The company claims these acoustic waves prevent bacteria attaching and forming a biofilm, and also reduce friction between the catheter and the person's internal tissues. It claims this reduces the pain, discomfort, and spasm associated with indwelling urinary catheters.
UroShield includes 2 components: a driver, which provides the power, and a single-use actuator, which is clipped to the catheter and generates the ultrasonic waves. UroShield can be used with urethral and suprapubic catheters of any material and size ranging from 12 to 22 French gauge. UroShield is worn continuously. The life expectancy of the driver is 2 years while the actuator, according to the instructions for use, should be replaced every 30 days. If the catheter is replaced within 30 days, the actuator can be removed and reattached to the new catheter. UroShield is a CE‑marked class IIa medical device. UroShield 3.0 is the current version available in the NHS.
# Care pathway
UroShield is an add-on to standard care to prevent catheter-associated UTI. NICE's guideline on healthcare-associated infections says that the risk of blockages, encrustations, and catheter-associated infections in long-term urinary catheters should be minimised through patient-specific regimens. These include reviewing the frequency of planned catheter changes, increasing fluid intake, and documenting catheter blockages. Catheters should be changed only when clinically necessary or according to the manufacturer's recommendations. Urinary catheter tools such as a catheter passport, catheter card, and inpatient care plan are used to allow healthcare professionals to document catheter care and share information between care services.
# Innovative aspects
UroShield generates ultrasonic acoustic waves that produce microvibrations. The company claims this prevents bacteria adhering to the catheter surface. It also claims it may alter the quorum sensing (cell-to-cell communication) of the microbes, which helps to delay and disrupt the formation of a biofilm and its extracellular matrix. These mechanisms are believed to generate the bactericidal effects of the device. The clinical experts all considered UroShield to be novel and innovative.
# Intended use
UroShield is intended to reduce the risk of catheter-associated UTIs in adults with urethral or suprapubic indwelling urinary catheters. It is not intended for use in children. This guidance considers the use of UroShield in hospital and community care. UroShield is not MRI compatible and should be removed from the catheter before entering an MRI suite. It is not intended as a treatment for an active UTI.
# Costs
The costs of UroShield are £349 for the driver and £50 per actuator (excluding VAT).For more details, see the website for UroShield.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The clinical evidence comprises 8 studies, including 1 peer-reviewed randomised controlled trial
Eight studies were relevant to the decision problem in the scope:
randomised controlled trial (Markowitz et al. 2018)
before-and-after study (da Silva et al. 2021)
case series (Turan et al. 2012)
company reports (Zalut 2007, which is an unpublished case series, and Zillich et al. 2014, which is a non-peer-reviewed randomised study)
conference abstracts or posters (Ikinger et al.'s 2007 randomised controlled trial, Nagy et al.'s 2011 comparative study)
clinical trial report (Shenfeld and Haris's 2010 unpublished randomised controlled trial).
Of these, 3 studies were peer reviewed (da Silva et al. 2021, Markowitz et al. 2018, Turan et al. 2012) and only 1 study was done in the UK (da Silva et al. 2021).
## The evidence base is heterogenous in population and duration of use
Patient populations varied across studies. The clinical evidence included 4 studies on short-term (28 days or fewer) catheterisation (Ikinger et al. 2007, Shenfeld and Haris 2010, Zalut 2007, Zillich et al. 2014), 3 studies on long-term (more than 28 days) catheterisation (da Silva et al. 2021, Markowitz et al. 2018, Nagy et al. 2011), and 1 study of unknown duration (Turan et al. 2012).
The studies' treatment setting varied. Three studies evaluated use in the community (da Silva et al. 2021, Markowitz et al. 2018, Zalut 2007), while 2 studies were based in hospital (Shenfeld and Haris 2010, Turan et al. 2012). The treatment setting was not clearly reported in 3 studies (Ikinger et al. 2007, Nagy et al. 2011, Zillich et al. 2014).For full details of the clinical evidence, see section 4 of the assessment report.
## The evidence base for UroShield is limited in quantity and quality
The EAC formally appraised only 2 studies (da Silva et al. 2021, Markowitz et al. 2018) because the remaining studies lacked details about study design and methods. It assessed Markowitz et al. (2018) as having an overall low risk of bias. But the study had a small sample size and statistical multiplicity in the data analysis, which may have increased the risk of a type 1 error. The EAC said da Silva et al. (2021) reported limited detail of participants and study methods. It considered that the evidence for the benefit of UroShield in people with short-term catheters is very limited and cannot be used to definitively support any clinical benefit at this time.
## Evidence suggests that UroShield may significantly reduce bacteriuria
Three studies showed that using UroShield resulted in significantly less bacteriuria than comparators (Markowitz et al. 2018, Nagy et al. 2011, Zillich et al. 2014). But 2 studies reported no statistically significant difference (Ikinger et al. 2007, Shenfeld and Haris 2010). The most significant improvement was in people with long-term indwelling urinary catheters.
The company did a fixed effects meta-analysis of 4 studies to estimate the effect of UroShield on bacteriuria (Markowitz et al. 2018, Nagy et al. 2011, Shenfeld and Haris 2010, Zillich et al. 2014). The risk ratio for bacteriuria was 0.25 (95% confidence interval 0.11 to 0.57) in favour of UroShield, indicating a potential 75% reduction in bacteriuria with UroShield compared with comparators. The EAC reran the meta-analysis using both a fixed effects and random effects approach and got similar results to the company (fixed effects: risk ratio 0.27, 95% confident interval 0.12 to 0.57; random effects: risk ratio 0.34, 95% confidence interval 0.17 to 0.71).
## Evidence suggests long-term use of UroShield may reduce UTI
Three studies reported urinary tract infection (UTI) as an outcome. People using UroShield had fewer new UTIs requiring antibiotics than those using the sham devices (Markowitz et al. 2018) and had fewer UTIs after approximately 12 weeks of use compared with baseline (da Silva et al. 2021). Nagy et al. (2011) found no symptomatic UTIs in either treatment arm.
## Evidence suggests UroShield may reduce catheter-related complaints and improve quality of life
Da Silva et al. (2021) found significantly fewer catheter blockages and unplanned catheter changes after long-term use of UroShield. Five studies also reported improvements in patient-reported complaints with UroShield compared with baseline or comparators. These included lower levels of pain, discomfort, spasm, and itching and burning. Da Silva et al. (2021) and a patient survey reported that UroShield is easy to use and associated with positive outcomes, including fewer catheter-associated UTIs, more time between catheter changes, and improved quality of life.
# Cost evidence
## The company's cost model shows UroShield to be cost saving in all hospital settings and in community patients with recurrent UTI
The company submitted 2 simple decision tree models, which compared the costs and health outcomes associated with using UroShield as an addition to standard care in hospital and community settings. The settings and populations considered were:
all hospital patients
hospital patients with short-term catheterisation (28 days or less)
hospital patients with long-term catheterisation (more than 28 days)
patients in the intensive care unit (ICU)
all community patients
community patients with a recurrent UTI.Hospital settings had a time horizon of the duration of catheterisation or the duration of treatment for catheter-associated UTI. Community settings were presented as a rolling 30‑day model with the same costs and benefits every 30 days. The company's base case showed UroShield saved £1.65 to £42.05 per person in hospital and £7.77 per person in community patients with recurrent UTI. The company model found UroShield incurred costs of £39.95 per person in the all-community patients population. This was because of the low cost of treating community-based catheter-associated UTIs and the relatively low base rate of infection.For full details of the cost evidence, see section 9 of the assessment report.
## The EAC accepted the assumptions in the company's model and identified additional assumptions
The company included several assumptions in its model, which are outlined in table 11 of the assessment report. The EAC accepted these assumptions but changed driver use from 100% to 80% because it considered it unlikely that it would be used every day in its lifespan. The EAC also identified and accepted additional assumptions in the model. This included the key assumption that the reduction in significant bacteriuria in the meta-analysis can be extrapolated to symptomatic catheter-associated UTIs requiring treatment. The models also assume that the definition of 'recurrent' UTIs in community patients can be applied to catheter-associated UTI.
## The EAC amended the risk of catheter-associated bloodstream infection and the rate of failure of first-line treatment in the community
The EAC agreed with most of the values of clinical parameters used in the company's model. It amended the risk that catheter-associated UTIs would progress to a catheter-associated bloodstream infection (CABSI) to 6.6% from the 4.8% used by the company. The EAC also changed the proportion of infections in the community that do not respond to first-line treatment to 14%.
## The EAC updated costs for treating catheter-associated UTIs in community and hospital settings
The average cost of treating catheter-associated UTIs in the community was £386.72 in the company's model. The EAC amended this to £453.54 to account for treatment failures and CABSI. In the hospital model, the EAC updated the cost of a bed day in the ICU to the 2019 to 2020 reference costs (£1,620). The mean cost per catheter-associated UTI was calculated from the cost per catheter-associated UTI per patient, plus the cost of CABSIs for the proportion of patients who have them. The company calculated the mean cost per catheter-associated UTI in hospital as £2,131 and in the ICU as £2,964. The EAC calculated these values as £2,192 and £4,436, respectively.
## The EAC's changes to the model did not change UroShield from cost saving or cost incurring in any population
The EAC's base case showed UroShield to save between £2.40 and £70.13 per person in hospital, and £16.63 per person in community patients with recurrent UTI. UroShield continued to be cost incurring by £39.34 in the all-community patients population. The greatest difference to the company's model was in the ICU, with the EAC's model finding UroShield was £40.64 more cost saving than the company's base case.
## The effectiveness of UroShield and the risk of catheter-associated UTIs are the key cost drivers
The company submitted a one-way sensitivity analysis that varied parameters by the ranges taken from the source evidence or by 25% less than or 25% more than the base values. Its results suggested that the effectiveness of UroShield is the key cost driver in all models. The EAC also did one-way and two-way sensitivity analyses in all 6 populations. For hospital settings, the parameters with the largest impact on cost savings were the effectiveness of UroShield, the rate of catheter-associated UTI, and the cost of treating them. Changes in any of these parameters could convert the base case to cost incurring in populations with small cost savings (all-hospital and short-term use). For the all-community population, only a risk of catheter-associated UTIs greater than 25% (compared with a base rate of 8.5%) independently converts the base case to cost saving. The EAC noted that these rates may occur in nursing homes. In the recurrent UTI community group, UroShield's effectiveness is the only parameter that can independently convert the base case to cost incurring.
## The reduction in catheter blockages independent of catheter-associated UTIs may reduce the costs of using UroShield in community settings
The EAC did an additional two-way sensitivity analysis (see the assessment report addendum on blockages and bacteriuria threshold), altering the risk of catheter-associated UTIs and the risk of catheter blockage. This was done to explore how reducing catheter blockages independent of catheter-associated UTIs may affect the base case. The EAC assumed an equivalent effectiveness for UroShield on blockages and catheter-associated UTI (as suggested by da Silva et al. 2021). Based on this, the risk of blockage at which the base case for UroShield becomes cost-neutral is 1.87 blockages per patient per 30 days. For patients at high risk of catheter-associated UTI, UroShield is always cost saving. UroShield was also found to be cost saving for people who do not get catheter-associated UTIs but who have more than 3 blockages per 30 days that require a catheter change.
## Increasing staff time for catheter changes does not change whether UroShield is cost saving or incurring in community settings
The EAC explored the effect of increased nursing time for unscheduled visits on the cost modelling for the community populations. Results showed that if nurse visit time was increased to 45 minutes, as suggested by the experts, the cost savings increased in the population in the community with recurrent infections. UroShield continued to be cost incurring in the all-community population. Further details and the results of a threshold analysis are in the assessment report addendum on increased staff time for catheter change.# Committee discussion
# Unmet need
## UroShield is potentially life changing and could address an important unmet need among people with long-term catheters in the community
The patient expert and patient survey comments described UroShield as simple and easy to use. The patient expert reported several benefits from using UroShield in the past 3 years. These included a significant reduction in urinary tract infections (UTIs) and no catheter blockages. They liked that UroShield was not a drug and said that since using the device they no longer needed to take prophylactic antibiotics. The committee heard during consultation several comments strongly supporting these patient benefits. UroShield was described by the patient expert, patient survey, and several consultees as life changing and transformational. The committee heard how recurrent UTIs can have a devastating impact on a person's quality of life. It considered that preventing catheter-associated UTIs and blockages is a significant unmet need, especially in people in the community with long-term catheters. It concluded that UroShield showed promise in addressing this unmet need and strongly encouraged further research in this patient population.
# Clinical-effectiveness overview
## The evidence shows that UroShield may reduce bacteriuria, infection, and catheter-related complaints but there are considerable uncertainties
The committee considered that the clinical evidence showed that UroShield had promise for reducing bacteriuria, infection, and catheter-related complaints including blockages. However, it considered that the limited clinical evidence raised uncertainties about the effectiveness of UroShield in preventing catheter-associated UTIs. The 2 key studies (da Silva et al. 2021, Markowitz et al. 2018) had methodological concerns. While Markowitz et al. (2018) was a double-blinded randomised controlled trial, it was limited by a small sample size (n=55), risk of multiplicity in the data analysis, and its reporting of significant improvement in bacterial load to a threshold of 100,000 colony forming units (CFU). The committee also noted the limitations of the study by da Silva et al. (2021), such as the small sample size (n=23), and the uncontrolled before-and-after study design. This meant it could not control for other potential changes to standard care with the introduction of UroShield, such as increased catheter care and attention.
## More information is needed about whether UroShield's effect is maintained after people stop using it
Markowitz et al. (2018) reported continued positive effects of UroShield on bacterial load and the number of new UTIs requiring antibiotics for up to 60 days after stopping its use. The committee considered that this prolonged effect did not align with the instructions for use, which specify that the device should be used continuously. The company said that, while it advised continuous use of the device for optimal effects, real-world use may differ. It reported that laboratory testing suggested it took some time for bacteria to re-establish on catheters after people stopped using UroShield. The company attributed this prolonged effect to changes in the quorum sensing (cell-to-cell communication) of the bacteria. The committee considered that more information into the prolonged effect of UroShield would be valuable and may help patients better understand how to use the device effectively.
# Outcome measures
## There is uncertainty about using bacteriuria as a proxy outcome for catheter-associated UTI
Bacteriuria was the most reported outcome in the clinical evidence. The clinical experts said that bacteria are the root cause of both catheter-associated UTI and blockages. But they advised that bacteriuria only indicates the presence of bacteria in the urine and not catheter-associated UTI, and it may not cause symptoms in everyone. The committee recognised that bacteriuria is easy to measure but considered that the presence of a catheter-associated UTI is a more reliable outcome. It acknowledged that symptoms from other health conditions may present similarly to the symptoms of a UTI. Therefore, for the purposes of further research on UroShield, the committee considered a pragmatic definition of catheter-associated UTI would be a reasonable choice to reflect how it is captured in clinical practice, that is, clinical judgement of UTI symptoms, visual inspection of urine, and microbiological inspection of bacteriuria.
## More evidence is needed on the effect of UroShield on catheter blockages independent of catheter-associated UTI
The committee heard during consultation and from the clinical experts that catheter blockages are a major source of patient complaints and unscheduled healthcare visits, which may affect around 33% to 50% of people with long-term catheters. Catheters can become blocked with or without an associated UTI. The committee recognised that the patient and clinical experts and several consultees strongly supported using UroShield to prevent or reduce catheter blockages. It considered that UroShield had the potential to address an important unmet need and that its use could result in cost savings associated with a reduction in blockages. But there is little clinical evidence on the effect of UroShield on blockages, with only 1 study (da Silva et al. 2021) reporting catheter blockages as an outcome. The committee therefore considered that more evidence was needed on the effectiveness of UroShield in preventing catheter blockages independent of catheter-associated UTI.
# Other patient benefits or issues
## The main challenge to using UroShield is its short battery life
The main challenge reported by the patient expert and patient survey was UroShield's battery life, which lasts around 6 to 7 hours. The patient expert said that they charged it overnight from the mains electricity. They also recharged the device during the day as needed using either the mains electricity or a rechargeable battery pack they had bought themselves. The company said that it was planning to improve battery life.
## Many people report benefits from using UroShield, but it may not be appropriate for everyone
The evidence and comments from the patient and clinical experts and several consultees showed that most people have positive experiences of using UroShield. But the device may not suit everyone. Some people may have difficulty handling the device, for example people with neurological conditions that affect manual dexterity. Some people may also find the hum emitted from the device annoying. The patient expert said that this low-level hum is less noticeable with time. The company said that the hum may reassure people that the device is still working, and believed it is hardly noticeable once the device is worn under clothes. The committee accepted that patient preferences and their capacity to manage the device are important considerations.
# Relevance to the NHS
## The evidence is broadly generalisable to NHS practice
The evidence on UroShield included people with short- and long-term catheterisation in hospital and community care. Only 1 study was in the UK (da Silva et al. 2021). The clinical experts said that the evidence was broadly generalisable to the NHS but noted a few differences in practice, such as the frequency of catheter changes. The company said that the instructions for use recommend the actuator is changed every 30 days to align with practice in the US. The patient expert noted that their catheter and actuator are changed every 6 weeks. The company said that it is continuing work on the technology to make it more country specific. The committee considered that more evidence for using UroShield in addition to standard care in the NHS was needed.
# NHS considerations overview
## UroShield may most benefit people who need a long-term catheter in community care
The clinical experts said that people in long-term care in the community who have a long-term catheter have the highest rates of catheter-associated UTIs and catheter blockages. They said that UroShield would most benefit people with a high risk of catheter-associated UTI. Some factors related to increased risk of catheter-associated UTIs were:
long-term catheterisation
genetic predisposition to UTI
history of catheterisation or UTI
comorbidities such as neurogenic bladder, diabetes, and multiple sclerosis
female sex.Also, UTIs are a noted cause of morbidity and antibiotic use in older people. The clinical experts advised that catheter-associated UTI may present differently in elderly people and may be associated with confusion. This can affect the presentation and self-reporting of UTIs, so additional steps to prevent morbidity are especially important. The clinical and patient experts believed people with recurrent UTIs would be highly motivated to use UroShield. From comments during consultation, the committee recognised that UroShield may be most appropriate for people with a long-term catheter who have frequent infections or blockages. The clinical experts advised that these people cannot be identified in advance. But they said structured protocols could be developed by community teams to identify appropriate patients who are already experiencing frequent infections or blockages. The committee considered this approach may be reasonable to guide patient selection.
## UroShield is not widely used in the NHS so healthcare professionals and patients may need support
UroShield has only been used by about 80 patients in the NHS. The clinical experts said that patient education and counselling is important to understand how to wear and use the device. This may be especially important for people who use it outside their home. Healthcare professionals may also need training because most would be unfamiliar with the technology. Training and support are available through the company, including online training sessions, a specialist nurse adviser, and a helpdesk team.
# Side effects and adverse events
## Evidence shows UroShield is safe to use
The evidence did not identify any device-related adverse events. Clinical and patient experts, and the patient survey, did not attribute any adverse events to UroShield. The committee noted that some patients could use UroShield for years and it considered that real-world evidence on using UroShield for longer periods would be valuable.
# Cost modelling
## The meta-analysis data on UroShield's effectiveness is too uncertain to use in the cost modelling
The committee considered that the economic case for UroShield was uncertain because the effectiveness of UroShield relied on the findings of the meta-analysis. The committee had notable concerns with the meta-analysis, including the quantity and quality of the evidence used, the heterogeneity of the studies, and the use of bacteriuria as a proxy for catheter-associated UTIs.
# Cost savings
## UroShield has the potential to be cost saving if it is effective
The committee considered that the results from the cost models suggested that UroShield could be cost saving in hospital, and in the community for people with recurrent infection or blockages. But it noted that this depends on whether it is effective in preventing catheter-associated UTIs or blockages.
# Further research
## Further research is needed on the effectiveness of UroShield
The committee concluded that more research is needed on the effectiveness of UroShield in preventing catheter-associated UTIs and blockages. There is an ongoing non-comparative study by the University of Southampton (National Institute for Health Research clinical research network portfolio CPMS ID 48290) in 30 people with long-term catheters in the community who have frequent infection or blockages. The committee considered that while this study may provide additional evidence on patient experiences and the effect of UroShield on the microbiota in the urine, it will not resolve the uncertainties in effectiveness. A randomised controlled trial (at the individual or group level) is considered to be the most robust and efficient design to confirm the promising results of the studies presented. The external assessment centre (EAC) advised that a well-designed before and after study may also be appropriate. The committee considered that the study should be powered to detect statistically significant differences in clinically confirmed catheter-associated UTIs (see section 4.4). Secondary outcomes of interest should include catheter blockages and bacteriuria. Patient-reported outcomes and resource utilisation outcomes would also be welcomed.
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{'Recommendations': 'More research is recommended on UroShield for preventing catheter-associated urinary tract infections (UTIs). It has potential to provide significant patient and healthcare system benefits but uncertainties in the evidence need to be addressed.\n\nResearch should be comparative, and it should address uncertainties about the effectiveness of UroShield in preventing catheter-associated UTIs and other catheter-related complaints such as blockages. Find out more in the further research section of this guidance.\n\nWhy the committee made these recommendations\n\nStandard care for preventing catheter-associated UTIs includes good hygiene, reviewing the frequency of planned catheter changes, increasing fluid intake, and documenting blockages. UroShield is an add-on to standard care.\n\nThe evidence on UroShield is limited but it suggests it may reduce bacteria in the urine (bacteriuria), infections, and catheter-related problems. Most of the studies measured bacteria in the urine. But it is not certain that this is the best way to detect changes in catheter-associated UTIs and the effectiveness of UroShield.\n\nThere is strong expert and patient support for UroShield. Patients and clinical experts anecdotally describe fewer infections, catheter blockages, and catheter-related problems when using UroShield. It may especially help people with long-term catheters in the community and may address a significant unmet clinical need.\n\nCost analyses suggest UroShield may be cost saving in hospital and in people with repeated UTIs or catheter blockages in community care. But because the clinical effectiveness of UroShield is uncertain and the published evidence very limited, the cost savings are also uncertain. More research is therefore recommended.', 'The technology': "# Technology\n\nUroShield is an ultrasound device designed to reduce the risk of catheter-associated urinary tract infection (UTI) by reducing bacterial colonisation and biofilm formation on indwelling urinary catheters. The technology works by generating low-intensity 90\xa0kHz ultrasonic surface acoustic waves, which propagate throughout the catheter's length on its inner and outer lumens. The company claims these acoustic waves prevent bacteria attaching and forming a biofilm, and also reduce friction between the catheter and the person's internal tissues. It claims this reduces the pain, discomfort, and spasm associated with indwelling urinary catheters.\n\nUroShield includes 2\xa0components: a driver, which provides the power, and a single-use actuator, which is clipped to the catheter and generates the ultrasonic waves. UroShield can be used with urethral and suprapubic catheters of any material and size ranging from 12 to 22\xa0French gauge. UroShield is worn continuously. The life expectancy of the driver is 2\xa0years while the actuator, according to the instructions for use, should be replaced every 30\xa0days. If the catheter is replaced within 30\xa0days, the actuator can be removed and reattached to the new catheter. UroShield is a CE‑marked class\xa0IIa medical device. UroShield\xa03.0 is the current version available in the NHS.\n\n# Care pathway\n\nUroShield is an add-on to standard care to prevent catheter-associated UTI. NICE's guideline on healthcare-associated infections says that the risk of blockages, encrustations, and catheter-associated infections in long-term urinary catheters should be minimised through patient-specific regimens. These include reviewing the frequency of planned catheter changes, increasing fluid intake, and documenting catheter blockages. Catheters should be changed only when clinically necessary or according to the manufacturer's recommendations. Urinary catheter tools such as a catheter passport, catheter card, and inpatient care plan are used to allow healthcare professionals to document catheter care and share information between care services.\n\n# Innovative aspects\n\nUroShield generates ultrasonic acoustic waves that produce microvibrations. The company claims this prevents bacteria adhering to the catheter surface. It also claims it may alter the quorum sensing (cell-to-cell communication) of the microbes, which helps to delay and disrupt the formation of a biofilm and its extracellular matrix. These mechanisms are believed to generate the bactericidal effects of the device. The clinical experts all considered UroShield to be novel and innovative.\n\n# Intended use\n\nUroShield is intended to reduce the risk of catheter-associated UTIs in adults with urethral or suprapubic indwelling urinary catheters. It is not intended for use in children. This guidance considers the use of UroShield in hospital and community care. UroShield is not MRI compatible and should be removed from the catheter before entering an MRI suite. It is not intended as a treatment for an active UTI.\n\n# Costs\n\nThe costs of UroShield are £349 for the driver and £50 per actuator (excluding VAT).For more details, see the website for UroShield.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The clinical evidence comprises 8\xa0studies, including 1\xa0peer-reviewed randomised controlled trial\n\nEight studies were relevant to the decision problem in the scope:\n\nrandomised controlled trial (Markowitz et al. 2018)\n\nbefore-and-after study (da\xa0Silva et al. 2021)\n\ncase series (Turan et al. 2012)\n\ncompany reports (Zalut 2007, which is an unpublished case series, and Zillich et al. 2014, which is a non-peer-reviewed randomised study)\n\nconference abstracts or posters (Ikinger et al.'s 2007 randomised controlled trial, Nagy et al.'s 2011 comparative study)\n\nclinical trial report (Shenfeld and Haris's 2010 unpublished randomised controlled trial).\n\nOf these, 3\xa0studies were peer reviewed (da\xa0Silva et al. 2021, Markowitz et al. 2018, Turan et al. 2012) and only 1\xa0study was done in the UK (da\xa0Silva et al. 2021).\n\n## The evidence base is heterogenous in population and duration of use\n\nPatient populations varied across studies. The clinical evidence included 4\xa0studies on short-term (28\xa0days or fewer) catheterisation (Ikinger et al. 2007, Shenfeld and Haris 2010, Zalut 2007, Zillich et al. 2014), 3\xa0studies on long-term (more than 28\xa0days) catheterisation (da\xa0Silva et al. 2021, Markowitz et al. 2018, Nagy et al. 2011), and 1\xa0study of unknown duration (Turan et al. 2012).\n\nThe studies' treatment setting varied. Three studies evaluated use in the community (da\xa0Silva et al. 2021, Markowitz et al. 2018, Zalut 2007), while 2\xa0studies were based in hospital (Shenfeld and Haris 2010, Turan et al. 2012). The treatment setting was not clearly reported in 3\xa0studies (Ikinger et al. 2007, Nagy et al. 2011, Zillich et al. 2014).For full details of the clinical evidence, see section\xa04 of the assessment report.\n\n## The evidence base for UroShield is limited in quantity and quality\n\nThe EAC formally appraised only 2\xa0studies (da\xa0Silva et al. 2021, Markowitz et al. 2018) because the remaining studies lacked details about study design and methods. It assessed Markowitz et al. (2018) as having an overall low risk of bias. But the study had a small sample size and statistical multiplicity in the data analysis, which may have increased the risk of a type\xa01 error. The EAC said da\xa0Silva et al. (2021) reported limited detail of participants and study methods. It considered that the evidence for the benefit of UroShield in people with short-term catheters is very limited and cannot be used to definitively support any clinical benefit at this time.\n\n## Evidence suggests that UroShield may significantly reduce bacteriuria\n\nThree studies showed that using UroShield resulted in significantly less bacteriuria than comparators (Markowitz et al. 2018, Nagy et al. 2011, Zillich et al. 2014). But 2\xa0studies reported no statistically significant difference (Ikinger et al. 2007, Shenfeld and Haris 2010). The most significant improvement was in people with long-term indwelling urinary catheters.\n\nThe company did a fixed effects meta-analysis of 4\xa0studies to estimate the effect of UroShield on bacteriuria (Markowitz et al. 2018, Nagy et al. 2011, Shenfeld and Haris 2010, Zillich et al. 2014). The risk ratio for bacteriuria was 0.25 (95%\xa0confidence interval 0.11 to 0.57) in favour of UroShield, indicating a potential 75% reduction in bacteriuria with UroShield compared with comparators. The EAC reran the meta-analysis using both a fixed effects and random effects approach and got similar results to the company (fixed effects: risk ratio\xa00.27, 95%\xa0confident interval 0.12 to 0.57; random effects: risk ratio\xa00.34, 95%\xa0confidence interval 0.17 to 0.71).\n\n## Evidence suggests long-term use of UroShield may reduce UTI\n\nThree studies reported urinary tract infection (UTI) as an outcome. People using UroShield had fewer new UTIs requiring antibiotics than those using the sham devices (Markowitz et al. 2018) and had fewer UTIs after approximately 12\xa0weeks of use compared with baseline (da\xa0Silva et al. 2021). Nagy et al. (2011) found no symptomatic UTIs in either treatment arm.\n\n## Evidence suggests UroShield may reduce catheter-related complaints and improve quality of life\n\nDa\xa0Silva et al. (2021) found significantly fewer catheter blockages and unplanned catheter changes after long-term use of UroShield. Five studies also reported improvements in patient-reported complaints with UroShield compared with baseline or comparators. These included lower levels of pain, discomfort, spasm, and itching and burning. Da\xa0Silva et al. (2021) and a patient survey reported that UroShield is easy to use and associated with positive outcomes, including fewer catheter-associated UTIs, more time between catheter changes, and improved quality of life.\n\n# Cost evidence\n\n## The company's cost model shows UroShield to be cost saving in all hospital settings and in community patients with recurrent UTI\n\nThe company submitted 2\xa0simple decision tree models, which compared the costs and health outcomes associated with using UroShield as an addition to standard care in hospital and community settings. The settings and populations considered were:\n\nall hospital patients\n\nhospital patients with short-term catheterisation (28\xa0days or less)\n\nhospital patients with long-term catheterisation (more than 28\xa0days)\n\npatients in the intensive care unit (ICU)\n\nall community patients\n\ncommunity patients with a recurrent UTI.Hospital settings had a time horizon of the duration of catheterisation or the duration of treatment for catheter-associated UTI. Community settings were presented as a rolling 30‑day model with the same costs and benefits every 30 days. The company's base case showed UroShield saved £1.65 to £42.05 per person in hospital and £7.77 per person in community patients with recurrent UTI. The company model found UroShield incurred costs of £39.95 per person in the all-community patients population. This was because of the low cost of treating community-based catheter-associated UTIs and the relatively low base rate of infection.For full details of the cost evidence, see section 9 of the assessment report.\n\n## The EAC accepted the assumptions in the company's model and identified additional assumptions\n\nThe company included several assumptions in its model, which are outlined in table\xa011 of the assessment report. The EAC accepted these assumptions but changed driver use from 100% to 80% because it considered it unlikely that it would be used every day in its lifespan. The EAC also identified and accepted additional assumptions in the model. This included the key assumption that the reduction in significant bacteriuria in the meta-analysis can be extrapolated to symptomatic catheter-associated UTIs requiring treatment. The models also assume that the definition of 'recurrent' UTIs in community patients can be applied to catheter-associated UTI.\n\n## The EAC amended the risk of catheter-associated bloodstream infection and the rate of failure of first-line treatment in the community\n\nThe EAC agreed with most of the values of clinical parameters used in the company's model. It amended the risk that catheter-associated UTIs would progress to a catheter-associated bloodstream infection (CABSI) to 6.6% from the 4.8% used by the company. The EAC also changed the proportion of infections in the community that do not respond to first-line treatment to 14%.\n\n## The EAC updated costs for treating catheter-associated UTIs in community and hospital settings\n\nThe average cost of treating catheter-associated UTIs in the community was £386.72 in the company's model. The EAC amended this to £453.54 to account for treatment failures and CABSI. In the hospital model, the EAC updated the cost of a bed day in the ICU to the 2019 to 2020 reference costs (£1,620). The mean cost per catheter-associated UTI was calculated from the cost per catheter-associated UTI per patient, plus the cost of CABSIs for the proportion of patients who have them. The company calculated the mean cost per catheter-associated UTI in hospital as £2,131 and in the ICU as £2,964. The EAC calculated these values as £2,192 and £4,436, respectively.\n\n## The EAC's changes to the model did not change UroShield from cost saving or cost incurring in any population\n\nThe EAC's base case showed UroShield to save between £2.40 and £70.13 per person in hospital, and £16.63 per person in community patients with recurrent UTI. UroShield continued to be cost incurring by £39.34 in the all-community patients population. The greatest difference to the company's model was in the ICU, with the EAC's model finding UroShield was £40.64 more cost saving than the company's base case.\n\n## The effectiveness of UroShield and the risk of catheter-associated UTIs are the key cost drivers\n\nThe company submitted a one-way sensitivity analysis that varied parameters by the ranges taken from the source evidence or by 25% less than or 25% more than the base values. Its results suggested that the effectiveness of UroShield is the key cost driver in all models. The EAC also did one-way and two-way sensitivity analyses in all 6\xa0populations. For hospital settings, the parameters with the largest impact on cost savings were the effectiveness of UroShield, the rate of catheter-associated UTI, and the cost of treating them. Changes in any of these parameters could convert the base case to cost incurring in populations with small cost savings (all-hospital and short-term use). For the all-community population, only a risk of catheter-associated UTIs greater than 25% (compared with a base rate of 8.5%) independently converts the base case to cost saving. The EAC noted that these rates may occur in nursing homes. In the recurrent UTI community group, UroShield's effectiveness is the only parameter that can independently convert the base case to cost incurring.\n\n## The reduction in catheter blockages independent of catheter-associated UTIs may reduce the costs of using UroShield in community settings\n\nThe EAC did an additional two-way sensitivity analysis (see the assessment report addendum on blockages and bacteriuria threshold), altering the risk of catheter-associated UTIs and the risk of catheter blockage. This was done to explore how reducing catheter blockages independent of catheter-associated UTIs may affect the base case. The EAC assumed an equivalent effectiveness for UroShield on blockages and catheter-associated UTI (as suggested by da\xa0Silva et al. 2021). Based on this, the risk of blockage at which the base case for UroShield becomes cost-neutral is 1.87\xa0blockages per patient per 30\xa0days. For patients at high risk of catheter-associated UTI, UroShield is always cost saving. UroShield was also found to be cost saving for people who do not get catheter-associated UTIs but who have more than 3\xa0blockages per 30\xa0days that require a catheter change.\n\n## Increasing staff time for catheter changes does not change whether UroShield is cost saving or incurring in community settings\n\nThe EAC explored the effect of increased nursing time for unscheduled visits on the cost modelling for the community populations. Results showed that if nurse visit time was increased to 45\xa0minutes, as suggested by the experts, the cost savings increased in the population in the community with recurrent infections. UroShield continued to be cost incurring in the all-community population. Further details and the results of a threshold analysis are in the assessment report addendum on increased staff time for catheter change.", 'Committee discussion': "# Unmet need\n\n## UroShield is potentially life changing and could address an important unmet need among people with long-term catheters in the community\n\nThe patient expert and patient survey comments described UroShield as simple and easy to use. The patient expert reported several benefits from using UroShield in the past 3\xa0years. These included a significant reduction in urinary tract infections (UTIs) and no catheter blockages. They liked that UroShield was not a drug and said that since using the device they no longer needed to take prophylactic antibiotics. The committee heard during consultation several comments strongly supporting these patient benefits. UroShield was described by the patient expert, patient survey, and several consultees as life changing and transformational. The committee heard how recurrent UTIs can have a devastating impact on a person's quality of life. It considered that preventing catheter-associated UTIs and blockages is a significant unmet need, especially in people in the community with long-term catheters. It concluded that UroShield showed promise in addressing this unmet need and strongly encouraged further research in this patient population.\n\n# Clinical-effectiveness overview\n\n## The evidence shows that UroShield may reduce bacteriuria, infection, and catheter-related complaints but there are considerable uncertainties\n\nThe committee considered that the clinical evidence showed that UroShield had promise for reducing bacteriuria, infection, and catheter-related complaints including blockages. However, it considered that the limited clinical evidence raised uncertainties about the effectiveness of UroShield in preventing catheter-associated UTIs. The 2\xa0key studies (da\xa0Silva et al. 2021, Markowitz et al. 2018) had methodological concerns. While Markowitz et al. (2018) was a double-blinded randomised controlled trial, it was limited by a small sample size (n=55), risk of multiplicity in the data analysis, and its reporting of significant improvement in bacterial load to a threshold of 100,000\xa0colony forming units (CFU). The committee also noted the limitations of the study by da\xa0Silva et al. (2021), such as the small sample size (n=23), and the uncontrolled before-and-after study design. This meant it could not control for other potential changes to standard care with the introduction of UroShield, such as increased catheter care and attention.\n\n## More information is needed about whether UroShield's effect is maintained after people stop using it\n\nMarkowitz et al. (2018) reported continued positive effects of UroShield on bacterial load and the number of new UTIs requiring antibiotics for up to 60\xa0days after stopping its use. The committee considered that this prolonged effect did not align with the instructions for use, which specify that the device should be used continuously. The company said that, while it advised continuous use of the device for optimal effects, real-world use may differ. It reported that laboratory testing suggested it took some time for bacteria to re-establish on catheters after people stopped using UroShield. The company attributed this prolonged effect to changes in the quorum sensing (cell-to-cell communication) of the bacteria. The committee considered that more information into the prolonged effect of UroShield would be valuable and may help patients better understand how to use the device effectively.\n\n# Outcome measures\n\n## There is uncertainty about using bacteriuria as a proxy outcome for catheter-associated UTI\n\nBacteriuria was the most reported outcome in the clinical evidence. The clinical experts said that bacteria are the root cause of both catheter-associated UTI and blockages. But they advised that bacteriuria only indicates the presence of bacteria in the urine and not catheter-associated UTI, and it may not cause symptoms in everyone. The committee recognised that bacteriuria is easy to measure but considered that the presence of a catheter-associated UTI is a more reliable outcome. It acknowledged that symptoms from other health conditions may present similarly to the symptoms of a UTI. Therefore, for the purposes of further research on UroShield, the committee considered a pragmatic definition of catheter-associated UTI would be a reasonable choice to reflect how it is captured in clinical practice, that is, clinical judgement of UTI symptoms, visual inspection of urine, and microbiological inspection of bacteriuria.\n\n## More evidence is needed on the effect of UroShield on catheter blockages independent of catheter-associated UTI\n\nThe committee heard during consultation and from the clinical experts that catheter blockages are a major source of patient complaints and unscheduled healthcare visits, which may affect around 33% to 50% of people with long-term catheters. Catheters can become blocked with or without an associated UTI. The committee recognised that the patient and clinical experts and several consultees strongly supported using UroShield to prevent or reduce catheter blockages. It considered that UroShield had the potential to address an important unmet need and that its use could result in cost savings associated with a reduction in blockages. But there is little clinical evidence on the effect of UroShield on blockages, with only 1\xa0study (da\xa0Silva et al. 2021) reporting catheter blockages as an outcome. The committee therefore considered that more evidence was needed on the effectiveness of UroShield in preventing catheter blockages independent of catheter-associated UTI.\n\n# Other patient benefits or issues\n\n## The main challenge to using UroShield is its short battery life\n\nThe main challenge reported by the patient expert and patient survey was UroShield's battery life, which lasts around 6 to 7\xa0hours. The patient expert said that they charged it overnight from the mains electricity. They also recharged the device during the day as needed using either the mains electricity or a rechargeable battery pack they had bought themselves. The company said that it was planning to improve battery life.\n\n## Many people report benefits from using UroShield, but it may not be appropriate for everyone\n\nThe evidence and comments from the patient and clinical experts and several consultees showed that most people have positive experiences of using UroShield. But the device may not suit everyone. Some people may have difficulty handling the device, for example people with neurological conditions that affect manual dexterity. Some people may also find the hum emitted from the device annoying. The patient expert said that this low-level hum is less noticeable with time. The company said that the hum may reassure people that the device is still working, and believed it is hardly noticeable once the device is worn under clothes. The committee accepted that patient preferences and their capacity to manage the device are important considerations.\n\n# Relevance to the NHS\n\n## The evidence is broadly generalisable to NHS practice\n\nThe evidence on UroShield included people with short- and long-term catheterisation in hospital and community care. Only 1\xa0study was in the UK (da\xa0Silva et al. 2021). The clinical experts said that the evidence was broadly generalisable to the NHS but noted a few differences in practice, such as the frequency of catheter changes. The company said that the instructions for use recommend the actuator is changed every 30\xa0days to align with practice in the US. The patient expert noted that their catheter and actuator are changed every 6\xa0weeks. The company said that it is continuing work on the technology to make it more country specific. The committee considered that more evidence for using UroShield in addition to standard care in the NHS was needed.\n\n# NHS considerations overview\n\n## UroShield may most benefit people who need a long-term catheter in community care\n\nThe clinical experts said that people in long-term care in the community who have a long-term catheter have the highest rates of catheter-associated UTIs and catheter blockages. They said that UroShield would most benefit people with a high risk of catheter-associated UTI. Some factors related to increased risk of catheter-associated UTIs were:\n\nlong-term catheterisation\n\ngenetic predisposition to UTI\n\nhistory of catheterisation or UTI\n\ncomorbidities such as neurogenic bladder, diabetes, and multiple sclerosis\n\nfemale sex.Also, UTIs are a noted cause of morbidity and antibiotic use in older people. The clinical experts advised that catheter-associated UTI may present differently in elderly people and may be associated with confusion. This can affect the presentation and self-reporting of UTIs, so additional steps to prevent morbidity are especially important. The clinical and patient experts believed people with recurrent UTIs would be highly motivated to use UroShield. From comments during consultation, the committee recognised that UroShield may be most appropriate for people with a long-term catheter who have frequent infections or blockages. The clinical experts advised that these people cannot be identified in advance. But they said structured protocols could be developed by community teams to identify appropriate patients who are already experiencing frequent infections or blockages. The committee considered this approach may be reasonable to guide patient selection.\n\n## UroShield is not widely used in the NHS so healthcare professionals and patients may need support\n\nUroShield has only been used by about 80\xa0patients in the NHS. The clinical experts said that patient education and counselling is important to understand how to wear and use the device. This may be especially important for people who use it outside their home. Healthcare professionals may also need training because most would be unfamiliar with the technology. Training and support are available through the company, including online training sessions, a specialist nurse adviser, and a helpdesk team.\n\n# Side effects and adverse events\n\n## Evidence shows UroShield is safe to use\n\nThe evidence did not identify any device-related adverse events. Clinical and patient experts, and the patient survey, did not attribute any adverse events to UroShield. The committee noted that some patients could use UroShield for years and it considered that real-world evidence on using UroShield for longer periods would be valuable.\n\n# Cost modelling\n\n## The meta-analysis data on UroShield's effectiveness is too uncertain to use in the cost modelling\n\nThe committee considered that the economic case for UroShield was uncertain because the effectiveness of UroShield relied on the findings of the meta-analysis. The committee had notable concerns with the meta-analysis, including the quantity and quality of the evidence used, the heterogeneity of the studies, and the use of bacteriuria as a proxy for catheter-associated UTIs.\n\n# Cost savings\n\n## UroShield has the potential to be cost saving if it is effective\n\nThe committee considered that the results from the cost models suggested that UroShield could be cost saving in hospital, and in the community for people with recurrent infection or blockages. But it noted that this depends on whether it is effective in preventing catheter-associated UTIs or blockages.\n\n# Further research\n\n## Further research is needed on the effectiveness of UroShield\n\nThe committee concluded that more research is needed on the effectiveness of UroShield in preventing catheter-associated UTIs and blockages. There is an ongoing non-comparative study by the University of Southampton (National Institute for Health Research clinical research network [NIHR CRN] portfolio CPMS\xa0ID\xa048290) in 30\xa0people with long-term catheters in the community who have frequent infection or blockages. The committee considered that while this study may provide additional evidence on patient experiences and the effect of UroShield on the microbiota in the urine, it will not resolve the uncertainties in effectiveness. A randomised controlled trial (at the individual or group level) is considered to be the most robust and efficient design to confirm the promising results of the studies presented. The external assessment centre (EAC) advised that a well-designed before and after study may also be appropriate. The committee considered that the study should be powered to detect statistically significant differences in clinically confirmed catheter-associated UTIs (see section\xa04.4). Secondary outcomes of interest should include catheter blockages and bacteriuria. Patient-reported outcomes and resource utilisation outcomes would also be welcomed."}
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https://www.nice.org.uk/guidance/mtg69
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Evidence-based recommendations on UroShield for preventing catheter-associated urinary tract infections.
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e31aa398d647d505087f0bf43c30c7d0601368f9
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nice
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Sotorasib for previously treated KRAS G12C mutation-positive advanced non-small-cell lung cancer
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Sotorasib for previously treated KRAS G12C mutation-positive advanced non-small-cell lung cancer
Evidence-based recommendations on sotorasib (Lumykras) for previously treated KRAS G12C mutation-positive locally advanced or metastatic non-small-cell lung cancer in adults.
# Recommendations
Sotorasib is recommended for use within the Cancer Drugs Fund as an option for treating KRAS G12C mutation-positive locally advanced or metastatic non-small-cell lung cancer in adults whose disease has progressed on, or who cannot tolerate, platinum-based chemotherapy or anti-PD-1/PD-L1 immunotherapy. It is recommended only if the conditions in the managed access agreement for sotorasib are followed.
This recommendation is not intended to affect treatment with sotorasib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for previously treated KRAS G12C mutation-positive, locally advanced or metastatic non-small-cell lung cancer includes docetaxel or docetaxel plus nintedanib. Sotorasib is a targeted treatment for the KRAS G12C mutation.
Sotorasib has only been indirectly compared with current treatment. The results suggest that, after platinum-based chemotherapy, sotorasib increases the time before the cancer gets worse and how long people live compared with current treatment.
Sotorasib likely meets NICE's criteria to be a life-extending treatment at the end of life. But there is uncertainty in the clinical evidence. Sotorasib has the potential to be cost effective, but more evidence is needed to address the uncertainties before it can be recommended for routine use.
The evidence on sotorasib is promising. But, more data is being collected from the primary clinical trial and from an ongoing randomised controlled trial comparing sotorasib with docetaxel. Collecting additional data through the Cancer Drugs Fund may resolve some uncertainty in the clinical evidence. So, sotorasib is recommended for use in the Cancer Drugs Fund.# Information about sotorasib
# Anticipated marketing authorisation indication
Sotorasib (Lumykras, Amgen) is indicated 'as monotherapy for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small-cell lung cancer (NSCLC), who have progressed on, or are intolerant to, platinum-based chemotherapy and/or anti‑PD‑1/PD‑L1 immunotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for sotorasib.
# Price
The anticipated list price of sotorasib is £6,907.35 for a 30‑day supply of 240 tablets, each containing 120 mg (excluding VAT, company submission). The company has a commercial arrangement (managed access agreement including a commercial access agreement). This makes sotorasib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Amgen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## There is a high unmet need for targeted treatments for KRAS G12C mutation-positive locally advanced or metastatic NSCLC
The KRAS oncogene is the most commonly mutated gene in lung cancer. The KRAS G12C mutation is the most common and occurs in 12% of non-small-cell lung cancer (NSCLC) tumours in the UK. This mutation is more common in non-squamous NSCLC and does not usually occur with other known mutations such as EGFR, ALK and ROS‑1. These other known mutations may have targeted treatments available but there is currently no targeted treatment for the KRAS G12C mutation. People with KRAS G12C mutation-positive locally advanced or metastatic NSCLC usually have chemotherapy, a non-targeted treatment associated with adverse effects that affect health-related quality of life. The clinical expert highlighted that people with KRAS G12C mutation-positive NSCLC have a poor prognosis. The clinical and patient experts noted that there is an unmet need for effective and tolerable treatments in this population. They also highlighted that the lack of targeted treatment options can have a psychological impact. This condition is associated with difficult-to-treat symptoms, and the patient expert submission emphasised the psychological impact of these on patients and their carers. The clinical and patient experts stated that a targeted treatment for the KRAS G12C mutation in NSCLC would be welcomed. The committee concluded that there is an unmet need for targeted treatments for KRAS G12C mutation-positive locally advanced or metastatic NSCLC, and that these would have physical and psychological benefits.
# Treatment pathway
## Sotorasib is positioned after platinum-based chemotherapy, so docetaxel and docetaxel plus nintedanib are relevant comparators
The clinical experts explained that most people with untreated locally advanced or metastatic NSCLC would be offered immunotherapy with chemotherapy. Treatment with docetaxel or docetaxel plus nintedanib may be offered if the disease progresses. The clinical lead for the Cancer Drugs Fund highlighted that of all people with untreated locally advanced or metastatic NSCLC who have immunotherapy, about 40% have immunotherapy alone rather than with chemotherapy. In this population, platinum-doublet chemotherapy would be offered at disease progression, or through a clinical trial, before docetaxel or docetaxel plus nintedanib is considered. In its submission, the company chose to only compare sotorasib with docetaxel and docetaxel plus nintedanib. No evidence was provided to compare sotorasib with platinum-doublet chemotherapy. The company explained that 90% of people in the CodeBreaK100 trial (see section 3.3) had previously had platinum-doublet chemotherapy. Also, a retrospective UK analysis supported that most people who recently had docetaxel had likely had previous immunotherapy and platinum-doublet chemotherapy. The company stated that sotorasib is positioned in the treatment pathway after platinum-based chemotherapy. The clinical expert explained that platinum-doublet chemotherapy, either with or without immunotherapy, is usually the main treatment choice. The committee concluded that sotorasib is positioned after platinum-based chemotherapy, therefore docetaxel monotherapy and docetaxel plus nintedanib are the relevant comparators.
# Clinical evidence
## The clinical evidence for sotorasib is from CodeBreaK100, a phase 2, single-arm trial
The clinical effectiveness evidence for sotorasib is from the CodeBreaK100 trial. This is a phase 2, single-arm, multicentre, open label trial in 250 adults with KRAS G12C mutation-positive advanced tumours; 126 participants had NSCLC. People in the trial previously had 1 (43%), 2 (35%) or 3 lines (22%) of anticancer therapy, measurable disease per RECIST 1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Most people (90%) had previously had platinum-doublet chemotherapy (see section 3.2). People took 960 mg sotorasib (8 tablets of 120 mg) once a day until disease progression, treatment discontinuation or the end of the study. The primary outcome of the trial was an objective response rate of 37.1% (95% confidence interval 28.6 to 46.2), with the latest data-cut from March 2021. A pre-specified clinical significance benchmark of the lower bound of the 95% confidence interval excluding 23% was determined. The objective response rate was calculated as the sum of complete response (3.2%) and partial response (33.9%). This was assessed by a blinded independent central review per RECIST 1.1 criteria. The company noted that CodeBreaK100 was not specifically powered for overall and progression-free survival outcomes, but it was powered for the primary outcome. The committee acknowledged that the clinical evidence from the CodeBreaK100 trial is relevant.
# Indirect treatment comparison
## An indirect comparison is appropriate because there are no head-to-head trials with comparator treatments, but this increases uncertainty
There were no direct comparative data and no common trial arms for anchored indirect treatment comparisons or network meta-analyses. Therefore, the company used an unanchored indirect treatment comparison (as recommended in the NICE Decision Support Unit Technical Support Document 18) for sotorasib versus docetaxel and sotorasib versus docetaxel plus nintedanib. A matching-adjusted indirect comparison (MAIC) was used for the primary analysis of sotorasib versus docetaxel. Results from CodeBreaK100 were used for sotorasib. Results from SELECT‑1, a randomised controlled trial comparing selumetinib plus docetaxel with docetaxel alone, were used for docetaxel. For the secondary analysis of sotorasib versus docetaxel plus nintedanib, the company regarded an MAIC as unfeasible. Therefore, a piecewise approach to hazard ratio estimates applied to the docetaxel arm of SELECT‑1 was done using results from LUME-Lung 1, a randomised controlled trial comparing docetaxel with docetaxel plus nintedanib. A supplementary analysis of sotorasib versus docetaxel was also done using a propensity score weighting analysis (PSWA) approach, using data from CodeBreaK100 for sotorasib and the chemotherapy arm of the Amgen Flatiron Health real-world evidence study. The committee concluded that an indirect treatment comparison is appropriate because there are no head-to-head trials, but noted there were several issues with the comparisons that introduced considerable uncertainty.
## Sotorasib increases overall and progression-free survival compared with docetaxel and docetaxel plus nintedanib in the indirect comparison
The indirect treatment comparison showed that sotorasib is statistically superior in overall and progression-free survival compared with docetaxel. This was based on the latest March 2021 data-cut of the CodeBreaK100 trial (the exact results are confidential and cannot be reported here). The supplementary analysis supported these results. For the secondary analysis, the estimation of survival was implemented in the model and extrapolated over the time horizon. This showed a mean gain in overall and progression-free survival for sotorasib compared with docetaxel plus nintedanib (the exact results are confidential and cannot be reported here). The committee concluded that the indirect treatment comparisons show a survival benefit with sotorasib compared with docetaxel and docetaxel plus nintedanib.
## The unanchored MAIC using SELECT-1 data is appropriate for decision-making but has substantial uncertainty
The company chose 4 covariates in the primary MAIC analysis for matching: ECOG performance score, mean age, metastatic disease at baseline and smoking status. These covariates were all perfectly matched to SELECT‑1 (the exact results are confidential and cannot be reported here). Some covariates identified as 'very important' by clinical experts were excluded from matching by the company because of missing data or trial differences. The ERG noted that excluding brain metastases affected prognosis identified by subgroup analysis. The company mentioned that active brain metastasis was excluded from the trials. The proportion of people with brain metastases was higher in CodeBreaK100 than in LUME‑Lung 1. The company stated that if the proportion of inactive brain metastases in SELECT-1 was similar to CodeBreaK100, any bias would favour the docetaxel arm and result in conservative results. The ERG highlighted that an analysis including KRAS mutation status would be informative. But, it acknowledged the company's reasoning that overall survival and progression-free survival are similar in the absence of targeted therapies in the overall KRAS and KRAS G12C-specific population. However, it explained that it could have been possible to select KRAS G12C mutation data from SELECT‑1 data. The ERG considered that the company's supplementary analysis using a PSWA may be less biased than the MAIC. It explained that the Amgen Flatiron Health real-world evidence data was adjusted to make it more comparable to the CodeBreaK100 population, and that there was little difference in the effective sample size compared with the MAIC. It also noted that the PSWA was adjusted for 13 covariates including brain metastases. However, the ERG highlighted that there remains considerable uncertainty in this approach. It noted that a PSWA limited to docetaxel-only data from the Flatiron study would have been informative. The committee agreed that using SELECT‑1 instead of LUME‑Lung 1 for the unanchored MAIC was appropriate. This is because the trial population was more comparable to CodeBreaK100, and it is also a more recent trial. The committee recognised that there are substantial uncertainties with this approach, but concluded that the primary analysis using SELECT‑1 for the MAIC is appropriate for decision-making.
## Docetaxel plus nintedanib modelling is uncertain, and applying a hazard ratio of 1 between 0 and 6 months is appropriate
In the secondary indirect treatment comparison of sotorasib versus docetaxel plus nintedanib, the ERG highlighted uncertainties in the modelling. The company modelled docetaxel and nintedanib in line with NICE's technology appraisal on nintedanib for previously treated locally advanced, metastatic, or locally recurrent non-small-cell lung cancer. This was because a company-sourced UK advisory board confirmed that a MAIC was 'unlikely to be appropriate'. The ERG highlighted the uncertainty with not applying adjustments to ECOG, WHO or smoking status when these differed in SELECT‑1 and LUME‑Lung 1. It also mentioned that the model's overall survival curve was not in line with the Kaplan–Meier curve in LUME‑Lung 1, with an unlikely major increase in mortality in the first 6 months. That is, the modelling implied a worse survival for docetaxel plus nintedanib compared with docetaxel alone. The Kaplan–Meier curve showed a slight benefit of docetaxel compared with docetaxel plus nintedanib in the first 4 months, which then transformed into a greater than 1 year survival benefit for docetaxel in the modelled overall survival curves. The clinical expert mentioned that in clinical practice, docetaxel is not expected to be better than docetaxel plus nintedanib in the first 6 months. The clinical expert also highlighted that nintedanib has greater toxicity so more people may stop treatment earlier, but added that this is unlikely to be a major driver. The company suggested a possible explanation of the curve could be that nintedanib is anti-angiogenic, so it prevents the formation of blood vessels that support tumour growth. Therefore, it can take more time to have an effect and possibly explain the delay in survival. In addition, the ERG suggested using 1 cut-off point at 6 months rather than 2 at 6 and 26 months because this did not show a good fit. Therefore, the ERG preferred a hazard ratio of 1 between 0 to 6 months. The company disagreed with invalidating LUME‑Lung-1, a 2‑arm phase 3 trial. The committee highlighted the importance of face validity and concluded that there are uncertainties in the docetaxel plus nintedanib modelling, and that a hazard ratio of 1 between 0 and 6 months is appropriate.
# Assumptions in the economic model
## Treatment effect waning at 3 and 5 years from the start of treatment are plausible
The company did not apply treatment effect waning because it considered the impact of discontinuation on overall and progression-free survival to be implemented into the hazard function, and therefore, survival estimates. From the CodeBreaK100 March 2021 data-cut, 81.7% of people had discontinued treatment, about 40% were alive and about 20% had not yet progressed. The company stated that half the people who were alive will have kept taking sotorasib at that point. Because sotorasib is taken until progression or unacceptable toxicity in CodeBreaK100, applying treatment effect waning could lead to biased cost-effectiveness estimates. The clinical expert suggested that it was difficult to know how the treatment effect waning should be applied for sotorasib. However, they suggested that sotorasib should be considered in a similar way to other oral treatments for NSCLC. The clinical lead for the Cancer Drugs Fund referred to an example of oral tyrosine kinase inhibitors showing high response rates. They noted that the disease can progress and people remain relatively well for some time before having symptoms. The clinical expert agreed with this. The company highlighted that sotorasib is not a tyrosine kinase inhibitor and that its mechanism of action and response rate would be different. The ERG disagreed with the company's assumption that sotorasib would have a continued benefit and highlighted that the evidence is still immature. In its base case, the ERG preferred to apply treatment effect waning at 2 years and gradually decrease the hazard ratio to 1 over 5 years. This was considered optimistic by the ERG. In addition, the ERG carried out additional scenario analyses with treatment effect waning at 3 and 5 years after starting treatment with no gradual decrease in the hazard ratio. This is in line with some other NSCLC appraisals. The committee noted that no direct trial evidence after the latest follow up at 15 months means that the treatment effect beyond this period is uncertain. The committee concluded that applying treatment effect waning 3 years and 5 years from the start of treatment may be plausible and it would consider these in its decision-making.
# Health-related quality of life
## Utility value estimates using the time-to-death and health-state approaches may be plausible
The company used time-to-death utilities in its base case and used health-state utilities as a sensitivity analysis. Although the ERG was not opposed to using time-to-death utilities, it preferred a health-state approach to utilities. This was because the ERG said that the time‑to‑death utilities did not seem well informed and they were comprised of a small sample size, especially near death. The committee understood that the health-related quality of life data was from the September 2020 data-cut, therefore it was more immature. The ERG noted that the health-state utility approach means that each health state is populated with more people. The committee noted that for a health-state utility approach, the proportion of people in the progressed state that are closer to death are not apparent because averages are taken. The clinical expert highlighted that people need to be well enough to assess quality of life after progression. Therefore, the average is more likely representing people who recently stopped treatment. The committee considered that if a randomised controlled trial was done, the health-related quality of life in both arms should be the same at the start of treatment. Therefore, this may need to be considered in the approach to modelling health-related quality of life in the future. The company mentioned that it is open to using health-state utilities if there is a difference for sotorasib compared with chemotherapy after progression. The committee concluded that there are uncertainties in using time-to-death and health-state utilities, but because both approaches may be plausible, it would consider these in its decision-making.
## Sotorasib is an oral treatment with associated benefits, and a disutility for the comparative intravenous treatment may be plausible
Sotorasib is an oral targeted treatment. It is more tolerable and less resource intensive than chemotherapy. The clinical expert described the issues associated with intravenous treatments, such as adverse events and delays in treatment because of capacity issues in chemotherapy units, particularly during the COVID‑19 pandemic. The clinical expert highlighted the benefits of oral treatment from an NHS and patient perspective, and the preference for it. The patient expert described the benefits of having treatment at home and reducing inpatient time at the hospital. The company applied a utility decrement of 0.025 per cycle of treatment to account for the cytotoxicity and intravenous administration of docetaxel and nintedanib. This was based on a study comparing erlotinib with docetaxel in advanced NSCLC (Lewis et al., 2010). The utilities in that study were derived through a visual analogue scale in the progression-free health state. The ERG noted that the utilities (0.451 and 0.426 for oral and intravenous therapy, respectively) in that study were lower than in CodeBreaK100 (0.734). The ERG said it was not opposed to a treatment-related disutility for intravenous administration but highlighted the lack of justification for the size of disutility. It also considered the exclusion of any potential disutility associated with sotorasib dosing and frequency as an issue. This is because sotorasib is taken as 8 tablets once a day compared with docetaxel that is administered intravenously once every 3 weeks. In its submission, the company assumed equal on-treatment progression-free survival utilities for a targeted therapy compared with chemotherapy. It acknowledged that a differential is seen in other NICE appraisals. The company identified a progression-free survival utility of 0.687 from LUME‑Lung 1, resulting in a decrement of 0.047 after applying the progression-free survival base-case utility. As a result, the company determined that scenarios with a health-state utility approach and either 0.025 or 0.04 progression-free survival on-treatment utility differential were appropriate to explore. The committee concluded that it would consider both a disutility and no disutility associated with intravenous administration in its decision-making.
## It is appropriate to apply an equalised relative dose intensity for sotorasib and its comparators
The company applied a relative dose intensity that was lower for sotorasib (89.0%) compared with docetaxel (90.3%) and nintedanib (92.1%). The company stated that there was no reason to assume that the relative dose intensity is truly lower for sotorasib, and any differences may be from random sampling errors. The ERG suggested it was reasonable to apply an average 90.5% relative dose intensity instead. The ERG preferred this conservative approach because of the impact on treatment costs and the immaturity of trial data. The company disagreed with equalised relative dose intensity because it considered the trial data more valid. The clinical expert mentioned that the dose of sotorasib can be modified depending on the level of unacceptable toxicity, whereas for chemotherapy, the maximum dose is normally applied. The committee noted that the proportion of people needing dose modifications in CodeBreaK100 was similar to SELECT-1. The committee concluded that it is appropriate to assume equalised relative dose intensities for sotorasib and its comparators.
# End of life
## Sotorasib may meet the end of life criteria but there is uncertainty in the extension of life criterion
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company stated that for non-targeted therapies, real-world evidence studies suggest less than 10 months overall survival with second-line treatment and less than 7 months overall survival with third-line treatment. This was supported with a median overall survival of 7.9 months in SELECT‑1 and median overall survival of 10.9 months in LUME‑Lung 1. The committee accepted that sotorasib meets the short life expectancy criterion for end of life. It noted a median overall survival gain from the indirect treatment comparisons of sotorasib with docetaxel alone (see section 3.5) from the latest March 2021 data-cut, at around 15 months of follow up (the exact results are confidential and cannot be reported here). In addition, the model estimated an undiscounted mean overall survival gain for sotorasib compared with docetaxel and docetaxel plus nintedanib (the exact results are confidential and cannot be reported here). The committee agreed that sotorasib was likely to extend life by over 3 months and therefore meets the extension to life criterion. However, it noted that there were uncertainties with the unanchored indirect treatment comparison methods (see section 3.4). The committee concluded that sotorasib may meet both end of life criteria, but the length of life extension is uncertain.
# Cost-effectiveness estimates
## The most likely cost-effectiveness estimates are highly uncertain
NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty with an uncontrolled single-arm trial as the primary source of clinical evidence (see section 3.3), the unanchored indirect treatment comparisons (see section 3.4), and other unresolvable issues. The committee outlined its preferred modelling assumptions with the current evidence, which should be applied to future cost-effectiveness analyses for sotorasib with docetaxel monotherapy and docetaxel plus nintedanib:
initial hazard ratio of 1 between 0 and 6 months for docetaxel plus nintedanib modelling (see section 3.7)
equalised relative dose intensity between treatment arms (see section 3.11)
consideration of treatment waning effect at 3 and 5 years from the start of treatment (see section 3.8)
consideration of time-to-death and health-state utilities (see section 3.9)
application and non-application of disutility associated with intravenous administration (see section 3.10).
## Sotorasib is not recommended for routine use in the NHS
The committee noted the uncertainties informing the cost-effectiveness estimates, including a single-arm trial as the primary clinical evidence and issues with the unanchored indirect treatment comparison. After applying confidential discounts for sotorasib and its comparators, and considering its preferences, the cost-effectiveness estimates were higher than what NICE normally considers an acceptable use of NHS resources. The cost-effectiveness results cannot be reported here because of the confidential discounts. The committee concluded it could not recommend sotorasib for routine use in the NHS.
# Cancer Drugs Fund
## Sotorasib is recommended for use in the Cancer Drugs Fund
Having concluded that sotorasib could not be recommended for routine use, the committee then considered if it could be recommended for treating previously treated KRAS G12C mutation-positive locally advanced or metastatic NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company has expressed an interest in the technology being considered for funding through the Cancer Drugs Fund. The clinical lead for the Cancer Drugs Fund mentioned that sotorasib needs to have plausible potential to be cost effective. The committee acknowledged that some of the clinical uncertainty may be addressed by collecting data on sotorasib through the Cancer Drugs Fund. The company explained that the phase 3 CodeBreaK200 trial, comparing sotorasib with docetaxel in a KRAS G12C mutation-positive population, is currently ongoing. It stated that this trial will measure overall and progression-free survival, and health-related quality of life. It will also collect data from people with previously treated disease. The committee agreed that some uncertainty may be resolved with data from the CodeBreak200 trial. The committee recalled its conclusion that the current cost-effectiveness results were highly uncertain. It agreed that, with longer follow-up data from CodeBreaK100 on mean overall and progression-free survival, and direct comparative evidence with docetaxel from CodeBreaK200, sotorasib has the potential to be cost effective. Also, that additional evidence may change the preferred modelling assumptions outlined in section 3.13. The committee concluded that sotorasib met the criteria to be considered for inclusion in the Cancer Drugs Fund. So, it recommended sotorasib for use within the Cancer Drugs Fund for previously treated KRAS G12C mutation-positive advanced NSCLC.
# Other factors
## There are no equality issues
No equality or social value judgement issues were identified.
## Sotorasib has a novel mechanism of action in this treatment area, but all benefits are captured in the modelling
The patient and clinical experts emphasised the value of sotorasib as the first targeted treatment option for previously treated KRAS G12C mutation-positive, locally advanced or metastatic NSCLC. The committee considered the innovative nature of sotorasib (see section 3.1). It agreed that sotorasib could be considered an important treatment option for this population. The committee concluded that it did not think there were any additional benefits associated with sotorasib that had not been captured in the economic analysis.
# Conclusion
## Further data is needed to reduce uncertainties in the cost-effectiveness estimates, so sotorasib is recommended in the Cancer Drugs Fund
The committee considered all the available evidence for sotorasib in this appraisal. After considering its preferred modelling assumptions and NICE's end of life criteria, the committee concluded that sotorasib could not be recommended for routine use in the NHS. It considered that further follow-up data from CodeBreaK100 and direct comparative data with docetaxel from CodeBreaK200 may reduce some uncertainty in the cost-effectiveness estimates (see section 3.15). Therefore, sotorasib is recommended for use in the Cancer Drugs Fund for previously treated KRAS G12C mutation-positive advanced NSCLC.
|
{'Recommendations': "Sotorasib is recommended for use within the Cancer Drugs Fund as an option for treating KRAS G12C mutation-positive locally advanced or metastatic non-small-cell lung cancer in adults whose disease has progressed on, or who cannot tolerate, platinum-based chemotherapy or anti-PD-1/PD-L1 immunotherapy. It is recommended only if the conditions in the managed access agreement for sotorasib are followed.\n\nThis recommendation is not intended to affect treatment with sotorasib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for previously treated KRAS G12C mutation-positive, locally advanced or metastatic non-small-cell lung cancer includes docetaxel or docetaxel plus nintedanib. Sotorasib is a targeted treatment for the KRAS G12C mutation.\n\nSotorasib has only been indirectly compared with current treatment. The results suggest that, after platinum-based chemotherapy, sotorasib increases the time before the cancer gets worse and how long people live compared with current treatment.\n\nSotorasib likely meets NICE's criteria to be a life-extending treatment at the end of life. But there is uncertainty in the clinical evidence. Sotorasib has the potential to be cost effective, but more evidence is needed to address the uncertainties before it can be recommended for routine use.\n\nThe evidence on sotorasib is promising. But, more data is being collected from the primary clinical trial and from an ongoing randomised controlled trial comparing sotorasib with docetaxel. Collecting additional data through the Cancer Drugs Fund may resolve some uncertainty in the clinical evidence. So, sotorasib is recommended for use in the Cancer Drugs Fund.", 'Information about sotorasib': "# Anticipated marketing authorisation indication\n\nSotorasib (Lumykras, Amgen) is indicated 'as monotherapy for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small-cell lung cancer (NSCLC), who have progressed on, or are intolerant to, platinum-based chemotherapy and/or anti‑PD‑1/PD‑L1 immunotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for sotorasib.\n\n# Price\n\nThe anticipated list price of sotorasib is £6,907.35 for a 30‑day supply of 240\xa0tablets, each containing 120\xa0mg (excluding VAT, company submission). The company has a commercial arrangement (managed access agreement including a commercial access agreement). This makes sotorasib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Amgen, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## There is a high unmet need for targeted treatments for KRAS G12C mutation-positive locally advanced or metastatic NSCLC\n\nThe KRAS oncogene is the most commonly mutated gene in lung cancer. The KRAS G12C mutation is the most common and occurs in 12% of non-small-cell lung cancer (NSCLC) tumours in the UK. This mutation is more common in non-squamous NSCLC and does not usually occur with other known mutations such as EGFR, ALK and ROS‑1. These other known mutations may have targeted treatments available but there is currently no targeted treatment for the KRAS G12C mutation. People with KRAS G12C mutation-positive locally advanced or metastatic NSCLC usually have chemotherapy, a non-targeted treatment associated with adverse effects that affect health-related quality of life. The clinical expert highlighted that people with KRAS G12C mutation-positive NSCLC have a poor prognosis. The clinical and patient experts noted that there is an unmet need for effective and tolerable treatments in this population. They also highlighted that the lack of targeted treatment options can have a psychological impact. This condition is associated with difficult-to-treat symptoms, and the patient expert submission emphasised the psychological impact of these on patients and their carers. The clinical and patient experts stated that a targeted treatment for the KRAS\xa0G12C mutation in NSCLC would be welcomed. The committee concluded that there is an unmet need for targeted treatments for KRAS\xa0G12C mutation-positive locally advanced or metastatic NSCLC, and that these would have physical and psychological benefits.\n\n# Treatment pathway\n\n## Sotorasib is positioned after platinum-based chemotherapy, so docetaxel and docetaxel plus nintedanib are relevant comparators\n\nThe clinical experts explained that most people with untreated locally advanced or metastatic NSCLC would be offered immunotherapy with chemotherapy. Treatment with docetaxel or docetaxel plus nintedanib may be offered if the disease progresses. The clinical lead for the Cancer Drugs Fund highlighted that of all people with untreated locally advanced or metastatic NSCLC who have immunotherapy, about 40% have immunotherapy alone rather than with chemotherapy. In this population, platinum-doublet chemotherapy would be offered at disease progression, or through a clinical trial, before docetaxel or docetaxel plus nintedanib is considered. In its submission, the company chose to only compare sotorasib with docetaxel and docetaxel plus nintedanib. No evidence was provided to compare sotorasib with platinum-doublet chemotherapy. The company explained that 90% of people in the CodeBreaK100 trial (see section\xa03.3) had previously had platinum-doublet chemotherapy. Also, a retrospective UK analysis supported that most people who recently had docetaxel had likely had previous immunotherapy and platinum-doublet chemotherapy. The company stated that sotorasib is positioned in the treatment pathway after platinum-based chemotherapy. The clinical expert explained that platinum-doublet chemotherapy, either with or without immunotherapy, is usually the main treatment choice. The committee concluded that sotorasib is positioned after platinum-based chemotherapy, therefore docetaxel monotherapy and docetaxel plus nintedanib are the relevant comparators.\n\n# Clinical evidence\n\n## The clinical evidence for sotorasib is from CodeBreaK100, a phase\xa02, single-arm trial\n\nThe clinical effectiveness evidence for sotorasib is from the CodeBreaK100 trial. This is a phase\xa02, single-arm, multicentre, open label trial in 250\xa0adults with KRAS G12C mutation-positive advanced tumours; 126\xa0participants had NSCLC. People in the trial previously had 1 (43%), 2 (35%) or 3\xa0lines (22%) of anticancer therapy, measurable disease per RECIST 1.1 criteria and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Most people (90%) had previously had platinum-doublet chemotherapy (see section\xa03.2). People took 960\xa0mg sotorasib (8\xa0tablets of 120\xa0mg) once a day until disease progression, treatment discontinuation or the end of the study. The primary outcome of the trial was an objective response rate of 37.1% (95% confidence interval 28.6 to 46.2), with the latest data-cut from March\xa02021. A pre-specified clinical significance benchmark of the lower bound of the 95% confidence interval excluding 23% was determined. The objective response rate was calculated as the sum of complete response (3.2%) and partial response (33.9%). This was assessed by a blinded independent central review per RECIST\xa01.1 criteria. The company noted that CodeBreaK100 was not specifically powered for overall and progression-free survival outcomes, but it was powered for the primary outcome. The committee acknowledged that the clinical evidence from the CodeBreaK100 trial is relevant.\n\n# Indirect treatment comparison\n\n## An indirect comparison is appropriate because there are no head-to-head trials with comparator treatments, but this increases uncertainty\n\nThere were no direct comparative data and no common trial arms for anchored indirect treatment comparisons or network meta-analyses. Therefore, the company used an unanchored indirect treatment comparison (as recommended in the NICE Decision Support Unit Technical Support Document 18) for sotorasib versus docetaxel and sotorasib versus docetaxel plus nintedanib. A matching-adjusted indirect comparison (MAIC) was used for the primary analysis of sotorasib versus docetaxel. Results from CodeBreaK100 were used for sotorasib. Results from SELECT‑1, a randomised controlled trial comparing selumetinib plus docetaxel with docetaxel alone, were used for docetaxel. For the secondary analysis of sotorasib versus docetaxel plus nintedanib, the company regarded an MAIC as unfeasible. Therefore, a piecewise approach to hazard ratio estimates applied to the docetaxel arm of SELECT‑1 was done using results from LUME-Lung\xa01, a randomised controlled trial comparing docetaxel with docetaxel plus nintedanib. A supplementary analysis of sotorasib versus docetaxel was also done using a propensity score weighting analysis (PSWA) approach, using data from CodeBreaK100 for sotorasib and the chemotherapy arm of the Amgen Flatiron Health real-world evidence study. The committee concluded that an indirect treatment comparison is appropriate because there are no head-to-head trials, but noted there were several issues with the comparisons that introduced considerable uncertainty.\n\n## Sotorasib increases overall and progression-free survival compared with docetaxel and docetaxel plus nintedanib in the indirect comparison\n\nThe indirect treatment comparison showed that sotorasib is statistically superior in overall and progression-free survival compared with docetaxel. This was based on the latest March\xa02021 data-cut of the CodeBreaK100 trial (the exact results are confidential and cannot be reported here). The supplementary analysis supported these results. For the secondary analysis, the estimation of survival was implemented in the model and extrapolated over the time horizon. This showed a mean gain in overall and progression-free survival for sotorasib compared with docetaxel plus nintedanib (the exact results are confidential and cannot be reported here). The committee concluded that the indirect treatment comparisons show a survival benefit with sotorasib compared with docetaxel and docetaxel plus nintedanib.\n\n## The unanchored MAIC using SELECT-1 data is appropriate for decision-making but has substantial uncertainty\n\nThe company chose 4\xa0covariates in the primary MAIC analysis for matching: ECOG performance score, mean age, metastatic disease at baseline and smoking status. These covariates were all perfectly matched to SELECT‑1 (the exact results are confidential and cannot be reported here). Some covariates identified as 'very important' by clinical experts were excluded from matching by the company because of missing data or trial differences. The ERG noted that excluding brain metastases affected prognosis identified by subgroup analysis. The company mentioned that active brain metastasis was excluded from the trials. The proportion of people with brain metastases was higher in CodeBreaK100 than in LUME‑Lung\xa01. The company stated that if the proportion of inactive brain metastases in SELECT-1 was similar to CodeBreaK100, any bias would favour the docetaxel arm and result in conservative results. The ERG highlighted that an analysis including KRAS mutation status would be informative. But, it acknowledged the company's reasoning that overall survival and progression-free survival are similar in the absence of targeted therapies in the overall KRAS and KRAS G12C-specific population. However, it explained that it could have been possible to select KRAS G12C mutation data from SELECT‑1 data. The ERG considered that the company's supplementary analysis using a PSWA may be less biased than the MAIC. It explained that the Amgen Flatiron Health real-world evidence data was adjusted to make it more comparable to the CodeBreaK100 population, and that there was little difference in the effective sample size compared with the MAIC. It also noted that the PSWA was adjusted for 13\xa0covariates including brain metastases. However, the ERG highlighted that there remains considerable uncertainty in this approach. It noted that a PSWA limited to docetaxel-only data from the Flatiron study would have been informative. The committee agreed that using SELECT‑1 instead of LUME‑Lung\xa01 for the unanchored MAIC was appropriate. This is because the trial population was more comparable to CodeBreaK100, and it is also a more recent trial. The committee recognised that there are substantial uncertainties with this approach, but concluded that the primary analysis using SELECT‑1 for the MAIC is appropriate for decision-making.\n\n## Docetaxel plus nintedanib modelling is uncertain, and applying a hazard ratio of 1 between 0\xa0and 6\xa0months is appropriate\n\nIn the secondary indirect treatment comparison of sotorasib versus docetaxel plus nintedanib, the ERG highlighted uncertainties in the modelling. The company modelled docetaxel and nintedanib in line with NICE's technology appraisal on nintedanib for previously treated locally advanced, metastatic, or locally recurrent non-small-cell lung cancer. This was because a company-sourced UK advisory board confirmed that a MAIC was 'unlikely to be appropriate'. The ERG highlighted the uncertainty with not applying adjustments to ECOG, WHO or smoking status when these differed in SELECT‑1 and LUME‑Lung\xa01. It also mentioned that the model's overall survival curve was not in line with the Kaplan–Meier curve in LUME‑Lung\xa01, with an unlikely major increase in mortality in the first 6\xa0months. That is, the modelling implied a worse survival for docetaxel plus nintedanib compared with docetaxel alone. The Kaplan–Meier curve showed a slight benefit of docetaxel compared with docetaxel plus nintedanib in the first 4\xa0months, which then transformed into a greater than 1\xa0year survival benefit for docetaxel in the modelled overall survival curves. The clinical expert mentioned that in clinical practice, docetaxel is not expected to be better than docetaxel plus nintedanib in the first 6\xa0months. The clinical expert also highlighted that nintedanib has greater toxicity so more people may stop treatment earlier, but added that this is unlikely to be a major driver. The company suggested a possible explanation of the curve could be that nintedanib is anti-angiogenic, so it prevents the formation of blood vessels that support tumour growth. Therefore, it can take more time to have an effect and possibly explain the delay in survival. In addition, the ERG suggested using 1 cut-off point at 6\xa0months rather than 2 at 6\xa0and 26\xa0months because this did not show a good fit. Therefore, the ERG preferred a hazard ratio of 1 between 0 to 6\xa0months. The company disagreed with invalidating LUME‑Lung-1, a 2‑arm phase\xa03 trial. The committee highlighted the importance of face validity and concluded that there are uncertainties in the docetaxel plus nintedanib modelling, and that a hazard ratio of 1 between 0\xa0and 6\xa0months is appropriate.\n\n# Assumptions in the economic model\n\n## Treatment effect waning at 3\xa0and 5\xa0years from the start of treatment are plausible\n\nThe company did not apply treatment effect waning because it considered the impact of discontinuation on overall and progression-free survival to be implemented into the hazard function, and therefore, survival estimates. From the CodeBreaK100 March\xa02021 data-cut, 81.7% of people had discontinued treatment, about 40% were alive and about 20% had not yet progressed. The company stated that half the people who were alive will have kept taking sotorasib at that point. Because sotorasib is taken until progression or unacceptable toxicity in CodeBreaK100, applying treatment effect waning could lead to biased cost-effectiveness estimates. The clinical expert suggested that it was difficult to know how the treatment effect waning should be applied for sotorasib. However, they suggested that sotorasib should be considered in a similar way to other oral treatments for NSCLC. The clinical lead for the Cancer Drugs Fund referred to an example of oral tyrosine kinase inhibitors showing high response rates. They noted that the disease can progress and people remain relatively well for some time before having symptoms. The clinical expert agreed with this. The company highlighted that sotorasib is not a tyrosine kinase inhibitor and that its mechanism of action and response rate would be different. The ERG disagreed with the company's assumption that sotorasib would have a continued benefit and highlighted that the evidence is still immature. In its base case, the ERG preferred to apply treatment effect waning at 2\xa0years and gradually decrease the hazard ratio to 1 over 5\xa0years. This was considered optimistic by the ERG. In addition, the ERG carried out additional scenario analyses with treatment effect waning at 3 and 5\xa0years after starting treatment with no gradual decrease in the hazard ratio. This is in line with some other NSCLC appraisals. The committee noted that no direct trial evidence after the latest follow up at 15\xa0months means that the treatment effect beyond this period is uncertain. The committee concluded that applying treatment effect waning 3\xa0years and 5\xa0years from the start of treatment may be plausible and it would consider these in its decision-making.\n\n# Health-related quality of life\n\n## Utility value estimates using the time-to-death and health-state approaches may be plausible\n\nThe company used time-to-death utilities in its base case and used health-state utilities as a sensitivity analysis. Although the ERG was not opposed to using time-to-death utilities, it preferred a health-state approach to utilities. This was because the ERG said that the time‑to‑death utilities did not seem well informed and they were comprised of a small sample size, especially near death. The committee understood that the health-related quality of life data was from the September\xa02020 data-cut, therefore it was more immature. The ERG noted that the health-state utility approach means that each health state is populated with more people. The committee noted that for a health-state utility approach, the proportion of people in the progressed state that are closer to death are not apparent because averages are taken. The clinical expert highlighted that people need to be well enough to assess quality of life after progression. Therefore, the average is more likely representing people who recently stopped treatment. The committee considered that if a randomised controlled trial was done, the health-related quality of life in both arms should be the same at the start of treatment. Therefore, this may need to be considered in the approach to modelling health-related quality of life in the future. The company mentioned that it is open to using health-state utilities if there is a difference for sotorasib compared with chemotherapy after progression. The committee concluded that there are uncertainties in using time-to-death and health-state utilities, but because both approaches may be plausible, it would consider these in its decision-making.\n\n## Sotorasib is an oral treatment with associated benefits, and a disutility for the comparative intravenous treatment may be plausible\n\nSotorasib is an oral targeted treatment. It is more tolerable and less resource intensive than chemotherapy. The clinical expert described the issues associated with intravenous treatments, such as adverse events and delays in treatment because of capacity issues in chemotherapy units, particularly during the COVID‑19 pandemic. The clinical expert highlighted the benefits of oral treatment from an NHS and patient perspective, and the preference for it. The patient expert described the benefits of having treatment at home and reducing inpatient time at the hospital. The company applied a utility decrement of 0.025 per cycle of treatment to account for the cytotoxicity and intravenous administration of docetaxel and nintedanib. This was based on a study comparing erlotinib with docetaxel in advanced NSCLC (Lewis et al., 2010). The utilities in that study were derived through a visual analogue scale in the progression-free health state. The ERG noted that the utilities (0.451 and 0.426 for oral and intravenous therapy, respectively) in that study were lower than in CodeBreaK100 (0.734). The ERG said it was not opposed to a treatment-related disutility for intravenous administration but highlighted the lack of justification for the size of disutility. It also considered the exclusion of any potential disutility associated with sotorasib dosing and frequency as an issue. This is because sotorasib is taken as 8\xa0tablets once a day compared with docetaxel that is administered intravenously once every 3\xa0weeks. In its submission, the company assumed equal on-treatment progression-free survival utilities for a targeted therapy compared with chemotherapy. It acknowledged that a differential is seen in other NICE appraisals. The company identified a progression-free survival utility of 0.687 from LUME‑Lung\xa01, resulting in a decrement of 0.047 after applying the progression-free survival base-case utility. As a result, the company determined that scenarios with a health-state utility approach and either 0.025 or 0.04 progression-free survival on-treatment utility differential were appropriate to explore. The committee concluded that it would consider both a disutility and no disutility associated with intravenous administration in its decision-making.\n\n## It is appropriate to apply an equalised relative dose intensity for sotorasib and its comparators\n\nThe company applied a relative dose intensity that was lower for sotorasib (89.0%) compared with docetaxel (90.3%) and nintedanib (92.1%). The company stated that there was no reason to assume that the relative dose intensity is truly lower for sotorasib, and any differences may be from random sampling errors. The ERG suggested it was reasonable to apply an average 90.5% relative dose intensity instead. The ERG preferred this conservative approach because of the impact on treatment costs and the immaturity of trial data. The company disagreed with equalised relative dose intensity because it considered the trial data more valid. The clinical expert mentioned that the dose of sotorasib can be modified depending on the level of unacceptable toxicity, whereas for chemotherapy, the maximum dose is normally applied. The committee noted that the proportion of people needing dose modifications in CodeBreaK100 was similar to SELECT-1. The committee concluded that it is appropriate to assume equalised relative dose intensities for sotorasib and its comparators.\n\n# End of life\n\n## Sotorasib may meet the end of life criteria but there is uncertainty in the extension of life criterion\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company stated that for non-targeted therapies, real-world evidence studies suggest less than 10\xa0months overall survival with second-line treatment and less than 7\xa0months overall survival with third-line treatment. This was supported with a median overall survival of 7.9\xa0months in SELECT‑1 and median overall survival of 10.9\xa0months in LUME‑Lung\xa01. The committee accepted that sotorasib meets the short life expectancy criterion for end of life. It noted a median overall survival gain from the indirect treatment comparisons of sotorasib with docetaxel alone (see section\xa03.5) from the latest March\xa02021 data-cut, at around 15\xa0months of follow up (the exact results are confidential and cannot be reported here). In addition, the model estimated an undiscounted mean overall survival gain for sotorasib compared with docetaxel and docetaxel plus nintedanib (the exact results are confidential and cannot be reported here). The committee agreed that sotorasib was likely to extend life by over 3\xa0months and therefore meets the extension to life criterion. However, it noted that there were uncertainties with the unanchored indirect treatment comparison methods (see section\xa03.4). The committee concluded that sotorasib may meet both end of life criteria, but the length of life extension is uncertain.\n\n# Cost-effectiveness estimates\n\n## The most likely cost-effectiveness estimates are highly uncertain\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty with an uncontrolled single-arm trial as the primary source of clinical evidence (see section\xa03.3), the unanchored indirect treatment comparisons (see section\xa03.4), and other unresolvable issues. The committee outlined its preferred modelling assumptions with the current evidence, which should be applied to future cost-effectiveness analyses for sotorasib with docetaxel monotherapy and docetaxel plus nintedanib:\n\ninitial hazard ratio of 1 between 0\xa0and 6\xa0months for docetaxel plus nintedanib modelling (see section\xa03.7)\n\nequalised relative dose intensity between treatment arms (see section\xa03.11)\n\nconsideration of treatment waning effect at 3\xa0and 5\xa0years from the start of treatment (see section\xa03.8)\n\nconsideration of time-to-death and health-state utilities (see section\xa03.9)\n\napplication and non-application of disutility associated with intravenous administration (see section\xa03.10).\n\n## Sotorasib is not recommended for routine use in the NHS\n\nThe committee noted the uncertainties informing the cost-effectiveness estimates, including a single-arm trial as the primary clinical evidence and issues with the unanchored indirect treatment comparison. After applying confidential discounts for sotorasib and its comparators, and considering its preferences, the cost-effectiveness estimates were higher than what NICE normally considers an acceptable use of NHS resources. The cost-effectiveness results cannot be reported here because of the confidential discounts. The committee concluded it could not recommend sotorasib for routine use in the NHS.\n\n# Cancer Drugs Fund\n\n## Sotorasib is recommended for use in the Cancer Drugs Fund\n\nHaving concluded that sotorasib could not be recommended for routine use, the committee then considered if it could be recommended for treating previously treated KRAS G12C mutation-positive locally advanced or metastatic NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The company has expressed an interest in the technology being considered for funding through the Cancer Drugs Fund. The clinical lead for the Cancer Drugs Fund mentioned that sotorasib needs to have plausible potential to be cost effective. The committee acknowledged that some of the clinical uncertainty may be addressed by collecting data on sotorasib through the Cancer Drugs Fund. The company explained that the phase\xa03 CodeBreaK200 trial, comparing sotorasib with docetaxel in a KRAS G12C mutation-positive population, is currently ongoing. It stated that this trial will measure overall and progression-free survival, and health-related quality of life. It will also collect data from people with previously treated disease. The committee agreed that some uncertainty may be resolved with data from the CodeBreak200 trial. The committee recalled its conclusion that the current cost-effectiveness results were highly uncertain. It agreed that, with longer follow-up data from CodeBreaK100 on mean overall and progression-free survival, and direct comparative evidence with docetaxel from CodeBreaK200, sotorasib has the potential to be cost effective. Also, that additional evidence may change the preferred modelling assumptions outlined in section\xa03.13. The committee concluded that sotorasib met the criteria to be considered for inclusion in the Cancer Drugs Fund. So, it recommended sotorasib for use within the Cancer Drugs Fund for previously treated KRAS G12C mutation-positive advanced NSCLC.\n\n# Other factors\n\n## There are no equality issues\n\nNo equality or social value judgement issues were identified.\n\n## Sotorasib has a novel mechanism of action in this treatment area, but all benefits are captured in the modelling\n\nThe patient and clinical experts emphasised the value of sotorasib as the first targeted treatment option for previously treated KRAS G12C mutation-positive, locally advanced or metastatic NSCLC. The committee considered the innovative nature of sotorasib (see section\xa03.1). It agreed that sotorasib could be considered an important treatment option for this population. The committee concluded that it did not think there were any additional benefits associated with sotorasib that had not been captured in the economic analysis.\n\n# Conclusion\n\n## Further data is needed to reduce uncertainties in the cost-effectiveness estimates, so sotorasib is recommended in the Cancer Drugs Fund\n\nThe committee considered all the available evidence for sotorasib in this appraisal. After considering its preferred modelling assumptions and NICE's end of life criteria, the committee concluded that sotorasib could not be recommended for routine use in the NHS. It considered that further follow-up data from CodeBreaK100 and direct comparative data with docetaxel from CodeBreaK200 may reduce some uncertainty in the cost-effectiveness estimates (see section 3.15). Therefore, sotorasib is recommended for use in the Cancer Drugs Fund for previously treated KRAS G12C mutation-positive advanced NSCLC."}
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https://www.nice.org.uk/guidance/ta781
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Evidence-based recommendations on sotorasib (Lumykras) for previously treated KRAS G12C mutation-positive locally advanced or metastatic non-small-cell lung cancer in adults.
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c1a10316568cdd0f16baeba20e5273ac748b05cf
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nice
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Liposuction for chronic lipoedema
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Liposuction for chronic lipoedema
Evidence-based recommendations on liposuction for chronic lipoedema in adults. This involves using suction to remove abnormal fat.
# Recommendations
Evidence on the safety of liposuction for chronic lipoedema is inadequate but raises concerns of major adverse events such as fluid imbalance, fat embolism, deep vein thrombosis, and toxicity from local anaesthetic agents. Evidence on the efficacy is also inadequate, based mainly on retrospective studies with methodological limitations. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should report:
patient selection, including age, effects of hormonal changes (which should include effects seen during puberty and menopause) and the severity and site of disease
details of the number and duration of procedures, the liposuction technique used (including the type of anaesthesia and fluid balance during the procedure), and any procedure-related complications
long-term outcomes, including weight and body mass index changes
patient-reported outcomes, including quality of life.
Patient selection should be done by a multidisciplinary team, including clinicians with expertise in managing lipoedema.
The procedure should only be done in specialist centres by surgeons experienced in this procedure.# The condition, current treatments and procedure
# The condition
Lipoedema is characterised by an abnormal, usually symmetrical, accumulation of fat in the legs, hips, buttocks, and occasionally arms. It is a different condition from obesity and from lymphoedema. The aetiology of lipoedema is unknown, but hormonal changes, weight gain and genetics are each thought to be involved. Lipoedema is considerably more prevalent in women and very rarely affects men. Symptoms include swollen, heavy legs that are painful to touch and bruise easily. Feet do not usually have fat accumulation. The size and shape of legs, and the resultant mobility issues and pain, can have a profoundly negative effect on quality of life, and physical and mental health.
# Current treatments
Treatment typically involves healthy lifestyle changes, conservative therapy and, in severe cases, surgery. The fat associated with lipoedema is usually resistant to diet modification and exercise. Conservative therapy, including compression and manual lymphatic drainage (a specialist type of light massage that is mainly used to reduce swelling caused by fluid) is sometimes used to treat lipoedema, but is ineffective at removing abnormal fat. The main surgical treatment for lipoedema is liposuction. In people who also have obesity, there is emerging evidence that bariatric surgery may help reduce fat from both lipoedema-affected and unaffected areas of the body.
# The procedure
The aim of liposuction for lipoedema is to reduce limb bulk, reduce pain, and to improve mobility and functioning. Liposuction for chronic lipoedema can be done under general or local anaesthesia. Several small incisions are made in the limb. Liposuction for chronic lipoedema usually involves infiltrating the limb with large volumes of fluid (tumescence) to allow the cannula to glide through the tissue with minimal damage to blood vessels and lymphatics. Liposuction can also be done using a tourniquet with no or minimal initial fluid infiltration. Tumescent liposuction needs an infiltration pump to deliver the tumescent fluid. Cannulas, connected to a vacuum pump, are then inserted into the incisions and oedematous adipose tissue is removed by vacuum aspiration. Using vibrating cannulas (power-assisted liposuction) or water-jet-assisted liposuction can help remove fat more easily. Water-jet-assisted liposuction needs less initial infiltration because fluid is simultaneously infiltrated and aspirated during liposuction. Liposuction is done around and all the way along the limb. In tumescent liposuction, both fat and tumescent fluid are suctioned out together.
The procedure can take 1 to 4 hours depending on the size of the treatment area. Immediately after liposuction, a compression bandage is applied to the limb to control any bleeding and to prevent postoperative oedema. Antibiotics are typically prescribed as prophylaxis after the operation. When the wounds are healed after the procedure, a custom-made compression garment is worn. This may need to be revised until the oedema volume has been reduced as much as possible.
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{'Recommendations': 'Evidence on the safety of liposuction for chronic lipoedema is inadequate but raises concerns of major adverse events such as fluid imbalance, fat embolism, deep vein thrombosis, and toxicity from local anaesthetic agents. Evidence on the efficacy is also inadequate, based mainly on retrospective studies with methodological limitations. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should report:\n\npatient selection, including age, effects of hormonal changes (which should include effects seen during puberty and menopause) and the severity and site of disease\n\ndetails of the number and duration of procedures, the liposuction technique used (including the type of anaesthesia and fluid balance during the procedure), and any procedure-related complications\n\nlong-term outcomes, including weight and body mass index changes\n\npatient-reported outcomes, including quality of life.\n\nPatient selection should be done by a multidisciplinary team, including clinicians with expertise in managing lipoedema.\n\nThe procedure should only be done in specialist centres by surgeons experienced in this procedure.', 'The condition, current treatments and procedure': '# The condition\n\nLipoedema is characterised by an abnormal, usually symmetrical, accumulation of fat in the legs, hips, buttocks, and occasionally arms. It is a different condition from obesity and from lymphoedema. The aetiology of lipoedema is unknown, but hormonal changes, weight gain and genetics are each thought to be involved. Lipoedema is considerably more prevalent in women and very rarely affects men. Symptoms include swollen, heavy legs that are painful to touch and bruise easily. Feet do not usually have fat accumulation. The size and shape of legs, and the resultant mobility issues and pain, can have a profoundly negative effect on quality of life, and physical and mental health.\n\n# Current treatments\n\nTreatment typically involves healthy lifestyle changes, conservative therapy and, in severe cases, surgery. The fat associated with lipoedema is usually resistant to diet modification and exercise. Conservative therapy, including compression and manual lymphatic drainage (a specialist type of light massage that is mainly used to reduce swelling caused by fluid) is sometimes used to treat lipoedema, but is ineffective at removing abnormal fat. The main surgical treatment for lipoedema is liposuction. In people who also have obesity, there is emerging evidence that bariatric surgery may help reduce fat from both lipoedema-affected and unaffected areas of the body.\n\n# The procedure\n\nThe aim of liposuction for lipoedema is to reduce limb bulk, reduce pain, and to improve mobility and functioning. Liposuction for chronic lipoedema can be done under general or local anaesthesia. Several small incisions are made in the limb. Liposuction for chronic lipoedema usually involves infiltrating the limb with large volumes of fluid (tumescence) to allow the cannula to glide through the tissue with minimal damage to blood vessels and lymphatics. Liposuction can also be done using a tourniquet with no or minimal initial fluid infiltration. Tumescent liposuction needs an infiltration pump to deliver the tumescent fluid. Cannulas, connected to a vacuum pump, are then inserted into the incisions and oedematous adipose tissue is removed by vacuum aspiration. Using vibrating cannulas (power-assisted liposuction) or water-jet-assisted liposuction can help remove fat more easily. Water-jet-assisted liposuction needs less initial infiltration because fluid is simultaneously infiltrated and aspirated during liposuction. Liposuction is done around and all the way along the limb. In tumescent liposuction, both fat and tumescent fluid are suctioned out together.\n\nThe procedure can take 1\xa0to 4\xa0hours depending on the size of the treatment area. Immediately after liposuction, a compression bandage is applied to the limb to control any bleeding and to prevent postoperative oedema. Antibiotics are typically prescribed as prophylaxis after the operation. When the wounds are healed after the procedure, a custom-made compression garment is worn. This may need to be revised until the oedema volume has been reduced as much as possible.'}
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https://www.nice.org.uk/guidance/ipg721
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Evidence-based recommendations on liposuction for chronic lipoedema in adults. This involves using suction to remove abnormal fat.
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48b6416063a9e9973c61a4bd34ca2e8a6335dcda
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nice
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Nivolumab with ipilimumab for untreated advanced renal cell carcinoma
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Nivolumab with ipilimumab for untreated advanced renal cell carcinoma
Evidence-based recommendations on nivolumab (Opdivo) with ipilimumab (Yervoy) for untreated advanced renal cell carcinoma in adults.
# Recommendations
Nivolumab with ipilimumab is recommended, within its marketing authorisation, as an option for untreated advanced renal cell carcinoma in adults:
whose disease is intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria and
-nly if the company provides nivolumab with ipilimumab according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for nivolumab with ipilimumab for untreated advanced renal cell carcinoma.
Current NHS treatment for untreated advanced renal cell carcinoma with intermediate to poor risk is usually sunitinib, pazopanib, cabozantinib or tivozanib. Because cabozantinib and tivozanib were not established clinical practice in the NHS at the time of the original appraisal of nivolumab with ipilimumab, they were not included in the scope for this review.
The new clinical trial evidence shows that nivolumab with ipilimumab improves how long people live compared with sunitinib. Sunitinib and pazopanib are considered to be similarly effective.
The most likely cost-effectiveness estimates for nivolumab with ipilimumab are within the range that NICE usually considers an acceptable use of NHS resources. Therefore, it is recommended for routine use in the NHS.# Information about nivolumab with ipilimumab
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol Myers Squibb) with ipilimumab (Yervoy, Bristol Myers Squibb) has a marketing authorisation for 'the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma'.
# Dosage in the marketing authorisation
The dosage schedule is available in summary of product characteristic for nivolumab.
# Price
The list price of nivolumab is £2,633 per 240 mg per 24‑ml vial (excluding VAT; BNF online, accessed January 2022). The list price of ipilimumab is £15,000 per 200 mg per 40‑ml vial (excluding VAT; BNF online, accessed January 2022). The company has commercial arrangements for nivolumab with ipilimumab (simple discount patient access schemes). These make nivolumab and ipilimumab available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discounts.# Committee discussion
The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate 214 study for people with intermediate- or poor-risk advanced or metastatic renal cell carcinoma. In addition, data was collected on the use of nivolumab with ipilimumab for intermediate- and poor-risk disease in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.
# New treatment option
## People with untreated intermediate- or poor-risk renal cell carcinoma would welcome a new treatment option
For intermediate- or poor-risk advanced renal cell carcinoma, tyrosine kinase inhibitors such as pazopanib, sunitinib, tivozanib and cabozantinib are current standard care in the NHS. They can cause adverse effects such as fatigue, hand and foot syndrome, and chronic diarrhoea, which can substantially affect quality of life. The committee agreed that people with intermediate- or poor-risk advanced renal cell carcinoma would welcome a new treatment option.
# Comparators
## Sunitinib and pazopanib are the appropriate comparators, although other treatments are now routinely available
The committee was aware that the treatment pathway for untreated advanced renal cell carcinoma had changed since the original appraisal. The committee considered several pieces of NICE technology appraisal guidance on oral tyrosine kinase inhibitors, noting that NICE now recommends that people may be offered any of sunitinib, pazopanib, tivozanib or cabozantinib. Cabozantinib and tivozanib were not included in the original appraisal because of when these pieces of guidance were published. NICE recommended the combination of avelumab and axitinib for use within the Cancer Drugs Fund for this indication, but NICE does not consider this routine practice, so they cannot be considered comparators. The NHS England clinical lead for the Cancer Drugs Fund reiterated a point he had made during the original appraisal: that nivolumab with ipilimumab is the first checkpoint inhibitor in untreated renal cell carcinoma and would likely displace tyrosine kinase inhibitors if recommended for routine use in the NHS. The committee concluded that pazopanib and sunitinib are the relevant comparators in this appraisal, but noted the potential shifting of lines of treatment in the treatment pathway.
## Sunitinib and pazopanib can be considered clinically equivalent
The clinical experts in the original appraisal noted that, in practice, sunitinib and pazopanib are considered clinically equivalent. The committee recalled that previous appraisals also considered sunitinib and pazopanib to be clinically equivalent, and there was no new evidence to change this conclusion. The committee concluded that pazopanib and sunitinib can be considered clinically equivalent.
# Clinical evidence
## Updated CheckMate 214 data still shows that nivolumab with ipilimumab is more clinically effective than sunitinib
The main source of evidence came from CheckMate 214, an open-label randomised control trial, with sunitinib as the comparator. The co-primary endpoints of the trial were overall survival and progression-free survival, amended in the protocol by the company to include overall response rate. The trial stratified people by risk of death using a prognostic risk score, as defined by the International Metastatic Renal Cell Carcinoma Database Consortium scoring system. Risk level is determined using 6 risk factors including Karnofsky performance status score, time from original diagnosis, and levels of haemoglobin, serum calcium, neutrophils and platelets. The likelihood of survival is considered intermediate ('intermediate risk') when there are 1 or 2 risk factors, and poor ('poor risk') when there are 3 or more risk factors present. The population in the trial was wider than the population in the marketing authorisation, which limits treatment to people with disease that is intermediate or poor risk. The company stated that the trial had sufficient power to investigate clinical outcomes in a combined intermediate- or poor-risk group (n=847; 667 intermediate and 180 poor risk, respectively). The trial also included 249 people with favourable-risk disease, but this group was not included in the marketing authorisation. In the original appraisal, the company presented 2 interim data cuts with the most recent from August 2018, with a minimum of 30 months' follow up (referred to as the '30-month data cut'). For the review of this guidance, the company presented a further data cut from February 2021, reflecting a median follow up of 67.7 months and a minimum of 60 months' follow up (referred to as the '60-month data cut'). The updated evidence from the 60-month data cut showed improved overall survival that was consistent with the extrapolations in the original submission. Median overall survival did not change from the 30-month to the 60-month data cut for sunitinib: 27 months (95% confidence interval 22 to 33 months for the 30-month data cut, and 22 to 34 months for the 60-month data cut). Median overall survival in the nivolumab with ipilimumab arm was not reached at 30 months (95% CI 36 months to not evaluable), but was 47 months at 60 months (95% CI 35 to 57). The hazard ratio between treatment arms for overall survival did not show a substantial change, from 0.66 (95% CI 0.54 to 0.80) at 30 months to 0.68 (CI 0.58 to 0.81) at 60 months, mostly associated with better than predicted survival of people in the sunitinib treatment arm. The committee concluded that the updated clinical evidence for nivolumab with ipilimumab closely matched the extrapolations from the original appraisal, showing that nivolumab with ipilimumab is more clinically effective than sunitinib.
## Supplementary clinical evidence came from the Systemic Anti-Cancer Therapy dataset
Public Health England submitted data from the Systemic Anti-Cancer Therapy (SACT) dataset, including data from 814 people who had nivolumab with ipilimumab through the Cancer Drugs Fund during the period of April 2019 to November 2020. The SACT data had a median follow up of 10.8 months, ranging from 5 to 24.7 months. The committee noted that naively comparing the data from SACT with data from CheckMate 214 showed worse survival for people in the NHS compared with participants in the trial. The committee considered that differences in characteristics of the patients in the NHS and in the trial likely accounted for this, notably that the SACT data include a higher proportion of people with poor-risk disease (see section 3.7). The committee considered that the distribution of characteristics in the SACT dataset was likely to better represent people who had nivolumab with ipilimumab in NHS clinical practice. However, the SACT dataset provided no comparative evidence because it included only people who had nivolumab with ipilimumab. The committee concluded that the relative effect of nivolumab with ipilimumab compared with sunitinib from CheckMate 214 was the most appropriate source of evidence on the clinical efficacy of nivolumab with ipilimumab, and for economic modelling.
## Nivolumab with ipilimumab appears to be more effective in poor-risk than in intermediate-risk disease
In the original appraisal, the company had presented estimates of relative effectiveness separated by risk status for the intermediate- and poor-risk subgroups. The committee visually inspected the Kaplan–Meier curves and concluded that the curves suggested that treatment was more effective in poor-risk disease than in intermediate disease. The committee was aware this could represent poor-risk disease responding poorly to sunitinib rather than responding particularly well to nivolumab with ipilimumab. The ERG had requested CheckMate 214 outcomes from the 60-month data cut stratified by risk status, but the company had not provided this, noting that the trial was 'not powered' for outcomes by subgroups. The committee recognised that if the study had more participants, the trial would very likely have shown significant effect modification by risk status. The company considered these estimates by subgroup to be confidential so they cannot be presented here. The committee was also aware that the marketing authorisation does not include favourable disease. The ERG noted that in the SACT data, overall survival appears to be lower for people with poor-risk disease. Before the meeting, the clinical experts noted that a recent post hoc analysis from CheckMate 214 showed that people with sarcomatoid disease may have a particular benefit with nivolumab with ipilimumab over sunitinib at 42 months' follow up. A clinical expert noted that sarcomatoid histology has a higher tumour mutational burden and may benefit from immunotherapy to a greater extent. They also noted that these people are likely to have poor-risk disease. The committee noted that the company chose not to present any analyses stratified by risk status from the 60-month data cut. The committee nonetheless concluded that there is likely to be a difference in relative effectiveness by risk, but that it would have preferred to see outcomes by subgroup from the updated trial data cut.
## The SACT dataset should inform the proportion of people with poor-risk disease in the economic model
CheckMate 214 included 21% of people with a high risk of death (poor-risk disease), and the clinical experts in the previous appraisal considered that this proportion was likely larger in NHS practice. If intermediate- and poor-risk disease respond differently to treatment (see section 3.6), the absolute treatment effect in the combined group would depend on the distribution of baseline risk, which in turn would affect cost effectiveness. The SACT data, which was expected to inform the true proportion of people with intermediate- and poor-risk renal cell carcinoma in the NHS, included 35% of people with poor-risk disease (with the remainder having intermediate-risk disease). The committee considered that the SACT dataset included more people with poor-risk disease than it might otherwise have done because of the COVID-19 pandemic. The company presented evidence from several audits reporting delayed referrals, consultant appointments and diagnosis during the pandemic. It considered that this supported the larger proportion of people with poor-risk disease in the SACT dataset. The ERG considered that the SACT dataset better represented NHS patients who would have nivolumab with ipilimumab than the trial. It noted there was limited evidence that the pandemic influenced risk levels in SACT, noting that 87% of the included people had an Eastern Cooperative Oncology Group performance status of 0 or 1. The NHS England clinical lead for the Cancer Drugs Fund did not consider that the pandemic affected the proportion of people with poor-risk disease in the NHS. The committee concluded that the SACT dataset should inform the proportion of people with poor-risk disease in the economic model. However, it would have preferred to see the proportions of each risk group from the SACT dataset used to weight the effectiveness estimates of each risk group using the CheckMate 214 trial outcomes. It considered that this analysis would likely reduce the cost-effectiveness estimates because the incremental benefit over sunitinib or pazopanib for poor-risk disease is likely to be higher than for intermediate-risk disease.
## Treatment crossover may favour sunitinib and would have a minimal effect on the cost-effectiveness results
In the original guidance, for the 30-month data cut, the company had amended the trial protocol to allow people randomised to sunitinib to switch ('crossover') to nivolumab with ipilimumab, and had not adjusted the trial results for this. While acknowledging that the crossover likely biased the hazard ratio towards zero, the committee wished to see long-term survival predictions for nivolumab with ipilimumab based on further data collection from CheckMate 214, adjusted for treatment switching. In the company's new submission, it did not adjust for treatment switching because it considered few people had switched treatments. The ERG noted that the unadjusted results likely favoured the comparator. The committee would have preferred to see adjusted results, but acknowledged the likely impact on the cost-effectiveness estimates was minimal given the relatively small number of people switching treatment. The impact of adjusting for treatment switching is uncertain, however it may favour sunitinib.
## Modelling second-line treatments based on the CheckMate 214 trial is appropriate
In the original appraisal, the committee concluded that second-line treatments in CheckMate 214 did not reflect NHS clinical practice. For example, some people randomised to nivolumab with ipilimumab in CheckMate 214 received immunotherapies again at later lines of treatment. The committee preferred an analysis that included both costs and benefits of treatments used in second-line treatment and beyond that reflected NHS clinical practice. During the original appraisal it considered that SACT data could inform this. In its new submission to NICE, the company used second-line and beyond treatment data from CheckMate 214 because of differences in follow up between the trial and SACT (minimum 60 months compared with minimum 5 months, respectively). It also provided a scenario using the proportions of second-line treatments from the SACT dataset. The ERG agreed that using treatments from the longer CheckMate 214 trial was appropriate. The clinical experts considered that the SACT treatments best matched NHS clinical practice. They noted that after sunitinib, people will often have either nivolumab or cabozantinib; whereas after nivolumab with ipilimumab, people will have a tyrosine kinase inhibitor – usually cabozantinib, but sometimes sunitinib, tivozanib, or lenvatinib with everolimus (see section 3.2). The committee noted that the NHS would not offer immunotherapy twice, and heard from the clinical experts that there is little evidence that a second round of immunotherapy works. The committee was concerned about using CheckMate 214 as a source of data for second-line and beyond treatments if any of these treatments not used in the NHS influenced survival outcomes. It considered that the true cost-effectiveness results may be somewhere between those based on trial data and those based on SACT data. It also noted that removing additional costs of nivolumab monotherapy after treatment with nivolumab with ipilimumab in the CheckMate 214 trial (because immunotherapy would likely not be offered twice) would reduce the cost-effectiveness estimates. The committee preferred to use evidence on effectiveness and costs from the same source, and concluded that it was appropriate to use CheckMate 214 data for second-line and beyond treatments.
# Adverse events
## Nivolumab with ipilimumab is well tolerated compared with tyrosine kinase inhibitors
In the original appraisal, the clinical experts explained that in their experience, nivolumab with ipilimumab is well tolerated and has a preferable adverse event profile compared with tyrosine kinase inhibitors. The committee acknowledged that nivolumab and ipilimumab are associated with some rare but unpleasant and potentially serious adverse events that are specific to immunotherapy. The clinical experts stated that clinicians are experienced in recognising and managing these serious adverse events. The committee maintained its conclusion that nivolumab with ipilimumab is well tolerated compared with tyrosine kinase inhibitors.
# The company's economic model
## The company's model structure matches the committee's preferred assumptions from the original appraisal
The company used a partitioned survival model to estimate the cost effectiveness of nivolumab plus ipilimumab compared with sunitinib and pazopanib. The model included 6 health states: progression-free on treatment, progression-free off treatment, post-progression on treatment, post-progression off treatment, terminal care, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival, overall survival, and their difference. The cycle length was 1 week and the time horizon was 40 years. The committee noted that the company's original economic model included an 'immunological effect' that resulted in people taking nivolumab with ipilimumab being effectively cured. It had previously concluded that this was not appropriately implemented and therefore the company did not explicitly include it in its resubmission; the ERG considered this approach appropriate. The committee concluded that the model structure was acceptable and closely matched its preferred assumptions from the original appraisal.
# Survival modelling in the economic model
## The overall survival extrapolations are appropriate
The committee recognised that the trial evidence did not span the whole time horizon of the model. The company explored the most appropriate hazard function to extrapolate overall survival for each of the treatments using the updated 60-month data from CheckMate 214. The committee originally concluded that both the company and the ERG's preferred extrapolations for overall survival were clinically plausible (log-normal and Kaplan–Meier with exponential extrapolation, respectively), but the absence of long-term data prevented it from determining which was most appropriate. It noted that the log-normal distribution predicted that a small proportion of people, not explicitly modelled as having been cured, would effectively be cured. Using the updated 60-month CheckMate 214 data, the company again considered that the log-normal curve was the most appropriate to extrapolate overall survival, based on goodness-of-fit to the data and clinical validation of predicted risk of death over time. The ERG was satisfied that the company used appropriate methods to select the model, but questioned the plausibility of its projections for overall survival in the long term. The ERG highlighted that a large proportion of gains in both life years and quality-adjusted life years (QALYs) for nivolumab plus ipilimumab compared with sunitinib in the model occurred in the extrapolated period. The ERG emphasised that a large proportion of these patients remained in the progression-free state. The committee noted that the company's scenario analyses using alternative extrapolations increased the cost-effectiveness estimates, demonstrating the importance of the choice of extrapolation method. The committee considered that the updated data supported the company's choice of the log-normal hazard function and that a proportion of people in CheckMate 214 would effectively be 'cured' with immunotherapy. The committee concluded that the extrapolations of overall survival were appropriate but, to explore uncertainty, it considered sensitivity analyses using other assumptions around extrapolating how the rate of death changes over time in its decision-making.
## The company and ERG assumed that death rates for nivolumab with ipilimumab and sunitinib or pazopanib would equalise at different times
In its updated base case, the company assumed that nivolumab with ipilimumab would lead to a lower death rate than sunitinib or pazopanib, until the point at which the curve extrapolating overall survival for nivolumab with ipilimumab equalled the general population mortality curve, approximately 21 years from the start of treatment. The ERG was concerned that this approach was not supported by the CheckMate 214 trial data, which showed higher death rates for nivolumab with ipilimumab than for sunitinib at several time points. The ERG considered that the annualised hazard rates for each of the treatments equalised at approximately 4.5 years. Moreover, the ERG noted that clinical advice suggests death rates decrease over time, which the CheckMate 214 trial did not show for nivolumab with ipilimumab. The ERG considered that second-line treatments may have equalised the hazards for death between treatments, notably because a high proportion of people treated with sunitinib then received nivolumab monotherapy as a second-line or later treatment. The ERG provided 2 scenarios in which the hazards equalised at 4.5 years, 1 in which the death rate for sunitinib or pazopanib was set to the rate for nivolumab with ipilimumab, and 1 in which the death rate for nivolumab with ipilimumab was set to the rate for sunitinib or pazopanib. Both showed a range of potential effects of equalised hazards for death.
## The company submitted further data and analyses to support its view
The company did not consider that the ERG's analysis of hazard rates used a recognised methodology, and countered the ERG's scenarios with its own evidence:
It submitted data on people in the CheckMate 214 trial who were alive after 5 years, demonstrating that a larger proportion of people treated with nivolumab and ipilimumab were progression free than those in the sunitinib arm. It considered that this was evidence of a sustained response. However, the ERG noted that some people in the sunitinib arm also had a sustained response for 5 years. The ERG further noted the high proportion of people in the sunitinib arm who later had nivolumab monotherapy.
The company considered that the increased hazard of death at the end of the observed trial period in the nivolumab with ipilimumab arm was an artefact. To support this conclusion, it submitted smoothed hazard plots based on datasets truncated at different months within the trial duration. The ERG considered that the smoothed hazard plots made it difficult to see changes in hazards that were occurring over time. It also felt that nivolumab monotherapy would be more likely to have a different effect after sunitinib treatment than other second-line treatments would have after nivolumab with ipilimumab, which could result in a convergence of hazards.
## The death rates are likely to equalise somewhere between the company and ERG's base case assumptions
The committee considered there was substantial uncertainty in the rates of death at the end of the trial and the extrapolations. It considered that it would have liked to see plots of the hazard ratio over time implied by the survival extrapolations used in the economic model, and further sensitivity analysis that assumed different effects of gradual convergence of the death hazards. It preferred the smoothed hazard plots to demonstrate hazards observed during the trial, but recognised that the ERG's analysis of convergence of death hazards at 4.5 years may represent the earliest plausible estimate of the time point of convergence. It concluded that the death hazards between arms would be likely to equalise, probably between 4.5 and 21 years, between the company's base case and the ERG scenarios. The committee concluded that it was appropriate to consider incremental cost-effectiveness ratios (ICERs) resulting from this range.
# Utility values
## It is not appropriate to assume different utilities based on treatment arm for the entire time horizon, but this minimally impacts the ICERs
In the original appraisal, the committee considered that the quality of life estimates should reflect whether disease had progressed, which treatment a person had, and being on or off treatment. The company added utilities by progression status in its new model. The ERG noted that people in the new model were assumed to have different utilities depending on the treatment, even after stopping treatment, and for the remainder of the time horizon. The ERG considered this unjustified, noting that utility values are likely to equalise as people receive further treatments. The ERG provided a scenario using the same utility values for health states in both treatment arms over the modelled period. A patient expert noted that she did not feel very different on or off treatment or before or after progression, apart from when she experienced a side effect. A clinical expert noted that treatment-related adverse events may drive utility when on treatment. The committee considered it was appropriate to consider disutility associated with treatment when on treatment, but that having different utilities when off treatment, particularly if stopping treatment because of an adverse event, was not appropriate for the whole modelled time horizon. Based on the scenario provided by the ERG, the committee concluded that these different utility values are likely to have minimal impact on the ICERs.
# Cost-effectiveness estimate
## The most likely cost-effectiveness estimate is within what NICE considers an acceptable use of NHS resources
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee concluded that the true ICERs for nivolumab and ipilimumab compared with sunitinib or pazopanib may lie between those of the company's base case and the ERG scenarios (see section 3.15). The cost-effectiveness results are commercial in confidence and cannot be reported here. The committee noted that most of the ICERs were towards the higher end of the range normally considered an acceptable use of NHS resources (£20,000 to £30,000 per QALY gained) but that there was some uncertainty around where the true ICER lies. It also noted that several preferred assumptions that had not been incorporated into the models were likely to decrease the ICERs:
increasing the proportion of people with poor-risk disease included in the model, reflecting the proportion in the SACT dataset (see section 3.7)
adjusting results for treatment crossover in CheckMate 214 from sunitinib to nivolumab with ipilimumab (see section 3.8)
removing additional costs of nivolumab monotherapy after nivolumab with ipilimumab, which does not represent clinical practice (see section 3.9).Taking these factors into account, the committee concluded that nivolumab with ipilimumab was likely to be an acceptable use of NHS resources.
# Equality
## There are no equalities issues
No equality issues were identified.
# Conclusion
## Nivolumab with ipilimumab is recommended for routine use
The committee concluded that nivolumab with ipilimumab was more effective than treatments currently offered in the NHS for renal cell carcinoma and that the most plausible cost-effectiveness estimates were within what NICE considers an acceptable use of NHS resources. Therefore, nivolumab with ipilimumab is recommended for adults with untreated advanced renal cell carcinoma that is intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria.
|
{'Recommendations': 'Nivolumab with ipilimumab is recommended, within its marketing authorisation, as an option for untreated advanced renal cell carcinoma in adults:\n\nwhose disease is intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria and\n\nonly if the company provides nivolumab with ipilimumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for nivolumab with ipilimumab for untreated advanced renal cell carcinoma.\n\nCurrent NHS treatment for untreated advanced renal cell carcinoma with intermediate to poor risk is usually sunitinib, pazopanib, cabozantinib or tivozanib. Because cabozantinib and tivozanib were not established clinical practice in the NHS at the time of the original appraisal of nivolumab with ipilimumab, they were not included in the scope for this review.\n\nThe new clinical trial evidence shows that nivolumab with ipilimumab improves how long people live compared with sunitinib. Sunitinib and pazopanib are considered to be similarly effective.\n\nThe most likely cost-effectiveness estimates for nivolumab with ipilimumab are within the range that NICE usually considers an acceptable use of NHS resources. Therefore, it is recommended for routine use in the NHS.', 'Information about nivolumab with ipilimumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol Myers Squibb) with ipilimumab (Yervoy, Bristol Myers Squibb) has a marketing authorisation for 'the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in summary of product characteristic for nivolumab.\n\n# Price\n\nThe list price of nivolumab is £2,633 per 240\xa0mg per 24‑ml vial (excluding VAT; BNF online, accessed January\xa02022). The list price of ipilimumab is £15,000 per 200\xa0mg per 40‑ml vial (excluding VAT; BNF online, accessed January\xa02022). The company has commercial arrangements for nivolumab with ipilimumab (simple discount patient access schemes). These make nivolumab and ipilimumab available to the NHS with discounts. The sizes of the discounts are commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate\xa0214 study for people with intermediate- or poor-risk advanced or metastatic renal cell carcinoma. In addition, data was collected on the use of nivolumab with ipilimumab for intermediate- and poor-risk disease in the NHS through the Cancer Drugs Fund using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\n# New treatment option\n\n## People with untreated intermediate- or poor-risk renal cell carcinoma would welcome a new treatment option\n\nFor intermediate- or poor-risk advanced renal cell carcinoma, tyrosine kinase inhibitors such as pazopanib, sunitinib, tivozanib and cabozantinib are current standard care in the NHS. They can cause adverse effects such as fatigue, hand and foot syndrome, and chronic diarrhoea, which can substantially affect quality of life. The committee agreed that people with intermediate- or poor-risk advanced renal cell carcinoma would welcome a new treatment option.\n\n# Comparators\n\n## Sunitinib and pazopanib are the appropriate comparators, although other treatments are now routinely available\n\nThe committee was aware that the treatment pathway for untreated advanced renal cell carcinoma had changed since the original appraisal. The committee considered several pieces of NICE technology appraisal guidance on oral tyrosine kinase inhibitors, noting that NICE now recommends that people may be offered any of sunitinib, pazopanib, tivozanib or cabozantinib. Cabozantinib and tivozanib were not included in the original appraisal because of when these pieces of guidance were published. NICE recommended the combination of avelumab and axitinib for use within the Cancer Drugs Fund for this indication, but NICE does not consider this routine practice, so they cannot be considered comparators. The NHS England clinical lead for the Cancer Drugs Fund reiterated a point he had made during the original appraisal: that nivolumab with ipilimumab is the first checkpoint inhibitor in untreated renal cell carcinoma and would likely displace tyrosine kinase inhibitors if recommended for routine use in the NHS. The committee concluded that pazopanib and sunitinib are the relevant comparators in this appraisal, but noted the potential shifting of lines of treatment in the treatment pathway.\n\n## Sunitinib and pazopanib can be considered clinically equivalent\n\nThe clinical experts in the original appraisal noted that, in practice, sunitinib and pazopanib are considered clinically equivalent. The committee recalled that previous appraisals also considered sunitinib and pazopanib to be clinically equivalent, and there was no new evidence to change this conclusion. The committee concluded that pazopanib and sunitinib can be considered clinically equivalent.\n\n# Clinical evidence\n\n## Updated CheckMate 214 data still shows that nivolumab with ipilimumab is more clinically effective than sunitinib\n\nThe main source of evidence came from CheckMate\xa0214, an open-label randomised control trial, with sunitinib as the comparator. The co-primary endpoints of the trial were overall survival and progression-free survival, amended in the protocol by the company to include overall response rate. The trial stratified people by risk of death using a prognostic risk score, as defined by the International Metastatic Renal Cell Carcinoma Database Consortium scoring system. Risk level is determined using 6\xa0risk factors including Karnofsky performance status score, time from original diagnosis, and levels of haemoglobin, serum calcium, neutrophils and platelets. The likelihood of survival is considered intermediate ('intermediate risk') when there are 1 or 2\xa0risk factors, and poor ('poor risk') when there are 3 or more risk factors present. The population in the trial was wider than the population in the marketing authorisation, which limits treatment to people with disease that is intermediate or poor risk. The company stated that the trial had sufficient power to investigate clinical outcomes in a combined intermediate- or poor-risk group (n=847; 667 intermediate and 180 poor risk, respectively). The trial also included 249\xa0people with favourable-risk disease, but this group was not included in the marketing authorisation. In the original appraisal, the company presented 2\xa0interim data cuts with the most recent from August\xa02018, with a minimum of 30\xa0months' follow up (referred to as the '30-month data cut'). For the review of this guidance, the company presented a further data cut from February\xa02021, reflecting a median follow up of 67.7\xa0months and a minimum of 60\xa0months' follow up (referred to as the '60-month data cut'). The updated evidence from the 60-month data cut showed improved overall survival that was consistent with the extrapolations in the original submission. Median overall survival did not change from the 30-month to the 60-month data cut for sunitinib: 27\xa0months (95% confidence interval [CI] 22\xa0to 33\xa0months for the 30-month data cut, and 22\xa0to 34\xa0months for the 60-month data cut). Median overall survival in the nivolumab with ipilimumab arm was not reached at 30\xa0months (95% CI 36\xa0months to not evaluable), but was 47\xa0months at 60\xa0months (95% CI 35 to 57). The hazard ratio between treatment arms for overall survival did not show a substantial change, from 0.66 (95% CI 0.54 to 0.80) at 30\xa0months to 0.68 (CI 0.58 to 0.81) at 60\xa0months, mostly associated with better than predicted survival of people in the sunitinib treatment arm. The committee concluded that the updated clinical evidence for nivolumab with ipilimumab closely matched the extrapolations from the original appraisal, showing that nivolumab with ipilimumab is more clinically effective than sunitinib.\n\n## Supplementary clinical evidence came from the Systemic Anti-Cancer Therapy dataset\n\nPublic Health England submitted data from the Systemic Anti-Cancer Therapy (SACT) dataset, including data from 814\xa0people who had nivolumab with ipilimumab through the Cancer Drugs Fund during the period of April\xa02019 to November\xa02020. The SACT data had a median follow up of 10.8\xa0months, ranging from 5\xa0to 24.7\xa0months. The committee noted that naively comparing the data from SACT with data from CheckMate\xa0214 showed worse survival for people in the NHS compared with participants in the trial. The committee considered that differences in characteristics of the patients in the NHS and in the trial likely accounted for this, notably that the SACT data include a higher proportion of people with poor-risk disease (see section\xa03.7). The committee considered that the distribution of characteristics in the SACT dataset was likely to better represent people who had nivolumab with ipilimumab in NHS clinical practice. However, the SACT dataset provided no comparative evidence because it included only people who had nivolumab with ipilimumab. The committee concluded that the relative effect of nivolumab with ipilimumab compared with sunitinib from CheckMate\xa0214 was the most appropriate source of evidence on the clinical efficacy of nivolumab with ipilimumab, and for economic modelling.\n\n## Nivolumab with ipilimumab appears to be more effective in poor-risk than in intermediate-risk disease\n\nIn the original appraisal, the company had presented estimates of relative effectiveness separated by risk status for the intermediate- and poor-risk subgroups. The committee visually inspected the Kaplan–Meier curves and concluded that the curves suggested that treatment was more effective in poor-risk disease than in intermediate disease. The committee was aware this could represent poor-risk disease responding poorly to sunitinib rather than responding particularly well to nivolumab with ipilimumab. The ERG had requested CheckMate\xa0214 outcomes from the 60-month data cut stratified by risk status, but the company had not provided this, noting that the trial was 'not powered' for outcomes by subgroups. The committee recognised that if the study had more participants, the trial would very likely have shown significant effect modification by risk status. The company considered these estimates by subgroup to be confidential so they cannot be presented here. The committee was also aware that the marketing authorisation does not include favourable disease. The ERG noted that in the SACT data, overall survival appears to be lower for people with poor-risk disease. Before the meeting, the clinical experts noted that a recent post hoc analysis from CheckMate 214 showed that people with sarcomatoid disease may have a particular benefit with nivolumab with ipilimumab over sunitinib at 42\xa0months' follow up. A clinical expert noted that sarcomatoid histology has a higher tumour mutational burden and may benefit from immunotherapy to a greater extent. They also noted that these people are likely to have poor-risk disease. The committee noted that the company chose not to present any analyses stratified by risk status from the 60-month data cut. The committee nonetheless concluded that there is likely to be a difference in relative effectiveness by risk, but that it would have preferred to see outcomes by subgroup from the updated trial data cut.\n\n## The SACT dataset should inform the proportion of people with poor-risk disease in the economic model\n\nCheckMate\xa0214 included 21% of people with a high risk of death (poor-risk disease), and the clinical experts in the previous appraisal considered that this proportion was likely larger in NHS practice. If intermediate- and poor-risk disease respond differently to treatment (see section\xa03.6), the absolute treatment effect in the combined group would depend on the distribution of baseline risk, which in turn would affect cost effectiveness. The SACT data, which was expected to inform the true proportion of people with intermediate- and poor-risk renal cell carcinoma in the NHS, included 35% of people with poor-risk disease (with the remainder having intermediate-risk disease). The committee considered that the SACT dataset included more people with poor-risk disease than it might otherwise have done because of the COVID-19 pandemic. The company presented evidence from several audits reporting delayed referrals, consultant appointments and diagnosis during the pandemic. It considered that this supported the larger proportion of people with poor-risk disease in the SACT dataset. The ERG considered that the SACT dataset better represented NHS patients who would have nivolumab with ipilimumab than the trial. It noted there was limited evidence that the pandemic influenced risk levels in SACT, noting that 87% of the included people had an Eastern Cooperative Oncology Group performance status of 0 or 1. The NHS England clinical lead for the Cancer Drugs Fund did not consider that the pandemic affected the proportion of people with poor-risk disease in the NHS. The committee concluded that the SACT dataset should inform the proportion of people with poor-risk disease in the economic model. However, it would have preferred to see the proportions of each risk group from the SACT dataset used to weight the effectiveness estimates of each risk group using the CheckMate\xa0214 trial outcomes. It considered that this analysis would likely reduce the cost-effectiveness estimates because the incremental benefit over sunitinib or pazopanib for poor-risk disease is likely to be higher than for intermediate-risk disease.\n\n## Treatment crossover may favour sunitinib and would have a minimal effect on the cost-effectiveness results\n\nIn the original guidance, for the 30-month data cut, the company had amended the trial protocol to allow people randomised to sunitinib to switch ('crossover') to nivolumab with ipilimumab, and had not adjusted the trial results for this. While acknowledging that the crossover likely biased the hazard ratio towards zero, the committee wished to see long-term survival predictions for nivolumab with ipilimumab based on further data collection from CheckMate\xa0214, adjusted for treatment switching. In the company's new submission, it did not adjust for treatment switching because it considered few people had switched treatments. The ERG noted that the unadjusted results likely favoured the comparator. The committee would have preferred to see adjusted results, but acknowledged the likely impact on the cost-effectiveness estimates was minimal given the relatively small number of people switching treatment. The impact of adjusting for treatment switching is uncertain, however it may favour sunitinib.\n\n## Modelling second-line treatments based on the CheckMate 214 trial is appropriate\n\nIn the original appraisal, the committee concluded that second-line treatments in CheckMate\xa0214 did not reflect NHS clinical practice. For example, some people randomised to nivolumab with ipilimumab in CheckMate\xa0214 received immunotherapies again at later lines of treatment. The committee preferred an analysis that included both costs and benefits of treatments used in second-line treatment and beyond that reflected NHS clinical practice. During the original appraisal it considered that SACT data could inform this. In its new submission to NICE, the company used second-line and beyond treatment data from CheckMate\xa0214 because of differences in follow up between the trial and SACT (minimum 60\xa0months compared with minimum 5\xa0months, respectively). It also provided a scenario using the proportions of second-line treatments from the SACT dataset. The ERG agreed that using treatments from the longer CheckMate\xa0214 trial was appropriate. The clinical experts considered that the SACT treatments best matched NHS clinical practice. They noted that after sunitinib, people will often have either nivolumab or cabozantinib; whereas after nivolumab with ipilimumab, people will have a tyrosine kinase inhibitor – usually cabozantinib, but sometimes sunitinib, tivozanib, or lenvatinib with everolimus (see section\xa03.2). The committee noted that the NHS would not offer immunotherapy twice, and heard from the clinical experts that there is little evidence that a second round of immunotherapy works. The committee was concerned about using CheckMate\xa0214 as a source of data for second-line and beyond treatments if any of these treatments not used in the NHS influenced survival outcomes. It considered that the true cost-effectiveness results may be somewhere between those based on trial data and those based on SACT data. It also noted that removing additional costs of nivolumab monotherapy after treatment with nivolumab with ipilimumab in the CheckMate\xa0214 trial (because immunotherapy would likely not be offered twice) would reduce the cost-effectiveness estimates. The committee preferred to use evidence on effectiveness and costs from the same source, and concluded that it was appropriate to use CheckMate\xa0214 data for second-line and beyond treatments.\n\n# Adverse events\n\n## Nivolumab with ipilimumab is well tolerated compared with tyrosine kinase inhibitors\n\nIn the original appraisal, the clinical experts explained that in their experience, nivolumab with ipilimumab is well tolerated and has a preferable adverse event profile compared with tyrosine kinase inhibitors. The committee acknowledged that nivolumab and ipilimumab are associated with some rare but unpleasant and potentially serious adverse events that are specific to immunotherapy. The clinical experts stated that clinicians are experienced in recognising and managing these serious adverse events. The committee maintained its conclusion that nivolumab with ipilimumab is well tolerated compared with tyrosine kinase inhibitors.\n\n# The company's economic model\n\n## The company's model structure matches the committee's preferred assumptions from the original appraisal\n\nThe company used a partitioned survival model to estimate the cost effectiveness of nivolumab plus ipilimumab compared with sunitinib and pazopanib. The model included 6\xa0health states: progression-free on treatment, progression-free off treatment, post-progression on treatment, post-progression off treatment, terminal care, and dead. The probability of being in a given health state was defined by the area under the curves for progression-free survival, overall survival, and their difference. The cycle length was 1\xa0week and the time horizon was 40\xa0years. The committee noted that the company's original economic model included an 'immunological effect' that resulted in people taking nivolumab with ipilimumab being effectively cured. It had previously concluded that this was not appropriately implemented and therefore the company did not explicitly include it in its resubmission; the ERG considered this approach appropriate. The committee concluded that the model structure was acceptable and closely matched its preferred assumptions from the original appraisal.\n\n# Survival modelling in the economic model\n\n## The overall survival extrapolations are appropriate\n\nThe committee recognised that the trial evidence did not span the whole time horizon of the model. The company explored the most appropriate hazard function to extrapolate overall survival for each of the treatments using the updated 60-month data from CheckMate\xa0214. The committee originally concluded that both the company and the ERG's preferred extrapolations for overall survival were clinically plausible (log-normal and Kaplan–Meier with exponential extrapolation, respectively), but the absence of long-term data prevented it from determining which was most appropriate. It noted that the log-normal distribution predicted that a small proportion of people, not explicitly modelled as having been cured, would effectively be cured. Using the updated 60-month CheckMate\xa0214 data, the company again considered that the log-normal curve was the most appropriate to extrapolate overall survival, based on goodness-of-fit to the data and clinical validation of predicted risk of death over time. The ERG was satisfied that the company used appropriate methods to select the model, but questioned the plausibility of its projections for overall survival in the long term. The ERG highlighted that a large proportion of gains in both life years and quality-adjusted life years (QALYs) for nivolumab plus ipilimumab compared with sunitinib in the model occurred in the extrapolated period. The ERG emphasised that a large proportion of these patients remained in the progression-free state. The committee noted that the company's scenario analyses using alternative extrapolations increased the cost-effectiveness estimates, demonstrating the importance of the choice of extrapolation method. The committee considered that the updated data supported the company's choice of the log-normal hazard function and that a proportion of people in CheckMate\xa0214 would effectively be 'cured' with immunotherapy. The committee concluded that the extrapolations of overall survival were appropriate but, to explore uncertainty, it considered sensitivity analyses using other assumptions around extrapolating how the rate of death changes over time in its decision-making.\n\n## The company and ERG assumed that death rates for nivolumab with ipilimumab and sunitinib or pazopanib would equalise at different times\n\nIn its updated base case, the company assumed that nivolumab with ipilimumab would lead to a lower death rate than sunitinib or pazopanib, until the point at which the curve extrapolating overall survival for nivolumab with ipilimumab equalled the general population mortality curve, approximately 21\xa0years from the start of treatment. The ERG was concerned that this approach was not supported by the CheckMate\xa0214 trial data, which showed higher death rates for nivolumab with ipilimumab than for sunitinib at several time points. The ERG considered that the annualised hazard rates for each of the treatments equalised at approximately 4.5\xa0years. Moreover, the ERG noted that clinical advice suggests death rates decrease over time, which the CheckMate\xa0214 trial did not show for nivolumab with ipilimumab. The ERG considered that second-line treatments may have equalised the hazards for death between treatments, notably because a high proportion of people treated with sunitinib then received nivolumab monotherapy as a second-line or later treatment. The ERG provided 2\xa0scenarios in which the hazards equalised at 4.5\xa0years, 1 in which the death rate for sunitinib or pazopanib was set to the rate for nivolumab with ipilimumab, and 1 in which the death rate for nivolumab with ipilimumab was set to the rate for sunitinib or pazopanib. Both showed a range of potential effects of equalised hazards for death.\n\n## The company submitted further data and analyses to support its view\n\nThe company did not consider that the ERG's analysis of hazard rates used a recognised methodology, and countered the ERG's scenarios with its own evidence:\n\nIt submitted data on people in the CheckMate\xa0214 trial who were alive after 5\xa0years, demonstrating that a larger proportion of people treated with nivolumab and ipilimumab were progression free than those in the sunitinib arm. It considered that this was evidence of a sustained response. However, the ERG noted that some people in the sunitinib arm also had a sustained response for 5\xa0years. The ERG further noted the high proportion of people in the sunitinib arm who later had nivolumab monotherapy.\n\nThe company considered that the increased hazard of death at the end of the observed trial period in the nivolumab with ipilimumab arm was an artefact. To support this conclusion, it submitted smoothed hazard plots based on datasets truncated at different months within the trial duration. The ERG considered that the smoothed hazard plots made it difficult to see changes in hazards that were occurring over time. It also felt that nivolumab monotherapy would be more likely to have a different effect after sunitinib treatment than other second-line treatments would have after nivolumab with ipilimumab, which could result in a convergence of hazards.\n\n## The death rates are likely to equalise somewhere between the company and ERG's base case assumptions\n\nThe committee considered there was substantial uncertainty in the rates of death at the end of the trial and the extrapolations. It considered that it would have liked to see plots of the hazard ratio over time implied by the survival extrapolations used in the economic model, and further sensitivity analysis that assumed different effects of gradual convergence of the death hazards. It preferred the smoothed hazard plots to demonstrate hazards observed during the trial, but recognised that the ERG's analysis of convergence of death hazards at 4.5\xa0years may represent the earliest plausible estimate of the time point of convergence. It concluded that the death hazards between arms would be likely to equalise, probably between 4.5\xa0and 21\xa0years, between the company's base case and the ERG scenarios. The committee concluded that it was appropriate to consider incremental cost-effectiveness ratios (ICERs) resulting from this range.\n\n# Utility values\n\n## It is not appropriate to assume different utilities based on treatment arm for the entire time horizon, but this minimally impacts the ICERs\n\nIn the original appraisal, the committee considered that the quality of life estimates should reflect whether disease had progressed, which treatment a person had, and being on or off treatment. The company added utilities by progression status in its new model. The ERG noted that people in the new model were assumed to have different utilities depending on the treatment, even after stopping treatment, and for the remainder of the time horizon. The ERG considered this unjustified, noting that utility values are likely to equalise as people receive further treatments. The ERG provided a scenario using the same utility values for health states in both treatment arms over the modelled period. A patient expert noted that she did not feel very different on or off treatment or before or after progression, apart from when she experienced a side effect. A clinical expert noted that treatment-related adverse events may drive utility when on treatment. The committee considered it was appropriate to consider disutility associated with treatment when on treatment, but that having different utilities when off treatment, particularly if stopping treatment because of an adverse event, was not appropriate for the whole modelled time horizon. Based on the scenario provided by the ERG, the committee concluded that these different utility values are likely to have minimal impact on the ICERs.\n\n# Cost-effectiveness estimate\n\n## The most likely cost-effectiveness estimate is within what NICE considers an acceptable use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee concluded that the true ICERs for nivolumab and ipilimumab compared with sunitinib or pazopanib may lie between those of the company's base case and the ERG scenarios (see section\xa03.15). The cost-effectiveness results are commercial in confidence and cannot be reported here. The committee noted that most of the ICERs were towards the higher end of the range normally considered an acceptable use of NHS resources (£20,000 to £30,000 per QALY gained) but that there was some uncertainty around where the true ICER lies. It also noted that several preferred assumptions that had not been incorporated into the models were likely to decrease the ICERs:\n\nincreasing the proportion of people with poor-risk disease included in the model, reflecting the proportion in the SACT dataset (see section\xa03.7)\n\nadjusting results for treatment crossover in CheckMate\xa0214 from sunitinib to nivolumab with ipilimumab (see section\xa03.8)\n\nremoving additional costs of nivolumab monotherapy after nivolumab with ipilimumab, which does not represent clinical practice (see section\xa03.9).Taking these factors into account, the committee concluded that nivolumab with ipilimumab was likely to be an acceptable use of NHS resources.\n\n# Equality\n\n## There are no equalities issues\n\nNo equality issues were identified.\n\n# Conclusion\n\n## Nivolumab with ipilimumab is recommended for routine use\n\nThe committee concluded that nivolumab with ipilimumab was more effective than treatments currently offered in the NHS for renal cell carcinoma and that the most plausible cost-effectiveness estimates were within what NICE considers an acceptable use of NHS resources. Therefore, nivolumab with ipilimumab is recommended for adults with untreated advanced renal cell carcinoma that is intermediate or poor risk as defined in the International Metastatic Renal Cell Carcinoma Database Consortium criteria."}
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https://www.nice.org.uk/guidance/ta780
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Evidence-based recommendations on nivolumab (Opdivo) with ipilimumab (Yervoy) for untreated advanced renal cell carcinoma in adults.
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Hypertension in adults: diagnosis and management
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Hypertension in adults: diagnosis and management
This guideline covers identifying and treating primary hypertension (high blood pressure) in people aged 18 and over, including people with type 2 diabetes. It aims to reduce the risk of cardiovascular problems such as heart attacks and strokes by helping healthcare professionals to diagnose hypertension accurately and treat it effectively.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The recommendations on measuring blood pressure and diagnosing hypertension in this guideline apply to all adults, including those with type 2 diabetes. The recommendations on treatment and monitoring link to NICE guidelines on chronic kidney disease, type 1 diabetes and hypertension in pregnancy at points in the care pathway where treatment differs. The recommendations on treatment and monitoring apply to adults with type 2 diabetes and replace recommendations on diagnosing and managing hypertension in NICE's guideline on type 2 diabetes in adults.
# Measuring blood pressure
Ensure that healthcare professionals taking blood pressure measurements have adequate initial training and periodic review of their performance.
Because automated devices may not measure blood pressure accurately if there is pulse irregularity (for example, due to atrial fibrillation), palpate the radial or brachial pulse before measuring blood pressure. If pulse irregularity is present, measure blood pressure manually using direct auscultation over the brachial artery.
Healthcare providers must ensure that devices for measuring blood pressure are properly validated, maintained and regularly recalibrated according to manufacturers' instructions. See the British and Irish Hypertension Society's website for a list of validated blood pressure monitoring devices.
When measuring blood pressure in the clinic or in the home, standardise the environment and provide a relaxed, temperate setting, with the person quiet and seated, and their arm outstretched and supported. Use an appropriate cuff size for the person's arm.
In people with symptoms of postural hypotension (falls or postural dizziness):
measure blood pressure with the person either supine or seated
measure blood pressure again with the person standing for at least 1 minute before measurement.
If the systolic blood pressure falls by 20 mmHg or more when the person is standing:
review medication
measure subsequent blood pressures with the person standing
consider referral to specialist care if symptoms of postural hypotension persist.
# Diagnosing hypertension
When considering a diagnosis of hypertension, measure blood pressure in both arms:
If the difference in readings between arms is more than 15 mmHg, repeat the measurements.
If the difference in readings between arms remains more than 15 mmHg on the second measurement, measure subsequent blood pressures in the arm with the higher reading.
If blood pressure measured in the clinic is 140/90 mmHg or higher:
Take a second measurement during the consultation.
If the second measurement is substantially different from the first, take a third measurement.Record the lower of the last 2 measurements as the clinic blood pressure.
If clinic blood pressure is between 140/90 mmHg and 180/120 mmHg, offer ambulatory blood pressure monitoring (ABPM) to confirm the diagnosis of hypertension. See the section on identifying who to refer for people with a clinic blood pressure 180/120 mmHg or higher.
If ABPM is unsuitable or the person is unable to tolerate it, offer home blood pressure monitoring (HBPM) to confirm the diagnosis of hypertension.
While waiting for confirmation of a diagnosis of hypertension, carry out:
investigations for target organ damage (see recommendation 1.3.3), followed by
formal assessment of cardiovascular risk using a cardiovascular risk assessment tool (see the section on full formal risk assessment in NICE's guideline on cardiovascular disease).
When using ABPM to confirm a diagnosis of hypertension, ensure that at least 2 measurements per hour are taken during the person's usual waking hours (for example, between 08:00 and 22:00). Use the average value of at least 14 measurements taken during the person's usual waking hours to confirm a diagnosis of hypertension.
When using HBPM to confirm a diagnosis of hypertension, ensure that:
for each blood pressure recording, 2 consecutive measurements are taken, at least 1 minute apart and with the person seated and
blood pressure is recorded twice daily, ideally in the morning and evening and
blood pressure recording continues for at least 4 days, ideally for 7 days.Discard the measurements taken on the first day and use the average value of all the remaining measurements to confirm a diagnosis of hypertension.
Confirm diagnosis of hypertension in people with a:
clinic blood pressure of 140/90 mmHg or higher and
ABPM daytime average or HBPM average of 135/85 mmHg or higher.
If hypertension is not diagnosed but there is evidence of target organ damage, consider carrying out investigations for alternative causes of the target organ damage (for information on investigations, see NICE's guidelines on chronic kidney disease and chronic heart failure).
If hypertension is not diagnosed, measure the person's clinic blood pressure at least every 5 years subsequently, and consider measuring it more frequently if the person's clinic blood pressure is close to 140/90 mmHg.
## Annual blood pressure measurement for people with type 2 diabetes
Measure blood pressure at least annually in an adult with type 2 diabetes without previously diagnosed hypertension or renal disease. Offer and reinforce preventive lifestyle advice.
## Specialist investigations for possible secondary causes of hypertension
Consider the need for specialist investigations in people with signs and symptoms suggesting a secondary cause of hypertension.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnosing hypertension .
Full details of the evidence and the committee's discussion are in evidence review A: diagnosis.
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# Assessing cardiovascular risk and target organ damage
For guidance on the early identification and management of chronic kidney disease, see NICE's guideline on chronic kidney disease.
Use a formal estimation of cardiovascular risk to discuss prognosis and healthcare options with people with hypertension, both for raised blood pressure and other modifiable risk factors.
Estimate cardiovascular risk in line with the recommendations on identifying and assessing cardiovascular disease risk in NICE's guideline on cardiovascular disease. Use clinic blood pressure measurements to calculate cardiovascular risk.
For all people with hypertension offer to:
test for the presence of protein in the urine by sending a urine sample for estimation of the albumin:creatinine ratio and test for haematuria using a reagent strip
take a blood sample to measure glycated haemoglobin (HbA1C), electrolytes, creatinine, estimated glomerular filtration rate, total cholesterol and HDL cholesterol
examine the fundi for the presence of hypertensive retinopathy
arrange for a 12‑lead electrocardiograph to be performed.
# Treating and monitoring hypertension
## Lifestyle interventions
For guidance on the prevention of obesity and cardiovascular disease, see NICE's guidelines on obesity prevention and cardiovascular disease prevention.
Offer lifestyle advice to people with suspected or diagnosed hypertension, and continue to offer it periodically.
Ask about people's diet and exercise patterns because a healthy diet and regular exercise can reduce blood pressure. Offer appropriate guidance and written or audiovisual materials to promote lifestyle changes.
Ask about people's alcohol consumption and encourage a reduced intake if they drink excessively, because this can reduce blood pressure and has broader health benefits. See the recommendations for practice in NICE's guideline on alcohol-use disorders.
Discourage excessive consumption of coffee and other caffeine-rich products.
Encourage people to keep their dietary sodium intake low, either by reducing or substituting sodium salt, as this can reduce blood pressure. Note that salt substitutes containing potassium chloride should not be used by older people, people with diabetes, pregnant women, people with kidney disease and people taking some antihypertensive drugs, such as ACE inhibitors and angiotensin II receptor blockers. Encourage salt reduction in these groups.
Do not offer calcium, magnesium or potassium supplements as a method for reducing blood pressure.
Offer advice and help to smokers to stop smoking. See NICE's guideline on tobacco.
Inform people about local initiatives by, for example, healthcare teams or patient organisations that provide support and promote healthy lifestyle change, especially those that include group work for motivating lifestyle change.
For a short explanation of why the committee deleted the recommendation on relaxation therapies and how this might affect practice, see the rationale and impact section on relaxation therapies .
Full details of the evidence and the committee's discussion are in evidence review H: relaxation therapies.
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## Starting antihypertensive drug treatment
NICE has produced a patient decision aid on treatment options for hypertension to help people and their healthcare professionals discuss the different types of treatment and make a decision that is right for each person.
For advice on shared decision making for medicines, see the information on patient decision aids in NICE's guideline on medicines optimisation.
To support adherence and ensure that people with hypertension make the most effective use of their medicines, see NICE's guideline on medicines adherence.
Offer antihypertensive drug treatment in addition to lifestyle advice to adults of any age with persistent stage 2 hypertension. Use clinical judgement for people of any age with frailty or multimorbidity (see also NICE's guideline on multimorbidity).
Discuss starting antihypertensive drug treatment, in addition to lifestyle advice, with adults aged under 80 with persistent stage 1 hypertension who have 1 or more of the following:
target organ damage
established cardiovascular disease
renal disease
diabetes
an estimated 10‑year risk of cardiovascular disease of 10% or more. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity).
Discuss with the person their individual cardiovascular disease risk and their preferences for treatment, including no treatment, and explain the risks and benefits before starting antihypertensive drug treatment. Continue to offer lifestyle advice and support them to make lifestyle changes (see the section on lifestyle interventions), whether or not they choose to start antihypertensive drug treatment.
Consider antihypertensive drug treatment in addition to lifestyle advice for adults aged under 60 with stage 1 hypertension and an estimated 10‑year risk below 10%. Bear in mind that 10‑year cardiovascular risk may underestimate the lifetime probability of developing cardiovascular disease.
Consider antihypertensive drug treatment in addition to lifestyle advice for people aged over 80 with stage 1 hypertension if their clinic blood pressure is over 150/90 mmHg. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity).
For adults aged under 40 with hypertension, consider seeking specialist evaluation of secondary causes of hypertension and a more detailed assessment of the long-term balance of treatment benefit and risks.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on starting antihypertensive drug treatment .
Full details of the evidence and the committee's discussion are in evidence review C: initiating treatment.
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## Monitoring treatment and blood pressure targets
For specific recommendations on blood pressure control in people with other conditions or who are pregnant, see also the NICE guidelines on chronic kidney disease, type 1 diabetes and hypertension in pregnancy.
Use clinic blood pressure measurements to monitor the response to lifestyle changes or drug treatment in people with hypertension.
Measure standing as well as seated blood pressure (see recommendation 1.1.6) in people with hypertension and:
with type 2 diabetes or
with symptoms of postural hypotension or
aged 80 and over. In people with a significant postural drop or symptoms of postural hypotension, treat to a blood pressure target based on standing blood pressure.
Advise people with hypertension who choose to self-monitor their blood pressure to use HBPM. (NHS England is supporting the use of HBPM through the blood pressure@home scheme.)
Consider ABPM or HBPM, in addition to clinic blood pressure measurements, for people with hypertension identified as having a white-coat effect or masked hypertension (in which clinic and non-clinic blood pressure results are conflicting). Be aware that the corresponding measurements for ABPM and HBPM are 5 mmHg lower than for clinic measurements (see recommendation 1.2.8 for diagnostic thresholds).
For people who choose to use HBPM, provide:
training and advice on using home blood pressure monitors
information about what to do if they are not achieving their target blood pressure.Be aware that the corresponding measurements for HBPM are 5 mmHg lower than for clinic measurements (see recommendation 1.2.8 for diagnostic thresholds).
For adults with hypertension aged under 80, reduce clinic blood pressure to below 140/90 mmHg and ensure that it is maintained below that level.
For adults with hypertension aged 80 and over, reduce clinic blood pressure to below 150/90 mmHg and ensure that it is maintained below that level. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity).
When using ABPM or HBPM to monitor the response to treatment in adults with hypertension, use the average blood pressure level taken during the person's usual waking hours (see recommendations 1.2.6 and 1.2.7). Reduce blood pressure and ensure that it is maintained:
below 135/85 mmHg for adults aged under 80
below 145/85 mmHg for adults aged 80 and over. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity).
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment and blood pressure targets for people without cardiovascular disease .
Full details of the evidence and the committee's discussion are in evidence review B: monitoring the response to treatment.
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Use the same blood pressure targets for people with and without cardiovascular disease.
For a short explanation of why the committee made the recommendation on blood pressure targets for people with cardiovascular disease and how this might affect practice, see the rationale and impact section on monitoring treatment and blood pressure targets for people with cardiovascular disease .
Full details of the evidence and the committee's discussion are in the evidence review J: blood pressure targets.
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Provide an annual review of care for adults with hypertension to monitor blood pressure, provide people with support, and discuss their lifestyle, symptoms and medication.
For an adult with type 2 diabetes on antihypertensive drug treatment when diabetes is diagnosed, review blood pressure control and medications used. Make changes only if there is poor control or if current drug treatment is not appropriate because of microvascular complications or metabolic problems.
## Choosing antihypertensive drug treatment (for people with or without type 2 diabetes)
The recommendations in this section apply to people with hypertension with or without type 2 diabetes. They replace the recommendations on diagnosing and managing hypertension in NICE's guideline on type 2 diabetes in adults. For guidance on choosing antihypertensive drug treatment in people with type 1 diabetes, see also the section on control of cardiovascular risk in NICE's guideline on type 1 diabetes.
Note that ACE inhibitors and angiotensin II receptor antagonists should not be used in pregnant or breastfeeding women or women planning pregnancy unless absolutely necessary, in which case the potential risks and benefits should be discussed. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, recommendations on how to use for breastfeeding and the related clarification on breastfeeding.
For guidance on choice of hypertensive agent in people with chronic kidney disease, see NICE's guideline on chronic kidney disease. If possible, offer treatment with drugs taken only once a day.
Prescribe non-proprietary drugs if these are appropriate and minimise cost.
Offer people with isolated systolic hypertension (systolic blood pressure 160 mmHg or more) the same treatment as people with both raised systolic and diastolic blood pressure.
Offer antihypertensive drug treatment to women of childbearing potential with diagnosed hypertension in line with the recommendations in this guideline. For women considering pregnancy or who are pregnant or breastfeeding, manage hypertension in line with the recommendations on management of pregnancy with chronic hypertension, and on antihypertensive treatment while breastfeeding in NICE's guideline on hypertension in pregnancy.
When choosing antihypertensive drug treatment for adults of Black African or African–Caribbean family origin, consider an angiotensin II receptor blocker (ARB), in preference to an angiotensin-converting enzyme (ACE) inhibitor. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.
For people with cardiovascular disease:
Follow the recommendations for disease-specific indications in the NICE guideline on their condition (for example, when prescribing an ACE inhibitor or an ARB for secondary prevention of myocardial infarction). Relevant recommendations include:
drug therapy for secondary prevention in the NICE guideline on acute coronary syndromes
treatment after stabilisation in the NICE guideline on acute heart failure
treating heart failure with reduced ejection fraction in the NICE guideline on chronic heart failure
drugs for secondary prevention of cardiovascular disease in the NICE guideline on stable angina
blood pressure management in the NICE guideline on type 1 diabetes in adults.
If their blood pressure remains uncontrolled, offer antihypertensive drug treatment in line with the recommendations in this section.
For a short explanation of why the committee made the recommendation on choosing antihypertensive drug treatment for people with cardiovascular disease and how this might affect practice, see the rationale and impact section on choosing antihypertensive drug treatment for people with cardiovascular disease .
Full details of the evidence and the committee's discussion are in the evidence review K: pharmacological treatment in cardiovascular disease.
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Offer an ACE inhibitor or an ARB to adults starting step 1 antihypertensive treatment who:
have type 2 diabetes and are of any age or family origin (see also recommendation 1.4.30 for adults of Black African or African–Caribbean family origin) or
are aged under 55 but not of Black African or African–Caribbean family origin. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.
If an ACE inhibitor is not tolerated, for example because of cough, offer an ARB to treat hypertension. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.
Do not combine an ACE inhibitor with an ARB to treat hypertension.
Offer a calcium-channel blocker (CCB) to adults starting step 1 antihypertensive treatment who:
are aged 55 or over and do not have type 2 diabetes or
are of Black African or African–Caribbean family origin and do not have type 2 diabetes (of any age).
If a CCB is not tolerated, for example because of oedema, offer a thiazide-like diuretic to treat hypertension.
If there is evidence of heart failure, offer a thiazide-like diuretic and follow NICE's guideline on chronic heart failure.
If starting or changing diuretic treatment for hypertension, offer a thiazide-like diuretic, such as indapamide in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide.
For adults with hypertension already having treatment with bendroflumethiazide or hydrochlorothiazide, who have stable, well-controlled blood pressure, continue with their current treatment.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on step 1 treatment .
Full details of the evidence and the committee's discussion are in evidence review E: step 1 treatment.
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Before considering next step treatment for hypertension discuss with the person if they are taking their medicine as prescribed and support adherence in line with NICE's guideline on medicines adherence.
If hypertension is not controlled in adults taking step 1 treatment of an ACE inhibitor or ARB, offer the choice of 1 of the following drugs in addition to step 1 treatment:
a CCB or
a thiazide-like diuretic.
If hypertension is not controlled in adults taking step 1 treatment of a CCB, offer the choice of 1 of the following drugs in addition to step 1 treatment:
an ACE inhibitor or
an ARB or
a thiazide-like diuretic.
If hypertension is not controlled in adults of Black African or African–Caribbean family origin who do not have type 2 diabetes taking step 1 treatment, consider an ARB, in preference to an ACE inhibitor, in addition to step 1 treatment.
Before considering next step treatment for hypertension:
review the person's medications to ensure they are being taken at the optimal tolerated doses and
discuss adherence (see recommendation 1.4.40).
If hypertension is not controlled in adults taking step 2 treatment, offer a combination of:
an ACE inhibitor or ARB (see also recommendation 1.4.30 for people of Black African or African–Caribbean family origin) and
a CCB and
a thiazide-like diuretic.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on step 2 and 3 treatment .
Full details of the evidence and the committee's discussion are in evidence review F: step 2 and step 3 treatment.
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If hypertension is not controlled in adults taking the optimal tolerated doses of an ACE inhibitor or an ARB plus a CCB and a thiazide-like diuretic, regard them as having resistant hypertension.
Before considering further treatment for a person with resistant hypertension:
Confirm elevated clinic blood pressure measurements using ambulatory or home blood pressure recordings.
Assess for postural hypotension.
Discuss adherence (see recommendation 1.4.40).
For people with confirmed resistant hypertension, consider adding a fourth antihypertensive drug as step 4 treatment or seeking specialist advice. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.
Consider further diuretic therapy with low-dose spironolactone for adults with resistant hypertension starting step 4 treatment who have a blood potassium level of 4.5 mmol/l or less. Use particular caution in people with a reduced estimated glomerular filtration rate because they have an increased risk of hyperkalaemia. In March 2019, this was an off-label use of some preparations of spironolactone. See NICE's information on prescribing medicines.
When using further diuretic therapy for step 4 treatment of resistant hypertension, monitor blood sodium and potassium and renal function within 1 month of starting treatment and repeat as needed thereafter.
Consider an alpha-blocker or beta-blocker for adults with resistant hypertension starting step 4 treatment who have a blood potassium level of more than 4.5 mmol/l.
If blood pressure remains uncontrolled in people with resistant hypertension taking the optimal tolerated doses of 4 drugs, seek specialist advice.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on step 4 treatment .
Full details of the evidence and the committee's discussion are in evidence review G: step 4 treatment.
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# Identifying who to refer for same-day specialist review
If a person has severe hypertension (clinic blood pressure of 180/120 mmHg or higher), but no symptoms or signs indicating same-day referral (see recommendation 1.5.2), carry out investigations for target organ damage (see recommendation 1.3.3) as soon as possible:
If target organ damage is identified, consider starting antihypertensive drug treatment immediately, without waiting for the results of ABPM or HBPM.
If no target organ damage is identified, confirm diagnosis by:
repeating clinic blood pressure measurement within 7 days, or
considering monitoring using ABPM (or HBPM if ABPM is not suitable or not tolerated), following recommendations 1.2.6 and 1.2.7, and ensuring a clinical review within 7 days.
Refer people for specialist assessment, carried out on the same day, if they have a clinic blood pressure of 180/120 mmHg and higher with:
signs of retinal haemorrhage or papilloedema (accelerated hypertension) or
life-threatening symptoms such as new onset confusion, chest pain, signs of heart failure, or acute kidney injury.
Refer people for specialist assessment, carried out on the same day, if they have suspected phaeochromocytoma (for example, labile or postural hypotension, headache, palpitations, pallor, abdominal pain or diaphoresis).
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on identifying who to refer for same-day specialist review .
Full details of the evidence and the committee's discussion are in evidence review I: same-day specialist review.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.
## Accelerated hypertension
A severe increase in blood pressure to 180/120 mmHg or higher (and often over 220/120 mmHg) with signs of retinal haemorrhage and/or papilloedema (swelling of the optic nerve). It is usually associated with new or progressive target organ damage and is also known as malignant hypertension.
## Established cardiovascular disease
Medical history of ischaemic heart disease, cerebrovascular disease, peripheral vascular disease, aortic aneurysm or heart failure. Cardiovascular disease is a general term for conditions affecting the heart or blood vessels. It is usually associated with a build-up of fatty deposits inside the arteries (atherosclerosis) and an increased risk of blood clots. It can also be associated with damage to arteries in organs such as the brain, heart, kidneys and eyes through deposition of glassy material within the artery walls (arteriosclerosis). Cardiovascular disease is 1 of the main causes of death and disability in the UK, but it can often largely be prevented by leading a healthy lifestyle.
## Masked hypertension
Clinic blood pressure measurements are normal (less than 140/90 mmHg), but blood pressure measurements are higher when taken outside the clinic using average daytime ambulatory blood pressure monitoring (ABPM) or average home blood pressure monitoring (HBPM) blood pressure measurements.
## Persistent hypertension
High blood pressure at repeated clinical encounters.
## Stage 1 hypertension
Clinic blood pressure ranging from 140/90 mmHg to 159/99 mmHg and subsequent ABPM daytime average or HBPM average blood pressure ranging from 135/85 mmHg to 149/94 mmHg.
## Stage 2 hypertension
Clinic blood pressure of 160/100 mmHg or higher but less than 180/120 mmHg and subsequent ABPM daytime average or HBPM average blood pressure of 150/95 mmHg or higher.
## Stage 3 or severe hypertension
Clinic systolic blood pressure of 180 mmHg or higher or clinic diastolic blood pressure of 120 mmHg or higher.
## Target organ damage
Damage to organs such as the heart, brain, kidneys and eyes. Examples are left ventricular hypertrophy, chronic kidney disease, hypertensive retinopathy or increased urine albumin:creatinine ratio.
## White-coat effect
A discrepancy of more than 20/10 mmHg between clinic and average daytime ABPM or average HBPM blood pressure measurements at the time of diagnosis.# Recommendations for research
The 2019 and 2022 guideline committees have made the following recommendations for research.
# Automated blood pressure monitoring in people with atrial fibrillation
Which automated blood pressure monitors are suitable for people with hypertension and atrial fibrillation?
For a short explanation of why the committee made the recommendation for research, see the rationale on monitoring treatment and blood pressure targets for people without cardiovascular disease .
Full details of the evidence and the committee's discussion are in evidence review B: monitoring the response to treatment.
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# Thresholds for interventions in adults aged under 40
In adults aged under 40 with hypertension (with or without type 2 diabetes), what are the appropriate risk and blood pressure thresholds for starting treatment?
For a short explanation of why the committee made the recommendation for research, see the rationale on starting antihypertensive drug treatment .
Full details of the evidence and the committee's discussion are in evidence review C: initiating treatment.
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# Blood pressure targets for people aged over 80
What is the optimum blood pressure target for people aged over 80 with treated primary hypertension (with or without cardiovascular disease)?
For a short explanation of why the committee made the recommendation for research, see the rationale on blood pressure targets for people with cardiovascular disease .
Full details of the evidence and the committee's discussion are in the evidence review K: pharmacological treatment in cardiovascular disease.
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# Step 1 treatment
Are there subgroups of people with hypertension who should start on dual therapy?
For a short explanation of why the committee made the recommendation for research, see the rationale on step 1 treatment .
Full details of the evidence and the committee's discussion are in evidence review E: step 1 treatment.
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# Relaxation therapies
What is the clinical and cost effectiveness of relaxation therapies for managing primary hypertension in adults in terms of reducing cardiovascular events and improving quality of life?
For a short explanation of why the committee made the recommendation for research, see the rationale on relaxation therapies .
Full details of the evidence and the committee's discussion are in evidence review H: relaxation therapies.
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# Same-day hospital specialist assessment
Which people with extreme hypertension (220/120 mmHg or higher) or emergency symptoms should be referred for same-day hospital specialist assessment?
For a short explanation of why the committee made the recommendation for research, see the see rationale on identifying who to refer for same-day specialist review .
Full details of the evidence and the committee's discussion are in evidence review I: same-day specialist review.
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# Blood pressure targets for people with aortic aneurysm
What are the optimal blood pressure targets in adults with hypertension and aortic aneurysm, and does this vary by age?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on blood pressure targets for people with cardiovascular disease .
Full details of the evidence and the committee's discussion are in the evidence review J: blood pressure targets.
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# Blood pressure targets for people with prior ischaemic or haemorrhagic stroke
What are the optimal blood pressure targets in adults with prior ischaemic or haemorrhagic stroke, and does this vary by age?
For a short explanation of why the committee made the recommendation for research, see the rationale and impact section on blood pressure targets for people with cardiovascular disease .
Full details of the evidence and the committee's discussion are in the evidence review J: blood pressure targets.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Diagnosing hypertension
Recommendations 1.2.1 to 1.2.5 and 1.2.8
## Why the committee made the recommendations
Overall, there was limited new evidence on the accuracy of different methods of measuring blood pressure. Most of the studies identified were small, and the populations and protocols for measurement varied making interpretation difficult. However, the committee agreed that it was important to focus on the evidence from these more recent studies (post‑2000) because the evidence should reflect the current use of electronic sphygmomanometers, which have replaced mercury-based sphygmomanometers.
The evidence did not show that changing the current blood pressure thresholds for clinic measurement or home blood pressure monitoring (HBPM) would improve diagnostic accuracy compared with ambulatory blood pressure monitoring (ABPM), so the committee agreed the 2011 thresholds for diagnosis should be retained. The committee noted that these are in line with most international guidance.
Limited evidence suggested that clinic blood pressure measurement is less accurate than HBPM or ABPM when used to diagnose hypertension. The committee members acknowledged that these findings were in line with their clinical experience and agreed that clinic blood pressure measurement alone would not be an adequate method to diagnose hypertension.
The committee discussed repeat clinic blood pressure measurements when there is a difference in blood pressure between arms and noted that clinical practice varied. Based on their experience and knowledge, the committee members agreed that a cut-off of 15 mmHg would be more suitable than 20 mmHg, which was specified in the 2011 recommendations. This is in line with recent evidence that suggests a small difference in arm blood pressure is associated with an increased risk of cardiovascular events, possibly due to vascular damage.
ABPM correlates well with invasive blood pressure measurement and can identify both white-coat and masked hypertension. Based on the evidence in the 2011 guideline and the committee's experience and knowledge, it was agreed that ABPM remains the gold standard for the accurate measurement of blood pressure in primary care. ABPM has therefore been retained as the preferred method for the diagnosis of hypertension. In addition, economic evidence obtained by updating the health economic model for the 2011 guideline confirmed that ABPM is still likely to be the most cost-effective method for diagnosis, even with the inclusion of new data for improved accuracy of home and clinic measurement.
The evidence showed that validated HBPM is an accurate method of diagnosing hypertension for people in sinus rhythm. The committee's experience in clinical practice supported this, and the committee agreed that it is a suitable alternative when ABPM is unsuitable or not tolerated. The committee noted that the British and Irish Hypertension Society maintains a list of validated blood pressure devices for home use. The British and Irish Hypertension Society is an independent reviewer of published work and this does not imply any endorsement of specific devices by NICE.
The evidence did not suggest that there were any benefits of adding telemonitoring to HBPM. Therefore, the committee agreed that it could not make a recommendation on telemonitoring for the diagnosis of hypertension.
## How the recommendations might affect practice
The recommendations reinforce current good practice. However, the committee noted that implementation of the 2011 recommendations on ABPM has been challenging and that there is still variation in practice. A change in practice and additional resources and training will be needed in areas where there is currently no access to ABPM devices. However, ABPM was found to be the most cost-effective method of diagnosis, and it is anticipated that the long-term benefits of accurate diagnosis and treatment (such as avoiding over diagnosis and unnecessary treatment) will outweigh any initial costs.
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# Relaxation therapies
## Why the committee deleted the recommendation on relaxation therapies
The evidence on relaxation therapies was limited to a single small study. The study suggested some benefit in reducing angina and myocardial infarction, but it also suggested an increase in stroke. The committee agreed that the study was not adequate to assess the effectiveness of these therapies or to make a recommendation.
The 2011 guideline stated that relaxation therapies could reduce blood pressure, but it did not recommend their routine use in practice. The committee noted that this was based on evidence for reducing blood pressure only, and there was no evidence of a direct benefit to people with hypertension, such as improving quality of life or reducing cardiovascular events. The committee agreed there was insufficient evidence of benefit to recommend that people pursue this option themselves and agreed to remove this recommendation. It is not the intention of the committee to stop people from trying relaxation therapies if they wish to, but to make people aware that there is less evidence for benefit of this intervention compared with other lifestyle interventions or pharmacological treatment. The committee agreed that the clinical focus for non-pharmacological treatment of hypertension should be on encouraging people to make lifestyle changes, such as taking regular exercise and maintaining a healthy weight.
The committee agreed that further research would be useful to determine whether relaxation therapies are a clinically effective treatment for hypertension in terms of reducing cardiovascular events or improving quality of life (see the recommendation for research on relaxation therapies). They also noted that a larger study would be needed to obtain meaningful results.
## How this might affect practice
Relaxation therapies were not recommended for routine use in the 2011 guideline, and they are not used in current practice for the management of primary hypertension in adults. The 2011 recommendation advised that people may try them as part of their treatment to reduce blood pressure, but committee consensus was that uptake has been low. Therefore, current practice will not be affected by the removal of the 2011 recommendation.
# Starting antihypertensive drug treatment
Recommendations 1.4.9 to 1.4.14
## Why the committee made the recommendations
The evidence suggested that antihypertensive drug treatment was effective at reducing cardiovascular events in people with a clinic blood pressure of 160/100 mmHg or more (stage 2 hypertension).
A large study also suggested there was benefit of treating people with stage 1 hypertension. However, other studies in people with a low cardiovascular risk did not identify a benefit of treatment, and the committee agreed that the benefit of treatment across different cardiovascular risk groups was uncertain. The evidence was used to develop an economic model to compare the cost effectiveness of antihypertensive treatment with no treatment in people with stage 1 hypertension at different levels of cardiovascular risk. For people aged 60, the model showed that treatment was cost effective at a 10‑year cardiovascular risk level of 10%, but there was some uncertainty at around 5% risk. Further analysis showed that it was cost effective to offer antihypertensive treatment to people aged 40 and 50 with stage 1 hypertension at a 5% risk and aged 70 and 75 at a 10% or 15% risk. QRISK was specified as the risk tool because it is recommended by NICE for risk calculation and most likely to be used in practice.
Taking into account the evidence and the results of the model, the committee were confident that people under 80 with stage 1 hypertension and a cardiovascular risk above 10% should have a discussion with their healthcare professional about starting antihypertensive treatment, alongside lifestyle changes, and that this would be a clinically and cost-effective use of NHS resources. The committee also agreed that antihypertensive treatment should be considered for people under 60 with a risk below 10%, with the degree of uncertainty in treating people at low risk reflected in the strength of the recommendation.
The committee members were mindful of the additional population that would be affected by lowering the threshold and were aware that the decision to start drug treatment would depend on the person's preferences and their individual risk of cardiovascular disease. The recommendations highlight the importance of discussing the person's preferences for treatment and encouraging lifestyle changes.
Some studies investigated the benefits of treating hypertension in people with lower cardiovascular risk or people with blood pressure below 140/90 mmHg. However, some of these studies were not directly relevant because they included a high proportion of participants with chronic kidney disease and previous cardiovascular events. For this reason, several studies could not be used to inform the recommendations. For details of these studies see evidence review C: initiating treatment.
The committee discussed the lack of evidence to inform a threshold for starting treatment in people aged under 40. It was agreed that this is an important area for future research and the recommendation for research was carried forward from the 2011 guideline (see the recommendation for research on thresholds for interventions in adults aged under 40).
The committee agreed that there was no evidence to suggest that thresholds for starting treatment should be different in people with type 2 diabetes. The previous recommendations for people with type 2 diabetes (in NICE's guideline on type 2 diabetes in adults) suggested starting antihypertensive drug treatment if lifestyle interventions alone did not reduce blood pressure to below 140/80 mmHg or 130/80 mmHg in the presence of kidney, cerebrovascular or eye disease. However, this was based on evidence from 2 small studies in which the participants did not have hypertension. Further evidence for lower treatment thresholds in people with type 2 diabetes was limited within this review, with the committee aware of some evidence to suggest that lower blood pressure thresholds did not reduce the rate of cardiovascular events in people without additional risk factors. The committee therefore agreed that there was insufficient evidence to recommend a different threshold for starting treatment for this subgroup.
There was no evidence identified on thresholds for people aged over 80, and no prior recommendation for this age group with hypertension below stage 2; therefore, the committee agreed that the threshold for starting treatment in people aged over 80 should be consistent with the target for treatment in this population (150/90 mmHg or lower).
The committee discussed the additional risks of starting treatment in older people, particularly those who are frail or have multiple comorbidities. Based on their expertise and experience, they agreed that the use of clinical judgement should be highlighted in decision making for people with frailty or multimorbidity, and that it should apply to people of any age. The committee agreed that a number of factors should be considered when discussing treatment options in this group and noted that healthcare professionals should refer to NICE's guideline on multimorbidity for further advice.
## How the recommendations might affect practice
The recommendations will have a significant impact on practice because more people will now be eligible for treatment. It is difficult to predict the extent of the impact because there is variability in how the 2011 recommendation with a threshold of 20% is being implemented in practice. However, it is believed, based on some recently published UK data, that potentially around 50% of people with stage 1 hypertension and risk below 20% are already being treated with antihypertensive drugs (Association of guideline and policy changes with incidence of lifestyle advice and treatment for uncomplicated mild hypertension in primary care. Sheppard et al. 2018).
People with stage 1 hypertension should already be monitored every year, but reducing the threshold will increase the number of people being prescribed antihypertensive drugs and increase staff time and consultations involved in starting and monitoring their drug treatment. However, there will be a reduction in cardiovascular events resulting in savings, although it is acknowledged that the costs and savings may fall in different sectors of the NHS.
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# Monitoring treatment and blood pressure targets
Recommendations 1.4.15 to 1.4.22
## Monitoring treatment
The committee agreed that there was not enough evidence to strongly recommend home blood pressure monitoring (HBPM) for monitoring treatment in adults with hypertension. The evidence on monitoring was limited, with relatively small studies comparing different combinations of HBPM (with or without telemonitoring and with or without pharmacist input), pharmacy monitoring and clinic monitoring. It suggested that people had improved blood pressure control with HBPM with telemonitoring, with or without pharmacy input, compared with clinic monitoring, and the greatest blood pressure reduction was achieved with pharmacist input. However, the evidence was insufficient for the committee to make a recommendation.
The committee decided to retain the 2011 recommendation on using clinic blood pressure, but also agreed that the updated guideline should support home monitoring for people who wish to use it. The committee discussed the importance of patient choice and agreed that home monitoring should be an option, if it is suitable and the person is willing and motivated to use it. HBPM is already widely used in practice, especially for people with a white-coat effect. The committee agreed this would be reflected in the recommendation supported by the evidence and consensus opinion. Based on their experience, the committee agreed that training and advice would be needed for people using HBPM to ensure that people take measurements correctly and know when to contact their healthcare professional if they are not achieving their target blood pressure.
The 2011 guideline included a recommendation for further research for the best method of monitoring hypertension in people with atrial fibrillation. No evidence was identified in the updated reviews to inform recommendations for this group and therefore the committee agreed that this recommendation for research should be retained to inform future updates of the guideline (see the recommendation for research on automated blood pressure monitoring).
The committee agreed they could not make a recommendation on telemonitoring because the evidence was not sufficient to show a clear benefit and the studies were inconsistent in the telemonitoring methods used.
The recommendations reflect current practice, so there should be no change in practice. They will encourage appropriate and suitable training to be given so that both people with hypertension and their healthcare professionals are confident that blood pressure is being measured properly using home monitoring devices.
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## Blood pressure targets for people without cardiovascular disease
Recommendations 1.4.15 to 1.4.22
No evidence was identified to determine whether cardiovascular risk or blood pressure targets should be used. The committee agreed that in the absence of evidence the focus should be on blood pressure targets, based on their expertise and experience of current practice.
The evidence for blood pressure targets showed that there were both benefits and harms associated with a lower clinic systolic blood pressure target of 120 mmHg compared with 140 mmHg in people with primary hypertension without type 2 diabetes. Although the evidence suggested some benefit in reducing mortality and cardiovascular events, the lower blood pressure target was associated with a greater risk of harms, such as injury from falls and acute kidney injury. The committee agreed that the long-term implications of these adverse events were unclear and that further research is needed.
This evidence came from the SPRINT trial, which was a large study undertaken in the US. The committee discussed concerns about the population included in the study and the applicability to UK practice of the methods used. The study used automated blood pressure devices with a time delay and an isolated rest period, which is not common practice in the UK. The committee considered that the use of these devices would lead to lower blood pressure readings than in routine UK clinical practice. They also had concerns that some medicines were stopped when blood pressure targets were achieved, which may have had an impact on the results. The committee also discussed concerns about applicability of the population; for example, the participants had high cardiovascular risk levels, including many with pre-existing cardiovascular disease or renal impairment, and were already receiving treatment before the study started. These concerns made the evidence difficult to interpret and use to inform the recommendations. Further details of the committee's discussion of this study is included in evidence review D: targets.
Evidence from a smaller study also showed some benefit of lowering clinic systolic blood pressure targets to 130 mmHg. However, the committee noted that the study was based on people already receiving treatment and that it lacked information on adverse events.
The committee agreed that there was no evidence to suggest that blood pressure targets should be different in people with type 2 diabetes. Evidence for lower targets in people with type 2 diabetes was also limited, with some evidence to suggest that lower blood pressure targets did not reduce the rate of cardiovascular events. Previous recommendations for people with type 2 diabetes (in NICE's guideline on type 2 diabetes in adults) suggested a blood pressure target below 130/80 mmHg in the presence of target organ damage such as kidney, cerebrovascular or eye disease. The committee noted that the evidence behind this recommendation was based on 2 small studies in people without hypertension. They also had concerns about the relevance of the study design. The committee were also aware of trial data showing less benefit in populations with type 2 diabetes with fewer additional risk factors. The committee therefore agreed that there was insufficient evidence to recommend a different blood pressure target for this subgroup. It was noted that people with later-stage chronic kidney disease are covered by other NICE guidelines.
Overall, the committee agreed that the evidence was unclear and insufficient to determine whether a lower target would be beneficial and whether it would outweigh the associated harms. Therefore, the 2011 clinic blood pressure target of 140/90 mmHg for adults under 80 years was retained and applies to people with or without type 2 diabetes. The corresponding HBPM and ambulatory blood pressure monitoring (ABPM) targets were also retained at 135/85 mmHg. The recommendations emphasise the importance of achieving and maintaining a level consistently below the person's blood pressure target, whether this target be based on clinic blood pressure, HBPM or ABPM.
Based on their experience, the committee members felt that people with postural hypotension are at risk of adverse events if a sitting or lying blood pressure is used for monitoring, because this measurement would overestimate daytime blood pressure and result in overtreatment. For example, a patient with a sitting systolic blood pressure of 140 mmHg might have a much lower blood pressure when standing and be at an increased risk of falls if treated based on their sitting blood pressure. The committee decided to recommend that 3 groups who are at risk of postural hypotension (people over 80 years, with type 2 diabetes and with symptoms of postural hypotension) should have their standing blood pressure measured, and their treatment modified accordingly if they have postural hypotension. The standing blood pressure should be used for future monitoring.
The recommendations should reinforce current good practice. However, the new recommendations place more emphasis on maintaining blood pressure consistently below the blood pressure targets. As a result, this could lead to a higher use of antihypertensive drugs and an increase in consultations to maintain target blood pressure. For people with type 2 diabetes and target organ damage (not covered by other guidelines), the slightly higher target blood pressure compared to that recommended previously may reduce adverse events and may lead to fewer appointments and reduced drug use.
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## Blood pressure targets for people with cardiovascular disease
Recommendation 1.4.23
The evidence did not show a robust or consistent clinical benefit from using lower blood pressure targets for people with cardiovascular disease compared with standard blood pressure targets.
The vast majority of people in the control arms of the studies achieved blood pressures well below 140/90 mmHg. In the committee's experience of practice, some people with hypertension can have their blood pressure maintained at 140/90 mmHg, rather than below this level. To address this issue, the committee amended the 2019 recommendations on blood pressure targets to emphasise the importance of reducing and maintaining blood pressure below 140/90 mmHg.
The committee made recommendations for research for:
People aged over 80, because there was no evidence specifically for this group. The only evidence was from mixed age groups, and the committee agreed that this evidence was too limited to support a new practice recommendation.
People with aortic aneurysm, because there was no evidence for this group.
People who have had a stroke, because there was limited evidence that lower blood pressure targets reduced the risk of future strokes, but there was also evidence on the possible harms of lower targets. Evidence for both potential benefit and harm was too limited to inform a recommendation.
The new recommendation reflects current practice for most types of cardiovascular disease, so there should be no change in practice or increase in resource use.
The Royal College of Physicians Intercollegiate Stroke Working Party guideline recommends a lower blood pressure target for people after stroke. However, the national quality indicators used in primary care do not use a lower blood pressure target for people with cardiovascular disease (including stroke and transient ischaemic attack).
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# Choosing antihypertensive drug treatment for people with cardiovascular disease
Recommendation 1.4.31
## Why the committee made the recommendation
New evidence in this area was not reviewed as part of the 2022 update. Instead, the evidence from previous versions of the guideline was reassessed to look at outcomes for people with cardiovascular disease. Only evidence up to 2010 was re-analysed, because the 2019 update did not review evidence for people with cardiovascular disease.
There was no difference in clinically relevant outcomes between people with and without cardiovascular disease.
Evidence was limited for people with stroke, transient ischaemic attack, or coronary artery disease. This evidence did not cover enough treatment comparisons to allow the committee to draw any firm conclusions.
There are NICE guidelines on acute coronary syndromes and chronic heart failure, and these guidelines make recommendations on drug treatment that overlap with treatment for hypertension. To avoid confusion over the treatment pathway, the committee highlighted that these condition-specific recommendations should be applied first (for example, when prescribing an ACE inhibitor or an ARB for secondary prevention of myocardial infarction).
## How the recommendations might affect practice
The recommendation reflects current practice for most types of cardiovascular disease.
The committee were aware that, after a stroke, the thiazide-like diuretic indapamide is sometimes used first, rather than a calcium channel blocker. However, it is unclear how common this is. As people with cardiovascular disease are commonly prescribed more than 1 antihypertensive drug, any impact on prescribing would be limited.
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# Step 1 treatment
Recommendations 1.4.32 to 1.4.39
## Why the committee made the recommendations
The committee reviewed the evidence for starting treatment for primary hypertension with a single antihypertensive medicine compared with starting with 2 antihypertensive medicines at once (dual therapy). Additionally, the committee reviewed the evidence on whether specific subgroups of people with hypertension might benefit from starting on dual therapy, for example people with type 2 diabetes, older people, or those of particular family origins.
Some limited evidence from a single study showed that initial dual therapy may reduce cardiovascular events in people with hypertension and type 2 diabetes, but the committee members were disappointed that more comprehensive data was not available. The committee discussed the benefits of optimising treatment for hypertension early and agreed that this can substantially improve quality of life. However, there was not enough evidence to determine confidently the benefits or harms of starting treatment with dual therapy. In response to the lack of available evidence, the committee developed a recommendation for research on step 1 treatment to determine if particular subgroups would benefit from starting dual therapy, to inform future guidance.
In the absence of compelling new evidence on step 1 dual therapy, the committee agreed that the previous recommendations for step 1 treatment should be retained (with minor changes for clarity), because they were based on robust clinical and cost-effectiveness evidence. One exception to this was the 2006 recommendation for considering beta-blockers in certain groups of younger people. The committee discussed this recommendation and agreed that beta-blockers are rarely used as step 1 antihypertensive treatment in current practice and there is no established relationship between beta-blocker use in primary hypertension and a reduction in cardiovascular events. For these reasons, the committee decided that the recommendation should not be retained. The committee noted that this is consistent with most international guidelines.
This guideline also updates and replaces the section on blood pressure management from NICE's guideline on type 2 diabetes in adults. That guideline recommended that adults with type 2 diabetes of any age should start on an angiotensin-converting enzyme (ACE) inhibitor as step 1 treatment (except women with a possibility of becoming pregnant and people of Black African or African–Caribbean family origin). The committee discussed the evidence for this and agreed that it was sufficient to support and retain this recommendation. The committee agreed it should be broadened to include the choice of an ACE inhibitor or an angiotensin II receptor blocker (ARB; also referred to as A‑type drugs), because they are now cost equivalent, and the committee also agreed they are clinically equivalent.
For people of Black African or African–Caribbean family origin with type 2 diabetes, the previous recommendation was to offer step 1 dual therapy with an ACE inhibitor and either a diuretic (D‑type drug) or a calcium channel blocker (CCB; C‑type drug). However, these recommendations were based on monotherapy studies and when the committee looked at this evidence alongside the new dual therapy evidence review, they concluded that it was insufficient to recommend starting dual therapy in any subgroup of people with type 2 diabetes. The committee noted that people with type 2 diabetes who are older or are of Black African or African–Caribbean family origin may not achieve their target blood pressure on ACE inhibitor or ARB monotherapy and may need to start step 2 drug therapy in the short term.
## How the recommendations might affect practice
Overall, the recommendations for step 1 treatment reflect current practice for people who do not have type 2 diabetes. For people of Black African or African–Caribbean family origin who have type 2 diabetes, the recommendation to start antihypertensive monotherapy rather than dual therapy may result in an extra clinical appointment if the dose needs to be adjusted. However, it may also reduce potential harms from initial overtreatment of blood pressure.
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# Step 2 and 3 treatment
Recommendations 1.4.40 to 1.4.45
## Why the committee made the recommendations
No evidence for step 2 or step 3 treatment was identified that was relevant to determining the best sequence for step 2 and step 3 antihypertensive treatment. Some of the studies available on drug treatments for hypertension were not included in this review because they were designed to inform step 1 treatment. Others did not reflect UK clinical practice. For details of these studies see evidence review F: step 2 and step 3 treatment.
Based on evidence from the previous version of the guideline and their clinical expertise, the committee members agreed to retain the same choice of drugs from the 2011 guideline, which reflect current best practice. The committee agreed that, in the absence of evidence of which treatment(s) are most effective for step 2 or step 3, the recommendation should be to offer any of these treatments based on an individualised approach informed by risks and benefits of each treatment and the person with hypertension's preference.
The committee noted that the changes to the step 1 recommendations for some people with type 2 diabetes do not necessitate a change in the step 2 recommendations since the same options for combination treatment at step 2 are available.
The committee agreed that the choice of drug should be discussed and agreed with the person, based on the person's step 1 treatment, the risks and benefits of each treatment option, and taking into account the person's preferences and other clinical factors. The updated recommendations reflect this, giving the choice of possible treatment options. A NICE patient decision aid on treatment choices for high blood pressure has been developed to support healthcare professionals and people with hypertension to discuss their treatment options and make informed decisions.
## How the recommendations might affect practice
The recommendations are unlikely to alter current practice. The options for drug treatment remain the same and most step 2 or 3 treatment decisions are already based on an individualised approach.
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# Step 4 treatment
Recommendations 1.4.46 to 1.4.52
## Why the committee made the recommendations
No evidence on step 4 treatment was identified that could be used to formulate new recommendations. However, the committee reviewed the 2011 recommendations and agreed that they should be retained and updated to reflect current best practice.
The committee discussed the importance of confirming resistant hypertension before starting step 4 treatment. Based on their clinical experience and knowledge of best current practice, the committee members agreed that a recommendation to highlight this would help prevent overtreatment and ensure that people receive the right care.
Despite the lack of evidence formally reviewed, the committee discussed the recommendation based on their clinical experience, taking the 2011 recommendations into account. The committee agreed that although the evidence for spironolactone did not meet the criteria for inclusion in the updated review for the guideline because the key study had a very short follow up and did not report any of the cardiovascular outcomes specified in this review protocol, the use of an aldosterone antagonist is now common clinical practice. Therefore, there was no reason to suggest that this recommendation should be changed.
In the 2011 guideline, high-dose thiazide diuretics were recommended as a potential step 4 treatment in people with high blood potassium levels. The committee felt that there was a lack of evidence for this approach and noted that the studies did not show an improvement in cardiovascular outcomes at higher doses, albeit in people without resistant hypertension. The committee agreed that the recommendation for considering alpha- or beta-blockers should be retained based on significant clinical experience of their safe and effective use and because adding a further drug is likely to have a greater effect on blood pressure than increasing the thiazide diuretic dose.
## How the recommendations might affect practice
The recommendations represent current good practice and so should not change practice. High-dose thiazide diuretics are not commonly used as step 4 therapy and so removing this should not change practice.
There might be a small reduction in step 4 treatment with more thorough checks to confirm resistant hypertension. However, this may also result in an increase in blood pressure measurements to appropriately confirm resistant hypertension where this is not already being done.
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# Identifying who to refer for same-day specialist review
Recommendations 1.5.1 to 1.5.3
## Why the committee made the recommendations
There was no evidence identified to inform recommendations on this topic. The committee reviewed the 2011 recommendations and agreed that they should be updated by consensus based on their clinical expertise. In particular they agreed it would be helpful to clarify which features warranted same-day referral, which would need further investigation and when repeat blood pressure measurement should be taken.
The committee noted that it can be difficult to differentiate between accelerated hypertension and severe hypertension. They discussed the advantages and disadvantages of broader criteria for same-day referral, which would increase referrals to hospital but reduce the risk of missing people who need urgent treatment. The committee decided it would be beneficial to add some emergency symptoms to the existing recommendation, which will help healthcare professionals to decide when to refer.
Based on their experience, the committee members agreed that some people with severe hypertension could be receiving unnecessary treatment because the 2011 guideline recommended treatment based on severe hypertension alone. The committee agreed that this could be prevented if investigations for target organ damage were carried out quickly before offering treatment in people with severely raised blood pressure and no other symptoms of concern. The committee also agreed that checking blood pressure again within 7 days in people with no target organ damage would ensure that people with severe hypertension are followed up and offered suitable treatment.
The committee agreed that further research is needed in this area, particularly for people with extreme hypertension (220/120 mmHg or higher) or emergency symptoms. The committee members developed a recommendation for research on same-day hospital specialist assessment to help inform future recommendations.
## How the recommendations might affect practice
The emergency symptoms listed in the recommendation may lead to more referrals to hospital. However, people with emergency symptoms will benefit from urgent treatment because accelerated hypertension can be fatal if untreated.
There may be some additional resource use from doing target organ damage tests more quickly and re-measuring blood pressure within 7 days. However, the number of people started on treatment immediately may be reduced because of undertaking investigations first.
The population with severe hypertension is very small, and the proportion with severe hypertension and additional symptoms that suggest accelerated hypertension is even smaller; therefore, resource impact is unlikely to be substantial.
Return to recommendations# Context
High blood pressure (hypertension) is one of the most important, treatable causes of premature morbidity and mortality in the world. It is a major risk factor for stroke, myocardial infarction, heart failure, chronic kidney disease, cognitive decline and premature death. In 2015, it was reported that high blood pressure affected more than 1 in 4 adults in England (31% of men; 26% of women) – around 13.5 million people – and contributed to 75,000 deaths. The clinical management of hypertension accounts for 12% of visits to primary care and up to £2.1 billion of healthcare expenditure. Managing the cardiovascular events caused by hypertension also consumes considerable resources.
The guideline covers adults (over 18 years) with suspected or diagnosed hypertension, including those with type 2 diabetes.
update
Between 2010 and 2020, progress has been made to improve the diagnosis and management of hypertension: the population average blood pressure in England has fallen by about 3 mmHg systolic and the proportion of adults with untreated high blood pressure has decreased. However, the Public Health England Blood Pressure Action Plan called for further action to reduce the population average blood pressure by 5 mmHg through improved prevention, detection and management (Public Health England's Tackling high blood pressure: from evidence into action, 2015 and Tackling high blood pressure: an update, 2018).
Since the publication of the 2011 NICE guideline on hypertension, new studies have been published in key areas of management; in particular, the optimal method and threshold for diagnosis of hypertension, managing blood pressure in lower risk populations and reducing blood pressure to lower targets in people with hypertension (including those with type 2 diabetes). The updated guideline makes new recommendations in these areas, based on the evidence, that aim to improve care and reduce variation in current practice.
Treating resistant hypertension (when more than 3 drugs are needed to treat hypertension) remains challenging. New data was also reviewed in this area and the recommendations updated.
There is uncertainty in current practice about which people with symptomatic very high blood pressure (accelerated hypertension) to refer for immediate assessment. The available evidence was reviewed and new recommendations made to provide guidance for primary care on when to refer.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in\xa0NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines\xa0explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations on measuring blood pressure and diagnosing hypertension in this guideline apply to all adults, including those with type\xa02 diabetes. The recommendations on treatment and monitoring link to NICE guidelines on chronic kidney disease, type\xa01 diabetes and hypertension in pregnancy at points in the care pathway where treatment differs. The recommendations on treatment and monitoring apply to adults with type\xa02 diabetes and replace recommendations on diagnosing and managing hypertension in NICE's guideline on type\xa02 diabetes in adults.\n\n# Measuring blood pressure\n\nEnsure that healthcare professionals taking blood pressure measurements have adequate initial training and periodic review of their performance. \n\nBecause automated devices may not measure blood pressure accurately if there is pulse irregularity (for example, due to atrial fibrillation), palpate the radial or brachial pulse before measuring blood pressure. If pulse irregularity is present, measure blood pressure manually using direct auscultation over the brachial artery. \n\nHealthcare providers must ensure that devices for measuring blood pressure are properly validated, maintained and regularly recalibrated according to manufacturers' instructions. See the British and Irish Hypertension Society's website for a list of validated blood pressure monitoring devices. \n\nWhen measuring blood pressure in the clinic or in the home, standardise the environment and provide a relaxed, temperate setting, with the person quiet and seated, and their arm outstretched and supported. Use an appropriate cuff size for the person's arm. [2011, amended 2019]\n\nIn people with symptoms of postural hypotension (falls or postural dizziness):\n\nmeasure blood pressure with the person either supine or seated\n\nmeasure blood pressure again with the person standing for at least 1\xa0minute before measurement. [2004, amended 2011]\n\nIf the systolic blood pressure falls by 20\xa0mmHg or more when the person is standing:\n\nreview medication\n\nmeasure subsequent blood pressures with the person standing\n\nconsider referral to specialist care if symptoms of postural hypotension persist. [2004, amended 2011]\n\n# Diagnosing hypertension\n\nWhen considering a diagnosis of hypertension, measure blood pressure in both arms:\n\nIf the difference in readings between arms is more than 15\xa0mmHg, repeat the measurements.\n\nIf the difference in readings between arms remains more than 15\xa0mmHg on the second measurement, measure subsequent blood pressures in the arm with the higher reading. \n\nIf blood pressure measured in the clinic is 140/90\xa0mmHg or higher:\n\nTake a second measurement during the consultation.\n\nIf the second measurement is substantially different from the first, take a third measurement.Record the lower of the last 2\xa0measurements as the clinic blood pressure. \n\nIf clinic blood pressure is between 140/90\xa0mmHg and 180/120\xa0mmHg, offer ambulatory blood pressure monitoring (ABPM) to confirm the diagnosis of hypertension. See the section on identifying who to refer for people with a clinic blood pressure 180/120\xa0mmHg or higher. \n\nIf ABPM is unsuitable or the person is unable to tolerate it, offer home blood pressure monitoring (HBPM) to confirm the diagnosis of hypertension. \n\nWhile waiting for confirmation of a diagnosis of hypertension, carry out:\n\ninvestigations for target organ damage (see recommendation 1.3.3), followed by\n\nformal assessment of cardiovascular risk using a cardiovascular risk assessment tool (see the section on full formal risk assessment in NICE's guideline on cardiovascular disease). \n\nWhen using ABPM to confirm a diagnosis of hypertension, ensure that at least 2\xa0measurements per hour are taken during the person's usual waking hours (for example, between 08:00 and 22:00). Use the average value of at least 14\xa0measurements taken during the person's usual waking hours to confirm a diagnosis of hypertension. \n\nWhen using HBPM to confirm a diagnosis of hypertension, ensure that:\n\nfor each blood pressure recording, 2\xa0consecutive measurements are taken, at least 1\xa0minute apart and with the person seated and\n\nblood pressure is recorded twice daily, ideally in the morning and evening and\n\nblood pressure recording continues for at least 4\xa0days, ideally for 7\xa0days.Discard the measurements taken on the first day and use the average value of all the remaining measurements to confirm a diagnosis of hypertension. \n\nConfirm diagnosis of hypertension in people with a:\n\nclinic blood pressure of 140/90\xa0mmHg or higher and\n\nABPM daytime average or HBPM average of 135/85\xa0mmHg or higher. \n\nIf hypertension is not diagnosed but there is evidence of target organ damage, consider carrying out investigations for alternative causes of the target organ damage (for information on investigations, see NICE's guidelines on chronic kidney disease and chronic heart failure). \n\nIf hypertension is not diagnosed, measure the person's clinic blood pressure at least every 5\xa0years subsequently, and consider measuring it more frequently if the person's clinic blood pressure is close to 140/90\xa0mmHg. \n\n## Annual blood pressure measurement for people with type\xa02 diabetes\n\nMeasure blood pressure at least annually in an adult with type\xa02 diabetes without previously diagnosed hypertension or renal disease. Offer and reinforce preventive lifestyle advice. \n\n## Specialist investigations for possible secondary causes of hypertension\n\nConsider the need for specialist investigations in people with signs and symptoms suggesting a secondary cause of hypertension. [2004, amended 2011]\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on diagnosing hypertension\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diagnosis.\n\nLoading. Please wait.\n\n# Assessing cardiovascular risk and target organ damage\n\nFor guidance on the early identification and management of chronic kidney disease, see NICE's guideline on chronic kidney disease.\n\nUse a formal estimation of cardiovascular risk to discuss prognosis and healthcare options with people with hypertension, both for raised blood pressure and other modifiable risk factors. \n\nEstimate cardiovascular risk in line with the recommendations on identifying and assessing cardiovascular disease risk in NICE's guideline on cardiovascular disease. Use clinic blood pressure measurements to calculate cardiovascular risk. \n\nFor all people with hypertension offer to:\n\ntest for the presence of protein in the urine by sending a urine sample for estimation of the albumin:creatinine ratio and test for haematuria using a reagent strip\n\ntake a blood sample to measure glycated haemoglobin (HbA1C), electrolytes, creatinine, estimated glomerular filtration rate, total cholesterol and HDL cholesterol\n\nexamine the fundi for the presence of hypertensive retinopathy\n\narrange for a 12‑lead electrocardiograph to be performed. [2011, amended 2019]\n\n# Treating and monitoring hypertension\n\n## Lifestyle interventions\n\nFor guidance on the prevention of obesity and cardiovascular disease, see NICE's guidelines on obesity prevention and cardiovascular disease prevention.\n\nOffer lifestyle advice to people with suspected or diagnosed hypertension, and continue to offer it periodically. \n\nAsk about people's diet and exercise patterns because a healthy diet and regular exercise can reduce blood pressure. Offer appropriate guidance and written or audiovisual materials to promote lifestyle changes. \n\nAsk about people's alcohol consumption and encourage a reduced intake if they drink excessively, because this can reduce blood pressure and has broader health benefits. See the recommendations for practice in NICE's guideline on alcohol-use disorders. [2004, amended 2019]\n\nDiscourage excessive consumption of coffee and other caffeine-rich products. \n\nEncourage people to keep their dietary sodium intake low, either by reducing or substituting sodium salt, as this can reduce blood pressure. Note that salt substitutes containing potassium chloride should not be used by older people, people with diabetes, pregnant women, people with kidney disease and people taking some antihypertensive drugs, such as ACE inhibitors and angiotensin\xa0II receptor blockers. Encourage salt reduction in these groups. [2004, amended 2019]\n\nDo not offer calcium, magnesium or potassium supplements as a method for reducing blood pressure. \n\nOffer advice and help to smokers to stop smoking. See NICE's guideline on tobacco. \n\nInform people about local initiatives by, for example, healthcare teams or patient organisations that provide support and promote healthy lifestyle change, especially those that include group work for motivating lifestyle change. \n\nFor a short explanation of why the committee deleted the recommendation on relaxation therapies and how this might affect practice, see the rationale and impact section on relaxation therapies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: relaxation therapies.\n\nLoading. Please wait.\n\n## Starting antihypertensive drug treatment\n\nNICE has produced a patient decision aid on treatment options for hypertension to help people and their healthcare professionals discuss the different types of treatment and make a decision that is right for each person.\n\nFor advice on shared decision making for medicines, see the information on patient decision aids in NICE's guideline on medicines optimisation.\n\nTo support adherence and ensure that people with hypertension make the most effective use of their medicines, see NICE's guideline on medicines adherence.\n\nOffer antihypertensive drug treatment in addition to lifestyle advice to adults of any age with persistent stage\xa02 hypertension. Use clinical judgement for people of any age with frailty or multimorbidity (see also NICE's guideline on multimorbidity). \n\nDiscuss starting antihypertensive drug treatment, in addition to lifestyle advice, with adults aged under\xa080 with persistent stage\xa01 hypertension who have 1 or more of the following:\n\ntarget organ damage\n\nestablished cardiovascular disease\n\nrenal disease\n\ndiabetes\n\nan estimated 10‑year risk of cardiovascular disease of 10% or more. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity). \n\nDiscuss with the person their individual cardiovascular disease risk and their preferences for treatment, including no treatment, and explain the risks and benefits before starting antihypertensive drug treatment. Continue to offer lifestyle advice and support them to make lifestyle changes (see the section on lifestyle interventions), whether or not they choose to start antihypertensive drug treatment. \n\nConsider antihypertensive drug treatment in addition to lifestyle advice for adults aged under\xa060 with stage\xa01 hypertension and an estimated 10‑year risk below 10%. Bear in mind that 10‑year cardiovascular risk may underestimate the lifetime probability of developing cardiovascular disease. \n\nConsider antihypertensive drug treatment in addition to lifestyle advice for people aged over\xa080 with stage\xa01 hypertension if their clinic blood pressure is over 150/90\xa0mmHg. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity). \n\nFor adults aged under\xa040 with hypertension, consider seeking specialist evaluation of secondary causes of hypertension and a more detailed assessment of the long-term balance of treatment benefit and risks. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on starting antihypertensive drug treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: initiating treatment.\n\nLoading. Please wait.\n\n## Monitoring treatment and blood pressure targets\n\nFor specific recommendations on blood pressure control in people with other conditions or who are pregnant, see also the NICE guidelines on chronic kidney disease, type 1 diabetes and hypertension in pregnancy.\n\nUse clinic blood pressure measurements to monitor the response to lifestyle changes or drug treatment in people with hypertension. \n\nMeasure standing as well as seated blood pressure (see recommendation 1.1.6) in people with hypertension and:\n\nwith type\xa02 diabetes or\n\nwith symptoms of postural hypotension or\n\naged 80\xa0and over. In people with a significant postural drop or symptoms of postural hypotension, treat to a blood pressure target based on standing blood pressure. \n\nAdvise people with hypertension who choose to self-monitor their blood pressure to use HBPM. (NHS England is supporting the use of HBPM through the blood pressure@home scheme.) \n\nConsider ABPM or HBPM, in addition to clinic blood pressure measurements, for people with hypertension identified as having a white-coat effect or masked hypertension (in which clinic and non-clinic blood pressure results are conflicting). Be aware that the corresponding measurements for ABPM and HBPM are 5\xa0mmHg lower than for clinic measurements (see recommendation\xa01.2.8 for diagnostic thresholds). \n\nFor people who choose to use HBPM, provide:\n\ntraining and advice on using home blood pressure monitors\n\ninformation about what to do if they are not achieving their target blood pressure.Be aware that the corresponding measurements for HBPM are 5\xa0mmHg lower than for clinic measurements (see recommendation\xa01.2.8 for diagnostic thresholds). \n\nFor adults with hypertension aged under\xa080, reduce clinic blood pressure to below 140/90\xa0mmHg and ensure that it is maintained below that level. [2019, amended 2022]\n\nFor adults with hypertension aged 80\xa0and over, reduce clinic blood pressure to below 150/90\xa0mmHg and ensure that it is maintained below that level. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity). [2019, amended 2022]\n\nWhen using ABPM or HBPM to monitor the response to treatment in adults with hypertension, use the average blood pressure level taken during the person's usual waking hours (see recommendations\xa01.2.6 and 1.2.7). Reduce blood pressure and ensure that it is maintained:\n\nbelow 135/85\xa0mmHg for adults aged under\xa080\n\nbelow 145/85\xa0mmHg for adults aged 80\xa0and over. Use clinical judgement for people with frailty or multimorbidity (see also NICE's guideline on multimorbidity). [2019, amended 2022]\n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on monitoring treatment and blood pressure targets for people without cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: monitoring the response to treatment.\n\nLoading. Please wait.\n\nUse the same blood pressure targets for people with and without cardiovascular disease. \n\nFor a short explanation of why the committee made the recommendation on blood pressure targets for people with cardiovascular disease and how this might affect practice, see the rationale and impact section on monitoring treatment and blood pressure targets for people with cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review J: blood pressure targets.\n\nLoading. Please wait.\n\nProvide an annual review of care for adults with hypertension to monitor blood pressure, provide people with support, and discuss their lifestyle, symptoms and medication. \n\nFor an adult with type\xa02 diabetes on antihypertensive drug treatment when diabetes is diagnosed, review blood pressure control and medications used. Make changes only if there is poor control or if current drug treatment is not appropriate because of microvascular complications or metabolic problems. \n\n## Choosing antihypertensive drug treatment (for people with or without type\xa02 diabetes)\n\nThe recommendations in this section apply to people with hypertension with or without type\xa02 diabetes. They replace the recommendations on diagnosing and managing hypertension in NICE's guideline on type\xa02 diabetes in adults. For guidance on choosing antihypertensive drug treatment in people with type\xa01 diabetes, see also the section on control of cardiovascular risk in NICE's guideline on type\xa01 diabetes.\n\nNote that ACE inhibitors and angiotensin II receptor antagonists should not be used in pregnant or breastfeeding women or women planning pregnancy unless absolutely necessary, in which case the potential risks and benefits should be discussed. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, recommendations on how to use for breastfeeding and the related clarification on breastfeeding.\n\nFor guidance on choice of hypertensive agent in people with chronic kidney disease, see NICE's guideline on chronic kidney disease. If possible, offer treatment with drugs taken only once a day. \n\nPrescribe non-proprietary drugs if these are appropriate and minimise cost. \n\nOffer people with isolated systolic hypertension (systolic blood pressure 160\xa0mmHg or more) the same treatment as people with both raised systolic and diastolic blood pressure. \n\nOffer antihypertensive drug treatment to women of childbearing potential with diagnosed hypertension in line with the recommendations in this guideline. For women considering pregnancy or who are pregnant or breastfeeding, manage hypertension in line with the recommendations on management of pregnancy with chronic hypertension, and on antihypertensive treatment while breastfeeding in NICE's guideline on hypertension in pregnancy. [2010, amended 2019]\n\nWhen choosing antihypertensive drug treatment for adults of Black African or African–Caribbean family origin, consider an angiotensin\xa0II receptor blocker (ARB), in preference to an angiotensin-converting enzyme (ACE) inhibitor. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.\n\nFor people with cardiovascular disease:\n\nFollow the recommendations for disease-specific indications in the NICE guideline on their condition (for example, when prescribing an ACE inhibitor or an ARB for secondary prevention of myocardial infarction). Relevant recommendations include:\n\n\n\ndrug therapy for secondary prevention in the NICE guideline on acute coronary syndromes\n\ntreatment after stabilisation in the NICE guideline on acute heart failure\n\ntreating heart failure with reduced ejection fraction in the NICE guideline on chronic heart failure\n\ndrugs for secondary prevention of cardiovascular disease in the NICE guideline on stable angina\n\nblood pressure management in the NICE guideline on type\xa01 diabetes in adults.\n\n\n\nIf their blood pressure remains uncontrolled, offer antihypertensive drug treatment in line with the recommendations in this section. \n\nFor a short explanation of why the committee made the recommendation on choosing antihypertensive drug treatment for people with cardiovascular disease and how this might affect practice, see the rationale and impact section on choosing antihypertensive drug treatment for people with cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review K: pharmacological treatment in cardiovascular disease.\n\nLoading. Please wait.\n\nOffer an ACE inhibitor or an ARB to adults starting step\xa01 antihypertensive treatment who:\n\nhave type\xa02 diabetes and are of any age or family origin (see also recommendation 1.4.30 for adults of Black African or African–Caribbean family origin) or\n\nare aged under\xa055 but not of Black African or African–Caribbean family origin. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.\n\nIf an ACE inhibitor is not tolerated, for example because of cough, offer an ARB to treat hypertension. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.\n\nDo not combine an ACE inhibitor with an ARB to treat hypertension. \n\nOffer a calcium-channel blocker (CCB) to adults starting step\xa01 antihypertensive treatment who:\n\nare aged 55\xa0or over and do not have type\xa02 diabetes or\n\nare of Black African or African–Caribbean family origin and do not have type\xa02 diabetes (of any age). \n\nIf a CCB is not tolerated, for example because of oedema, offer a thiazide-like diuretic to treat hypertension. \n\nIf there is evidence of heart failure, offer a thiazide-like diuretic and follow NICE's guideline on chronic heart failure. \n\nIf starting or changing diuretic treatment for hypertension, offer a thiazide-like diuretic, such as indapamide in preference to a conventional thiazide diuretic such as bendroflumethiazide or hydrochlorothiazide. \n\nFor adults with hypertension already having treatment with bendroflumethiazide or hydrochlorothiazide, who have stable, well-controlled blood pressure, continue with their current treatment. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on step\xa01 treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: step\xa01 treatment.\n\nLoading. Please wait.\n\nBefore considering next step treatment for hypertension discuss with the person if they are taking their medicine as prescribed and support adherence in line with NICE's guideline on medicines adherence. \n\nIf hypertension is not controlled in adults taking step\xa01 treatment of an ACE inhibitor or ARB, offer the choice of 1 of the following drugs in addition to step\xa01 treatment:\n\na CCB or\n\na thiazide-like diuretic. \n\nIf hypertension is not controlled in adults taking step\xa01 treatment of a CCB, offer the choice of 1 of the following drugs in addition to step\xa01 treatment:\n\nan ACE inhibitor or\n\nan ARB or\n\na thiazide-like diuretic. \n\nIf hypertension is not controlled in adults of Black African or African–Caribbean family origin who do not have type\xa02 diabetes taking step\xa01 treatment, consider an ARB, in preference to an ACE inhibitor, in addition to step\xa01 treatment. \n\nBefore considering next step treatment for hypertension:\n\nreview the person's medications to ensure they are being taken at the optimal tolerated doses and\n\ndiscuss adherence (see recommendation\xa01.4.40). \n\nIf hypertension is not controlled in adults taking step\xa02 treatment, offer a combination of:\n\nan ACE inhibitor or ARB (see also recommendation\xa01.4.30 for people of Black African or African–Caribbean family origin) and\n\na CCB and\n\na thiazide-like diuretic. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on step\xa02 and 3 treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: step\xa02 and step\xa03 treatment.\n\nLoading. Please wait.\n\nIf hypertension is not controlled in adults taking the optimal tolerated doses of an ACE inhibitor or an ARB plus a CCB and a thiazide-like diuretic, regard them as having resistant hypertension. \n\nBefore considering further treatment for a person with resistant hypertension:\n\nConfirm elevated clinic blood pressure measurements using ambulatory or home blood pressure recordings.\n\nAssess for postural hypotension.\n\nDiscuss adherence (see recommendation 1.4.40). \n\nFor people with confirmed resistant hypertension, consider adding a fourth antihypertensive drug as step\xa04 treatment or seeking specialist advice. Follow the MHRA safety advice on ACE inhibitors and angiotensin II receptor antagonists: not for use in pregnancy, how to use for breastfeeding and clarification on breastfeeding.\n\nConsider further diuretic therapy with low-dose spironolactone for adults with resistant hypertension starting step\xa04 treatment who have a blood potassium level of 4.5\xa0mmol/l or less. Use particular caution in people with a reduced estimated glomerular filtration rate because they have an increased risk of hyperkalaemia. In March 2019, this was an off-label use of some preparations of spironolactone. See NICE's information on prescribing medicines.\n\nWhen using further diuretic therapy for step\xa04 treatment of resistant hypertension, monitor blood sodium and potassium and renal function within 1\xa0month of starting treatment and repeat as needed thereafter. \n\nConsider an alpha-blocker or beta-blocker for adults with resistant hypertension starting step\xa04 treatment who have a blood potassium level of more than 4.5\xa0mmol/l. \n\nIf blood pressure remains uncontrolled in people with resistant hypertension taking the optimal tolerated doses of 4\xa0drugs, seek specialist advice. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on step\xa04 treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: step\xa04 treatment.\n\nLoading. Please wait.\n\n# Identifying who to refer for same-day specialist review\n\nIf a person has severe hypertension (clinic blood pressure of 180/120\xa0mmHg or higher), but no symptoms or signs indicating same-day referral (see recommendation 1.5.2), carry out investigations for target organ damage (see recommendation\xa01.3.3) as soon as possible:\n\nIf target organ damage is identified, consider starting antihypertensive drug treatment immediately, without waiting for the results of ABPM or HBPM.\n\nIf no target organ damage is identified, confirm diagnosis by:\n\n\n\nrepeating clinic blood pressure measurement within 7\xa0days, or\n\nconsidering monitoring using ABPM (or HBPM if ABPM is not suitable or not tolerated), following recommendations 1.2.6 and 1.2.7, and ensuring a clinical review within 7 days. \n\n\n\nRefer people for specialist assessment, carried out on the same day, if they have a clinic blood pressure of 180/120\xa0mmHg and higher with:\n\nsigns of retinal haemorrhage or papilloedema (accelerated hypertension) or\n\nlife-threatening symptoms such as new onset confusion, chest pain, signs of heart failure, or acute kidney injury. \n\nRefer people for specialist assessment, carried out on the same day, if they have suspected phaeochromocytoma (for example, labile or postural hypotension, headache, palpitations, pallor, abdominal pain or diaphoresis). \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on identifying who to refer for same-day specialist review\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: same-day specialist review.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.\n\n## Accelerated hypertension\n\nA severe increase in blood pressure to 180/120\xa0mmHg or higher (and often over 220/120\xa0mmHg) with signs of retinal haemorrhage and/or papilloedema (swelling of the optic nerve). It is usually associated with new or progressive target organ damage and is also known as malignant hypertension.\n\n## Established cardiovascular disease\n\nMedical history of ischaemic heart disease, cerebrovascular disease, peripheral vascular disease, aortic aneurysm or heart failure. Cardiovascular disease is a general term for conditions affecting the heart or blood vessels. It is usually associated with a build-up of fatty deposits inside the arteries (atherosclerosis) and an increased risk of blood clots. It can also be associated with damage to arteries in organs such as the brain, heart, kidneys and eyes through deposition of glassy material within the artery walls (arteriosclerosis). Cardiovascular disease is 1 of the main causes of death and disability in the UK, but it can often largely be prevented by leading a healthy lifestyle.\n\n## Masked hypertension\n\nClinic blood pressure measurements are normal (less than 140/90\xa0mmHg), but blood pressure measurements are higher when taken outside the clinic using average daytime ambulatory blood pressure monitoring (ABPM) or average home blood pressure monitoring (HBPM) blood pressure measurements.\n\n## Persistent hypertension\n\nHigh blood pressure at repeated clinical encounters.\n\n## Stage\xa01 hypertension\n\nClinic blood pressure ranging from 140/90\xa0mmHg to 159/99\xa0mmHg and subsequent ABPM daytime average or HBPM average blood pressure ranging from 135/85\xa0mmHg to 149/94\xa0mmHg.\n\n## Stage\xa02 hypertension\n\nClinic blood pressure of 160/100\xa0mmHg or higher but less than 180/120\xa0mmHg and subsequent ABPM daytime average or HBPM average blood pressure of 150/95\xa0mmHg or higher.\n\n## Stage\xa03 or severe hypertension\n\nClinic systolic blood pressure of 180\xa0mmHg or higher or clinic diastolic blood pressure of 120\xa0mmHg or higher.\n\n## Target organ damage\n\nDamage to organs such as the heart, brain, kidneys and eyes. Examples are left ventricular hypertrophy, chronic kidney disease, hypertensive retinopathy or increased urine albumin:creatinine ratio.\n\n## White-coat effect\n\nA discrepancy of more than 20/10\xa0mmHg between clinic and average daytime ABPM or average HBPM blood pressure measurements at the time of diagnosis.", 'Recommendations for research': "The 2019 and 2022 guideline committees have made the following recommendations for research.\n\n# Automated blood pressure monitoring in people with atrial fibrillation\n\nWhich automated blood pressure monitors are suitable for people with hypertension and atrial fibrillation? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on monitoring treatment and blood pressure targets for people without cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: monitoring the response to treatment.\n\nLoading. Please wait.\n\n# Thresholds for interventions in adults aged under\xa040\n\nIn adults aged under\xa040 with hypertension (with or without type\xa02 diabetes), what are the appropriate risk and blood pressure thresholds for starting treatment? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on starting antihypertensive drug treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: initiating treatment.\n\nLoading. Please wait.\n\n# Blood pressure targets for people aged over\xa080\n\nWhat is the optimum blood pressure target for people aged over\xa080 with treated primary hypertension (with or without cardiovascular disease)? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on blood pressure targets for people with cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review K: pharmacological treatment in cardiovascular disease.\n\nLoading. Please wait.\n\n# Step 1 treatment\n\nAre there subgroups of people with hypertension who should start on dual therapy? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on step\xa01 treatment\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: step\xa01 treatment.\n\nLoading. Please wait.\n\n# Relaxation therapies\n\nWhat is the clinical and cost effectiveness of relaxation therapies for managing primary hypertension in adults in terms of reducing cardiovascular events and improving quality of life? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on relaxation therapies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: relaxation therapies.\n\nLoading. Please wait.\n\n# Same-day hospital specialist assessment\n\nWhich people with extreme hypertension (220/120\xa0mmHg or higher) or emergency symptoms should be referred for same-day hospital specialist assessment? \n\nFor a short explanation of why the committee made the recommendation for research, see the see rationale on identifying who to refer for same-day specialist review\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: same-day specialist review.\n\nLoading. Please wait.\n\n# Blood pressure targets for people with aortic aneurysm\n\nWhat are the optimal blood pressure targets in adults with hypertension and aortic aneurysm, and does this vary by age? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on blood pressure targets for people with cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review J: blood pressure targets.\n\nLoading. Please wait.\n\n# Blood pressure targets for people with prior ischaemic or haemorrhagic stroke\n\nWhat are the optimal blood pressure targets in adults with prior ischaemic or haemorrhagic stroke, and does this vary by age? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale and impact section on blood pressure targets for people with cardiovascular disease\xa0.\n\nFull details of the evidence and the committee's discussion are in the evidence review J: blood pressure targets.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Diagnosing hypertension\n\nRecommendations 1.2.1 to 1.2.5 and 1.2.8\n\n## Why the committee made the recommendations\n\nOverall, there was limited new evidence on the accuracy of different methods of measuring blood pressure. Most of the studies identified were small, and the populations and protocols for measurement varied making interpretation difficult. However, the committee agreed that it was important to focus on the evidence from these more recent studies (post‑2000) because the evidence should reflect the current use of electronic sphygmomanometers, which have replaced mercury-based sphygmomanometers.\n\nThe evidence did not show that changing the current blood pressure thresholds for clinic measurement or home blood pressure monitoring (HBPM) would improve diagnostic accuracy compared with ambulatory blood pressure monitoring (ABPM), so the committee agreed the 2011 thresholds for diagnosis should be retained. The committee noted that these are in line with most international guidance.\n\nLimited evidence suggested that clinic blood pressure measurement is less accurate than HBPM or ABPM when used to diagnose hypertension. The committee members acknowledged that these findings were in line with their clinical experience and agreed that clinic blood pressure measurement alone would not be an adequate method to diagnose hypertension.\n\nThe committee discussed repeat clinic blood pressure measurements when there is a difference in blood pressure between arms and noted that clinical practice varied. Based on their experience and knowledge, the committee members agreed that a cut-off of 15\xa0mmHg would be more suitable than 20\xa0mmHg, which was specified in the 2011 recommendations. This is in line with recent evidence that suggests a small difference in arm blood pressure is associated with an increased risk of cardiovascular events, possibly due to vascular damage.\n\nABPM correlates well with invasive blood pressure measurement and can identify both white-coat and masked hypertension. Based on the evidence in the 2011 guideline and the committee's experience and knowledge, it was agreed that ABPM remains the gold standard for the accurate measurement of blood pressure in primary care. ABPM has therefore been retained as the preferred method for the diagnosis of hypertension. In addition, economic evidence obtained by updating the health economic model for the 2011 guideline confirmed that ABPM is still likely to be the most cost-effective method for diagnosis, even with the inclusion of new data for improved accuracy of home and clinic measurement.\n\nThe evidence showed that validated HBPM is an accurate method of diagnosing hypertension for people in sinus rhythm. The committee's experience in clinical practice supported this, and the committee agreed that it is a suitable alternative when ABPM is unsuitable or not tolerated. The committee noted that the British and Irish Hypertension Society maintains a list of validated blood pressure devices for home use. The British and Irish Hypertension Society is an independent reviewer of published work and this does not imply any endorsement of specific devices by NICE.\n\nThe evidence did not suggest that there were any benefits of adding telemonitoring to HBPM. Therefore, the committee agreed that it could not make a recommendation on telemonitoring for the diagnosis of hypertension.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current good practice. However, the committee noted that implementation of the 2011 recommendations on ABPM has been challenging and that there is still variation in practice. A change in practice and additional resources and training will be needed in areas where there is currently no access to ABPM devices. However, ABPM was found to be the most cost-effective method of diagnosis, and it is anticipated that the long-term benefits of accurate diagnosis and treatment (such as avoiding over diagnosis and unnecessary treatment) will outweigh any initial costs.\n\nReturn to recommendations\n\n# Relaxation therapies\n\n## Why the committee deleted the recommendation on relaxation therapies\n\nThe evidence on relaxation therapies was limited to a single small study. The study suggested some benefit in reducing angina and myocardial infarction, but it also suggested an increase in stroke. The committee agreed that the study was not adequate to assess the effectiveness of these therapies or to make a recommendation.\n\nThe 2011 guideline stated that relaxation therapies could reduce blood pressure, but it did not recommend their routine use in practice. The committee noted that this was based on evidence for reducing blood pressure only, and there was no evidence of a direct benefit to people with hypertension, such as improving quality of life or reducing cardiovascular events. The committee agreed there was insufficient evidence of benefit to recommend that people pursue this option themselves and agreed to remove this recommendation. It is not the intention of the committee to stop people from trying relaxation therapies if they wish to, but to make people aware that there is less evidence for benefit of this intervention compared with other lifestyle interventions or pharmacological treatment. The committee agreed that the clinical focus for non-pharmacological treatment of hypertension should be on encouraging people to make lifestyle changes, such as taking regular exercise and maintaining a healthy weight.\n\nThe committee agreed that further research would be useful to determine whether relaxation therapies are a clinically effective treatment for hypertension in terms of reducing cardiovascular events or improving quality of life (see the recommendation for research on relaxation therapies). They also noted that a larger study would be needed to obtain meaningful results.\n\n## How this might affect practice\n\nRelaxation therapies were not recommended for routine use in the 2011 guideline, and they are not used in current practice for the management of primary hypertension in adults. The 2011 recommendation advised that people may try them as part of their treatment to reduce blood pressure, but committee consensus was that uptake has been low. Therefore, current practice will not be affected by the removal of the 2011 recommendation.\n\n# Starting antihypertensive drug treatment\n\nRecommendations 1.4.9 to 1.4.14\n\n## Why the committee made the recommendations\n\nThe evidence suggested that antihypertensive drug treatment was effective at reducing cardiovascular events in people with a clinic blood pressure of 160/100\xa0mmHg or more (stage\xa02 hypertension).\n\nA large study also suggested there was benefit of treating people with stage\xa01 hypertension. However, other studies in people with a low cardiovascular risk did not identify a benefit of treatment, and the committee agreed that the benefit of treatment across different cardiovascular risk groups was uncertain. The evidence was used to develop an economic model to compare the cost effectiveness of antihypertensive treatment with no treatment in people with stage\xa01 hypertension at different levels of cardiovascular risk. For people aged\xa060, the model showed that treatment was cost effective at a 10‑year cardiovascular risk level of 10%, but there was some uncertainty at around 5% risk. Further analysis showed that it was cost effective to offer antihypertensive treatment to people aged\xa040\xa0and 50 with stage\xa01 hypertension at a 5% risk and aged\xa070\xa0and 75 at a 10% or 15% risk. QRISK was specified as the risk tool because it is recommended by NICE for risk calculation and most likely to be used in practice.\n\nTaking into account the evidence and the results of the model, the committee were confident that people under\xa080 with stage\xa01 hypertension and a cardiovascular risk above 10% should have a discussion with their healthcare professional about starting antihypertensive treatment, alongside lifestyle changes, and that this would be a clinically and cost-effective use of NHS resources. The committee also agreed that antihypertensive treatment should be considered for people under\xa060 with a risk below 10%, with the degree of uncertainty in treating people at low risk reflected in the strength of the recommendation.\n\nThe committee members were mindful of the additional population that would be affected by lowering the threshold and were aware that the decision to start drug treatment would depend on the person's preferences and their individual risk of cardiovascular disease. The recommendations highlight the importance of discussing the person's preferences for treatment and encouraging lifestyle changes.\n\nSome studies investigated the benefits of treating hypertension in people with lower cardiovascular risk or people with blood pressure below 140/90\xa0mmHg. However, some of these studies were not directly relevant because they included a high proportion of participants with chronic kidney disease and previous cardiovascular events. For this reason, several studies could not be used to inform the recommendations. For details of these studies see evidence review C: initiating treatment.\n\nThe committee discussed the lack of evidence to inform a threshold for starting treatment in people aged under\xa040. It was agreed that this is an important area for future research and the recommendation for research was carried forward from the 2011 guideline (see the recommendation for research on thresholds for interventions in adults aged under 40).\n\nThe committee agreed that there was no evidence to suggest that thresholds for starting treatment should be different in people with type\xa02 diabetes. The previous recommendations for people with type\xa02 diabetes (in NICE's guideline on type\xa02 diabetes in adults) suggested starting antihypertensive drug treatment if lifestyle interventions alone did not reduce blood pressure to below 140/80\xa0mmHg or 130/80\xa0mmHg in the presence of kidney, cerebrovascular or eye disease. However, this was based on evidence from 2\xa0small studies in which the participants did not have hypertension. Further evidence for lower treatment thresholds in people with type\xa02 diabetes was limited within this review, with the committee aware of some evidence to suggest that lower blood pressure thresholds did not reduce the rate of cardiovascular events in people without additional risk factors. The committee therefore agreed that there was insufficient evidence to recommend a different threshold for starting treatment for this subgroup.\n\nThere was no evidence identified on thresholds for people aged over\xa080, and no prior recommendation for this age group with hypertension below stage\xa02; therefore, the committee agreed that the threshold for starting treatment in people aged over\xa080 should be consistent with the target for treatment in this population (150/90\xa0mmHg or lower).\n\nThe committee discussed the additional risks of starting treatment in older people, particularly those who are frail or have multiple comorbidities. Based on their expertise and experience, they agreed that the use of clinical judgement should be highlighted in decision making for people with frailty or multimorbidity, and that it should apply to people of any age. The committee agreed that a number of factors should be considered when discussing treatment options in this group and noted that healthcare professionals should refer to NICE's guideline on multimorbidity for further advice.\n\n## How the recommendations might affect practice\n\nThe recommendations will have a significant impact on practice because more people will now be eligible for treatment. It is difficult to predict the extent of the impact because there is variability in how the 2011 recommendation with a threshold of 20% is being implemented in practice. However, it is believed, based on some recently published UK data, that potentially around 50% of people with stage\xa01 hypertension and risk below 20% are already being treated with antihypertensive drugs (Association of guideline and policy changes with incidence of lifestyle advice and treatment for uncomplicated mild hypertension in primary care. Sheppard et al. 2018).\n\nPeople with stage\xa01 hypertension should already be monitored every year, but reducing the threshold will increase the number of people being prescribed antihypertensive drugs and increase staff time and consultations involved in starting and monitoring their drug treatment. However, there will be a reduction in cardiovascular events resulting in savings, although it is acknowledged that the costs and savings may fall in different sectors of the NHS.\n\nReturn to recommendations\n\n# Monitoring treatment and blood pressure targets\n\nRecommendations 1.4.15 to 1.4.22\n\n## Monitoring treatment\n\nThe committee agreed that there was not enough evidence to strongly recommend home blood pressure monitoring (HBPM) for monitoring treatment in adults with hypertension. The evidence on monitoring was limited, with relatively small studies comparing different combinations of HBPM (with or without telemonitoring and with or without pharmacist input), pharmacy monitoring and clinic monitoring. It suggested that people had improved blood pressure control with HBPM with telemonitoring, with or without pharmacy input, compared with clinic monitoring, and the greatest blood pressure reduction was achieved with pharmacist input. However, the evidence was insufficient for the committee to make a recommendation.\n\nThe committee decided to retain the 2011 recommendation on using clinic blood pressure, but also agreed that the updated guideline should support home monitoring for people who wish to use it. The committee discussed the importance of patient choice and agreed that home monitoring should be an option, if it is suitable and the person is willing and motivated to use it. HBPM is already widely used in practice, especially for people with a white-coat effect. The committee agreed this would be reflected in the recommendation supported by the evidence and consensus opinion. Based on their experience, the committee agreed that training and advice would be needed for people using HBPM to ensure that people take measurements correctly and know when to contact their healthcare professional if they are not achieving their target blood pressure.\n\nThe 2011 guideline included a recommendation for further research for the best method of monitoring hypertension in people with atrial fibrillation. No evidence was identified in the updated reviews to inform recommendations for this group and therefore the committee agreed that this recommendation for research should be retained to inform future updates of the guideline (see the recommendation for research on automated blood pressure monitoring).\n\nThe committee agreed they could not make a recommendation on telemonitoring because the evidence was not sufficient to show a clear benefit and the studies were inconsistent in the telemonitoring methods used.\n\nThe recommendations reflect current practice, so there should be no change in practice. They will encourage appropriate and suitable training to be given so that both people with hypertension and their healthcare professionals are confident that blood pressure is being measured properly using home monitoring devices.\n\nReturn to recommendations\n\n## Blood pressure targets for people without cardiovascular disease\n\nRecommendations 1.4.15 to 1.4.22\n\nNo evidence was identified to determine whether cardiovascular risk or blood pressure targets should be used. The committee agreed that in the absence of evidence the focus should be on blood pressure targets, based on their expertise and experience of current practice.\n\nThe evidence for blood pressure targets showed that there were both benefits and harms associated with a lower clinic systolic blood pressure target of 120\xa0mmHg compared with 140\xa0mmHg in people with primary hypertension without type\xa02 diabetes. Although the evidence suggested some benefit in reducing mortality and cardiovascular events, the lower blood pressure target was associated with a greater risk of harms, such as injury from falls and acute kidney injury. The committee agreed that the long-term implications of these adverse events were unclear and that further research is needed.\n\nThis evidence came from the SPRINT trial, which was a large study undertaken in the US. The committee discussed concerns about the population included in the study and the applicability to UK practice of the methods used. The study used automated blood pressure devices with a time delay and an isolated rest period, which is not common practice in the UK. The committee considered that the use of these devices would lead to lower blood pressure readings than in routine UK clinical practice. They also had concerns that some medicines were stopped when blood pressure targets were achieved, which may have had an impact on the results. The committee also discussed concerns about applicability of the population; for example, the participants had high cardiovascular risk levels, including many with pre-existing cardiovascular disease or renal impairment, and were already receiving treatment before the study started. These concerns made the evidence difficult to interpret and use to inform the recommendations. Further details of the committee's discussion of this study is included in evidence review D: targets.\n\nEvidence from a smaller study also showed some benefit of lowering clinic systolic blood pressure targets to 130\xa0mmHg. However, the committee noted that the study was based on people already receiving treatment and that it lacked information on adverse events.\n\nThe committee agreed that there was no evidence to suggest that blood pressure targets should be different in people with type\xa02 diabetes. Evidence for lower targets in people with type\xa02 diabetes was also limited, with some evidence to suggest that lower blood pressure targets did not reduce the rate of cardiovascular events. Previous recommendations for people with type\xa02 diabetes (in NICE's guideline on type\xa02 diabetes in adults) suggested a blood pressure target below 130/80\xa0mmHg in the presence of target organ damage such as kidney, cerebrovascular or eye disease. The committee noted that the evidence behind this recommendation was based on 2\xa0small studies in people without hypertension. They also had concerns about the relevance of the study design. The committee were also aware of trial data showing less benefit in populations with type\xa02 diabetes with fewer additional risk factors. The committee therefore agreed that there was insufficient evidence to recommend a different blood pressure target for this subgroup. It was noted that people with later-stage chronic kidney disease are covered by other NICE guidelines.\n\nOverall, the committee agreed that the evidence was unclear and insufficient to determine whether a lower target would be beneficial and whether it would outweigh the associated harms. Therefore, the 2011 clinic blood pressure target of 140/90\xa0mmHg for adults under 80\xa0years was retained and applies to people with or without type\xa02 diabetes. The corresponding HBPM and ambulatory blood pressure monitoring (ABPM) targets were also retained at 135/85\xa0mmHg. The recommendations emphasise the importance of achieving and maintaining a level consistently below the person's blood pressure target, whether this target be based on clinic blood pressure, HBPM or ABPM.\n\nBased on their experience, the committee members felt that people with postural hypotension are at risk of adverse events if a sitting or lying blood pressure is used for monitoring, because this measurement would overestimate daytime blood pressure and result in overtreatment. For example, a patient with a sitting systolic blood pressure of 140\xa0mmHg might have a much lower blood pressure when standing and be at an increased risk of falls if treated based on their sitting blood pressure. The committee decided to recommend that 3\xa0groups who are at risk of postural hypotension (people over 80\xa0years, with type\xa02 diabetes and with symptoms of postural hypotension) should have their standing blood pressure measured, and their treatment modified accordingly if they have postural hypotension. The standing blood pressure should be used for future monitoring.\n\nThe recommendations should reinforce current good practice. However, the new recommendations place more emphasis on maintaining blood pressure consistently below the blood pressure targets. As a result, this could lead to a higher use of antihypertensive drugs and an increase in consultations to maintain target blood pressure. For people with type\xa02 diabetes and target organ damage (not covered by other guidelines), the slightly higher target blood pressure compared to that recommended previously may reduce adverse events and may lead to fewer appointments and reduced drug use.\n\nReturn to recommendations\n\n## Blood pressure targets for people with cardiovascular disease\n\nRecommendation 1.4.23\n\nThe evidence did not show a robust or consistent clinical benefit from using lower blood pressure targets for people with cardiovascular disease compared with standard blood pressure targets.\n\nThe vast majority of people in the control arms of the studies achieved blood pressures well below 140/90\xa0mmHg. In the committee's experience of practice, some people with hypertension can have their blood pressure maintained at 140/90\xa0mmHg, rather than below this level. To address this issue, the committee amended the 2019 recommendations on blood pressure targets to emphasise the importance of reducing and maintaining blood pressure below 140/90\xa0mmHg.\n\nThe committee made recommendations for research for:\n\nPeople aged over\xa080, because there was no evidence specifically for this group. The only evidence was from mixed age groups, and the committee agreed that this evidence was too limited to support a new practice recommendation.\n\nPeople with aortic aneurysm, because there was no evidence for this group.\n\nPeople who have had a stroke, because there was limited evidence that lower blood pressure targets reduced the risk of future strokes, but there was also evidence on the possible harms of lower targets. Evidence for both potential benefit and harm was too limited to inform a recommendation.\n\nThe new recommendation reflects current practice for most types of cardiovascular disease, so there should be no change in practice or increase in resource use.\n\nThe Royal College of Physicians Intercollegiate Stroke Working Party guideline recommends a lower blood pressure target for people after stroke. However, the national quality indicators used in primary care do not use a lower blood pressure target for people with cardiovascular disease (including stroke and transient ischaemic attack).\n\nReturn to recommendation\n\n# Choosing antihypertensive drug treatment for people with cardiovascular disease\n\nRecommendation 1.4.31\n\n## Why the committee made the recommendation\n\nNew evidence in this area was not reviewed as part of the 2022 update. Instead, the evidence from previous versions of the guideline was reassessed to look at outcomes for people with cardiovascular disease. Only evidence up to 2010 was re-analysed, because the 2019 update did not review evidence for people with cardiovascular disease.\n\nThere was no difference in clinically relevant outcomes between people with and without cardiovascular disease.\n\nEvidence was limited for people with stroke, transient ischaemic attack, or coronary artery disease. This evidence did not cover enough treatment comparisons to allow the committee to draw any firm conclusions.\n\nThere are NICE guidelines on acute coronary syndromes and chronic heart failure, and these guidelines make recommendations on drug treatment that overlap with treatment for hypertension. To avoid confusion over the treatment pathway, the committee highlighted that these condition-specific recommendations should be applied first (for example, when prescribing an ACE inhibitor or an ARB for secondary prevention of myocardial infarction).\n\n## How the recommendations might affect practice\n\nThe recommendation reflects current practice for most types of cardiovascular disease.\n\nThe committee were aware that, after a stroke, the thiazide-like diuretic indapamide is sometimes used first, rather than a calcium channel blocker. However, it is unclear how common this is. As people with cardiovascular disease are commonly prescribed more than 1\xa0antihypertensive drug, any impact on prescribing would be limited.\n\nReturn to recommendation\n\n# Step 1 treatment\n\nRecommendations 1.4.32 to 1.4.39\n\n## Why the committee made the recommendations\n\nThe committee reviewed the evidence for starting treatment for primary hypertension with a single antihypertensive medicine compared with starting with 2\xa0antihypertensive medicines at once (dual therapy). Additionally, the committee reviewed the evidence on whether specific subgroups of people with hypertension might benefit from starting on dual therapy, for example people with type\xa02 diabetes, older people, or those of particular family origins.\n\nSome limited evidence from a single study showed that initial dual therapy may reduce cardiovascular events in people with hypertension and type\xa02 diabetes, but the committee members were disappointed that more comprehensive data was not available. The committee discussed the benefits of optimising treatment for hypertension early and agreed that this can substantially improve quality of life. However, there was not enough evidence to determine confidently the benefits or harms of starting treatment with dual therapy. In response to the lack of available evidence, the committee developed a recommendation for research on step\xa01 treatment to determine if particular subgroups would benefit from starting dual therapy, to inform future guidance.\n\nIn the absence of compelling new evidence on step\xa01 dual therapy, the committee agreed that the previous recommendations for step\xa01 treatment should be retained (with minor changes for clarity), because they were based on robust clinical and cost-effectiveness evidence. One exception to this was the 2006 recommendation for considering beta-blockers in certain groups of younger people. The committee discussed this recommendation and agreed that beta-blockers are rarely used as step\xa01 antihypertensive treatment in current practice and there is no established relationship between beta-blocker use in primary hypertension and a reduction in cardiovascular events. For these reasons, the committee decided that the recommendation should not be retained. The committee noted that this is consistent with most international guidelines.\n\nThis guideline also updates and replaces the section on blood pressure management from NICE's guideline on type\xa02 diabetes in adults. That guideline recommended that adults with type\xa02 diabetes of any age should start on an angiotensin-converting enzyme (ACE) inhibitor as step\xa01 treatment (except women with a possibility of becoming pregnant and people of Black African or African–Caribbean family origin). The committee discussed the evidence for this and agreed that it was sufficient to support and retain this recommendation. The committee agreed it should be broadened to include the choice of an ACE inhibitor or an angiotensin\xa0II receptor blocker (ARB; also referred to as A‑type drugs), because they are now cost equivalent, and the committee also agreed they are clinically equivalent.\n\nFor people of Black African or African–Caribbean family origin with type\xa02 diabetes, the previous recommendation was to offer step\xa01 dual therapy with an ACE inhibitor and either a diuretic (D‑type drug) or a calcium channel blocker (CCB; C‑type drug). However, these recommendations were based on monotherapy studies and when the committee looked at this evidence alongside the new dual therapy evidence review, they concluded that it was insufficient to recommend starting dual therapy in any subgroup of people with type\xa02 diabetes. The committee noted that people with type\xa02 diabetes who are older or are of Black African or African–Caribbean family origin may not achieve their target blood pressure on ACE inhibitor or ARB monotherapy and may need to start step\xa02 drug therapy in the short term.\n\n## How the recommendations might affect practice\n\nOverall, the recommendations for step\xa01 treatment reflect current practice for people who do not have type\xa02 diabetes. For people of Black African or African–Caribbean family origin who have type\xa02 diabetes, the recommendation to start antihypertensive monotherapy rather than dual therapy may result in an extra clinical appointment if the dose needs to be adjusted. However, it may also reduce potential harms from initial overtreatment of blood pressure.\n\nReturn to recommendations\n\n# Step 2 and 3 treatment\n\nRecommendations 1.4.40 to 1.4.45\n\n## Why the committee made the recommendations\n\nNo evidence for step\xa02 or step\xa03 treatment was identified that was relevant to determining the best sequence for step\xa02 and step\xa03 antihypertensive treatment. Some of the studies available on drug treatments for hypertension were not included in this review because they were designed to inform step\xa01 treatment. Others did not reflect UK clinical practice. For details of these studies see evidence review F: step\xa02 and step\xa03 treatment.\n\nBased on evidence from the previous version of the guideline and their clinical expertise, the committee members agreed to retain the same choice of drugs from the 2011 guideline, which reflect current best practice. The committee agreed that, in the absence of evidence of which treatment(s) are most effective for step\xa02 or step\xa03, the recommendation should be to offer any of these treatments based on an individualised approach informed by risks and benefits of each treatment and the person with hypertension's preference.\n\nThe committee noted that the changes to the step\xa01 recommendations for some people with type\xa02 diabetes do not necessitate a change in the step\xa02 recommendations since the same options for combination treatment at step\xa02 are available.\n\nThe committee agreed that the choice of drug should be discussed and agreed with the person, based on the person's step\xa01 treatment, the risks and benefits of each treatment option, and taking into account the person's preferences and other clinical factors. The updated recommendations reflect this, giving the choice of possible treatment options. A NICE patient decision aid on treatment choices for high blood pressure has been developed to support healthcare professionals and people with hypertension to discuss their treatment options and make informed decisions.\n\n## How the recommendations might affect practice\n\nThe recommendations are unlikely to alter current practice. The options for drug treatment remain the same and most step\xa02 or 3 treatment decisions are already based on an individualised approach.\n\nReturn to recommendations\n\n# Step 4 treatment\n\nRecommendations 1.4.46 to 1.4.52\n\n## Why the committee made the recommendations\n\nNo evidence on step\xa04 treatment was identified that could be used to formulate new recommendations. However, the committee reviewed the 2011 recommendations and agreed that they should be retained and updated to reflect current best practice.\n\nThe committee discussed the importance of confirming resistant hypertension before starting step\xa04 treatment. Based on their clinical experience and knowledge of best current practice, the committee members agreed that a recommendation to highlight this would help prevent overtreatment and ensure that people receive the right care.\n\nDespite the lack of evidence formally reviewed, the committee discussed the recommendation based on their clinical experience, taking the 2011 recommendations into account. The committee agreed that although the evidence for spironolactone did not meet the criteria for inclusion in the updated review for the guideline because the key study had a very short follow up and did not report any of the cardiovascular outcomes specified in this review protocol, the use of an aldosterone antagonist is now common clinical practice. Therefore, there was no reason to suggest that this recommendation should be changed.\n\nIn the 2011 guideline, high-dose thiazide diuretics were recommended as a potential step\xa04 treatment in people with high blood potassium levels. The committee felt that there was a lack of evidence for this approach and noted that the studies did not show an improvement in cardiovascular outcomes at higher doses, albeit in people without resistant hypertension. The committee agreed that the recommendation for considering alpha- or beta-blockers should be retained based on significant clinical experience of their safe and effective use and because adding a further drug is likely to have a greater effect on blood pressure than increasing the thiazide diuretic dose.\n\n## How the recommendations might affect practice\n\nThe recommendations represent current good practice and so should not change practice. High-dose thiazide diuretics are not commonly used as step\xa04 therapy and so removing this should not change practice.\n\nThere might be a small reduction in step\xa04 treatment with more thorough checks to confirm resistant hypertension. However, this may also result in an increase in blood pressure measurements to appropriately confirm resistant hypertension where this is not already being done.\n\nReturn to recommendations\n\n# Identifying who to refer for same-day specialist review\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThere was no evidence identified to inform recommendations on this topic. The committee reviewed the 2011 recommendations and agreed that they should be updated by consensus based on their clinical expertise. In particular they agreed it would be helpful to clarify which features warranted same-day referral, which would need further investigation and when repeat blood pressure measurement should be taken.\n\nThe committee noted that it can be difficult to differentiate between accelerated hypertension and severe hypertension. They discussed the advantages and disadvantages of broader criteria for same-day referral, which would increase referrals to hospital but reduce the risk of missing people who need urgent treatment. The committee decided it would be beneficial to add some emergency symptoms to the existing recommendation, which will help healthcare professionals to decide when to refer.\n\nBased on their experience, the committee members agreed that some people with severe hypertension could be receiving unnecessary treatment because the 2011 guideline recommended treatment based on severe hypertension alone. The committee agreed that this could be prevented if investigations for target organ damage were carried out quickly before offering treatment in people with severely raised blood pressure and no other symptoms of concern. The committee also agreed that checking blood pressure again within 7\xa0days in people with no target organ damage would ensure that people with severe hypertension are followed up and offered suitable treatment.\n\nThe committee agreed that further research is needed in this area, particularly for people with extreme hypertension (220/120\xa0mmHg or higher) or emergency symptoms. The committee members developed a recommendation for research on same-day hospital specialist assessment to help inform future recommendations.\n\n## How the recommendations might affect practice\n\nThe emergency symptoms listed in the recommendation may lead to more referrals to hospital. However, people with emergency symptoms will benefit from urgent treatment because accelerated hypertension can be fatal if untreated.\n\nThere may be some additional resource use from doing target organ damage tests more quickly and re-measuring blood pressure within 7\xa0days. However, the number of people started on treatment immediately may be reduced because of undertaking investigations first.\n\nThe population with severe hypertension is very small, and the proportion with severe hypertension and additional symptoms that suggest accelerated hypertension is even smaller; therefore, resource impact is unlikely to be substantial.\n\nReturn to recommendations", 'Context': "High blood pressure (hypertension) is one of the most important, treatable causes of premature morbidity and mortality in the world. It is a major risk factor for stroke, myocardial infarction, heart failure, chronic kidney disease, cognitive decline and premature death. In 2015, it was reported that high blood pressure affected more than 1\xa0in 4\xa0adults in England (31% of men; 26% of women) – around 13.5\xa0million people – and contributed to 75,000\xa0deaths. The clinical management of hypertension accounts for 12% of visits to primary care and up to £2.1\xa0billion of healthcare expenditure. Managing the cardiovascular events caused by hypertension also consumes considerable resources.\n\nThe guideline covers adults (over 18\xa0years) with suspected or diagnosed hypertension, including those with type\xa02 diabetes.\n\nupdate\n\nBetween 2010 and 2020, progress has been made to improve the diagnosis and management of hypertension: the population average blood pressure in England has fallen by about 3\xa0mmHg systolic and the proportion of adults with untreated high blood pressure has decreased. However, the Public Health England Blood Pressure Action Plan called for further action to reduce the population average blood pressure by 5\xa0mmHg through improved prevention, detection and management (Public Health England's Tackling high blood pressure: from evidence into action, 2015 and Tackling high blood pressure: an update, 2018).\n\nSince the publication of the 2011 NICE guideline on hypertension, new studies have been published in key areas of management; in particular, the optimal method and threshold for diagnosis of hypertension, managing blood pressure in lower risk populations and reducing blood pressure to lower targets in people with hypertension (including those with type\xa02 diabetes). The updated guideline makes new recommendations in these areas, based on the evidence, that aim to improve care and reduce variation in current practice.\n\nTreating resistant hypertension (when more than 3\xa0drugs are needed to treat hypertension) remains challenging. New data was also reviewed in this area and the recommendations updated.\n\nThere is uncertainty in current practice about which people with symptomatic very high blood pressure (accelerated hypertension) to refer for immediate assessment. The available evidence was reviewed and new recommendations made to provide guidance for primary care on when to refer."}
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https://www.nice.org.uk/guidance/ng136
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This guideline covers identifying and treating primary hypertension (high blood pressure) in people aged 18 and over, including people with type 2 diabetes. It aims to reduce the risk of cardiovascular problems such as heart attacks and strokes by helping healthcare professionals to diagnose hypertension accurately and treat it effectively.
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956e47509e52886649a7f807db121067a1d8cd75
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nice
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Integrated health and social care for people experiencing homelessness
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Integrated health and social care for people experiencing homelessness
This guideline covers providing integrated health and social care services for people experiencing homelessness. It aims to improve access to and engagement with health and social care, and ensure care is coordinated across different services.
# Context
This guideline includes recommendations on ways to improve access to and engagement with health and social care services for people experiencing homelessness. It also gives advice on how commissioners, planners, providers and practitioners across disciplines and agencies can work together to support and improve outcomes for people experiencing homelessness.
In this guideline, 'people experiencing homelessness' means people aged 16 and over who:
are sleeping rough
are temporary residents of hostel, B&B, nightly-paid, privately managed accommodation and other types of temporary accommodation
use day centres that provide support for people experiencing homelessness
are obliged to stay temporarily with other people
are squatting
are newly homeless
have a history of homelessness (as defined above), and are at high risk of becoming homeless again because of ongoing severe and multiple health and social care needs.
Underlying causes of homelessness include structural, societal and economic factors, and inequalities, such as poverty and deprivation, unaffordable housing, unemployment, exclusion and discrimination. People experiencing homelessness often experience severe and multiple disadvantage and unmet health and social care needs that may be contributing factors for becoming homeless as well as consequences of homelessness. Experience of psychological trauma and adverse childhood events are common in people experiencing homelessness, and the prevalence of people who are neuroatypical or have a brain injury is higher than in the general population. Homelessness and access to appropriate housing is a public health issue.
People experiencing homelessness have far worse health and social care outcomes than the general population. The average age of death for the homeless population is around 30 years lower than for the general population according to the Office for National Statistics' Deaths of homeless people in England and Wales: 2019 registrations.
'Inclusion health' is a term developed to address the health and care needs of groups that are traditionally excluded, including people experiencing homelessness. The needs of the homeless population overlap considerably with other inclusion health groups. Internationally, these groups have mortality rates that are 8 times higher than the general population for men and 12 times higher for women (Aldridge et al. 2017). Many of these premature deaths are from preventable and treatable conditions according to a 2019 study by the same authors (Aldridge et al. 2019). The Office for National Statistics' 2019 report showed that the causes of most deaths of people experiencing homelessness in England and Wales were registered as drug-related poisonings, suicides and alcohol-specific deaths.
People experiencing homelessness use more acute hospital services and emergency care than the general population. When admitted to a hospital, the length of hospital stay is usually much longer because of multiple unmet needs. Barriers to access and engagement with preventive, primary care and social care services can mean that problems remain untreated until they become very severe and complex. These barriers include stigma and discrimination; lack of trusted contacts; fragmented, siloed and rigid services; strict eligibility criteria; and lack of information sharing and appropriate communication.
In addition to a moral responsibility, there is an economic imperative to tackle homelessness. The costs of homelessness to society are significant. The report by Pleace and Culhane (2016), published by Crisis, estimated the total public sector costs of a person experiencing homelessness to be as much as £38,736 per year in England (based on 2019/20 prices). This estimate included the NHS costs (£4,298), mental health services (£2,099), drug and alcohol services (£1,320), criminal justice sector costs (£11,991) and homelessness services (£14,808). On average, it was estimated that preventing homelessness for 1 year would reduce the public expenditure by approximately £10,000 per person. In 2020/21, 11,580 single households were assessed as rough sleeping in England (Ministry of Housing, Communities & Local Government, 2021), and if these people were prevented from experiencing 1 year of homelessness, annual public spending would fall by as much as £115.8 million. If other forms of homelessness were included, these cost savings would be substantially higher. Given the financial implications of homelessness to society and the far worse health and social care outcomes, most interventions that address homelessness are likely to be cost effective or even cost saving from the wider public sector perspective.
The Ministry of Housing, Communities & Local Government's rough sleeping strategy outlines its commitment to ending rough sleeping and preventing homelessness. The homelessness legislation includes duties for local authorities to assess, prevent and relieve homelessness. The NHS Long Term Plan includes a commitment to improve access to specialist homelessness mental health support for people sleeping rough in areas with the highest rates of rough sleeping. During the COVID‑19 pandemic, local authorities, health services, and the voluntary and charity sector have worked in partnership to respond to homelessness, including the 'Everyone In' initiative, recognising that rough sleeping and homelessness are public health issues. This has shown that with appropriate funding, integrated working and prioritisation of the most vulnerable in the society, there are opportunities for positive change.
This guideline provides guidance on models of service provision, for services that are specific to people experiencing homelessness, as well as improving access and engagement with mainstream services. It aims to integrate services as much as possible as a way to improve outcomes for people experiencing homelessness and contribute to ending homelessness.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# General principles
Recognise that more effort and targeted approaches are often needed to ensure that health and social care for people experiencing homelessness is available, accessible, and provided to the same standards and quality as for the general population.
## Co-design and co-delivery of services
Recognise the value of co-designing and co-delivering services with people with lived experience of homelessness, to improve the quality of health and social care (see the section on the role of peers). See also the section on involving people in service design and improvement in NICE's guideline on people's experience in adult social care services and NICE's guideline on community engagement.
## Supporting engagement with services
Promote engagement by providing services that:
are person-centred, empathetic, non-judgemental
aim to address health inequalities
are inclusive and pay attention to the diverse experiences of people using the service.
Consider using psychologically informed environments and trauma-informed care. Recognise that people's behaviour and engagement with services is influenced by their traumatic experiences, socioeconomic circumstances and previous experiences of services.
## Sustaining engagement with services
Recognise the importance of longer contact times in developing and sustaining trusting relationships between frontline health and social care staff and people experiencing homelessness (see also recommendation 1.2.9 in the section on planning and commissioning).
Promote shared decision making, building self-reliance and using strengths-based approaches to care (also known as assets-based approaches). See also NICE's guideline on shared decision making.
Recognise that people experiencing homelessness, especially those with experience of rough sleeping, need services that provide a long-term commitment to care to promote recovery, stability and lasting positive outcomes (see the section on long-term support).
## Supporting re-engagement with services
Be aware that some people experiencing homelessness may find it difficult to look after themselves because of their circumstances and may find services difficult to engage with. For people who disengage from or refuse health and social care services:
actively support re-engagement
enable people to re-engage with services at the same point as they left, if appropriate.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on general principles .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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## Communication and information
Follow the recommendations on communication and information in NICE's guidelines on:
patient experience in adult NHS services
people's experience in adult social care services
service user experience in adult mental health
babies, children and young people's experience of healthcare.
Health and social care staff working with people experiencing homelessness should:
be empathetic, non-judgemental and use recovery-oriented language that avoids jargon and acronyms
use communication methods based on the person's preferences, for example, phone call, text message, email, letter, face to face
send clear information about contacts or appointments and reminders that reach people in time, and follow up people who do not attend.
Take into account each person's communication and information needs and preferences, and their circumstances. For example:
provide translation and interpretation services if needed
ensure that written information is available in different formats and languages, including Easy Read
provide extra support for people with low literacy levels or with speech, language and communication difficulties
consider the person's access to phone or internet.
Consider involving an advocate to support communication, even when this is not a statutory requirement. This may be someone nominated by the person or an independent advocate who can, for example:
support people to overcome stigma and previous negative and traumatic experiences
help people with low literacy levels to access information and services
reinforce information about available services and appointments.
Give people experiencing homelessness information about:
their rights to health and social care services, including for those with no or limited recourse to public funds
how to access health and social care services, including:
primary care services and how to register with a GP without a permanent address
specialist health services that can be accessed directly, such as maternity, blood-borne virus, drug and alcohol recovery, mental health, sexual health, and family planning services
-utreach services
local authority services, including housing services and social care
voluntary and charity sector services.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on communication and information .
Full details of the evidence and the committee's discussion are in evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Planning and commissioning
These recommendations are for commissioners of health and social care and housing services.
## Planning integrated multidisciplinary health and social care services
Commissioners of health, social care and housing services should work together to plan and fund integrated multidisciplinary health and social care services for people experiencing homelessness, and involve commissioners from other sectors, such as criminal justice and domestic abuse, as needed. These services should contribute to the government's aim of ending rough sleeping and preventing homelessness.
Recognise that people experiencing homelessness often need additional resources and a more targeted service delivery to:
ensure that resources are allocated according to need and disadvantage
take into account the social determinants of health
improve long-term outcomes and address health inequalities.
## Local homelessness health and social care needs assessment
Conduct and maintain an up-to-date local homelessness health and social care needs assessment and use this to design, plan and deliver services according to need. Include thorough engagement with service providers (including voluntary and charity sector service providers) and experts by experience.
Local homelessness health and social care needs assessments should:
quantify and characterise the population experiencing homelessness or at risk of homelessness, including health inequalities, diversity and inclusion issues and specific needs and identify trends
assess the quality and capacity of existing mainstream and specialist service provision to inform the need for service development and investment
assess access to and engagement with current services by people experiencing homelessness
identify opportunities for more integrated service delivery
take into consideration relevant findings from Safeguarding Adults Reviews.
## Recording housing status
Work with health and social care providers to improve recording of housing status so that the information can be used by services to:
best meet people's needs and
plan, audit and improve services.
## Developing services
When developing services for people experiencing homelessness, commissioners should:
work together to strategically plan and deliver health and social care across larger areas, recognising that people move between areas
work with other relevant services, such as prison and probation services and domestic abuse services
enable long-term support for those who need it (see the section on long-term support)
ensure that health and social care services are designed to meet the level and type of local need (see the section on models of multidisciplinary service provision)
define and measure outcomes, including health and social outcomes and service use
consider the likely benefits of using long-term contracts for providers
support statutory bodies to fulfil their legal responsibilities and use their powers
encourage and enable the contribution of peers (experts by experience) in supporting people experiencing homelessness and delivering and designing more effective services (see the section on the role of peers).
Consider providing services and support aimed at the needs of particular groups of people experiencing homelessness, as appropriate, such as:
women (also see the NICE guideline on pregnancy and complex social factors)
young people
-lder people
disabled people
people with no or limited recourse to public funds because of their immigration status
LGBT+ people
people from different minority ethnic or religious backgrounds.
Develop strategies across services to improve access to health and social care for people experiencing homelessness. See the section on improving access to and engagement with health and social care.
Ensure that there are processes to:
support people experiencing homelessness to register with a GP and
document and address any problems with GP registrations for people experiencing homelessness.
Consider reducing caseloads and lengthening contact time for health and social care practitioners working with people experiencing homelessness to enable them to use approaches that sustain engagement with services.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on planning and commissioning .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Models of multidisciplinary service provision
## Homelessness multidisciplinary teams
Provide care through specialist homelessness multidisciplinary teams across sectors and levels of care, tailored according to local needs.
Homelessness multidisciplinary teams should act as expert teams, providing and coordinating care across outreach, primary, secondary and emergency care, social care and housing services. Homelessness multidisciplinary teams may include:
experts by experience (see the section on the role of peers)
healthcare professionals with relevant specialist expertise (for example, drug and alcohol treatment, mental health, primary care, emergency care, palliative care)
social workers
housing options officers or homelessness prevention officers
-utreach and homelessness practitioners
voluntary and charity sector professionals
staff with practical expertise in accessing benefits and entitlements for people experiencing homelessness.
Homelessness multidisciplinary teams should have protocols and systems in place for communication and sharing information to support integrated working within the team and between services.
Homelessness multidisciplinary teams should:
identify people experiencing homelessness through outreach or when they present to health and social care services
support mainstream providers to identify and refer people to the homelessness multidisciplinary team
undertake and support assessments for safeguarding, physical and mental health, alcohol and drug treatment needs, and social care, including informing Care Act assessments (see the section on assessing people's needs)
support mainstream providers to ensure safe, timely and appropriate hospital discharge and engagement with onward care (see the section on transitions between different settings).
Homelessness multidisciplinary teams should:
-ffer person-centred case management by a designated practitioner within the multidisciplinary team and ensure continuity of care for as long as it is needed by the person
-ffer wraparound health and social care support that encompasses the person's needs, including:
physical health
mental health and psychological support (such as psychological therapies)
physical rehabilitation (such as occupational therapy and physiotherapy)
drug and alcohol treatment
social care
palliative care
communication support
practical support, such as help with benefits, housing and referral for legal advice.
Homelessness multidisciplinary teams should engage in reflective practice, including opportunities to share experience and learning with other relevant teams, including homelessness multidisciplinary teams, and to review complex or difficult situations.
Homelessness multidisciplinary teams should directly contribute to local needs assessments, service quality improvement, and reviews of complex or difficult situations including Safeguarding Adults Reviews.
Homelessness multidisciplinary teams should advise homelessness leads, when needed, in nearby areas that do not have a homelessness multidisciplinary team and share examples of good practice.
## Homelessness leads in mainstream services
In areas assessed as not needing a full-time homelessness multidisciplinary team because of low numbers of people experiencing homelessness, establish links with multidisciplinary teams in nearby areas and designate homelessness leads in all relevant mainstream services, for example, in primary, secondary and emergency care, palliative care and in adult and child social services.
The homelessness leads should:
support their organisation to provide appropriate care for people experiencing homelessness and implement this guideline
have detailed local knowledge of specialist services to support the care of people experiencing homelessness
work with and coordinate care with homelessness leads in other mainstream services
consult homelessness multidisciplinary teams in nearby areas, as needed.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on models of multidisciplinary service provision .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# The role of peers
Involve peers (experts by experience) in delivering and designing services, for example by:
directly delivering health and social care interventions, for example, as part of outreach
providing a user perspective to influence the design and development of services
providing training for health and social care staff
carrying out participatory research and data collection, for example, to support service audits, needs assessments and quality improvement.
Offer peer support to people experiencing homelessness, for example to help with:
understanding how others with similar experiences have changed their lives (role modelling)
developing self-efficacy
navigating services
supporting attendance at appointments
providing peer advocacy at appointments or in A&E
forming trusting relationships with practitioners and improving communication.
Support peers to deliver services effectively and maintain their own wellbeing and development by providing:
training, supervision and governance structures appropriate to the role and tailored to the person's needs
psychological and social support, for example reflective practice, according to their changing needs and circumstances
tailored support for professional development, including access to further training and inclusive employment opportunities.
Take into account the experience, background and language skills of peers and how these can be used to meet the needs and preferences of people experiencing homelessness.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on the role of peers .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Improving access to and engagement with health and social care
## Supporting access to and engagement with services
Design and deliver services in a way that reduces barriers to access and engagement with health and social care, for example, by providing:
-utreach services (see the section on outreach services)
low-threshold services
flexible opening and appointment times
self-referral
drop-in services
'one-stop shops' for multiple services
incentives and help to access care, such as transport support, vouchers or digital connectivity
advocates (see recommendation 1.1.12 in the section on communication and information)
peer support (see the section on the role of peers)
care navigation
psychologically informed environments and trauma-informed care.
Do not penalise people experiencing homelessness for missing appointments, for example, by discharging people from the service. Consider seeking specialist help, such as peer supporters or independent advocates, to support the person to attend appointments and re-engage with care after missing appointments (see the section on the role of peers).
Ensure that people can access help when needed, including through emergency care, and avoid policies that withdraw support and close cases after a standard duration, unless a safe transfer of care to another service has been agreed with the person or the person agrees that they no longer need the service.
Commissioners and service providers should follow the recommendations on improving access to services in NICE's guideline on common mental health problems.
Ensure that people experiencing homelessness with multiple health or social care needs are not excluded from services because of restrictive eligibility criteria. For example, people with mental health problems are not denied access to mental health services because they have drug and alcohol treatment needs (see also NICE's guideline on coexisting severe mental illness and substance misuse).
Ensure that people experiencing homelessness who are assessed as frail and in need of social care and support get long-term care packages, including residential care or supported housing, irrespective of their age.
Ensure that paper or digital forms needed to access health or social care or to get help with NHS costs are readily available and that people are supported to fill them in, including providing translation when needed.
Ensure that people experiencing homelessness can access online health and social care information and are supported to use online services, for example by providing internet access at places where people experiencing homelessness spend time, such as day centres or hostels.
Primary care service providers should ensure that people without an address can register with a GP practice, in line with the NHS Primary medical care policy and guidance manual.
Ensure that frontline health and social care staff who come into contact with people experiencing or at risk of homelessness are able to fulfil their duties under the Homelessness Reduction Act 2017.
Ensure that frontline health and social care staff are able to identify when a person needs to be referred for specialist homeless health and social care, and that processes are in place to support timely referral.
Consider moving people up waiting lists for health and social care appointments if they are experiencing homelessness because their circumstances may mean they are at higher risk of deterioration and premature death.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting access to and engagement with services .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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## Outreach services
Take health and social care services to people experiencing homelessness by providing multidisciplinary outreach care in non-traditional settings, such as on the street, hostels or day centres.
Offer outreach services that include support for people who:
have primary healthcare needs
have drug and alcohol treatment needs
have mental healthcare needs
fear engaging with services, for example, because of previous negative experiences from providers, discomfort using male-dominated services or concerns about eligibility including immigration status
may lack mental capacity or need support to recognise their care needs and engage with providers.
Use outreach to identify health problems earlier, promote health and support engagement with care, for example by:
supporting access to national screening programmes
assessing people for long-term conditions, infectious diseases and mental health needs
providing preventive health opportunities, such as vaccination, drug and alcohol treatment services, harm minimisation, smoking cessation and nutrition advice.
Offer collaborative, assertive outreach to start and maintain engagement with health and social care for people experiencing homelessness with coexisting severe mental health and drug or alcohol treatment needs. See also the section on maintaining contact with services in NICE's guideline on coexisting severe mental illness and substance misuse.
Consider assertive outreach for all people experiencing homelessness who could benefit from support but who find services difficult to engage with.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on outreach services .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Assessing individual needs
Be aware that health and social care practitioners have a statutory and professional duty to identify immediate risk of harm to self or others. See also the section on assessment and treatment under the Mental Health Act in NICE's guideline on service user experience in adult mental health.
Assess the health and social care needs of the person experiencing homelessness. When carrying out the assessment:
take into account their capacity, rights to autonomy and self-determination, and any safeguarding issues and
avoid unnecessary and potentially distressing repetition of their history if it is already on record
involve peers or advocates as appropriate (see also the section on the role of peers).
Include in the assessment:
A comprehensive assessment of the person's physical and mental health needs (including acute and long-term conditions) and social care needs. This should take into consideration their housing and benefits situation, bearing in mind the need to address health inequalities, and be responsive to diversity, and inclusion needs.
Asking if the person has children or dependents and assessing how this affects their needs.
Understanding the historical context of their situation, including past psychological trauma and experience of services.
In assessments to inform a health and social care plan for people who might benefit from high levels of support, use a multidisciplinary approach to enable a comprehensive and holistic assessment of their needs, involving:
the person, and their advocate if one is nominated or appointed
input from professionals with specialist expertise and practitioners who have detailed knowledge of the person's health and social care needs, including staff working in homelessness and housing services.
Use hospital admissions as an opportunity to offer a comprehensive, holistic needs assessment, including referral, if indicated.
Use the multidisciplinary assessment to inform the local authority-led care and support needs assessment, under the Care Act 2014 (see the section on care and support needs assessment and care planning in NICE's guideline on people's experience in adult social care services).
Review the person's needs, strengths and aspirations whenever their circumstances change or whenever they request a review, rather than using standard review periods.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing people's needs .
Full details of the evidence and the committee's discussion are in evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Intermediate care
Provide intermediate care services with intensive, multidisciplinary team support for people experiencing homelessness who have healthcare needs that cannot be safely managed in the community but who do not need inpatient hospital care. These may be for people who are:
discharged from hospital (step-down care)
referred from the community who are at acute risk of deterioration and hospitalisation (step-up care).See also NICE's guideline on intermediate care including reablement.
For a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on intermediate care .
Full details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.
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# Transitions between different settings
Homelessness multidisciplinary teams or leads should support people experiencing homelessness through transitions between settings (such as the street, hostels, Housing First and other supported housing, hospital, mental health services, social care, residential or community drug and alcohol treatment, and custody) and consider providing time-limited intensive support, which includes:
having a key practitioner coordinating care
building a relationship of trust
providing links to services in the community
gradually lowering the intensity of support, as appropriate.
Practitioners in any setting supporting people experiencing homelessness should:
ensure that all handovers of care responsibilities are planned and coordinated, and relevant information is shared if agreed
-ffer pre-emptive, structured support before, during and after transitions
recognise that people may be vulnerable during periods of transition, but also that there may be opportunities for intervention.
Clinical teams, working with hospital discharge teams and specialist homelessness multidisciplinary teams, where available, should have procedures to:
minimise self-discharge and
prevent discharge to the street. If self-discharge or discharge to the street happens, review the circumstances and implement learning.
For people moving between different care settings, follow the recommendations in NICE's guidelines on:
transition between inpatient mental health settings and community or care home settings
transition between inpatient hospital settings and community or care home settings for adults with social care needs
transition from children's to adults' services for young people using health or social care services.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section for transitions between different settings .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Housing with health and social care support
These recommendations are for commissioners and service providers working together across health, social care and housing services.
Recognise that providing accommodation suitable for the person's assessed health and social care needs (see the section on assessing people's needs) can support access to and engagement with health and social care services and long-term recovery and stability.
Provide wraparound health and social care support that is flexible to the person's changing needs and circumstances, and helps them maintain suitable accommodation.
Recognise the need for a range of accommodation types that are suitable for the varied needs of people experiencing homelessness, such as self-contained accommodation and accommodation with specialist onsite support for people who are particularly at risk or who might otherwise benefit from higher levels of support.
Be aware that moving to independent accommodation in the community with tenancy responsibilities can be an extremely challenging, stressful and isolating experience for some people. Provide emotional and practical support for as long as it is needed.
When a person experiencing homelessness moves into new accommodation, help them to assess the risks associated with their new living arrangement, while also recognising their strengths, and plan ways to mitigate the risks.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on housing with health and social care support .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Safeguarding
Also see the NICE guideline on domestic violence and abuse.
Designate a person to lead on safeguarding the welfare of people experiencing homelessness, including engagement and face-to-face practical safeguarding support.
Where a social worker is embedded in the homelessness multidisciplinary team, local authorities should consider appointing them to lead on safeguarding enquiries about people experiencing homelessness.
Local authorities should consider having a lead for people experiencing homelessness on the Safeguarding Adults Board.
Safeguarding Adults Boards should ensure that specific reference is made to people experiencing homeless in their annual reports and strategic plan.
Safeguarding Adults Boards should share recommendations and key learning related to homelessness from Safeguarding Adults Reviews with key stakeholders.
Safeguarding Adults Boards should establish ways of analysing and interrogating data on safeguarding notifications about people experiencing homelessness so that they can check that local safeguarding arrangements offer the necessary protection.
Commissioners and service providers should support health and social care staff to understand and apply laws relevant to people experiencing homelessness and who are in need of safeguarding. This should include ensuring that they can recognise signs of abuse and neglect (including self-neglect) and how to make a safeguarding referral.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on safeguarding .
Full details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.
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# Long-term support
For people who struggle to engage with services, plan long-term engagement to help meet the person's needs at their own pace.
Give priority to building a relationship of trust, for example by:
taking time with the person, particularly at the beginning of the relationship
being prepared to meet in an informal setting, such as a park or café (with appropriate lone worker policies in place)
having regular contact
ensuring consistency of practitioner, so that they meet with 1 person or a small team
aiming to meet immediate expressed needs to encourage long-term engagement.
Recognise that people experiencing homelessness do not always follow a linear recovery journey and that apparent progress may hide risks.
Consider providing 'open-door' services that people can self-refer to and access after any initial support ends, to reduce the risk of becoming homeless again because of unmet health, care and support needs.
Recognise that some people experiencing homelessness experience frailty at an earlier age (both physical and cognitive) than the general population and their long-term care should be tailored to meet this.
If a person experiencing homelessness is likely to be approaching the end of their life, for example, if death would not be unexpected in 6 to 12 months, discuss palliative care needs with the person and the multidisciplinary team, and provide coordinated palliative care to meet the person's needs.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on long-term support .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Staff support and development
Consider providing training for all health and social care practitioners, at a level suitable for their professional role, covering:
understanding the health and social care needs of people experiencing homelessness, and their rights to access services
homelessness as part of equality and diversity training, including being responsive to health inequalities, diversity issues and inclusion needs and understanding the impact of discrimination and stigma, and how intersectional, overlapping identities can affect people experiencing homelessness
psychologically informed environments and trauma-informed care
legal duties and powers
legal entitlements for migrants.
Healthcare professionals working within secondary care mental health services should follow the recommendations in the section on competence in NICE's guideline on coexisting severe mental illness (psychosis) and substance misuse.
Consider regular and ongoing support, professional supervision and reflective practice for staff working with people experiencing homelessness.
For a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on staff support and development .
Full details of the evidence and the committee's discussion are in:
evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches
evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal's Care and Support Jargon Buster.
## Assertive outreach
A proactive and persistent approach to outreach that involves repeated contact with people who are initially unable to or unwilling to engage.
## Care navigation
Helping people navigate the complex health and social care systems to overcome barriers in accessing services. This could be done by case workers, other practitioners or peers supporting the person, or by designated care navigators.
## Health inequalities
Systematic, unfair and avoidable differences across the population and between different groups within society in relation to health and social outcomes. They arise because of the conditions in which people are born, grow, live, work and age. These conditions influence people's opportunities, health and wellbeing.
## Homelessness leads
People working in mainstream health and social care services who, as part of their role, lead on homelessness issues within their service. Homelessness leads are designated in areas assessed as not needing a full-time homelessness multidisciplinary team.
## Homelessness multidisciplinary team
A multidisciplinary team involves a range of professionals across disciplines as well as agencies working together to assess and support the needs of a person experiencing homelessness.
## Inclusion needs
A need to have equal access and opportunities to participate in society and not facing barriers to services, social situations, different spaces and environments; being treated with dignity and not experiencing discrimination or intolerance due to the person's identity. See also health inequalities.
## Intermediate care
A range of integrated services that: promote faster recovery from illness; prevent unnecessary acute hospital admissions and premature admissions to long-term care; support timely discharge from hospital; and maximise independent living. Intermediate care is given on a time-limited basis, but duration can vary depending on the person's needs.
## Low-threshold services
Services that avoid restrictive eligibility criteria and make minimal demands on the client.
## Mainstream services
Services designed to be delivered to the general population.
## Outreach
Bringing health and care services to people who might not otherwise have access to or engage with existing services, provided in a mobile way in the locations where people are, for example on the street, in temporary accommodation facilities and in day centres. This can be done by mainstream services or dedicated outreach teams.
## Peers
People with lived experience of homelessness who are using their experience to support people experiencing homelessness through different means such as direct support, advocacy, research and co-production of services.
## People experiencing homelessness
In the context of this guideline, people experiencing homelessness is defined as people aged 16 and over who:
are sleeping rough (people without homes who sleep outside or somewhere not designed for habitation)
are temporary residents of hostel, B&B, nightly-paid, privately managed accommodation and other types of temporary accommodation
use day centres that provide support (such as food, showers, clothing and advice) for people experiencing homelessness
are obliged to stay temporarily with other people
are squatting
are newly homeless.
It also includes people with a history of homelessness (as defined above) who are at high risk of becoming homeless again because of ongoing severe and multiple health and social care needs.
## Psychologically informed environment
Service provision and practice that takes into account individuals' psychological and emotional needs, and their experiences of trauma. It includes building organisational awareness of psychological and emotional needs; physical environment and social spaces; staff training and ongoing support; service evaluation and learning; and reflective practice. For more information and resources, see the Homeless Link's webpage on trauma informed care and psychologically informed environments. See also trauma-informed care.
## Recovery-oriented language
Language that is person-centred, respectful, non-judgemental and strengths based. It conveys a sense of hope and commitment to the potential of every person and their recovery journey. It includes non-verbal aspects of communication and aims for consistency between verbal language and body language. If recovery is unlikely, this approach might focus on exploring what is important to the person and what living well means to them.
## Reflective practice
A process to:
reflect on previous practice
talk about why they made the decisions they made, and why they acted or behaved in particular ways
talk about their emotional responses to their actions and the actions of others
engage in continuous learning.
Reflective practice may also provide insight into personal values and beliefs, and help understand how these influence action and decision making.
## Safeguarding
The collective responsibility and process to protect the health, wellbeing and human rights of people at risk, enabling them to live safely, free from harm, abuse and neglect. See also the Think Local, Act Personal's Care and Support Jargon Buster definition for safeguarding.
## Safeguarding Adults Board
A statutory multi-agency group set up by a local authority made up of different professionals from a local authority, the NHS and police to prevent abuse or neglect of adults who have care and support needs, and to make sure that action is taken if abuse occurs. See also the Think Local, Act Personal's Care and Support Jargon Buster definition for Safeguarding Adults Board.
## Safeguarding Adults Review
A statutory multi-agency learning process arranged by a Safeguarding Adults Board that reviews cases if:
there is reasonable cause for concern that partner agencies could have worked more effectively to protect an adult and
serious abuse or neglect is known or suspected and
certain conditions are met, in line with section 44 of the Care Act 2014 and related statutory guidance.
## Severe and multiple disadvantage
Multiple and overlapping disadvantages that are often persistent and interrelated and affect a person's life. These disadvantages include the experience of homelessness, harmful drug or alcohol use, criminal justice involvement, poor mental health, and the experience of domestic violence and abuse. People experiencing severe and multiple disadvantage have often experienced underlying adverse childhood experiences, poverty, psychological trauma, stigma and discrimination. People with these experiences may have had sporadic and inconsistent contact with services or been serially excluded from services. People who experience severe and multiple disadvantage tend to have much poorer physical and mental health, have higher social care needs, and die at a much younger age than people without severe and multiple disadvantage.
## Social care staff
People working in social services and social care providing practical and emotional support to improve people's wellbeing and quality of life. This includes both local authority social workers with legal responsibilities to assess and protect people at risk of harm as well as frontline social care practitioners that may work in residential care, hostels and homelessness services in either the public sector or voluntary and charity sector.
## Social determinants of health
Social factors and wider determinants that influence health and wellbeing. These include circumstances in which people are born, grow up, live, work, and age, and the social and economic policies and systems, political agendas, social norms, environmental factors and other wider forces.
## Strengths-based approaches
Sometimes called assets-based approaches. These involve the person who uses services and the practitioners who support them working together to achieve the person's intended outcomes, in a way that draws on the person's strengths. The quality of the relationship between those providing support and those being supported is particularly important, as are the skills and experience that the person using support brings to the process (see Social Care Institute for Excellence's Care Act guidance on strengths-based approaches). See also NICE's quick guide on evidence for strengths and asset-based outcomes.
## Trauma-informed care
An approach to planning and providing services that involves understanding, recognising and responding to the effects of all types of trauma. It emphasises physical, relational and emotional safety, and helps survivors of trauma to rebuild narratives of connection, control and empowerment. See also psychologically informed environment.
## Wraparound health and social care support
A multidisciplinary team-based collaborative approach to support the person experiencing homelessness holistically, taking into consideration their individual needs, including physical and mental health needs, drug and alcohol treatment needs, care and social needs, and practical needs, in addition to their housing needs.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Psychologically informed environments
What is the effectiveness and acceptability of clinical psychology-led psychologically informed environments and psychological approaches for people experiencing homelessness?
For a short explanation of why the committee made this recommendation for research, see the rationale section on general principles .
Full details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.
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# Health and social care to support housing
What structural and systems factors help or hinder commissioning and delivery of wraparound health and social care that is integrated with housing, for people experiencing homelessness?
For a short explanation of why the committee made this recommendation for research, see the rationale section on housing with health and social care support .
Full details of the evidence and the committee's discussion are in evidence review C: views and experiences of health and social care for people experiencing homelessness.
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# Longer health and social care contacts
What is the effectiveness and cost effectiveness of longer health and social care contacts compared with usual care for people experiencing homelessness?
For a short explanation of why the committee made this recommendation for research, see the rationale section on planning and commissioning .
Full details of the evidence and the committee's discussion are in evidence reviews A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice or services.
# General principles
Recommendations 1.1.1 to 1.1.8
## Why the committee made the recommendations
There was qualitative evidence that people experiencing homelessness feel that they are offered less or lower quality care than the general population. Although the committee agreed that there were some limitations to the evidence, their experience corresponded with this. The evidence also highlighted various barriers to accessing care. Considering the multiple disadvantages and disproportionately poor outcomes observed in this population, the committee agreed that more effort and targeted approaches are often needed to level up outcomes. This also aligns with the NHS Constitution's first key principle of providing comprehensive service available to all, and its 'wider social duty to promote equality through the services it provides and to pay particular attention to groups or sections of society where improvements in health and life expectancy are not keeping pace with the rest of the population'.
Good qualitative evidence showed that people experiencing homelessness want to give feedback on processes and their care, but ways to do this were not always available. Based on their experience, the committee agreed that people often do not feel able to do this because of their experience of stigma and discrimination. However, involving people with lived experience of homelessness in service design is likely to improve services and people's engagement with services. Involving people in service design was also highlighted in the NICE guideline on people's experience in adult social care services, which references the Local Government and Public Involvement in Health Act 2007. The 2007 Act mandates local authorities to provide opportunities for people who use services to be involved in strategic decision making about services. NICE's guideline on community engagement also gives guidance on community engagement approaches for local authorities and health bodies.
The committee's experience as well as both qualitative and effectiveness evidence showed that using peers to deliver health and social care services can also be beneficial for people experiencing homelessness. The committee agreed that there are likely benefits for the peers themselves and for the service.
Good qualitative evidence highlighted that many people experiencing homelessness encounter or perceive stigma, discrimination and lack of understanding from health and social care practitioners. There was also limited evidence showing that many service providers are not aware of the impact that traumatic experiences can have on a person's life and how it can manifest in their behaviour. From their experience, the committee agreed that psychological trauma is common among most people experiencing homelessness, and is particularly prevalent among certain groups, such as women and young people. They also heard from experts who highlighted the importance of 'professional curiosity' in understanding the person's backstory and the use of trauma-informed practices. They agreed to highlight the importance of using approaches that take into account the impact of trauma and consider the person's past experiences as well as their current situation.
There was a lack of evidence on psychologically informed environments and psychological approaches to care, so the committee developed a research recommendation on the effectiveness and acceptability of clinical psychology-led psychologically informed environments and psychological approaches for people experiencing homelessness and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.
Good qualitative evidence showed that many people experiencing homelessness reported feelings of apprehension, fear and distrust when receiving care. Some people reported a lack of trust in service providers or in the healthcare system, mostly because of previous negative experiences. They felt judged, stereotyped and disrespected in healthcare settings, leading to unwillingness to engage with care.
There was good qualitative evidence highlighting that people reported positive experiences with care providers and increased engagement with services when they were able to develop a trusting relationship with a provider who paid attention, showed sincere interest and had time available for them. The importance of a genuine, friendly relationship in which the professional listens, remembers, uses humour and shows concern helps to build a trusting relationship, which in turn enables the person to feel safe in the health or social care environment. The committee agreed that this was key to promoting engagement. There was also good qualitative evidence that people experiencing homelessness value non-judgemental communication from professionals that is responsive to people's individual experiences and needs, for example, related to gender, culture, ethnicity and being part of the LGBT+ community. The committee also recognised the importance of service providers addressing the underlying inequalities that people may face, which are underpinned by social determinants of health that shape people's experiences and health and social care needs. The evidence emphasised the importance of staff understanding the impact that trauma may have.
Good qualitative evidence showed that people experiencing homelessness valued continuity of care and spoke positively about practitioners with whom they had formed trusting relationships. The evidence also emphasised respect as an essential component in sustaining trusting relationships. The committee's experience aligned with the evidence, and they emphasised that consistency and continuity of care throughout a person's journey can lead to improved engagement and better outcomes.
The qualitative evidence also showed that the length of appointments or contacts in current practice is often inadequate to meet the needs of many people experiencing homelessness, particularly those with severe and multiple disadvantage. Despite some limitations in the evidence, the committee agreed with this and discussed how longer appointment times can give an opportunity to better assess, engage and build trust with people who may otherwise rarely have contact with services, and who are marginalised and have disproportionately worse outcomes. Good qualitative evidence and information from experts emphasised that giving people agency – involving them and promoting shared decision making – helps to improve engagement in care. High-quality evidence from qualitative studies highlighted that focusing on the person's strengths and assets encouraged people experiencing homelessness to use services.
Good evidence from qualitative studies showed that people experiencing homelessness often experience lack of consistency and continuity from health and social care services, which can lead to disengagement. The evidence also showed that ongoing, sustained support and a service provider's patience and continued attempts to re-engage can improve the person's engagement when they might otherwise be resistant to support. The committee were aware that the Safeguarding Adults Reviews highlighted the prominence of 'self-neglect' in people experiencing homelessness. The committee discussed how some people experiencing homelessness find it difficult to look after their health and personal care because of their environment and circumstances. 'Self-neglect' can also include disengagement with health and social care whether or not the person has capacity. This is made more difficult by barriers to access and engagement with services. This emphasises the importance of actively supporting re-engagement. The committee discussed that re-engagement might not be successful if the person has to start and repeat the process from the beginning of the pathway, instead enabling re-entry from the point they left is more likely to support re-engagement, if appropriate.
## How the recommendations might affect services
The recommendations outline principles of good practice that in the committee's view should be happening across all services for people experiencing homelessness. However, practice is variable, and this may represent a change in practice for some services. Most recommendations would not lead to a significant resource impact, but may involve staff training and longer contact times. Any additional costs are likely to be offset by the benefits of improved engagement with care, for example, by accessing care before a crisis and reducing the burden on emergency services.
Economic analysis also suggested that reducing caseloads (and thus increasing time spent with clients) for practitioners working with people experiencing homelessness could be cost effective.
Return to recommendations
# Communication and information
Recommendations 1.1.9 to 1.1.13
## Why the committee made the recommendations
There was good qualitative evidence that people experiencing homelessness often experience stigma and discrimination and feel oppressed and unwelcome. Good evidence also reported that insensitive communication and closed body language are common experiences for them. Service users reported preferring simple language and explanations, instead of jargon, because it gives a sense of comfort and is more accessible.
The committee agreed with the evidence and discussed the merits of non-judgemental, recovery-oriented language. They agreed that the way in which practitioners communicate can have an impact on people's recovery journey, their willingness to engage with services, their sense of hope and their potential for recovery. The committee discussed the importance of using sensitive language that does not lead to the person feeling blamed for their issues (for example, avoiding phrases like substance 'abuse' or 'failed' to attend).
There was limited qualitative evidence on people's preferred communication methods, which reported that receiving appointment information by letter was ineffective for people without a reliable address. The committee discussed that letters are still the main method of communication for many service providers. Good qualitative evidence also showed that people without access to the internet and those without a phone have difficulties accessing healthcare (digital exclusion). The evidence corresponded with the committee's experience, recognising that various methods based on the person's preferences and communication needs should be available to improve timely contact and access to services.
The committee discussed that resources and forms are often written in a complex way and mostly available only in English. They agreed that this is a further barrier for people whose first language is not English. Good qualitative evidence also suggested that low literacy levels among some people experiencing homelessness can add to difficulties in accessing care. The committee agreed that this could include some migrants and people with learning disabilities or acquired brain injury. They therefore emphasised the need to tailor communication and information provision to people's needs and preferences, taking into account a wide range of possible speech, language and communication difficulties.
Good qualitative evidence showed that the presence of an advocate (including a peer advocate) helps people experiencing homelessness to gain confidence and a sense of control over their health and care needs. The committee had confidence in the evidence and agreed, based on their experience, that advocates (including peer advocates) can play a significant role in supporting people with correspondence and attending appointments, and in bridging the gap between practitioners and people experiencing homelessness. The committee were also aware that NICE is developing a guideline on advocacy services for adults with health and social care needs (publication expected September 2022).
The committee noted that the advocate could be someone who the person is familiar with, such as a family member or a friend. But they also noted that some people may be entitled to an independent advocate under certain circumstances. For example, the Care Act 2014 mandates that local authorities must arrange an independent advocate to support and represent a person to assist in their involvement in specified social care processes if the person has substantial difficulty in being involved in the process, and if they do not have an appropriate person to support them.
Moderate-quality evidence from qualitative studies showed that people experiencing homelessness felt that there was a lack of help or information about services available to them (such as overall entitlement to care, oral health, maternity services, screening and infectious diseases). This corresponded with the committee's experience, and they agreed that to improve engagement with health and social care services, it is important to give people information, support access, and make sure that they know their rights to health and social care. They considered this particularly relevant for migrant populations who may not be familiar with the local health and social care system and their entitlements, or who may have limited or no recourse to public funds.
## How the recommendations might affect services
These recommendations reinforce existing NICE guidelines on communication and information provision for the general population. However, there are some aspects that may need particular attention when working with people experiencing homelessness. There may be a need for some extra staff training on communication, and on the available health and social care services and support for people experiencing homelessness, including legal entitlements for care.
Giving everyone – including staff – the right information about what services are available will help relationship and trust building, and may lead to better access and engagement with services. For example, people may be more likely to access primary care services or specialist services directly instead of relying on emergency services. This can lead to problems being picked up and dealt with earlier, reducing morbidity and mortality, and associated costs such as for crisis care, and unplanned or emergency care.
Services already use various communication methods to support access to and engagement with services. But tailoring the method to each person's preferences and needs may need some reorganisation of current practice.
Advocate roles could be carried out by a professional or a peer supporter, or sometimes a family member or a friend. There are various advocacy models aimed at facilitating the relationship with service providers, and supporting people to access information and services or attend appointments. Any additional costs could be offset by the beneficial effect on the person's recovery including potential reductions in morbidity and mortality. For example, there is a link between non-attendance at appointments and increased morbidity and mortality in people experiencing homelessness.
Return to recommendations
# Planning and commissioning
Recommendations 1.2.1 to 1.2.10
## Why the committee made the recommendations
The rough sleeping strategy by the Ministry of Housing, Communities & Local Government highlights the need for agencies to work together to end rough sleeping and prevent homelessness. Cooperation and integrated working between agencies and partners are also mandated in legal frameworks including the Care Act 2014 and the National Health Service Act 2006.
Based on their experience, the committee discussed that integrated working among commissioners across different sectors is essential to bring all the knowledge and services together to ensure that there is a strategy and funding for coordinated and holistic support for people experiencing homelessness. Joined-up working is also likely to improve long-term outcomes; improve people's experience of services; minimise duplication of work and make services more efficient; improve understanding of the needs of the homeless population in the local area; and improve practitioners' work by making it easier to collaborate with colleagues.
People experiencing homelessness are to varying degrees disadvantaged and marginalised, and their outcomes are considerably worse than the general population, including having disproportionate rates of premature mortality. The committee discussed the concept of 'proportionate universalism', introduced in Marmot et al. (2010) Fair Society Healthy Lives (The Marmot Review), meaning that resourcing and delivering of services are done universally but at a scale and intensity proportionate to the level of need or disadvantage. The committee agreed that more resources and targeted approaches are justified to address the inequalities facing this population.
The committee agreed that to plan and commission adequate services to meet the needs of the homeless population in a local area, a comprehensive homelessness health and social care needs assessment should be carried out and kept up to date. This assessment will help understand the scale and nature of homelessness, and how existing services could be developed and integrated to better meet the needs of the people experiencing homelessness. The committee agreed that it should involve experts by experience to fully understand the needs, experiences, circumstances and service use of people experiencing homelessness. The committee also agreed that to improve services and to prevent abuse, neglect and death, service planning and design should be informed by Safeguarding Adults Reviews. They heard from an expert who also highlighted this.
The committee discussed, based on their experience, that data on the needs and service use of people experiencing homelessness can come from housing status in the person's health and care records if this is accurately recorded. Public Health England's Homelessness: applying 'All Our Health' advises frontline health and care professionals to ask about and record people's housing circumstances. The committee recognised that recording this information can create fear of stigmatisation in people experiencing homelessness. But they agreed that this was outweighed by the benefits of accurate data that can be used to improve services, both for the individual and as a whole, and ensure that there are adequate resources. The data can also be used to help identify and reduce health inequalities.
Many people experiencing homelessness have multiple intersecting issues or high support needs, such as physical and mental health issues, drug and alcohol treatment needs and social care needs. High-quality evidence from qualitative studies highlighted the importance of joint working to address complex unmet health and social care needs. The evidence suggested that many services work in silos with minimal coordination and cooperation between agencies. People felt that their issues were often dealt with individually by different providers rather than holistically addressing all of their intersecting needs. The committee heard from experts about adult social care and safeguarding, who similarly highlighted the need for joint commissioning and integrated working across agencies and professions.
The committee agreed, based on their experience and expertise, that commissioners working across larger areas and across sectors could help services collaborate to meet strategic aims, cover varying and intersecting needs, share resources and enable economies of scale. This could be at the level of integrated care systems or place-based systems, with collaboration across an area's health, social care and housing partners in different sectors, as well as with prison, probation and domestic abuse services.
The committee also agreed on the importance of enabling long-term, consistent support regardless of contract lengths so that people experiencing homelessness who may need high levels of support, including long-term medical care, can progress in their recovery journey. They agreed that long-term contracts can provide stability and can support the improvement and extent of services as long as there is flexibility to adapt to changing local needs.
The committee heard from expert witnesses about the importance of supporting service providers and practitioners to exercise their legal duties and powers when working with people experiencing homelessness. The committee agreed that the current systems do not always support public bodies and practitioners to do this, for example the duty to refer based on the Homelessness Reduction Act 2017.
The committee also agreed that commissioners should define and measure outcomes related to homelessness, including health and social care outcomes and service use, to inform local and national homelessness assessments, and help improve and design relevant policies and services.
Effectiveness evidence showed that peers (experts by experience) can be a useful and cost-effective way of supporting people experiencing homelessness and delivering services. Based on their knowledge and experience, the committee also agreed that peers are valuable in co-designing services. Involving peers can improve people's engagement with services, leading to better outcomes; improve the quality of services; and reduce pressure on practitioners, as well as having benefits to the peers themselves.
The committee agreed that the particular needs of specific population groups need to be considered. For example, women may have different needs and vulnerabilities compared with men, and young people compared with older people. People with limited or no recourse to public funds have particular disadvantages and risks for poor outcomes because of barriers to accessing care and support. Specialised support for the particular needs of LGBT+ people, disabled people or people with a particular family background or from a particular faith group may be helpful in reaching people and providing appropriate support. The committee agreed to give examples of groups that may need specific consideration, although they recognised the list is not exhaustive. The equality impact assessment for the guideline provides further information.
The committee discussed how the causes of homelessness are complex. Some people may experience homelessness as a result of disparities in access to or appropriateness of services because of a certain characteristic they have. People may face particular challenges because of their characteristics, such as their age, gender, disability status, family background or being a migrant, including different intersections of these, which may multiply inequalities.
Qualitative evidence of mixed quality from many different studies highlighted various barriers to accessing health and social care, such as transport costs and services being too far away, siloed or in multiple locations. The committee agreed that it is important for commissioners to consider ways to remove barriers to local services to improve access and engagement among people experiencing homelessness.
There was good qualitative evidence that people experiencing homelessness faced challenges registering for GP services and were sometimes refused registration if they did not have an address or ID. Being denied access to GP services can further alienate, cause distrust and prevent already marginalised people from engaging with services. The evidence also corroborated the committee's experience that when people are refused access to GP services, they turn to emergency care services.
The NHS Primary medical care policy and guidance manual outlines that everyone in England can register with a primary care provider free of charge. This includes people experiencing homelessness, people without a stable address, asylum seekers and refugees. The committee agreed that commissioners and planners need to ensure that there are processes in place to support GP registration, and document, challenge and redress refusals. There is also NHS England practical resource on improving access for all: reducing inequalities in access to general practice services.
Reducing caseloads for practitioners working with people experiencing homelessness would allow them to spend longer with each client. Longer contact time is likely to improve engagement with services, help build a trusted relationship and ultimately lead to improved outcomes and sustained recovery. There would also be likely benefits from improved staff satisfaction and retention, and continuity of care. The committee made a research recommendation to better understand the effectiveness and cost effectiveness of longer health and social care contacts for people experiencing homelessness and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.
## How the recommendations might affect services
Although there are legal requirements to collaborate under the Care Act 2014 and the National Health Service Act 2006, health, social care and housing services have different legislative and commissioning frameworks and the committee discussed that collaboration is sometimes challenging and the level of integration varies.
Services working in silos can increase the risk of undiagnosed or misdiagnosed conditions across the mental, physical and disability spectrum, cause morbidity and mortality, and result in substantial costs to services. Commissioners and planners will need to ensure that frameworks are in place to support integrated multidisciplinary health and social care services where this is not already happening. For example, by facilitating coordinated multi-agency and multidisciplinary working, and strengthening information sharing and communication systems.
Improving integrated service provision should lead to improved outcomes, more appropriate use of services, and a lower need for emergency care and hospital admissions, reducing associated costs. Services will need targeted efforts to improve outcomes and to meet the needs of people experiencing homelessness, and commissioners will need to plan for more funding per person than in mainstream services. However, this should lead to savings later on.
Joint Strategic Needs Assessments are done by public health teams within local authorities, but there is some variation in the extent to which the health and social care needs of people experiencing homelessness are considered, and service users and experts by experience are involved. When done thoroughly and with all the relevant information, including relevant findings from Safeguarding Adults Reviews, it can inform targeted and efficient provision (for example, specialist service provision) and identify opportunities for more integrated services. This will also ensure that services meet local needs, and improve access and engagement. This will reduce morbidity and mortality, and reduce public sector costs associated with homelessness.
Most services have ways to record data on housing status for audit purposes. This would not be a new practice, although some services might not be doing it or do not have processes flexible enough to record it in a meaningful way. Services could improve this by adjusting existing data-recording methods.
Compared with current practice, commissioners may need to look across a larger footprint to develop services. This approach will also enable them to account for mobility and people experiencing homelessness not being tied to a specific place. This may mean commissioning groups coming together to form partnerships.
Involving peers in delivering care or support and co-designing services is already happening in some areas and organisations, particularly in the voluntary and charity sector. It will involve costs in terms of training and support for peers and potential incentives or remunerations; however, involving peers can reduce pressure on practitioners and therefore result in cost savings. There was evidence that it can be cost effective.
Access and engagement with services may not be straightforward in this population, so commissioners will need to ensure multiple ways of enhancing access to care. There are examples of good practice across the country, but practice is variable. Services will have to consider approaches that can be tailored to the specific needs of the person. Currently, because of the lack of flexible services, people often end up in crisis and use expensive emergency services, or do not access services, resulting in disproportionately complex morbidity and premature mortality.
GP registration refusals are relatively common in current practice and commissioners and planners will need to reinforce NHS guidance and support GP practices to ensure that people experiencing homelessness can access GP services.
Finally, economic analysis carried out for the guideline suggested that reducing caseloads for practitioners who work with people experiencing homelessness could be cost effective.
Lower caseloads will mean that services will have to recruit more staff, which might be challenging in some areas. However, availability of trained staff should not be a barrier; for example, services may find it easier to recruit staff to junior roles and provide on-the-job training.
Return to recommendations
# Models of multidisciplinary service provision
Recommendations 1.3.1 to 1.3.10
## Why the committee made the recommendations
The committee discussed that people experiencing homelessness often have overlapping and intersecting care needs, which need the expertise and skills of different professionals to assess, plan and manage care jointly. They may also have needs and challenges that are not typical to the general population, so the committee recognised the value of practitioners with specialist knowledge on homelessness issues.
Good qualitative evidence from various studies described health and care systems as siloed, complex and fragmented, with little coordination between agencies and providers. There was also evidence from qualitative studies that people experiencing homelessness want more individualised care that meets their needs, and hope to develop trusting relationships with service providers.
There was limited effectiveness evidence available on multidisciplinary team approaches to health and social care support for people experiencing homelessness. There was evidence on the Housing First approach, mainly from Canada, involving intense case management or assertive community treatment by a multidisciplinary team for people with moderate to severe mental health problems experiencing homelessness. This showed a positive impact on housing status and tenancy sustainment. There was also some economic evidence showing that having multidisciplinary homelessness teams resulted in some cost savings and improved outcomes for people experiencing homelessness. Furthermore, the committee heard from experts who emphasised the importance of integrated and collaborative working, and a multidisciplinary approach with clear roles and responsibilities and effective communication and information sharing.
Based on the evidence and their own experience, the committee agreed that the best way to provide health and social care to people experiencing homelessness would be through specialist homelessness multidisciplinary teams. A combination of expertise from a variety of disciplines and agencies would enable holistic and individualised care based on the person's needs.
The committee discussed that a successful joined-up care approach, providing holistic wraparound support based on individual needs would integrate service providers from a range of health and social care settings.
The committee discussed the various experts who could form the multidisciplinary team. The qualitative evidence highlighted that people experiencing homelessness value support from peers who have similar experiences and can be role models in their recovery journey. Some qualitative evidence also reported the benefits of involving people with lived experience of homelessness in shaping and providing care. The committee agreed that experts by experience can bring an important service-user point of view to a multidisciplinary team to help better meet the needs of people experiencing homelessness. The committee discussed that other members of the multidisciplinary team could be an array of different professionals and practitioners spanning different agencies and disciplines, including healthcare, social work, housing, and the voluntary and charity sector. They discussed that voluntary and charity organisation staff often have the closest relationships to the client. The committee were aware that the characteristics of people experiencing homelessness vary across different areas and agreed that it is important to use the local needs assessment to tailor the composition of the team to local needs.
The committee discussed that multidisciplinary teams can provide person-centred, tailored support with personalised case management by a designated person working within the multidisciplinary team, which can improve continuity of care and help build trusted relationships with service providers that could improve engagement with services and long-term outcomes. Multidisciplinary teams can coordinate care based on the person's needs by providing care themselves or signposting to other services. Having a dedicated team with specialist knowledge can help streamline support and make it more efficient, avoid duplication of work and inappropriate referrals, and improve staff motivation. The committee were confident that there would be benefits for the person being supported, the team members and services in general.
The committee also discussed that the specialist multidisciplinary teams could bring value and expertise in working with other 'inclusion health' groups (groups of people who are traditionally socially excluded) who may be at risk of homelessness and whose needs often overlap considerably with people experiencing homelessness.
Homelessness multidisciplinary teams have a comprehensive understanding of the needs and service use of people experiencing homelessness, so the committee agreed that these teams make a crucial contribution to assessing local needs, improving quality of services, and reviewing complex cases including Safeguarding Adults Reviews.
The committee discussed that working with people experiencing homelessness can be challenging and can have a psychological impact on those providing care. They agreed that homelessness multidisciplinary teams should be given time, in a protected space, to reflect on their practice and experiences to promote continuous learning and professional wellbeing.
The committee also recognised that specialist homelessness multidisciplinary teams would not be feasible in areas where levels of homelessness are low. For example, in some areas services might encounter 1 person experiencing homelessness per month. In areas where forming a homelessness multidisciplinary team is not justified, the committee agreed that existing practitioners could act as homelessness leads in mainstream services, for example, in general practice, A&E departments, hospitals, drug and alcohol treatment services, mental health services, palliative care services, sexual assault referral centres, maternity care, disability services and adult and child social services. The homelessness leads would champion, coordinate, advise and collaborate with colleagues and professionals within and across services to enable appropriate provision of care and support for people experiencing homelessness. Partnering with homelessness multidisciplinary teams in nearby areas for advice could further improve care and support for people experiencing homelessness in these areas.
## How the recommendations might affect services
Models of service provision vary in current practice. In some areas with high rates of homelessness, there are no specialist homelessness multidisciplinary teams, or services are often focused on a single aspect of care or are mainly medically led; for example, mental health teams, drug and alcohol treatment services, community-based or hospital-based multidisciplinary teams, or housing-related multidisciplinary teams. Many multidisciplinary teams do not cover the wide range of support that is needed. Services will need to involve practitioners from across multiple agencies to make sure that the team has relevant expertise.
Recommendations on multidisciplinary teams may mean a change in service configuration. However, there may not be a need to employ new staff but to reorganise, collaborate with other agencies and form a team from existing professionals. Forming a multidisciplinary team may entail pulling together a team from different services working with a person experiencing homelessness. Alternatively, it may involve having a permanent integrated multidisciplinary team under single management within a service (that is, a coexisting co-located team), which would represent a more substantial change.
In areas with low rates of homelessness, having designated leads on homelessness may be a change in practice, but it is unlikely to have a significant resource impact because these are not expected to be entirely new job roles. These arrangements will be different across the country, and will depend on the demand and the level of need.
There is economic evidence that homelessness multidisciplinary teams represent value for money and are potentially cost saving. Having specialist multidisciplinary teams or designated leads should mean better integration and efficiency of services, more streamlined and personalised care and improved engagement with care and support, which in turn should lead to reduced morbidity, mortality and associated costs. There will likely be a reduction in wider public sector costs, including local authority homelessness services and the criminal justice system costs, because people will be more likely to progress in their recovery journey and maintain their accommodation. Such a service model can also mean better management of resources, for example, a reduction in inappropriate referrals, inappropriate use of hospital beds, and duplication of effort.
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# The role of peers
Recommendations 1.4.1 to 1.4.4
## Why the committee made the recommendations
There was some effectiveness evidence that suggested that peer support to navigate hepatitis C screening and services might help people to engage with services, and this was found to be cost effective. Other effectiveness studies also suggested that peers could increase uptake of tuberculosis screening and hepatitis vaccination to the same degree as professional staff. Although there were some concerns about the quality of the evidence on peer approaches, the committee were confident, based on their experience, that involving peers in delivering care or support and co‑designing services is efficient and beneficial, not only for the services and the people experiencing homelessness but also for the peers themselves. They also heard from expert witnesses who highlighted the value of involving people with lived experience in the development of policies, procedures and protocols.
The qualitative evidence also highlighted that people experiencing homelessness value support from peers who have similar experiences and have recovered and grown from that experience. The committee highlighted their experience and knowledge of the beneficial impact of being a peer, describing how peers can progress to become professionals if supported.
Based on the evidence and their expertise, the committee agreed to list ways in which peers may be able to support people experiencing homelessness and how peers can improve services. Peers can take up different roles in terms of intensity, responsibility and tasks, and may gradually progress in these roles. The committee emphasised that it is important to support peers with adequate supervision and governance structures, including confidentiality and data protection. Training needs of peers might include, for example, first aid and mental health first aid, safeguarding, trauma-informed care, advocacy and risk management.
Qualitative evidence highlighted the obstacles and challenges that peers might encounter, including supporting someone with similar issues to their own while trying to maintain their own recovery. The committee agreed that peers should be supported to continue their own recovery journey and development by encouraging them to progress to become professionally employed, which is beneficial in many ways for the person acting as peer support, the people they are supporting, and services.
The committee also discussed that it is important to consider how to match the peers with people they support. For example, some people may prefer or request peer support from someone with the same cultural or language background, but sometimes this may be a reason for a person to refuse peer support because of the risk of stigma or confidentiality breech.
## How the recommendations might affect services
There are existing peer networks, for example, for people recovering from drug or alcohol dependency issues. There are also peers working with people experiencing homelessness in some areas and in some organisations, in the voluntary and charity sector in particular. But the committee agreed that there is the potential to involve more experts by experience in service design and delivery. Peer support has the potential to improve access to and engagement with services, and reduce morbidity and mortality, and associated public sector homelessness costs. There may also be important benefits to peers themselves, leading to better long-term outcomes.
Peers could be recruited through homelessness services or in collaboration with voluntary and charity sector organisations and housing associations. Services will also need to provide support and training for peers as well as incentives or remuneration. Involving peers can reduce pressure on practitioners and can result in cost savings. Organisations may need to adjust their recruitment practices and policies to lower barriers to the employment of peers.
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# Supporting access to and engagement with services
Recommendations 1.5.1 to 1.5.12
## Why the committee made the recommendations
People experiencing homelessness are often unable to access health and social care because of barriers at systemic, local and individual levels. Various themes from mixed qualitative evidence highlighted examples, such as strict eligibility criteria, rigidity of appointment systems, limited opening times, short appointments, long waiting lists, siloed services in multiple locations, cost of transport and experiences of stigma and discrimination. The committee also drew on their own knowledge and experience of these barriers to access.
The committee agreed that an outreach model, in which the services go to the people instead of expecting people to come to them, is a helpful established approach to reaching people who do not access services. There is limited effectiveness evidence on outreach models, although evidence on a London-based outreach service to screen vulnerable people for hepatitis C and offer peer support for getting treatment in secondary care was shown to be cost effective. Moderate-quality evidence from qualitative studies suggested various benefits of outreach services, including increased access to immediate care and increased knowledge of health issues, available services, and healthcare entitlements. The evidence also highlighted that outreach services can be more flexible than traditional healthcare services and that bringing services to people builds a feeling of trust and connection with service providers while reducing the sense of isolation. The committee considered outreach services important to identify people who might otherwise be missed. They had confidence in the evidence and agreed that it corresponded with their experience.
There was good but limited effectiveness evidence that community drop-in services are helpful in reaching people and are preferred by service users. There was also good qualitative evidence that services are often complex, fragmented and difficult to navigate. The committee agreed that providing information and support to navigate care and services can improve people's access to and engagement with health and social care. Based on their knowledge and experience, the committee suggested approaches that could improve access and engagement. For example, low-threshold services that avoid restrictive eligibility criteria and make minimal demands on the client by offering support and care without trying to influence their habits; providing food, vouchers, transport support, internet access or other practical help can incentivise and enable people to engage with care; and providing psychologically informed environments and trauma-informed care can improve engagement with people who often have underlying negative and traumatic experiences.
The rigidity of appointment systems can lead to people being dropped from services if they miss appointments. There was some limited qualitative evidence illustrating the difficulties people experiencing homelessness face when they miss appointments. Some services have policies that prevent people accessing care at that service again or financial penalties for missing appointments. Based on the committee's experience, this is a major problem for many people experiencing homelessness and they agreed that services should show flexibility and understanding to facilitate engagement. The committee discussed the clear association between missed appointments and premature death and agreed that providing more flexible appointment systems and alternative ways of accessing care is therefore essential in improving outcomes.
High-quality evidence from qualitative studies highlighted that strict eligibility criteria to access healthcare services sometimes forced people into crisis situations before help could be provided, or excluded them from accessing services altogether. Based on the committee's expertise, this is particularly prevalent among people with coexisting mental health problems and drug or alcohol treatment needs, which are common among people experiencing homelessness. Sometimes, people with coexisting mental health problems and learning disability can be excluded from accessing the respective services.
Some services, particularly in social care, may have minimum age criteria that can stop people getting the support they need. Premature aging and frailty, defined by the British Geriatrics Society, the Royal College of General Practitioner, and Age UK as 'a distinctive health state related to the ageing process in which multiple body systems gradually lose their in-built reserves', are common among people experiencing homelessness with severe and multiple disadvantage, so care and support should be based on assessed need, not biological age. Flexibility in the eligibility criteria could prevent the situation from escalating and help people to receive support earlier, leading to better outcomes.
Good qualitative evidence highlighted that some people are unaware of the free or low-cost services available to them, particularly dental care, if relevant paperwork has been processed. The committee discussed their experience that often these forms that enable free access to essential services such as eye care, prescription costs and dental care (such as HC1 and HC2) are not readily available, or are only available electronically. The forms can be challenging to fill in and only available in English.
The committee considered digital exclusion to be a major barrier to accessing health and social care. Qualitative evidence showed that people without access to the internet and those without a phone experienced difficulties in accessing healthcare.
The NHS Primary medical care policy and guidance manual states that everyone in England can register with a primary care provider free of charge. This includes people experiencing homelessness, people without a stable address, asylum seekers and refugees. However, according to good qualitative evidence and the committee's experience, many people experiencing homelessness are still refused registration with a GP. Resources are available from the NHS on improving access for all: reducing inequalities in access to general practice services.
The committee were keen to highlight the legal duties of public sector workers as mandated by the Homelessness Reduction Act 2017. In particular, the duty to refer anyone who is identified as being homeless or at risk of homelessness to the local authority. They discussed that despite the legal requirement, this does not always happen in current practice because processes are not in place to do this, and frontline staff lack time and knowledge. An expert also highlighted the need for health and social services to improve legal knowledge among their staff. Guidance on duty to refer from the Department for Levelling Up, Housing & Communities and Ministry of Housing, Communities & Local Government gives an overview of the legal duty. The Department for Levelling Up, Housing and Communities' code of guidance advises local authorities on how they should exercise their homelessness functions in accordance with the Homelessness Reduction Act 2017. The committee discussed that every encounter with a person experiencing homelessness could be an opportunity for engagement with care and support. Approaches such as Making Every Contact Count and Making Every Adult Matter could be used to facilitate this and help frontline staff better understand the services available for onward referral.
The qualitative evidence highlighted that long waiting times are a barrier to accessing and engaging with health and social care, affecting people experiencing homelessness in particular. The committee agreed that people experiencing homelessness are a priority because their multiple disadvantages put them at an increased risk of deterioration and premature mortality and morbidity. They discussed that long waiting times can be particularly challenging for people experiencing homelessness and can mean that the opportunity to engage with them is missed altogether, for example, if the person moves to another area or forgets about the appointment. They also discussed that people experiencing homelessness may have particular difficulty coping psychologically with long waiting times because of the fundamental feeling of unsafety and exclusion that homelessness causes. Long waiting times could lead to further deterioration of physical and mental health, and could compound feelings of disengagement and exclusion.
## How the recommendations might affect services
Current practice is variable. For services that do not have multiple points of access to care or flexible services, these recommendations will represent a change in practice. Services will need a variety of approaches that can be tailored to specific needs. Currently, because of the lack of flexible services, people are using expensive emergency services or are not accessing services at all, resulting in excess morbidity and mortality, and associated high public sector homelessness costs. For example, inflexible appointment systems increase the risk of missing appointments, and there is a link between missed appointments and premature mortality. Missed appointments also cost the NHS millions of pounds a year; for example, missed GP appointments in the general population cost NHS England around £216 million a year in addition to the disruption for staff and other patients (Missed GP appointments costing NHS millions, NHS England 2019).
Transport costs are a considerable barrier to access to and engagement with services, and continuity of care. Practice is variable between different areas. People experiencing homelessness often have multiple morbidities, which could make them eligible for a free travel pass, but often do not have one because of bureaucratic challenges. Currently, a clinician (usually a doctor) needs to sign the paperwork for a free travel pass. Services could broaden the list of professionals able to approve applications, which could make free travel easier to access. The cost of providing free travel will be relatively low compared with the cost of missed appointments and the costs relating to unaddressed needs. For example, an annual bus pass in London costs approximately £900 (Transport for London bus and tram fares), but if a person with a leg ulcer misses multiple appointments, then this may lead to an infection and in some cases amputation, costing the NHS at least £8,000 (NHS England National cost collection for the NHS), in addition to the impact on the person. Services will need to work collaboratively to agree who will cover travel costs within their local system.
Some mental health or drug and alcohol recovery services will need to modify their eligibility criteria. This may lead to more people accessing services. But there may also be savings from avoiding crisis situations and unplanned care and providing more efficient support, leading to better long-term outcomes.
More practitioner time may be needed to help people with forms and other paperwork. But this can help prevent deterioration and the need for more expensive care, for example, emergency care, in the future.
In recent years, there has been an increase in the use of digital approaches to providing support within the homelessness sector. To avoid this leading to digital exclusion, some services may need to improve access to online health and social care information and support. There may be some costs associated with this, but providing access to digital services and information can improve engagement with services and avoid the need for costly emergency care.
A significant barrier to accessing health and care services for people experiencing homelessness is that GP practices ask for an address when registering. Recommendations on this reinforce NHS guidance and should result in more people registering with a GP and accessing services that they are eligible for and entitled to. This has the potential for substantial reductions in morbidity and mortality, and public sector costs associated with homelessness.
There is variation in the extent to which frontline staff are aware of their legal duties under the Homelessness Reduction Act 2017, including the duty to refer. Services may need to support their staff in legal literacy and to have the skills and knowledge to identify and support people experiencing homelessness. Training could be delivered in low-cost ways, such as remotely, using pre-recorded sessions, and could coincide with existing training. Both governmental and voluntary organisations have produced materials that are readily available online. The cost for this is therefore not expected to be significant and it could lead to better and more efficient care. Timely and appropriate care can avert the need for expensive crisis care and A&E visits, and reduce other public sector costs associated with homelessness.
Long waiting times for appointments in current practice are a significant barrier for engagement and timely care. Situations can quickly deteriorate, or the person might disengage because their needs are not being met. Shorter waiting times for people experiencing homelessness may avoid a crisis, lower the chances of needing expensive emergency services, and prevent complex morbidity and premature death.
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# Outreach services
Recommendations 1.5.13 to 1.5.17
## Why the committee made the recommendations
Qualitative evidence highlighted that people experiencing homelessness often face barriers to accessing services through standard routes, and are often disengaged with health and social care. Outreach is an established way to bring services to people who may otherwise find it hard to reach them. There is limited effectiveness evidence on outreach models, although evidence on a London-based outreach service to screen vulnerable people for hepatitis C and offer peer support for getting treatment in secondary care was shown to be cost effective.
Moderate-quality evidence from qualitative studies suggested various benefits of outreach services, including increased access to immediate care and increased knowledge of health issues, available services, and healthcare entitlements. The evidence also highlighted that outreach services can be more flexible than traditional healthcare services and that bringing services to people builds a feeling of trust and connection with service providers while reducing the sense of isolation. The committee considered outreach services important to identify people who might otherwise be missed.
Because people experiencing homelessness have a wide range of health and social care needs, the committee agreed that outreach teams should be multidisciplinary and also equipped to respond to needs of people with different, intersecting experiences relating to, for example, gender, ethnicity and being part of the LGBT+ community. Evidence from several economic studies showed that a multidisciplinary approach in general provided value for money in relation to the homeless population. While this was not specific to outreach teams, the committee agreed that given the severe and multiple disadvantage people experiencing homelessness often face, multidisciplinary outreach teams are justified and essential for meaningful response to people's needs.
Good qualitative evidence showed that some people who are resistant to support or who feel overwhelmed by it might feel more motivated if ongoing support is available, including repeated attempts to engage with the person without placing pressure on them. The committee agreed, based on their knowledge and experience, that an 'assertive outreach' approach is useful in improving engagement for those who may be reluctant to engage with services and who would benefit from a high level of support. 'Assertive outreach' is most often used for people with complex mental health needs and drug or alcohol treatment needs. This is in line with the recommendations about maintaining contact with services in the NICE guideline on coexisting severe mental illness and substance misuse. The committee agreed that this approach could also be considered for other people experiencing homelessness who are likely to benefit from health and social care but who are disengaged, for example, because of lack of trust or previous negative experiences.
## How the recommendations might affect services
Outreach is used in current practice in many areas to deliver a range of services, including primary care, mental health, opiate prescribing, and testing for chronic or infectious diseases such as hepatitis and tuberculosis, although the services provided through outreach vary depending on location. Outreach can happen in multiple settings, such as streets, parks, hostels, day centres or soup kitchens. Services generally understand its value in enabling access and engagement with health and social care, but commissioning of outreach services for people experiencing homelessness varies.
Additional resources may be needed to set up outreach in areas where it is not happening already. However, it has great potential to support this population, and improve engagement with services and long-term outcomes. It can also bring savings, for example, by avoiding missed appointments and visits to the A&E department.
Assertive outreach is used in some areas in current practice, particularly when engaging with people with complex mental health needs. It takes more practitioner time and may be more expensive, but persevering with people and improving engagement among people who would benefit from support is likely to substantially improve the health and wellbeing of people who have been marginalised, and reduce morbidity and mortality, and associated public sector homelessness costs.
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# Assessing people's needs
Recommendations 1.6.1 to 1.6.7
## Why the committee made the recommendations
There was no evidence on the effectiveness of different approaches to improving access to services through needs assessments, so the committee used their knowledge and experience to make the recommendations.
The committee were keen to emphasise the statutory and professional duty that health and social care professionals have to identify immediate risk of harm to self or others, in line with the Care Act 2014 and the Mental Health Act 1983, and professional codes such as the Nursing and Midwifery Council Code, General Medical Council's Good medical practice and Social Work England's Professional standards. The committee were aware of case reviews and Safeguarding Adults Reviews on people experiencing homelessness showing that this risk had been missed, leading to death. This is particularly relevant in the context of homelessness because there is a significant link between homelessness and risk of abuse, neglect and violence, serious mental health problems, self-harm and self-neglect, underpinning the disproportionate rate of premature mortality in this population.
The committee agreed that a comprehensive, holistic health and social care needs assessment within the context of the individual's wider circumstances improves access to health and social care and support that matches the person's needs. They agreed that a multidisciplinary approach is needed to ensure that the full range of health and social care needs are identified, including considering risk and safeguarding issues. Collaborative working also reduces unnecessary duplication and improves communication between professionals working in different services.
The committee were concerned that assessment is commonly perceived by people experiencing homelessness as a process of exclusion. People often have to keep repeating their stories and the assessments can turn into an assessment of eligibility for support rather than a person-centred attempt to understand a person's needs and circumstances. The committee agreed that involving the person in their own assessment process and involving a peer or an advocate could help improve the assessment process. Peers and advocates (who may be peer advocates) can play an important role in bridging the gap between the person experiencing homelessness and professionals. They can make the assessment process feel less formal and therefore more acceptable or accessible to people experiencing homelessness.
The committee were aware that hospital admissions related to homelessness have been increasing. They agreed, based on their knowledge and experience, that hospital admissions are an opportunity for a comprehensive and holistic assessment of a person's needs to enable appropriate personalised care planning that integrates health, social care and housing needs. A hospital stay can be an opportunity to start addressing the often complex and underlying issues that have led people to their situation.
The committee agreed that a comprehensive understanding of the person's physical, mental and social care needs as well as the underlying circumstances of their situation will help when conducting the statutory care and support needs assessment under the Care Act 2014, which sets out local authorities' duties to assess people's needs and their eligibility for publicly funded care and support. The committee noted that the recommendations on care and support needs assessment and care planning in NICE's guideline on people's experience in adult social care services provides advice on conducting the care and support needs assessment under the Care Act.
The committee were also aware that some people may be entitled to an independent advocate under certain circumstances. For example, the Care Act 2014 mandates that local authorities must appoint an independent advocate to support and represent a person in the local authority-led care, and support needs assessment or safeguarding enquiry if the person has substantial difficulty in being involved in the process, and if they do not have an appropriate person to support them.
The committee pointed out that after the person's needs are established and support planned to meet these needs, many people experience difficulties with ongoing support. Because the needs assessment process can be challenging, the committee agreed that the person's support needs should be reviewed as needed, when their situation changes or if they request it, but not based on standard review periods.
## How the recommendations might affect services
Identifying immediate risk of harm to self or others reinforces a statutory and professional duty, and does not represent a change in practice.
A comprehensive assessment of health and social care and support needs involves a multidisciplinary approach, can be time-consuming and needs collaboration between professionals from different agencies. This should be happening across all services. However, practice is variable and these recommendations may represent a change in practice and result in a resource impact for some services.
Hospital admissions are good opportunities to provide a comprehensive and holistic assessment of safeguarding, physical and mental health, drug and alcohol treatment needs, and social care needs for people experiencing homelessness. This does not often happen in current practice and the committee thought that this was a missed opportunity to assess the person's comprehensive needs and start integrated care. The recommendations in this area may mean that services will need to plan for more tests, procedures and practitioner time. This could prolong a hospital stay, although discharge to the community would likely be safer and future admissions could be avoided. Such a proactive approach could have benefits in the long term, such as preventing people from getting into crisis because of unidentified needs, and reducing morbidity and mortality, and associated homelessness costs.
As a result of the recommendations, more people experiencing homelessness who may benefit from high levels of support may have an assessment of social care needs and go on to engage with services. But an appropriate assessment of the health and social care needs of some of the most marginalised people in society will ensure timely and appropriate care and support for them, with a potential for reduced morbidity, mortality and associated public sector costs.
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# Intermediate care
Recommendation 1.7.1
## Why the committee made the recommendation
Intermediate care is a multidisciplinary service that helps people to be as independent as possible and provides support and rehabilitation to people at risk of hospital admission or who have been in hospital. Evidence from several economic studies suggested that it is cost effective and potentially cost saving. The committee agreed that providing such services would help avoid hospital admissions and ensure safe and timely discharge from hospital and transition to the community. Intermediate care can also prevent or shorten expensive inpatient care and provide appropriate care and support to people in need of more intense support than otherwise provided in the community.
## How the recommendation might affect services
Intermediate care, including step-down and step-up care, would represent a change in practice because this service is currently rare for people experiencing homelessness. This would need some funding but there is evidence that intermediate care represents value for money. Furthermore, considering the immense human and societal costs of homelessness, providing care that can support recovery and prevent repeat homelessness is likely to be beneficial to society overall. Intermediate care can be delivered in the community, such as in suitable hostels, or in designated facilities.
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# Transitions between different settings
Recommendations 1.8.1 to 1.8.4
## Why the committee made the recommendations
The committee discussed that people experiencing homelessness can be vulnerable during transition periods. However, testimony by expert witnesses also highlighted that these can also be opportunities for engagement and intervention. The committee agreed that transition periods can be a chance to build foundations for lasting support in the community.
The committee noted that a phased, focused and person-centred approach to transitions is currently unusual. Often the person is discharged or moves between services, settings or areas without thorough planning, follow up or coordination. For example, sometimes the person's homeless status and related needs are identified only at the point of discharge from hospital into the community. Identifying needs and collaboration between professionals and agencies is therefore essential.
Effectiveness evidence comparing 'critical time intervention' (time-limited intensive support during a transition period) with usual care among people experiencing homelessness, including discharge from psychiatric inpatient care and moving from a homeless shelter to the community, showed benefits in terms of mental health service use, housing status and reduced psychiatric re-hospitalisation, although no difference in quality of life was reported. Despite some methodological limitations and mixed results in the evidence, the committee agreed that the general approach and key principles of critical time intervention should form the basis of recommendations on support for key transitions. This is because any transition between settings can be challenging, with a risk of people falling through the gaps, but with appropriate support, it can also be an opportunity for improved engagement and recovery.
The 'critical time intervention' model includes establishing a trusting and enduring relationship, and a gradual decrease in the intensity of support over a fixed period of time. The time period in the studies was 9 months, but the committee agreed that the length of time needed for intense support during transition would depend on the circumstances and needs of the person. The committee agreed that, to make successful transitions, it is fundamental to start support before the move and continue it during and after transition. This needs an effective and coordinated handover across teams and practitioners. Good qualitative evidence highlighted that staff from all types of services recognised that most care is provided in silos with minimal coordination between agencies and providers. The findings emphasised the need for a more coordinated approach with appropriate information sharing. Good-quality evidence from qualitative studies also emphasised the importance of information sharing between practitioners so that people do not have to repeatedly give the same information. A trusting relationship is also more likely when support is from a single person throughout, or a coordinated team, reducing the need to repeat life stories and any associated trauma. Critical time interventions are seen as a holistic approach to support. The committee wished to reflect this, emphasising the need to link people with other services and the wider community, according to their needs and preferences.
Irregular discharge (self-discharge against medical advice) represents a missed opportunity for services to engage with a person experiencing homelessness and to start integrated care. A common cause of self-discharge is when people experiencing homelessness have a history of problem opioid use and do not have access to the right dose of methadone according to their treatment plan in the community, so they self-discharge to address their withdrawal symptoms.
For some people with drug and alcohol treatment needs, a hospital admission is an opportunity to detox. If people experiencing homelessness return to the streets without appropriate support after detox, they have an increased risk of overdose and a risk that any care plans will fail. It is important that there are procedures to minimise self-discharges and prevent discharges to the street so that risks can be reduced, and discharges are as safe as possible. Reviewing incidents of self-discharge or discharge to the street can improve procedures and care in the future. The Department of Health and Social Care's Hospital discharge and community support: policy and operating model refers to the King's College London's support tool and briefing notes on transforming out-of-hospital care for people who are homeless, which outlines how safe and timely transfers of care can be delivered.
The committee also highlighted other NICE guidelines that cover important transition periods that may be applicable to people experiencing homelessness.
## How the recommendations might affect services
There is wide variation in the support provided during transitions between settings. The recommendations should increase sustained support and lead to a more coordinated response to needs. This in turn could lead to reduced re-attendance after leaving hospital or breakdown of tenancy, and reduced morbidity and mortality.
Procedures to review cases when a person experiencing homelessness has self-discharged or has been discharged to the street may be a change in practice for some hospitals. But, by learning from these situations and improving practice, there would be an opportunity to prevent irregular discharge in the future and improve outcomes for patients. Having a dedicated homelessness multidisciplinary team or designated homelessness lead working with the discharge team can help strengthen links to community services where people get methadone to ensure they continue to receive the right dose in hospitals. Enhanced connections with social services and local authorities will help link people experiencing homelessness to the right support. This may need additional resources, but reductions in morbidity, mortality and associated costs should offset additional costs in the long run. There was evidence that effective hospital discharge represents value for money.
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# Housing with health and social care support
Recommendations 1.9.1 to 1.9.5
## Why the committee made the recommendations
Access to suitable accommodation is a key determinant of health and social care outcomes. The committee discussed, based on their knowledge and experience, that there are various aspects of accommodation that can either hinder or help a person's recovery process and their engagement with health and social care. These might include practical and logistical considerations, such as the distance to health or social care services, accessibility, aids, and appropriate storage for medication.
There was good effectiveness evidence from the Housing First trials that people are more likely to stay housed if their accommodation has wraparound health and social care support. There was also evidence that this approach could be cost effective. The committee's experience of health and social care services designed to support housing was positive, and tenancy sustainment was commonly achieved through this wraparound approach. The committee agreed, based on their knowledge and experience, that the level of support depends on the person's needs, with some people needing specialist onsite support. These could be people with high levels of need or severe and multiple disadvantage who are vulnerable to abuse and exploitation, young people who have no experience of independent living, people who have experienced domestic abuse, or people with particular care needs who need support in everyday life because of premature aging, acquired brain injury or disability.
The committee discussed the lack of evidence on how to improve needs-based wraparound support for people with severe and multiple disadvantage and premature frailty, particularly those who have experience of rough sleeping. The committee made a research recommendation on the structural and systems factors in health and social care that could help or hinder commissioning and delivery of wraparound support integrated with housing and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.
Moving into independent accommodation may seem like a positive transition, but based on the committee's experience, this can be one of the most difficult times for people who may have a history of traumatic experiences, have severe and multiple disadvantage, feel profoundly unsafe or have low self-confidence. Such a transition often causes the person to reflect on what has happened to them, which can be triggering and cause re-experiencing of trauma. It can lead to relapses in recovery, including problems with drug or alcohol use. Furthermore, people living in temporary accommodation or on the streets can form bonds with their peers that provide mutual support and a sense of belonging. This may be replaced by a feeling of isolation and loneliness when moving into independent accommodation. Effectiveness evidence on 'critical time interventions' showed that time-limited intense support, gradually lowered over time during transition periods, did not sustain all benefits over time, so the committee agreed that emotional and practical support should be provided for as long as is needed in this situation.
The committee also agreed that an assessment of the risks that could jeopardise the person's recovery, alongside recognition of their strengths, can help recovery, inform appropriate support needs and help people to stay in housing.
## How the recommendations might affect services
There is variation in current availability and provision of health and social care support associated with housing. The recommendations aim to reduce variation in practice.
The Housing First model has been used in England to some extent and there is evidence that it represents value for money, but the associated wraparound support is variable and sometimes lacking. To provide wraparound care and support, better collaboration is needed between housing, health and social care services. Services may need to reorganise existing resources, including improving communication between agencies and services and allowing more practitioner time.
Local authorities should already have a range of housing options for differing support needs, although in some areas, accommodation with onsite support might be limited.
Additional costs of providing wraparound support with accommodation, according to needs, are likely to be offset by improved health and social care engagement and outcomes, sustained tenancy, reduced use of expensive emergency services and a reduced return to homelessness and associated costs.
Risk assessment at the start of residency is a low-cost intervention that can potentially mitigate significant harmful outcomes.
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# Safeguarding
Recommendations 1.10.1 to 1.10.7
## Why the committee made the recommendations
No effectiveness evidence was identified on the role of adult social work, and safeguarding in particular, in an integrated response to the needs of people experiencing homelessness. The recommendations on safeguarding are based on testimony by experts who were invited by the committee to speak about the role of social work and adult safeguarding.
The experts highlighted the importance of understanding the person's backstory and historical context that led to the current situation, recognising the link between homelessness and self-neglect, the impact of trauma and how risk-taking can be a coping strategy. Because of the value of having a trusting relationship with the person experiencing homelessness, the experts emphasised the importance of having a single key person as a safeguarding lead in an integrated service model.
Section 42 of the Care Act 2014 requires local authorities to make a safeguarding enquiry if an adult with care and support needs is experiencing or at risk of abuse or neglect. The committee agreed that a social worker within a homelessness multidisciplinary team would often be best placed to lead on these enquiries for people experiencing homelessness because of their professional expertise on the assessment and related legal duties and powers.
The experts suggested that safeguarding issues related to homeless populations have historically not been widely considered by Safeguarding Adults Boards. The committee agreed that having a homelessness lead in the Safeguarding Adults Boards could enhance learning and improve practice. The committee also agreed that Safeguarding Adults Boards have an important role in promoting understanding and best practice within local agencies related to safeguarding people experiencing homelessness, including through their statutory strategic plan and annual report and learning from Safeguarding Adults Reviews. By analysing and interrogating safeguarding notifications related to homelessness, the Safeguarding Adults Boards can also enhance their understanding of the appropriateness of local safeguarding arrangements.
Finally, the experts highlighted the need for health and social care staff to understand the legal duties and powers related to safeguarding people experiencing homelessness, so that their welfare could be protected, concerns could be identified and addressed early, and harm mitigated.
## How the recommendations might affect services
There are legal duties for safeguarding under the Care Act 2014 and the recommendations in this area only highlight the existing safeguarding responsibilities of service managers and local authorities. Teams involved in active safeguarding cases should already have legal literacy around safeguarding relevant legislation and the intersection of homelessness and multiple disadvantages, but may need more training.
Currently, based on the committee's experience, people experiencing homelessness often fall through the gaps, and safeguarding concerns are not identified and safeguarding notifications are not made. There may be a resource impact for services with practices that are sub-optimal and not aligned with legislation. Safeguarding will ensure that appropriate support plans are in place to manage the risks identified. For example, a person might be supported to move to more suitable accommodation.
Return to recommendations
# Long-term support
Recommendations 1.11.1 to 1.11.6
## Why the committee made the recommendations
People experiencing homelessness often need support due to severe and multiple disadvantage, including intersecting physical and mental health needs, psychological trauma, drug and alcohol treatment needs, and social care needs. The committee agreed that sustained effort and commitment from services is needed to support their recovery journey, which may often be non-linear.
Good-quality evidence from qualitative studies showed that people experiencing homelessness often experience a lack of consistency and continuity from health and social care services. There was also good qualitative evidence that ongoing, sustained support, and a service provider's patience and continued attempts to offer support, can improve the person's engagement when they might otherwise be resistant to support. Conversely, discontinuity or interruption of care could lead to disengagement with services.
There was plenty of good-quality evidence from qualitative studies emphasising the importance of a trusting and respectful relationship between the person experiencing homelessness and the person supporting them. The evidence showed that continuity of care enabled people to form a relationship with their care provider. The committee agreed, based on their experience, that a trusting relationship is rarely built through a short-term contact but usually needs consistent and sustained contact from 1 main lead or a small team of people who are part of integrated services across agencies.
Good qualitative evidence suggested that people experiencing homelessness often prioritise their immediate needs over receiving care. The committee discussed that addressing immediate needs can be an opportunity to build long-term engagement with services.
From their knowledge and experience, the committee were aware that people experiencing homelessness did not always follow a linear recovery journey and can encounter a relapse or crisis. Therefore, the committee thought it was important that services were flexible in allowing people to easily re-engage with services so that their situation would not escalate or deteriorate further.
Premature ageing and frailty is common in people experiencing severe and multiple disadvantage and homelessness, and the committee discussed that improvements in their wellbeing can be made if long-term care and support plans take this into account.
The committee also recognised that not all people will recover and risk of premature death is higher in people experiencing homelessness compared with the general population. Palliative care has often not been available for people experiencing homelessness and those who are approaching the end of their lives may remain in for example hostel accommodation without provision of appropriate end of life care that supports the person's preferences.
## How the recommendations might affect services
The recovery journey for some people can take a long time, and services need to be persistent, invest in building trust, and recognise that the process will often not be linear. Currently, long-term continued support is quite rare, and funding of services is often not aligned with such an approach. For example, tenancy sustainment teams are often underfunded and only offer time-limited support of varying quality. Offering long-term support could cost more because it may, for example, need lower caseloads, although for many people, the intensity and frequency of support will likely lessen over time. But the value of investing in systems that facilitate longer-term support and sustained care and engagement is likely to outweigh additional costs through, for example, reduced homelessness and morbidity and mortality, and associated public sector costs. Investing in longer-term support will likely help prevent people from returning to homelessness and needing more acute support. Services may need more capacity initially, but longer-term provision of timely help can stabilise people and prevent a crisis, which will be more detrimental for the person and more costly to services.
Currently, people experiencing homelessness have limited access to palliative care services. This should be improved with the introduction of homelessness multidisciplinary teams, coordinated care and improved access to specialist services, including palliative care. Palliative care services already exist, and should become more accessible to people experiencing homelessness.
Return to recommendations
# Staff support and development
Recommendations 1.12.1 to 1.12.3
## Why the committee made the recommendations
Good qualitative evidence showed that healthcare professionals felt ill-equipped and had insufficient knowledge of social determinants of health and homelessness, and the associated health needs for complicated health problems such as addiction and mental health problems. The evidence also showed that people experiencing homelessness felt that service providers did not understand the practicalities of being homeless and their specific needs. The committee discussed that further training and support was needed to strengthen the capacity of health and social care providers to address people's severe and multiple disadvantage and diverse needs.
The qualitative evidence also showed that training would raise awareness and improve provider knowledge in this area, and improve sensitivity and understanding for this population, so that care providers overcome preconceived ideas and judgemental behaviour. Good qualitative evidence showed that most people experiencing homelessness reported experience of discrimination on some level, with many recounting some form of prejudiced behaviour from service providers. The committee discussed that health and care providers should be trained to consider people's preferences rather than making assumptions about their needs and care solely based on their behaviour or appearance, for example. Furthermore, the committee discussed the importance of practitioners understanding and responding to the intersectionality of multiple disadvantages that people experiencing homelessness may face because of their characteristics.
Limited evidence from qualitative studies among service providers also showed that some lack awareness of the impact that trauma has on a young person's life and how it may manifest in their behaviour. The evidence suggested that providers who do not operate from a trauma-informed care approach may inadvertently serve as a barrier.
Experts also highlighted the importance of health and social care professionals' legal literacy and understanding of their duties and powers in relation to homelessness, mental capacity and safeguarding.
The committee were aware that there are various existing training and materials that organisations could use, such as e-learning for healthcare resources on tackling homelessness, free online training modules by the Faculty for Homeless and Inclusion Health and Public Health England's guidance on homelessness: applying 'All Our Health' and further resources in Health Education England's inclusion health education mapping and review.
Experts highlighted the importance of staff support and supervision, which enables reflection on experiences and practices to enable continuous learning for staff and development of both the staff and practices. The committee agreed that reflective practice and supervision can increase staff motivation and wellbeing, quality of care and services.
## How the recommendations might affect services
Currently, there is variation in training opportunities for health and social care staff who encounter people experiencing homelessness. Most statutory agencies regularly train their staff, but training on some issues relevant to homelessness, such as legal duties and powers, is not common practice for all services. This extra training could be delivered alongside existing staff training programmes in a variety of low-cost ways, for example, by remotely using pre-recorded sessions, and could coincide within existing training. Because of existing training and materials, there is no expected significant resource impact.
Training to understand the needs of people experiencing homelessness may mean that more people access specialist homelessness services. Training and ongoing support will facilitate joined-up and more connected services, for example, between specialist services and mainstream services, and ensure a holistic approach and a framework of support. Improved knowledge and understanding will improve access and care for people experiencing homelessness. Practitioners will be better placed to give information about available health and social care services, and enable services to meet people's needs before their problems escalate. For example, most people could be legally housed by local authorities and councils if more professionals had a better understanding of homelessness law and guidance.
The recommendations encourage services to include these elements in their training more consistently. They can also influence the development of professional competencies for trainees and future practitioners.
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{'Context': "This guideline includes recommendations on ways to improve access to and engagement with health and social care services for people experiencing homelessness. It also gives advice on how commissioners, planners, providers and practitioners across disciplines and agencies can work together to support and improve outcomes for people experiencing homelessness.\n\nIn this guideline, 'people experiencing homelessness' means people aged\xa016 and over who:\n\nare sleeping rough\n\nare temporary residents of hostel, B&B, nightly-paid, privately managed accommodation and other types of temporary accommodation\n\nuse day centres that provide support for people experiencing homelessness\n\nare obliged to stay temporarily with other people\n\nare squatting\n\nare newly homeless\n\nhave a history of homelessness (as defined above), and are at high risk of becoming homeless again because of ongoing severe and multiple health and social care needs.\n\nUnderlying causes of homelessness include structural, societal and economic factors, and inequalities, such as poverty and deprivation, unaffordable housing, unemployment, exclusion and discrimination. People experiencing homelessness often experience severe and multiple disadvantage and unmet health and social care needs that may be contributing factors for becoming homeless as well as consequences of homelessness. Experience of psychological trauma and adverse childhood events are common in people experiencing homelessness, and the prevalence of people who are neuroatypical or have a brain injury is higher than in the general population. Homelessness and access to appropriate housing is a public health issue.\n\nPeople experiencing homelessness have far worse health and social care outcomes than the general population. The average age of death for the homeless population is around 30\xa0years lower than for the general population according to the Office for National Statistics' Deaths of homeless people in England and Wales: 2019 registrations.\n\n'Inclusion health' is a term developed to address the health and care needs of groups that are traditionally excluded, including people experiencing homelessness. The needs of the homeless population overlap considerably with other inclusion health groups. Internationally, these groups have mortality rates that are 8\xa0times higher than the general population for men and 12\xa0times higher for women (Aldridge et al. 2017). Many of these premature deaths are from preventable and treatable conditions according to a 2019 study by the same authors (Aldridge et al. 2019). The Office for National Statistics' 2019 report showed that the causes of most deaths of people experiencing homelessness in England and Wales were registered as drug-related poisonings, suicides and alcohol-specific deaths.\n\nPeople experiencing homelessness use more acute hospital services and emergency care than the general population. When admitted to a hospital, the length of hospital stay is usually much longer because of multiple unmet needs. Barriers to access and engagement with preventive, primary care and social care services can mean that problems remain untreated until they become very severe and complex. These barriers include stigma and discrimination; lack of trusted contacts; fragmented, siloed and rigid services; strict eligibility criteria; and lack of information sharing and appropriate communication.\n\nIn addition to a moral responsibility, there is an economic imperative to tackle homelessness. The costs of homelessness to society are significant. The report by Pleace and Culhane (2016), published by Crisis, estimated the total public sector costs of a person experiencing homelessness to be as much as £38,736 per year in England (based on 2019/20 prices). This estimate included the NHS costs (£4,298), mental health services (£2,099), drug and alcohol services (£1,320), criminal justice sector costs (£11,991) and homelessness services (£14,808). On average, it was estimated that preventing homelessness for 1\xa0year would reduce the public expenditure by approximately £10,000 per person. In 2020/21, 11,580 single households were assessed as rough sleeping in England (Ministry of Housing, Communities & Local Government, 2021), and if these people were prevented from experiencing 1\xa0year of homelessness, annual public spending would fall by as much as £115.8\xa0million. If other forms of homelessness were included, these cost savings would be substantially higher. Given the financial implications of homelessness to society and the far worse health and social care outcomes, most interventions that address homelessness are likely to be cost effective or even cost saving from the wider public sector perspective.\n\nThe Ministry of Housing, Communities & Local Government's rough sleeping strategy outlines its commitment to ending rough sleeping and preventing homelessness. The homelessness legislation includes duties for local authorities to assess, prevent and relieve homelessness. The NHS Long Term Plan includes a commitment to improve access to specialist homelessness mental health support for people sleeping rough in areas with the highest rates of rough sleeping. During the COVID‑19 pandemic, local authorities, health services, and the voluntary and charity sector have worked in partnership to respond to homelessness, including the 'Everyone In' initiative, recognising that rough sleeping and homelessness are public health issues. This has shown that with appropriate funding, integrated working and prioritisation of the most vulnerable in the society, there are opportunities for positive change.\n\nThis guideline provides guidance on models of service provision, for services that are specific to people experiencing homelessness, as well as improving access and engagement with mainstream services. It aims to integrate services as much as possible as a way to improve outcomes for people experiencing homelessness and contribute to ending homelessness.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# General principles\n\nRecognise that more effort and targeted approaches are often needed to ensure that health and social care for people experiencing homelessness is available, accessible, and provided to the same standards and quality as for the general population.\n\n## Co-design and co-delivery of services\n\nRecognise the value of co-designing and co-delivering services with people with lived experience of homelessness, to improve the quality of health and social care (see the section on the role of peers). See also the section on involving people in service design and improvement in NICE's guideline on people's experience in adult social care services and NICE's guideline on community engagement.\n\n## Supporting engagement with services\n\nPromote engagement by providing services that:\n\nare person-centred, empathetic, non-judgemental\n\naim to address health inequalities\n\nare inclusive and pay attention to the diverse experiences of people using the service.\n\nConsider using psychologically informed environments and trauma-informed care. Recognise that people's behaviour and engagement with services is influenced by their traumatic experiences, socioeconomic circumstances and previous experiences of services.\n\n## Sustaining engagement with services\n\nRecognise the importance of longer contact times in developing and sustaining trusting relationships between frontline health and social care staff and people experiencing homelessness (see also recommendation 1.2.9 in the section on planning and commissioning).\n\nPromote shared decision making, building self-reliance and using strengths-based approaches to care (also known as assets-based approaches). See also NICE's guideline on shared decision making.\n\nRecognise that people experiencing homelessness, especially those with experience of rough sleeping, need services that provide a long-term commitment to care to promote recovery, stability and lasting positive outcomes (see the section on long-term support).\n\n## Supporting re-engagement with services\n\nBe aware that some people experiencing homelessness may find it difficult to look after themselves because of their circumstances and may find services difficult to engage with. For people who disengage from or refuse health and social care services:\n\nactively support re-engagement\n\nenable people to re-engage with services at the same point as they left, if appropriate.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on general principles\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n## Communication and information\n\nFollow the recommendations on communication and information in NICE's guidelines on:\n\npatient experience in adult NHS services\n\npeople's experience in adult social care services\n\nservice user experience in adult mental health\n\nbabies, children and young people's experience of healthcare.\n\nHealth and social care staff working with people experiencing homelessness should:\n\nbe empathetic, non-judgemental and use recovery-oriented language that avoids jargon and acronyms\n\nuse communication methods based on the person's preferences, for example, phone call, text message, email, letter, face to face\n\nsend clear information about contacts or appointments and reminders that reach people in time, and follow up people who do not attend.\n\nTake into account each person's communication and information needs and preferences, and their circumstances. For example:\n\nprovide translation and interpretation services if needed\n\nensure that written information is available in different formats and languages, including Easy Read\n\nprovide extra support for people with low literacy levels or with speech, language and communication difficulties\n\nconsider the person's access to phone or internet.\n\nConsider involving an advocate to support communication, even when this is not a statutory requirement. This may be someone nominated by the person or an independent advocate who can, for example:\n\nsupport people to overcome stigma and previous negative and traumatic experiences\n\nhelp people with low literacy levels to access information and services\n\nreinforce information about available services and appointments.\n\nGive people experiencing homelessness information about:\n\ntheir rights to health and social care services, including for those with no or limited recourse to public funds\n\nhow to access health and social care services, including:\n\n\n\nprimary care services and how to register with a GP without a permanent address\n\nspecialist health services that can be accessed directly, such as maternity, blood-borne virus, drug and alcohol recovery, mental health, sexual health, and family planning services\n\noutreach services\n\nlocal authority services, including housing services and social care\n\n\n\nvoluntary and charity sector services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on communication and information\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Planning and commissioning\n\nThese recommendations are for commissioners of health and social care and housing services.\n\n## Planning integrated multidisciplinary health and social care services\n\nCommissioners of health, social care and housing services should work together to plan and fund integrated multidisciplinary health and social care services for people experiencing homelessness, and involve commissioners from other sectors, such as criminal justice and domestic abuse, as needed. These services should contribute to the government's aim of ending rough sleeping and preventing homelessness.\n\nRecognise that people experiencing homelessness often need additional resources and a more targeted service delivery to:\n\nensure that resources are allocated according to need and disadvantage\n\ntake into account the social determinants of health\n\nimprove long-term outcomes and address health inequalities.\n\n## Local homelessness health and social care needs assessment\n\nConduct and maintain an up-to-date local homelessness health and social care needs assessment and use this to design, plan and deliver services according to need. Include thorough engagement with service providers (including voluntary and charity sector service providers) and experts by experience.\n\nLocal homelessness health and social care needs assessments should:\n\nquantify and characterise the population experiencing homelessness or at risk of homelessness, including health inequalities, diversity and inclusion issues and specific needs and identify trends\n\nassess the quality and capacity of existing mainstream and specialist service provision to inform the need for service development and investment\n\nassess access to and engagement with current services by people experiencing homelessness\n\nidentify opportunities for more integrated service delivery\n\ntake into consideration relevant findings from Safeguarding Adults Reviews.\n\n## Recording housing status\n\nWork with health and social care providers to improve recording of housing status so that the information can be used by services to:\n\nbest meet people's needs and\n\nplan, audit and improve services.\n\n## Developing services\n\nWhen developing services for people experiencing homelessness, commissioners should:\n\nwork together to strategically plan and deliver health and social care across larger areas, recognising that people move between areas\n\nwork with other relevant services, such as prison and probation services and domestic abuse services\n\nenable long-term support for those who need it (see the section on long-term support)\n\nensure that health and social care services are designed to meet the level and type of local need (see the section on models of multidisciplinary service provision)\n\ndefine and measure outcomes, including health and social outcomes and service use\n\nconsider the likely benefits of using long-term contracts for providers\n\nsupport statutory bodies to fulfil their legal responsibilities and use their powers\n\nencourage and enable the contribution of peers (experts by experience) in supporting people experiencing homelessness and delivering and designing more effective services (see the section on the role of peers).\n\nConsider providing services and support aimed at the needs of particular groups of people experiencing homelessness, as appropriate, such as:\n\nwomen (also see the NICE guideline on pregnancy and complex social factors)\n\nyoung people\n\nolder people\n\ndisabled people\n\npeople with no or limited recourse to public funds because of their immigration status\n\nLGBT+ people\n\npeople from different minority ethnic or religious backgrounds.\n\nDevelop strategies across services to improve access to health and social care for people experiencing homelessness. See the section on improving access to and engagement with health and social care.\n\nEnsure that there are processes to:\n\nsupport people experiencing homelessness to register with a GP and\n\ndocument and address any problems with GP registrations for people experiencing homelessness.\n\nConsider reducing caseloads and lengthening contact time for health and social care practitioners working with people experiencing homelessness to enable them to use approaches that sustain engagement with services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on planning and commissioning\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Models of multidisciplinary service provision\n\n## Homelessness multidisciplinary teams\n\nProvide care through specialist homelessness multidisciplinary teams across sectors and levels of care, tailored according to local needs.\n\nHomelessness multidisciplinary teams should act as expert teams, providing and coordinating care across outreach, primary, secondary and emergency care, social care and housing services. Homelessness multidisciplinary teams may include:\n\nexperts by experience (see the section on the role of peers)\n\nhealthcare professionals with relevant specialist expertise (for example, drug and alcohol treatment, mental health, primary care, emergency care, palliative care)\n\nsocial workers\n\nhousing options officers or homelessness prevention officers\n\noutreach and homelessness practitioners\n\nvoluntary and charity sector professionals\n\nstaff with practical expertise in accessing benefits and entitlements for people experiencing homelessness.\n\nHomelessness multidisciplinary teams should have protocols and systems in place for communication and sharing information to support integrated working within the team and between services.\n\nHomelessness multidisciplinary teams should:\n\nidentify people experiencing homelessness through outreach or when they present to health and social care services\n\nsupport mainstream providers to identify and refer people to the homelessness multidisciplinary team\n\nundertake and support assessments for safeguarding, physical and mental health, alcohol and drug treatment needs, and social care, including informing Care Act assessments (see the section on assessing people's needs)\n\nsupport mainstream providers to ensure safe, timely and appropriate hospital discharge and engagement with onward care (see the section on transitions between different settings).\n\nHomelessness multidisciplinary teams should:\n\noffer person-centred case management by a designated practitioner within the multidisciplinary team and ensure continuity of care for as long as it is needed by the person\n\noffer wraparound health and social care support that encompasses the person's needs, including:\n\n\n\nphysical health\n\nmental health and psychological support (such as psychological therapies)\n\nphysical rehabilitation (such as occupational therapy and physiotherapy)\n\ndrug and alcohol treatment\n\nsocial care\n\npalliative care\n\ncommunication support\n\npractical support, such as help with benefits, housing and referral for legal advice.\n\n\n\nHomelessness multidisciplinary teams should engage in reflective practice, including opportunities to share experience and learning with other relevant teams, including homelessness multidisciplinary teams, and to review complex or difficult situations.\n\nHomelessness multidisciplinary teams should directly contribute to local needs assessments, service quality improvement, and reviews of complex or difficult situations including Safeguarding Adults Reviews.\n\nHomelessness multidisciplinary teams should advise homelessness leads, when needed, in nearby areas that do not have a homelessness multidisciplinary team and share examples of good practice.\n\n## Homelessness leads in mainstream services\n\nIn areas assessed as not needing a full-time homelessness multidisciplinary team because of low numbers of people experiencing homelessness, establish links with multidisciplinary teams in nearby areas and designate homelessness leads in all relevant mainstream services, for example, in primary, secondary and emergency care, palliative care and in adult and child social services.\n\nThe homelessness leads should:\n\nsupport their organisation to provide appropriate care for people experiencing homelessness and implement this guideline\n\nhave detailed local knowledge of specialist services to support the care of people experiencing homelessness\n\nwork with and coordinate care with homelessness leads in other mainstream services\n\nconsult homelessness multidisciplinary teams in nearby areas, as needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on models of multidisciplinary service provision\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# The role of peers\n\nInvolve peers (experts by experience) in delivering and designing services, for example by:\n\ndirectly delivering health and social care interventions, for example, as part of outreach\n\nproviding a user perspective to influence the design and development of services\n\nproviding training for health and social care staff\n\ncarrying out participatory research and data collection, for example, to support service audits, needs assessments and quality improvement.\n\nOffer peer support to people experiencing homelessness, for example to help with:\n\nunderstanding how others with similar experiences have changed their lives (role modelling)\n\ndeveloping self-efficacy\n\nnavigating services\n\nsupporting attendance at appointments\n\nproviding peer advocacy at appointments or in A&E\n\nforming trusting relationships with practitioners and improving communication.\n\nSupport peers to deliver services effectively and maintain their own wellbeing and development by providing:\n\ntraining, supervision and governance structures appropriate to the role and tailored to the person's needs\n\npsychological and social support, for example reflective practice, according to their changing needs and circumstances\n\ntailored support for professional development, including access to further training and inclusive employment opportunities.\n\nTake into account the experience, background and language skills of peers and how these can be used to meet the needs and preferences of people experiencing homelessness.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on the role of peers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Improving access to and engagement with health and social care\n\n## Supporting access to and engagement with services\n\nDesign and deliver services in a way that reduces barriers to access and engagement with health and social care, for example, by providing:\n\noutreach services (see the section on outreach services)\n\nlow-threshold services\n\nflexible opening and appointment times\n\nself-referral\n\ndrop-in services\n\n'one-stop shops' for multiple services\n\nincentives and help to access care, such as transport support, vouchers or digital connectivity\n\nadvocates (see recommendation 1.1.12 in the section on communication and information)\n\npeer support (see the section on the role of peers)\n\ncare navigation\n\npsychologically informed environments and trauma-informed care.\n\nDo not penalise people experiencing homelessness for missing appointments, for example, by discharging people from the service. Consider seeking specialist help, such as peer supporters or independent advocates, to support the person to attend appointments and re-engage with care after missing appointments (see the section on the role of peers).\n\nEnsure that people can access help when needed, including through emergency care, and avoid policies that withdraw support and close cases after a standard duration, unless a safe transfer of care to another service has been agreed with the person or the person agrees that they no longer need the service.\n\nCommissioners and service providers should follow the recommendations on improving access to services in NICE's guideline on common mental health problems.\n\nEnsure that people experiencing homelessness with multiple health or social care needs are not excluded from services because of restrictive eligibility criteria. For example, people with mental health problems are not denied access to mental health services because they have drug and alcohol treatment needs (see also NICE's guideline on coexisting severe mental illness and substance misuse).\n\nEnsure that people experiencing homelessness who are assessed as frail and in need of social care and support get long-term care packages, including residential care or supported housing, irrespective of their age.\n\nEnsure that paper or digital forms needed to access health or social care or to get help with NHS costs are readily available and that people are supported to fill them in, including providing translation when needed.\n\nEnsure that people experiencing homelessness can access online health and social care information and are supported to use online services, for example by providing internet access at places where people experiencing homelessness spend time, such as day centres or hostels.\n\nPrimary care service providers should ensure that people without an address can register with a GP practice, in line with the NHS Primary medical care policy and guidance manual.\n\nEnsure that frontline health and social care staff who come into contact with people experiencing or at risk of homelessness are able to fulfil their duties under the Homelessness Reduction Act 2017.\n\nEnsure that frontline health and social care staff are able to identify when a person needs to be referred for specialist homeless health and social care, and that processes are in place to support timely referral.\n\nConsider moving people up waiting lists for health and social care appointments if they are experiencing homelessness because their circumstances may mean they are at higher risk of deterioration and premature death.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on supporting access to and engagement with services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n## Outreach services\n\nTake health and social care services to people experiencing homelessness by providing multidisciplinary outreach care in non-traditional settings, such as on the street, hostels or day centres.\n\nOffer outreach services that include support for people who:\n\nhave primary healthcare needs\n\nhave drug and alcohol treatment needs\n\nhave mental healthcare needs\n\nfear engaging with services, for example, because of previous negative experiences from providers, discomfort using male-dominated services or concerns about eligibility including immigration status\n\nmay lack mental capacity or need support to recognise their care needs and engage with providers.\n\nUse outreach to identify health problems earlier, promote health and support engagement with care, for example by:\n\nsupporting access to national screening programmes\n\nassessing people for long-term conditions, infectious diseases and mental health needs\n\nproviding preventive health opportunities, such as vaccination, drug and alcohol treatment services, harm minimisation, smoking cessation and nutrition advice.\n\nOffer collaborative, assertive outreach to start and maintain engagement with health and social care for people experiencing homelessness with coexisting severe mental health and drug or alcohol treatment needs. See also the section on maintaining contact with services in NICE's guideline on coexisting severe mental illness and substance misuse.\n\nConsider assertive outreach for all people experiencing homelessness who could benefit from support but who find services difficult to engage with.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on outreach services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Assessing individual needs\n\nBe aware that health and social care practitioners have a statutory and professional duty to identify immediate risk of harm to self or others. See also the section on assessment and treatment under the Mental Health Act in NICE's guideline on service user experience in adult mental health.\n\nAssess the health and social care needs of the person experiencing homelessness. When carrying out the assessment:\n\ntake into account their capacity, rights to autonomy and self-determination, and any safeguarding issues and\n\navoid unnecessary and potentially distressing repetition of their history if it is already on record\n\ninvolve peers or advocates as appropriate (see also the section on the role of peers).\n\nInclude in the assessment:\n\nA comprehensive assessment of the person's physical and mental health needs (including acute and long-term conditions) and social care needs. This should take into consideration their housing and benefits situation, bearing in mind the need to address health inequalities, and be responsive to diversity, and inclusion needs.\n\nAsking if the person has children or dependents and assessing how this affects their needs.\n\nUnderstanding the historical context of their situation, including past psychological trauma and experience of services.\n\nIn assessments to inform a health and social care plan for people who might benefit from high levels of support, use a multidisciplinary approach to enable a comprehensive and holistic assessment of their needs, involving:\n\nthe person, and their advocate if one is nominated or appointed\n\ninput from professionals with specialist expertise and practitioners who have detailed knowledge of the person's health and social care needs, including staff working in homelessness and housing services.\n\nUse hospital admissions as an opportunity to offer a comprehensive, holistic needs assessment, including referral, if indicated.\n\nUse the multidisciplinary assessment to inform the local authority-led care and support needs assessment, under the Care Act 2014 (see the section on care and support needs assessment and care planning in NICE's guideline on people's experience in adult social care services).\n\nReview the person's needs, strengths and aspirations whenever their circumstances change or whenever they request a review, rather than using standard review periods.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing people's needs\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Intermediate care\n\nProvide intermediate care services with intensive, multidisciplinary team support for people experiencing homelessness who have healthcare needs that cannot be safely managed in the community but who do not need inpatient hospital care. These may be for people who are:\n\ndischarged from hospital (step-down care)\n\nreferred from the community who are at acute risk of deterioration and hospitalisation (step-up care).See also NICE's guideline on intermediate care including reablement.\n\nFor a short explanation of why the committee made this recommendation and how it might affect services, see the rationale and impact section on intermediate care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\n\nLoading. Please wait.\n\n# Transitions between different settings\n\nHomelessness multidisciplinary teams or leads should support people experiencing homelessness through transitions between settings (such as the street, hostels, Housing First and other supported housing, hospital, mental health services, social care, residential or community drug and alcohol treatment, and custody) and consider providing time-limited intensive support, which includes:\n\nhaving a key practitioner coordinating care\n\nbuilding a relationship of trust\n\nproviding links to services in the community\n\ngradually lowering the intensity of support, as appropriate.\n\nPractitioners in any setting supporting people experiencing homelessness should:\n\nensure that all handovers of care responsibilities are planned and coordinated, and relevant information is shared if agreed\n\noffer pre-emptive, structured support before, during and after transitions\n\nrecognise that people may be vulnerable during periods of transition, but also that there may be opportunities for intervention.\n\nClinical teams, working with hospital discharge teams and specialist homelessness multidisciplinary teams, where available, should have procedures to:\n\nminimise self-discharge and\n\nprevent discharge to the street. If self-discharge or discharge to the street happens, review the circumstances and implement learning.\n\nFor people moving between different care settings, follow the recommendations in NICE's guidelines on:\n\ntransition between inpatient mental health settings and community or care home settings\n\ntransition between inpatient hospital settings and community or care home settings for adults with social care needs\n\ntransition from children's to adults' services for young people using health or social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section for transitions between different settings\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Housing with health and social care support\n\nThese recommendations are for commissioners and service providers working together across health, social care and housing services.\n\nRecognise that providing accommodation suitable for the person's assessed health and social care needs (see the section on assessing people's needs) can support access to and engagement with health and social care services and long-term recovery and stability.\n\nProvide wraparound health and social care support that is flexible to the person's changing needs and circumstances, and helps them maintain suitable accommodation.\n\nRecognise the need for a range of accommodation types that are suitable for the varied needs of people experiencing homelessness, such as self-contained accommodation and accommodation with specialist onsite support for people who are particularly at risk or who might otherwise benefit from higher levels of support.\n\nBe aware that moving to independent accommodation in the community with tenancy responsibilities can be an extremely challenging, stressful and isolating experience for some people. Provide emotional and practical support for as long as it is needed.\n\nWhen a person experiencing homelessness moves into new accommodation, help them to assess the risks associated with their new living arrangement, while also recognising their strengths, and plan ways to mitigate the risks.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on housing with health and social care support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Safeguarding\n\nAlso see the NICE guideline on domestic violence and abuse.\n\nDesignate a person to lead on safeguarding the welfare of people experiencing homelessness, including engagement and face-to-face practical safeguarding support.\n\nWhere a social worker is embedded in the homelessness multidisciplinary team, local authorities should consider appointing them to lead on safeguarding enquiries about people experiencing homelessness.\n\nLocal authorities should consider having a lead for people experiencing homelessness on the Safeguarding Adults Board.\n\nSafeguarding Adults Boards should ensure that specific reference is made to people experiencing homeless in their annual reports and strategic plan.\n\nSafeguarding Adults Boards should share recommendations and key learning related to homelessness from Safeguarding Adults Reviews with key stakeholders.\n\nSafeguarding Adults Boards should establish ways of analysing and interrogating data on safeguarding notifications about people experiencing homelessness so that they can check that local safeguarding arrangements offer the necessary protection.\n\nCommissioners and service providers should support health and social care staff to understand and apply laws relevant to people experiencing homelessness and who are in need of safeguarding. This should include ensuring that they can recognise signs of abuse and neglect (including self-neglect) and how to make a safeguarding referral.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on safeguarding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\n\nLoading. Please wait.\n\n# Long-term support\n\nFor people who struggle to engage with services, plan long-term engagement to help meet the person's needs at their own pace.\n\nGive priority to building a relationship of trust, for example by:\n\ntaking time with the person, particularly at the beginning of the relationship\n\nbeing prepared to meet in an informal setting, such as a park or café (with appropriate lone worker policies in place)\n\nhaving regular contact\n\nensuring consistency of practitioner, so that they meet with 1\xa0person or a small team\n\naiming to meet immediate expressed needs to encourage long-term engagement.\n\nRecognise that people experiencing homelessness do not always follow a linear recovery journey and that apparent progress may hide risks.\n\nConsider providing 'open-door' services that people can self-refer to and access after any initial support ends, to reduce the risk of becoming homeless again because of unmet health, care and support needs.\n\nRecognise that some people experiencing homelessness experience frailty at an earlier age (both physical and cognitive) than the general population and their long-term care should be tailored to meet this.\n\nIf a person experiencing homelessness is likely to be approaching the end of their life, for example, if death would not be unexpected in 6\xa0to\xa012\xa0months, discuss palliative care needs with the person and the multidisciplinary team, and provide coordinated palliative care to meet the person's needs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on long-term support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Staff support and development\n\nConsider providing training for all health and social care practitioners, at a level suitable for their professional role, covering:\n\nunderstanding the health and social care needs of people experiencing homelessness, and their rights to access services\n\nhomelessness as part of equality and diversity training, including being responsive to health inequalities, diversity issues and inclusion needs and understanding the impact of discrimination and stigma, and how intersectional, overlapping identities can affect people experiencing homelessness\n\npsychologically informed environments and trauma-informed care\n\nlegal duties and powers\n\nlegal entitlements for migrants.\n\nHealthcare professionals working within secondary care mental health services should follow the recommendations in the section on competence in NICE's guideline on coexisting severe mental illness (psychosis) and substance misuse.\n\nConsider regular and ongoing support, professional supervision and reflective practice for staff working with people experiencing homelessness.\n\nFor a short explanation of why the committee made these recommendations and how they might affect services, see the rationale and impact section on staff support and development\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches\n\nevidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local, Act Personal's Care and Support Jargon Buster.\n\n## Assertive outreach\n\nA proactive and persistent approach to outreach that involves repeated contact with people who are initially unable to or unwilling to engage.\n\n## Care navigation\n\nHelping people navigate the complex health and social care systems to overcome barriers in accessing services. This could be done by case workers, other practitioners or peers supporting the person, or by designated care navigators.\n\n## Health inequalities\n\nSystematic, unfair and avoidable differences across the population and between different groups within society in relation to health and social outcomes. They arise because of the conditions in which people are born, grow, live, work and age. These conditions influence people's opportunities, health and wellbeing.\n\n## Homelessness leads\n\nPeople working in mainstream health and social care services who, as part of their role, lead on homelessness issues within their service. Homelessness leads are designated in areas assessed as not needing a full-time homelessness multidisciplinary team.\n\n## Homelessness multidisciplinary team\n\nA multidisciplinary team involves a range of professionals across disciplines as well as agencies working together to assess and support the needs of a person experiencing homelessness.\n\n## Inclusion needs\n\nA need to have equal access and opportunities to participate in society and not facing barriers to services, social situations, different spaces and environments; being treated with dignity and not experiencing discrimination or intolerance due to the person's identity. See also health inequalities.\n\n## Intermediate care\n\nA range of integrated services that: promote faster recovery from illness; prevent unnecessary acute hospital admissions and premature admissions to long-term care; support timely discharge from hospital; and maximise independent living. Intermediate care is given on a time-limited basis, but duration can vary depending on the person's needs.\n\n## Low-threshold services\n\nServices that avoid restrictive eligibility criteria and make minimal demands on the client.\n\n## Mainstream services\n\nServices designed to be delivered to the general population.\n\n## Outreach\n\nBringing health and care services to people who might not otherwise have access to or engage with existing services, provided in a mobile way in the locations where people are, for example on the street, in temporary accommodation facilities and in day centres. This can be done by mainstream services or dedicated outreach teams.\n\n## Peers\n\nPeople with lived experience of homelessness who are using their experience to support people experiencing homelessness through different means such as direct support, advocacy, research and co-production of services.\n\n## People experiencing homelessness\n\nIn the context of this guideline, people experiencing homelessness is defined as people aged\xa016 and over who:\n\nare sleeping rough (people without homes who sleep outside or somewhere not designed for habitation)\n\nare temporary residents of hostel, B&B, nightly-paid, privately managed accommodation and other types of temporary accommodation\n\nuse day centres that provide support (such as food, showers, clothing and advice) for people experiencing homelessness\n\nare obliged to stay temporarily with other people\n\nare squatting\n\nare newly homeless.\n\nIt also includes people with a history of homelessness (as defined above) who are at high risk of becoming homeless again because of ongoing severe and multiple health and social care needs.\n\n## Psychologically informed environment\n\nService provision and practice that takes into account individuals' psychological and emotional needs, and their experiences of trauma. It includes building organisational awareness of psychological and emotional needs; physical environment and social spaces; staff training and ongoing support; service evaluation and learning; and reflective practice. For more information and resources, see the Homeless Link's webpage on trauma informed care and psychologically informed environments. See also trauma-informed care.\n\n## Recovery-oriented language\n\nLanguage that is person-centred, respectful, non-judgemental and strengths based. It conveys a sense of hope and commitment to the potential of every person and their recovery journey. It includes non-verbal aspects of communication and aims for consistency between verbal language and body language. If recovery is unlikely, this approach might focus on exploring what is important to the person and what living well means to them.\n\n## Reflective practice\n\nA process to:\n\nreflect on previous practice\n\ntalk about why they made the decisions they made, and why they acted or behaved in particular ways\n\ntalk about their emotional responses to their actions and the actions of others\n\nengage in continuous learning.\n\nReflective practice may also provide insight into personal values and beliefs, and help understand how these influence action and decision making.\n\n## Safeguarding\n\nThe collective responsibility and process to protect the health, wellbeing and human rights of people at risk, enabling them to live safely, free from harm, abuse and neglect. See also the Think Local, Act Personal's Care and Support Jargon Buster definition for safeguarding.\n\n## Safeguarding Adults Board\n\nA statutory multi-agency group set up by a local authority made up of different professionals from a local authority, the NHS and police to prevent abuse or neglect of adults who have care and support needs, and to make sure that action is taken if abuse occurs. See also the Think Local, Act Personal's Care and Support Jargon Buster definition for Safeguarding Adults Board.\n\n## Safeguarding Adults Review\n\nA statutory multi-agency learning process arranged by a Safeguarding Adults Board that reviews cases if:\n\nthere is reasonable cause for concern that partner agencies could have worked more effectively to protect an adult and\n\nserious abuse or neglect is known or suspected and\n\ncertain conditions are met, in line with section 44 of the Care Act 2014 and related statutory guidance.\n\n## Severe and multiple disadvantage\n\nMultiple and overlapping disadvantages that are often persistent and interrelated and affect a person's life. These disadvantages include the experience of homelessness, harmful drug or alcohol use, criminal justice involvement, poor mental health, and the experience of domestic violence and abuse. People experiencing severe and multiple disadvantage have often experienced underlying adverse childhood experiences, poverty, psychological trauma, stigma and discrimination. People with these experiences may have had sporadic and inconsistent contact with services or been serially excluded from services. People who experience severe and multiple disadvantage tend to have much poorer physical and mental health, have higher social care needs, and die at a much younger age than people without severe and multiple disadvantage.\n\n## Social care staff\n\nPeople working in social services and social care providing practical and emotional support to improve people's wellbeing and quality of life. This includes both local authority social workers with legal responsibilities to assess and protect people at risk of harm as well as frontline social care practitioners that may work in residential care, hostels and homelessness services in either the public sector or voluntary and charity sector.\n\n## Social determinants of health\n\nSocial factors and wider determinants that influence health and wellbeing. These include circumstances in which people are born, grow up, live, work, and age, and the social and economic policies and systems, political agendas, social norms, environmental factors and other wider forces.\n\n## Strengths-based approaches\n\nSometimes called assets-based approaches. These involve the person who uses services and the practitioners who support them working together to achieve the person's intended outcomes, in a way that draws on the person's strengths. The quality of the relationship between those providing support and those being supported is particularly important, as are the skills and experience that the person using support brings to the process (see Social Care Institute for Excellence's Care Act guidance on strengths-based approaches). See also NICE's quick guide on evidence for strengths and asset-based outcomes.\n\n## Trauma-informed care\n\nAn approach to planning and providing services that involves understanding, recognising and responding to the effects of all types of trauma. It emphasises physical, relational and emotional safety, and helps survivors of trauma to rebuild narratives of connection, control and empowerment. See also psychologically informed environment.\n\n## Wraparound health and social care support\n\nA multidisciplinary team-based collaborative approach to support the person experiencing homelessness holistically, taking into consideration their individual needs, including physical and mental health needs, drug and alcohol treatment needs, care and social needs, and practical needs, in addition to their housing needs.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Psychologically informed environments\n\nWhat is the effectiveness and acceptability of clinical psychology-led psychologically informed environments and psychological approaches for people experiencing homelessness?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on general principles\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\n\nLoading. Please wait.\n\n# Health and social care to support housing\n\nWhat structural and systems factors help or hinder commissioning and delivery of wraparound health and social care that is integrated with housing, for people experiencing homelessness?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on housing with health and social care support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: views and experiences of health and social care for people experiencing homelessness.\n\nLoading. Please wait.\n\n# Longer health and social care contacts\n\nWhat is the effectiveness and cost effectiveness of longer health and social care contacts compared with usual care for people experiencing homelessness?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on planning and commissioning\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence reviews\xa0A and B: effectiveness of approaches to improve access to and engagement with health and social care and joined up approaches.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice or services.\n\n# General principles\n\nRecommendations 1.1.1 to 1.1.8\n\n## Why the committee made the recommendations\n\nThere was qualitative evidence that people experiencing homelessness feel that they are offered less or lower quality care than the general population. Although the committee agreed that there were some limitations to the evidence, their experience corresponded with this. The evidence also highlighted various barriers to accessing care. Considering the multiple disadvantages and disproportionately poor outcomes observed in this population, the committee agreed that more effort and targeted approaches are often needed to level up outcomes. This also aligns with the NHS Constitution's first key principle of providing comprehensive service available to all, and its 'wider social duty to promote equality through the services it provides and to pay particular attention to groups or sections of society where improvements in health and life expectancy are not keeping pace with the rest of the population'.\n\nGood qualitative evidence showed that people experiencing homelessness want to give feedback on processes and their care, but ways to do this were not always available. Based on their experience, the committee agreed that people often do not feel able to do this because of their experience of stigma and discrimination. However, involving people with lived experience of homelessness in service design is likely to improve services and people's engagement with services. Involving people in service design was also highlighted in the NICE guideline on people's experience in adult social care services, which references the Local Government and Public Involvement in Health Act 2007. The 2007 Act mandates local authorities to provide opportunities for people who use services to be involved in strategic decision making about services. NICE's guideline on community engagement also gives guidance on community engagement approaches for local authorities and health bodies.\n\nThe committee's experience as well as both qualitative and effectiveness evidence showed that using peers to deliver health and social care services can also be beneficial for people experiencing homelessness. The committee agreed that there are likely benefits for the peers themselves and for the service.\n\nGood qualitative evidence highlighted that many people experiencing homelessness encounter or perceive stigma, discrimination and lack of understanding from health and social care practitioners. There was also limited evidence showing that many service providers are not aware of the impact that traumatic experiences can have on a person's life and how it can manifest in their behaviour. From their experience, the committee agreed that psychological trauma is common among most people experiencing homelessness, and is particularly prevalent among certain groups, such as women and young people. They also heard from experts who highlighted the importance of 'professional curiosity' in understanding the person's backstory and the use of trauma-informed practices. They agreed to highlight the importance of using approaches that take into account the impact of trauma and consider the person's past experiences as well as their current situation.\n\nThere was a lack of evidence on psychologically informed environments and psychological approaches to care, so the committee developed a research recommendation on the effectiveness and acceptability of clinical psychology-led psychologically informed environments and psychological approaches for people experiencing homelessness and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.\n\nGood qualitative evidence showed that many people experiencing homelessness reported feelings of apprehension, fear and distrust when receiving care. Some people reported a lack of trust in service providers or in the healthcare system, mostly because of previous negative experiences. They felt judged, stereotyped and disrespected in healthcare settings, leading to unwillingness to engage with care.\n\nThere was good qualitative evidence highlighting that people reported positive experiences with care providers and increased engagement with services when they were able to develop a trusting relationship with a provider who paid attention, showed sincere interest and had time available for them. The importance of a genuine, friendly relationship in which the professional listens, remembers, uses humour and shows concern helps to build a trusting relationship, which in turn enables the person to feel safe in the health or social care environment. The committee agreed that this was key to promoting engagement. There was also good qualitative evidence that people experiencing homelessness value non-judgemental communication from professionals that is responsive to people's individual experiences and needs, for example, related to gender, culture, ethnicity and being part of the LGBT+ community. The committee also recognised the importance of service providers addressing the underlying inequalities that people may face, which are underpinned by social determinants of health that shape people's experiences and health and social care needs. The evidence emphasised the importance of staff understanding the impact that trauma may have.\n\nGood qualitative evidence showed that people experiencing homelessness valued continuity of care and spoke positively about practitioners with whom they had formed trusting relationships. The evidence also emphasised respect as an essential component in sustaining trusting relationships. The committee's experience aligned with the evidence, and they emphasised that consistency and continuity of care throughout a person's journey can lead to improved engagement and better outcomes.\n\nThe qualitative evidence also showed that the length of appointments or contacts in current practice is often inadequate to meet the needs of many people experiencing homelessness, particularly those with severe and multiple disadvantage. Despite some limitations in the evidence, the committee agreed with this and discussed how longer appointment times can give an opportunity to better assess, engage and build trust with people who may otherwise rarely have contact with services, and who are marginalised and have disproportionately worse outcomes. Good qualitative evidence and information from experts emphasised that giving people agency – involving them and promoting shared decision making – helps to improve engagement in care. High-quality evidence from qualitative studies highlighted that focusing on the person's strengths and assets encouraged people experiencing homelessness to use services.\n\nGood evidence from qualitative studies showed that people experiencing homelessness often experience lack of consistency and continuity from health and social care services, which can lead to disengagement. The evidence also showed that ongoing, sustained support and a service provider's patience and continued attempts to re-engage can improve the person's engagement when they might otherwise be resistant to support. The committee were aware that the Safeguarding Adults Reviews highlighted the prominence of 'self-neglect' in people experiencing homelessness. The committee discussed how some people experiencing homelessness find it difficult to look after their health and personal care because of their environment and circumstances. 'Self-neglect' can also include disengagement with health and social care whether or not the person has capacity. This is made more difficult by barriers to access and engagement with services. This emphasises the importance of actively supporting re-engagement. The committee discussed that re-engagement might not be successful if the person has to start and repeat the process from the beginning of the pathway, instead enabling re-entry from the point they left is more likely to support re-engagement, if appropriate.\n\n## How the recommendations might affect services\n\nThe recommendations outline principles of good practice that in the committee's view should be happening across all services for people experiencing homelessness. However, practice is variable, and this may represent a change in practice for some services. Most recommendations would not lead to a significant resource impact, but may involve staff training and longer contact times. Any additional costs are likely to be offset by the benefits of improved engagement with care, for example, by accessing care before a crisis and reducing the burden on emergency services.\n\nEconomic analysis also suggested that reducing caseloads (and thus increasing time spent with clients) for practitioners working with people experiencing homelessness could be cost effective.\n\nReturn to recommendations\n\n# Communication and information\n\nRecommendations 1.1.9 to 1.1.13\n\n## Why the committee made the recommendations\n\nThere was good qualitative evidence that people experiencing homelessness often experience stigma and discrimination and feel oppressed and unwelcome. Good evidence also reported that insensitive communication and closed body language are common experiences for them. Service users reported preferring simple language and explanations, instead of jargon, because it gives a sense of comfort and is more accessible.\n\nThe committee agreed with the evidence and discussed the merits of non-judgemental, recovery-oriented language. They agreed that the way in which practitioners communicate can have an impact on people's recovery journey, their willingness to engage with services, their sense of hope and their potential for recovery. The committee discussed the importance of using sensitive language that does not lead to the person feeling blamed for their issues (for example, avoiding phrases like substance 'abuse' or 'failed' to attend).\n\nThere was limited qualitative evidence on people's preferred communication methods, which reported that receiving appointment information by letter was ineffective for people without a reliable address. The committee discussed that letters are still the main method of communication for many service providers. Good qualitative evidence also showed that people without access to the internet and those without a phone have difficulties accessing healthcare (digital exclusion). The evidence corresponded with the committee's experience, recognising that various methods based on the person's preferences and communication needs should be available to improve timely contact and access to services.\n\nThe committee discussed that resources and forms are often written in a complex way and mostly available only in English. They agreed that this is a further barrier for people whose first language is not English. Good qualitative evidence also suggested that low literacy levels among some people experiencing homelessness can add to difficulties in accessing care. The committee agreed that this could include some migrants and people with learning disabilities or acquired brain injury. They therefore emphasised the need to tailor communication and information provision to people's needs and preferences, taking into account a wide range of possible speech, language and communication difficulties.\n\nGood qualitative evidence showed that the presence of an advocate (including a peer advocate) helps people experiencing homelessness to gain confidence and a sense of control over their health and care needs. The committee had confidence in the evidence and agreed, based on their experience, that advocates (including peer advocates) can play a significant role in supporting people with correspondence and attending appointments, and in bridging the gap between practitioners and people experiencing homelessness. The committee were also aware that NICE is developing a guideline on advocacy services for adults with health and social care needs (publication expected September 2022).\n\nThe committee noted that the advocate could be someone who the person is familiar with, such as a family member or a friend. But they also noted that some people may be entitled to an independent advocate under certain circumstances. For example, the Care Act 2014 mandates that local authorities must arrange an independent advocate to support and represent a person to assist in their involvement in specified social care processes if the person has substantial difficulty in being involved in the process, and if they do not have an appropriate person to support them.\n\nModerate-quality evidence from qualitative studies showed that people experiencing homelessness felt that there was a lack of help or information about services available to them (such as overall entitlement to care, oral health, maternity services, screening and infectious diseases). This corresponded with the committee's experience, and they agreed that to improve engagement with health and social care services, it is important to give people information, support access, and make sure that they know their rights to health and social care. They considered this particularly relevant for migrant populations who may not be familiar with the local health and social care system and their entitlements, or who may have limited or no recourse to public funds.\n\n## How the recommendations might affect services\n\nThese recommendations reinforce existing NICE guidelines on communication and information provision for the general population. However, there are some aspects that may need particular attention when working with people experiencing homelessness. There may be a need for some extra staff training on communication, and on the available health and social care services and support for people experiencing homelessness, including legal entitlements for care.\n\nGiving everyone – including staff – the right information about what services are available will help relationship and trust building, and may lead to better access and engagement with services. For example, people may be more likely to access primary care services or specialist services directly instead of relying on emergency services. This can lead to problems being picked up and dealt with earlier, reducing morbidity and mortality, and associated costs such as for crisis care, and unplanned or emergency care.\n\nServices already use various communication methods to support access to and engagement with services. But tailoring the method to each person's preferences and needs may need some reorganisation of current practice.\n\nAdvocate roles could be carried out by a professional or a peer supporter, or sometimes a family member or a friend. There are various advocacy models aimed at facilitating the relationship with service providers, and supporting people to access information and services or attend appointments. Any additional costs could be offset by the beneficial effect on the person's recovery including potential reductions in morbidity and mortality. For example, there is a link between non-attendance at appointments and increased morbidity and mortality in people experiencing homelessness.\n\nReturn to recommendations\n\n# Planning and commissioning\n\nRecommendations 1.2.1 to 1.2.10\n\n## Why the committee made the recommendations\n\nThe rough sleeping strategy by the Ministry of Housing, Communities & Local Government highlights the need for agencies to work together to end rough sleeping and prevent homelessness. Cooperation and integrated working between agencies and partners are also mandated in legal frameworks including the Care Act 2014 and the National Health Service Act 2006.\n\nBased on their experience, the committee discussed that integrated working among commissioners across different sectors is essential to bring all the knowledge and services together to ensure that there is a strategy and funding for coordinated and holistic support for people experiencing homelessness. Joined-up working is also likely to improve long-term outcomes; improve people's experience of services; minimise duplication of work and make services more efficient; improve understanding of the needs of the homeless population in the local area; and improve practitioners' work by making it easier to collaborate with colleagues.\n\nPeople experiencing homelessness are to varying degrees disadvantaged and marginalised, and their outcomes are considerably worse than the general population, including having disproportionate rates of premature mortality. The committee discussed the concept of 'proportionate universalism', introduced in Marmot et al. (2010) Fair Society Healthy Lives (The Marmot Review), meaning that resourcing and delivering of services are done universally but at a scale and intensity proportionate to the level of need or disadvantage. The committee agreed that more resources and targeted approaches are justified to address the inequalities facing this population.\n\nThe committee agreed that to plan and commission adequate services to meet the needs of the homeless population in a local area, a comprehensive homelessness health and social care needs assessment should be carried out and kept up to date. This assessment will help understand the scale and nature of homelessness, and how existing services could be developed and integrated to better meet the needs of the people experiencing homelessness. The committee agreed that it should involve experts by experience to fully understand the needs, experiences, circumstances and service use of people experiencing homelessness. The committee also agreed that to improve services and to prevent abuse, neglect and death, service planning and design should be informed by Safeguarding Adults Reviews. They heard from an expert who also highlighted this.\n\nThe committee discussed, based on their experience, that data on the needs and service use of people experiencing homelessness can come from housing status in the person's health and care records if this is accurately recorded. Public Health England's Homelessness: applying 'All Our Health' advises frontline health and care professionals to ask about and record people's housing circumstances. The committee recognised that recording this information can create fear of stigmatisation in people experiencing homelessness. But they agreed that this was outweighed by the benefits of accurate data that can be used to improve services, both for the individual and as a whole, and ensure that there are adequate resources. The data can also be used to help identify and reduce health inequalities.\n\nMany people experiencing homelessness have multiple intersecting issues or high support needs, such as physical and mental health issues, drug and alcohol treatment needs and social care needs. High-quality evidence from qualitative studies highlighted the importance of joint working to address complex unmet health and social care needs. The evidence suggested that many services work in silos with minimal coordination and cooperation between agencies. People felt that their issues were often dealt with individually by different providers rather than holistically addressing all of their intersecting needs. The committee heard from experts about adult social care and safeguarding, who similarly highlighted the need for joint commissioning and integrated working across agencies and professions.\n\nThe committee agreed, based on their experience and expertise, that commissioners working across larger areas and across sectors could help services collaborate to meet strategic aims, cover varying and intersecting needs, share resources and enable economies of scale. This could be at the level of integrated care systems or place-based systems, with collaboration across an area's health, social care and housing partners in different sectors, as well as with prison, probation and domestic abuse services.\n\nThe committee also agreed on the importance of enabling long-term, consistent support regardless of contract lengths so that people experiencing homelessness who may need high levels of support, including long-term medical care, can progress in their recovery journey. They agreed that long-term contracts can provide stability and can support the improvement and extent of services as long as there is flexibility to adapt to changing local needs.\n\nThe committee heard from expert witnesses about the importance of supporting service providers and practitioners to exercise their legal duties and powers when working with people experiencing homelessness. The committee agreed that the current systems do not always support public bodies and practitioners to do this, for example the duty to refer based on the Homelessness Reduction Act 2017.\n\nThe committee also agreed that commissioners should define and measure outcomes related to homelessness, including health and social care outcomes and service use, to inform local and national homelessness assessments, and help improve and design relevant policies and services.\n\nEffectiveness evidence showed that peers (experts by experience) can be a useful and cost-effective way of supporting people experiencing homelessness and delivering services. Based on their knowledge and experience, the committee also agreed that peers are valuable in co-designing services. Involving peers can improve people's engagement with services, leading to better outcomes; improve the quality of services; and reduce pressure on practitioners, as well as having benefits to the peers themselves.\n\nThe committee agreed that the particular needs of specific population groups need to be considered. For example, women may have different needs and vulnerabilities compared with men, and young people compared with older people. People with limited or no recourse to public funds have particular disadvantages and risks for poor outcomes because of barriers to accessing care and support. Specialised support for the particular needs of LGBT+ people, disabled people or people with a particular family background or from a particular faith group may be helpful in reaching people and providing appropriate support. The committee agreed to give examples of groups that may need specific consideration, although they recognised the list is not exhaustive. The equality impact assessment for the guideline provides further information.\n\nThe committee discussed how the causes of homelessness are complex. Some people may experience homelessness as a result of disparities in access to or appropriateness of services because of a certain characteristic they have. People may face particular challenges because of their characteristics, such as their age, gender, disability status, family background or being a migrant, including different intersections of these, which may multiply inequalities.\n\nQualitative evidence of mixed quality from many different studies highlighted various barriers to accessing health and social care, such as transport costs and services being too far away, siloed or in multiple locations. The committee agreed that it is important for commissioners to consider ways to remove barriers to local services to improve access and engagement among people experiencing homelessness.\n\nThere was good qualitative evidence that people experiencing homelessness faced challenges registering for GP services and were sometimes refused registration if they did not have an address or ID. Being denied access to GP services can further alienate, cause distrust and prevent already marginalised people from engaging with services. The evidence also corroborated the committee's experience that when people are refused access to GP services, they turn to emergency care services.\n\nThe NHS Primary medical care policy and guidance manual outlines that everyone in England can register with a primary care provider free of charge. This includes people experiencing homelessness, people without a stable address, asylum seekers and refugees. The committee agreed that commissioners and planners need to ensure that there are processes in place to support GP registration, and document, challenge and redress refusals. There is also NHS England practical resource on improving access for all: reducing inequalities in access to general practice services.\n\nReducing caseloads for practitioners working with people experiencing homelessness would allow them to spend longer with each client. Longer contact time is likely to improve engagement with services, help build a trusted relationship and ultimately lead to improved outcomes and sustained recovery. There would also be likely benefits from improved staff satisfaction and retention, and continuity of care. The committee made a research recommendation to better understand the effectiveness and cost effectiveness of longer health and social care contacts for people experiencing homelessness and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.\n\n## How the recommendations might affect services\n\nAlthough there are legal requirements to collaborate under the Care Act 2014 and the National Health Service Act 2006, health, social care and housing services have different legislative and commissioning frameworks and the committee discussed that collaboration is sometimes challenging and the level of integration varies.\n\nServices working in silos can increase the risk of undiagnosed or misdiagnosed conditions across the mental, physical and disability spectrum, cause morbidity and mortality, and result in substantial costs to services. Commissioners and planners will need to ensure that frameworks are in place to support integrated multidisciplinary health and social care services where this is not already happening. For example, by facilitating coordinated multi-agency and multidisciplinary working, and strengthening information sharing and communication systems.\n\nImproving integrated service provision should lead to improved outcomes, more appropriate use of services, and a lower need for emergency care and hospital admissions, reducing associated costs. Services will need targeted efforts to improve outcomes and to meet the needs of people experiencing homelessness, and commissioners will need to plan for more funding per person than in mainstream services. However, this should lead to savings later on.\n\nJoint Strategic Needs Assessments are done by public health teams within local authorities, but there is some variation in the extent to which the health and social care needs of people experiencing homelessness are considered, and service users and experts by experience are involved. When done thoroughly and with all the relevant information, including relevant findings from Safeguarding Adults Reviews, it can inform targeted and efficient provision (for example, specialist service provision) and identify opportunities for more integrated services. This will also ensure that services meet local needs, and improve access and engagement. This will reduce morbidity and mortality, and reduce public sector costs associated with homelessness.\n\nMost services have ways to record data on housing status for audit purposes. This would not be a new practice, although some services might not be doing it or do not have processes flexible enough to record it in a meaningful way. Services could improve this by adjusting existing data-recording methods.\n\nCompared with current practice, commissioners may need to look across a larger footprint to develop services. This approach will also enable them to account for mobility and people experiencing homelessness not being tied to a specific place. This may mean commissioning groups coming together to form partnerships.\n\nInvolving peers in delivering care or support and co-designing services is already happening in some areas and organisations, particularly in the voluntary and charity sector. It will involve costs in terms of training and support for peers and potential incentives or remunerations; however, involving peers can reduce pressure on practitioners and therefore result in cost savings. There was evidence that it can be cost effective.\n\nAccess and engagement with services may not be straightforward in this population, so commissioners will need to ensure multiple ways of enhancing access to care. There are examples of good practice across the country, but practice is variable. Services will have to consider approaches that can be tailored to the specific needs of the person. Currently, because of the lack of flexible services, people often end up in crisis and use expensive emergency services, or do not access services, resulting in disproportionately complex morbidity and premature mortality.\n\nGP registration refusals are relatively common in current practice and commissioners and planners will need to reinforce NHS guidance and support GP practices to ensure that people experiencing homelessness can access GP services.\n\nFinally, economic analysis carried out for the guideline suggested that reducing caseloads for practitioners who work with people experiencing homelessness could be cost effective.\n\nLower caseloads will mean that services will have to recruit more staff, which might be challenging in some areas. However, availability of trained staff should not be a barrier; for example, services may find it easier to recruit staff to junior roles and provide on-the-job training.\n\nReturn to recommendations\n\n# Models of multidisciplinary service provision\n\nRecommendations 1.3.1 to 1.3.10\n\n## Why the committee made the recommendations\n\nThe committee discussed that people experiencing homelessness often have overlapping and intersecting care needs, which need the expertise and skills of different professionals to assess, plan and manage care jointly. They may also have needs and challenges that are not typical to the general population, so the committee recognised the value of practitioners with specialist knowledge on homelessness issues.\n\nGood qualitative evidence from various studies described health and care systems as siloed, complex and fragmented, with little coordination between agencies and providers. There was also evidence from qualitative studies that people experiencing homelessness want more individualised care that meets their needs, and hope to develop trusting relationships with service providers.\n\nThere was limited effectiveness evidence available on multidisciplinary team approaches to health and social care support for people experiencing homelessness. There was evidence on the Housing First approach, mainly from Canada, involving intense case management or assertive community treatment by a multidisciplinary team for people with moderate to severe mental health problems experiencing homelessness. This showed a positive impact on housing status and tenancy sustainment. There was also some economic evidence showing that having multidisciplinary homelessness teams resulted in some cost savings and improved outcomes for people experiencing homelessness. Furthermore, the committee heard from experts who emphasised the importance of integrated and collaborative working, and a multidisciplinary approach with clear roles and responsibilities and effective communication and information sharing.\n\nBased on the evidence and their own experience, the committee agreed that the best way to provide health and social care to people experiencing homelessness would be through specialist homelessness multidisciplinary teams. A combination of expertise from a variety of disciplines and agencies would enable holistic and individualised care based on the person's needs.\n\nThe committee discussed that a successful joined-up care approach, providing holistic wraparound support based on individual needs would integrate service providers from a range of health and social care settings.\n\nThe committee discussed the various experts who could form the multidisciplinary team. The qualitative evidence highlighted that people experiencing homelessness value support from peers who have similar experiences and can be role models in their recovery journey. Some qualitative evidence also reported the benefits of involving people with lived experience of homelessness in shaping and providing care. The committee agreed that experts by experience can bring an important service-user point of view to a multidisciplinary team to help better meet the needs of people experiencing homelessness. The committee discussed that other members of the multidisciplinary team could be an array of different professionals and practitioners spanning different agencies and disciplines, including healthcare, social work, housing, and the voluntary and charity sector. They discussed that voluntary and charity organisation staff often have the closest relationships to the client. The committee were aware that the characteristics of people experiencing homelessness vary across different areas and agreed that it is important to use the local needs assessment to tailor the composition of the team to local needs.\n\nThe committee discussed that multidisciplinary teams can provide person-centred, tailored support with personalised case management by a designated person working within the multidisciplinary team, which can improve continuity of care and help build trusted relationships with service providers that could improve engagement with services and long-term outcomes. Multidisciplinary teams can coordinate care based on the person's needs by providing care themselves or signposting to other services. Having a dedicated team with specialist knowledge can help streamline support and make it more efficient, avoid duplication of work and inappropriate referrals, and improve staff motivation. The committee were confident that there would be benefits for the person being supported, the team members and services in general.\n\nThe committee also discussed that the specialist multidisciplinary teams could bring value and expertise in working with other 'inclusion health' groups (groups of people who are traditionally socially excluded) who may be at risk of homelessness and whose needs often overlap considerably with people experiencing homelessness.\n\nHomelessness multidisciplinary teams have a comprehensive understanding of the needs and service use of people experiencing homelessness, so the committee agreed that these teams make a crucial contribution to assessing local needs, improving quality of services, and reviewing complex cases including Safeguarding Adults Reviews.\n\nThe committee discussed that working with people experiencing homelessness can be challenging and can have a psychological impact on those providing care. They agreed that homelessness multidisciplinary teams should be given time, in a protected space, to reflect on their practice and experiences to promote continuous learning and professional wellbeing.\n\nThe committee also recognised that specialist homelessness multidisciplinary teams would not be feasible in areas where levels of homelessness are low. For example, in some areas services might encounter 1\xa0person experiencing homelessness per month. In areas where forming a homelessness multidisciplinary team is not justified, the committee agreed that existing practitioners could act as homelessness leads in mainstream services, for example, in general practice, A&E departments, hospitals, drug and alcohol treatment services, mental health services, palliative care services, sexual assault referral centres, maternity care, disability services and adult and child social services. The homelessness leads would champion, coordinate, advise and collaborate with colleagues and professionals within and across services to enable appropriate provision of care and support for people experiencing homelessness. Partnering with homelessness multidisciplinary teams in nearby areas for advice could further improve care and support for people experiencing homelessness in these areas.\n\n## How the recommendations might affect services\n\nModels of service provision vary in current practice. In some areas with high rates of homelessness, there are no specialist homelessness multidisciplinary teams, or services are often focused on a single aspect of care or are mainly medically led; for example, mental health teams, drug and alcohol treatment services, community-based or hospital-based multidisciplinary teams, or housing-related multidisciplinary teams. Many multidisciplinary teams do not cover the wide range of support that is needed. Services will need to involve practitioners from across multiple agencies to make sure that the team has relevant expertise.\n\nRecommendations on multidisciplinary teams may mean a change in service configuration. However, there may not be a need to employ new staff but to reorganise, collaborate with other agencies and form a team from existing professionals. Forming a multidisciplinary team may entail pulling together a team from different services working with a person experiencing homelessness. Alternatively, it may involve having a permanent integrated multidisciplinary team under single management within a service (that is, a coexisting co-located team), which would represent a more substantial change.\n\nIn areas with low rates of homelessness, having designated leads on homelessness may be a change in practice, but it is unlikely to have a significant resource impact because these are not expected to be entirely new job roles. These arrangements will be different across the country, and will depend on the demand and the level of need.\n\nThere is economic evidence that homelessness multidisciplinary teams represent value for money and are potentially cost saving. Having specialist multidisciplinary teams or designated leads should mean better integration and efficiency of services, more streamlined and personalised care and improved engagement with care and support, which in turn should lead to reduced morbidity, mortality and associated costs. There will likely be a reduction in wider public sector costs, including local authority homelessness services and the criminal justice system costs, because people will be more likely to progress in their recovery journey and maintain their accommodation. Such a service model can also mean better management of resources, for example, a reduction in inappropriate referrals, inappropriate use of hospital beds, and duplication of effort.\n\nReturn to recommendations\n\n# The role of peers\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nThere was some effectiveness evidence that suggested that peer support to navigate hepatitis\xa0C screening and services might help people to engage with services, and this was found to be cost effective. Other effectiveness studies also suggested that peers could increase uptake of tuberculosis screening and hepatitis vaccination to the same degree as professional staff. Although there were some concerns about the quality of the evidence on peer approaches, the committee were confident, based on their experience, that involving peers in delivering care or support and co‑designing services is efficient and beneficial, not only for the services and the people experiencing homelessness but also for the peers themselves. They also heard from expert witnesses who highlighted the value of involving people with lived experience in the development of policies, procedures and protocols.\n\nThe qualitative evidence also highlighted that people experiencing homelessness value support from peers who have similar experiences and have recovered and grown from that experience. The committee highlighted their experience and knowledge of the beneficial impact of being a peer, describing how peers can progress to become professionals if supported.\n\nBased on the evidence and their expertise, the committee agreed to list ways in which peers may be able to support people experiencing homelessness and how peers can improve services. Peers can take up different roles in terms of intensity, responsibility and tasks, and may gradually progress in these roles. The committee emphasised that it is important to support peers with adequate supervision and governance structures, including confidentiality and data protection. Training needs of peers might include, for example, first aid and mental health first aid, safeguarding, trauma-informed care, advocacy and risk management.\n\nQualitative evidence highlighted the obstacles and challenges that peers might encounter, including supporting someone with similar issues to their own while trying to maintain their own recovery. The committee agreed that peers should be supported to continue their own recovery journey and development by encouraging them to progress to become professionally employed, which is beneficial in many ways for the person acting as peer support, the people they are supporting, and services.\n\nThe committee also discussed that it is important to consider how to match the peers with people they support. For example, some people may prefer or request peer support from someone with the same cultural or language background, but sometimes this may be a reason for a person to refuse peer support because of the risk of stigma or confidentiality breech.\n\n## How the recommendations might affect services\n\nThere are existing peer networks, for example, for people recovering from drug or alcohol dependency issues. There are also peers working with people experiencing homelessness in some areas and in some organisations, in the voluntary and charity sector in particular. But the committee agreed that there is the potential to involve more experts by experience in service design and delivery. Peer support has the potential to improve access to and engagement with services, and reduce morbidity and mortality, and associated public sector homelessness costs. There may also be important benefits to peers themselves, leading to better long-term outcomes.\n\nPeers could be recruited through homelessness services or in collaboration with voluntary and charity sector organisations and housing associations. Services will also need to provide support and training for peers as well as incentives or remuneration. Involving peers can reduce pressure on practitioners and can result in cost savings. Organisations may need to adjust their recruitment practices and policies to lower barriers to the employment of peers.\n\nReturn to recommendations\n\n# Supporting access to and engagement with services\n\nRecommendations 1.5.1 to 1.5.12\n\n## Why the committee made the recommendations\n\nPeople experiencing homelessness are often unable to access health and social care because of barriers at systemic, local and individual levels. Various themes from mixed qualitative evidence highlighted examples, such as strict eligibility criteria, rigidity of appointment systems, limited opening times, short appointments, long waiting lists, siloed services in multiple locations, cost of transport and experiences of stigma and discrimination. The committee also drew on their own knowledge and experience of these barriers to access.\n\nThe committee agreed that an outreach model, in which the services go to the people instead of expecting people to come to them, is a helpful established approach to reaching people who do not access services. There is limited effectiveness evidence on outreach models, although evidence on a London-based outreach service to screen vulnerable people for hepatitis\xa0C and offer peer support for getting treatment in secondary care was shown to be cost effective. Moderate-quality evidence from qualitative studies suggested various benefits of outreach services, including increased access to immediate care and increased knowledge of health issues, available services, and healthcare entitlements. The evidence also highlighted that outreach services can be more flexible than traditional healthcare services and that bringing services to people builds a feeling of trust and connection with service providers while reducing the sense of isolation. The committee considered outreach services important to identify people who might otherwise be missed. They had confidence in the evidence and agreed that it corresponded with their experience.\n\nThere was good but limited effectiveness evidence that community drop-in services are helpful in reaching people and are preferred by service users. There was also good qualitative evidence that services are often complex, fragmented and difficult to navigate. The committee agreed that providing information and support to navigate care and services can improve people's access to and engagement with health and social care. Based on their knowledge and experience, the committee suggested approaches that could improve access and engagement. For example, low-threshold services that avoid restrictive eligibility criteria and make minimal demands on the client by offering support and care without trying to influence their habits; providing food, vouchers, transport support, internet access or other practical help can incentivise and enable people to engage with care; and providing psychologically informed environments and trauma-informed care can improve engagement with people who often have underlying negative and traumatic experiences.\n\nThe rigidity of appointment systems can lead to people being dropped from services if they miss appointments. There was some limited qualitative evidence illustrating the difficulties people experiencing homelessness face when they miss appointments. Some services have policies that prevent people accessing care at that service again or financial penalties for missing appointments. Based on the committee's experience, this is a major problem for many people experiencing homelessness and they agreed that services should show flexibility and understanding to facilitate engagement. The committee discussed the clear association between missed appointments and premature death and agreed that providing more flexible appointment systems and alternative ways of accessing care is therefore essential in improving outcomes.\n\nHigh-quality evidence from qualitative studies highlighted that strict eligibility criteria to access healthcare services sometimes forced people into crisis situations before help could be provided, or excluded them from accessing services altogether. Based on the committee's expertise, this is particularly prevalent among people with coexisting mental health problems and drug or alcohol treatment needs, which are common among people experiencing homelessness. Sometimes, people with coexisting mental health problems and learning disability can be excluded from accessing the respective services.\n\nSome services, particularly in social care, may have minimum age criteria that can stop people getting the support they need. Premature aging and frailty, defined by the British Geriatrics Society, the Royal College of General Practitioner, and Age UK as 'a distinctive health state related to the ageing process in which multiple body systems gradually lose their in-built reserves', are common among people experiencing homelessness with severe and multiple disadvantage, so care and support should be based on assessed need, not biological age. Flexibility in the eligibility criteria could prevent the situation from escalating and help people to receive support earlier, leading to better outcomes.\n\nGood qualitative evidence highlighted that some people are unaware of the free or low-cost services available to them, particularly dental care, if relevant paperwork has been processed. The committee discussed their experience that often these forms that enable free access to essential services such as eye care, prescription costs and dental care (such as HC1 and HC2) are not readily available, or are only available electronically. The forms can be challenging to fill in and only available in English.\n\nThe committee considered digital exclusion to be a major barrier to accessing health and social care. Qualitative evidence showed that people without access to the internet and those without a phone experienced difficulties in accessing healthcare.\n\nThe NHS Primary medical care policy and guidance manual states that everyone in England can register with a primary care provider free of charge. This includes people experiencing homelessness, people without a stable address, asylum seekers and refugees. However, according to good qualitative evidence and the committee's experience, many people experiencing homelessness are still refused registration with a GP. Resources are available from the NHS on improving access for all: reducing inequalities in access to general practice services.\n\nThe committee were keen to highlight the legal duties of public sector workers as mandated by the Homelessness Reduction Act 2017. In particular, the duty to refer anyone who is identified as being homeless or at risk of homelessness to the local authority. They discussed that despite the legal requirement, this does not always happen in current practice because processes are not in place to do this, and frontline staff lack time and knowledge. An expert also highlighted the need for health and social services to improve legal knowledge among their staff. Guidance on duty to refer from the Department for Levelling Up, Housing & Communities and Ministry of Housing, Communities & Local Government gives an overview of the legal duty. The Department for Levelling Up, Housing and Communities' code of guidance advises local authorities on how they should exercise their homelessness functions in accordance with the Homelessness Reduction Act 2017. The committee discussed that every encounter with a person experiencing homelessness could be an opportunity for engagement with care and support. Approaches such as Making Every Contact Count and Making Every Adult Matter could be used to facilitate this and help frontline staff better understand the services available for onward referral.\n\nThe qualitative evidence highlighted that long waiting times are a barrier to accessing and engaging with health and social care, affecting people experiencing homelessness in particular. The committee agreed that people experiencing homelessness are a priority because their multiple disadvantages put them at an increased risk of deterioration and premature mortality and morbidity. They discussed that long waiting times can be particularly challenging for people experiencing homelessness and can mean that the opportunity to engage with them is missed altogether, for example, if the person moves to another area or forgets about the appointment. They also discussed that people experiencing homelessness may have particular difficulty coping psychologically with long waiting times because of the fundamental feeling of unsafety and exclusion that homelessness causes. Long waiting times could lead to further deterioration of physical and mental health, and could compound feelings of disengagement and exclusion.\n\n## How the recommendations might affect services\n\nCurrent practice is variable. For services that do not have multiple points of access to care or flexible services, these recommendations will represent a change in practice. Services will need a variety of approaches that can be tailored to specific needs. Currently, because of the lack of flexible services, people are using expensive emergency services or are not accessing services at all, resulting in excess morbidity and mortality, and associated high public sector homelessness costs. For example, inflexible appointment systems increase the risk of missing appointments, and there is a link between missed appointments and premature mortality. Missed appointments also cost the NHS millions of pounds a year; for example, missed GP appointments in the general population cost NHS England around £216\xa0million a year in addition to the disruption for staff and other patients (Missed GP appointments costing NHS millions, NHS England 2019).\n\nTransport costs are a considerable barrier to access to and engagement with services, and continuity of care. Practice is variable between different areas. People experiencing homelessness often have multiple morbidities, which could make them eligible for a free travel pass, but often do not have one because of bureaucratic challenges. Currently, a clinician (usually a doctor) needs to sign the paperwork for a free travel pass. Services could broaden the list of professionals able to approve applications, which could make free travel easier to access. The cost of providing free travel will be relatively low compared with the cost of missed appointments and the costs relating to unaddressed needs. For example, an annual bus pass in London costs approximately £900 (Transport for London bus and tram fares), but if a person with a leg ulcer misses multiple appointments, then this may lead to an infection and in some cases amputation, costing the NHS at least £8,000 (NHS England National cost collection for the NHS), in addition to the impact on the person. Services will need to work collaboratively to agree who will cover travel costs within their local system.\n\nSome mental health or drug and alcohol recovery services will need to modify their eligibility criteria. This may lead to more people accessing services. But there may also be savings from avoiding crisis situations and unplanned care and providing more efficient support, leading to better long-term outcomes.\n\nMore practitioner time may be needed to help people with forms and other paperwork. But this can help prevent deterioration and the need for more expensive care, for example, emergency care, in the future.\n\nIn recent years, there has been an increase in the use of digital approaches to providing support within the homelessness sector. To avoid this leading to digital exclusion, some services may need to improve access to online health and social care information and support. There may be some costs associated with this, but providing access to digital services and information can improve engagement with services and avoid the need for costly emergency care.\n\nA significant barrier to accessing health and care services for people experiencing homelessness is that GP practices ask for an address when registering. Recommendations on this reinforce NHS guidance and should result in more people registering with a GP and accessing services that they are eligible for and entitled to. This has the potential for substantial reductions in morbidity and mortality, and public sector costs associated with homelessness.\n\nThere is variation in the extent to which frontline staff are aware of their legal duties under the Homelessness Reduction Act 2017, including the duty to refer. Services may need to support their staff in legal literacy and to have the skills and knowledge to identify and support people experiencing homelessness. Training could be delivered in low-cost ways, such as remotely, using pre-recorded sessions, and could coincide with existing training. Both governmental and voluntary organisations have produced materials that are readily available online. The cost for this is therefore not expected to be significant and it could lead to better and more efficient care. Timely and appropriate care can avert the need for expensive crisis care and A&E visits, and reduce other public sector costs associated with homelessness.\n\nLong waiting times for appointments in current practice are a significant barrier for engagement and timely care. Situations can quickly deteriorate, or the person might disengage because their needs are not being met. Shorter waiting times for people experiencing homelessness may avoid a crisis, lower the chances of needing expensive emergency services, and prevent complex morbidity and premature death.\n\nReturn to recommendations\n\n# Outreach services\n\nRecommendations 1.5.13 to 1.5.17\n\n## Why the committee made the recommendations\n\nQualitative evidence highlighted that people experiencing homelessness often face barriers to accessing services through standard routes, and are often disengaged with health and social care. Outreach is an established way to bring services to people who may otherwise find it hard to reach them. There is limited effectiveness evidence on outreach models, although evidence on a London-based outreach service to screen vulnerable people for hepatitis\xa0C and offer peer support for getting treatment in secondary care was shown to be cost effective.\n\nModerate-quality evidence from qualitative studies suggested various benefits of outreach services, including increased access to immediate care and increased knowledge of health issues, available services, and healthcare entitlements. The evidence also highlighted that outreach services can be more flexible than traditional healthcare services and that bringing services to people builds a feeling of trust and connection with service providers while reducing the sense of isolation. The committee considered outreach services important to identify people who might otherwise be missed.\n\nBecause people experiencing homelessness have a wide range of health and social care needs, the committee agreed that outreach teams should be multidisciplinary and also equipped to respond to needs of people with different, intersecting experiences relating to, for example, gender, ethnicity and being part of the LGBT+ community. Evidence from several economic studies showed that a multidisciplinary approach in general provided value for money in relation to the homeless population. While this was not specific to outreach teams, the committee agreed that given the severe and multiple disadvantage people experiencing homelessness often face, multidisciplinary outreach teams are justified and essential for meaningful response to people's needs.\n\nGood qualitative evidence showed that some people who are resistant to support or who feel overwhelmed by it might feel more motivated if ongoing support is available, including repeated attempts to engage with the person without placing pressure on them. The committee agreed, based on their knowledge and experience, that an 'assertive outreach' approach is useful in improving engagement for those who may be reluctant to engage with services and who would benefit from a high level of support. 'Assertive outreach' is most often used for people with complex mental health needs and drug or alcohol treatment needs. This is in line with the recommendations about maintaining contact with services in the NICE guideline on coexisting severe mental illness and substance misuse. The committee agreed that this approach could also be considered for other people experiencing homelessness who are likely to benefit from health and social care but who are disengaged, for example, because of lack of trust or previous negative experiences.\n\n## How the recommendations might affect services\n\nOutreach is used in current practice in many areas to deliver a range of services, including primary care, mental health, opiate prescribing, and testing for chronic or infectious diseases such as hepatitis and tuberculosis, although the services provided through outreach vary depending on location. Outreach can happen in multiple settings, such as streets, parks, hostels, day centres or soup kitchens. Services generally understand its value in enabling access and engagement with health and social care, but commissioning of outreach services for people experiencing homelessness varies.\n\nAdditional resources may be needed to set up outreach in areas where it is not happening already. However, it has great potential to support this population, and improve engagement with services and long-term outcomes. It can also bring savings, for example, by avoiding missed appointments and visits to the A&E department.\n\nAssertive outreach is used in some areas in current practice, particularly when engaging with people with complex mental health needs. It takes more practitioner time and may be more expensive, but persevering with people and improving engagement among people who would benefit from support is likely to substantially improve the health and wellbeing of people who have been marginalised, and reduce morbidity and mortality, and associated public sector homelessness costs.\n\nReturn to recommendations\n\n# Assessing people's needs\n\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the recommendations\n\nThere was no evidence on the effectiveness of different approaches to improving access to services through needs assessments, so the committee used their knowledge and experience to make the recommendations.\n\nThe committee were keen to emphasise the statutory and professional duty that health and social care professionals have to identify immediate risk of harm to self or others, in line with the Care Act 2014 and the Mental Health Act 1983, and professional codes such as the Nursing and Midwifery Council Code, General Medical Council's Good medical practice and Social Work England's Professional standards. The committee were aware of case reviews and Safeguarding Adults Reviews on people experiencing homelessness showing that this risk had been missed, leading to death. This is particularly relevant in the context of homelessness because there is a significant link between homelessness and risk of abuse, neglect and violence, serious mental health problems, self-harm and self-neglect, underpinning the disproportionate rate of premature mortality in this population.\n\nThe committee agreed that a comprehensive, holistic health and social care needs assessment within the context of the individual's wider circumstances improves access to health and social care and support that matches the person's needs. They agreed that a multidisciplinary approach is needed to ensure that the full range of health and social care needs are identified, including considering risk and safeguarding issues. Collaborative working also reduces unnecessary duplication and improves communication between professionals working in different services.\n\nThe committee were concerned that assessment is commonly perceived by people experiencing homelessness as a process of exclusion. People often have to keep repeating their stories and the assessments can turn into an assessment of eligibility for support rather than a person-centred attempt to understand a person's needs and circumstances. The committee agreed that involving the person in their own assessment process and involving a peer or an advocate could help improve the assessment process. Peers and advocates (who may be peer advocates) can play an important role in bridging the gap between the person experiencing homelessness and professionals. They can make the assessment process feel less formal and therefore more acceptable or accessible to people experiencing homelessness.\n\nThe committee were aware that hospital admissions related to homelessness have been increasing. They agreed, based on their knowledge and experience, that hospital admissions are an opportunity for a comprehensive and holistic assessment of a person's needs to enable appropriate personalised care planning that integrates health, social care and housing needs. A hospital stay can be an opportunity to start addressing the often complex and underlying issues that have led people to their situation.\n\nThe committee agreed that a comprehensive understanding of the person's physical, mental and social care needs as well as the underlying circumstances of their situation will help when conducting the statutory care and support needs assessment under the Care Act 2014, which sets out local authorities' duties to assess people's needs and their eligibility for publicly funded care and support. The committee noted that the recommendations on care and support needs assessment and care planning in NICE's guideline on people's experience in adult social care services provides advice on conducting the care and support needs assessment under the Care Act.\n\nThe committee were also aware that some people may be entitled to an independent advocate under certain circumstances. For example, the Care Act 2014 mandates that local authorities must appoint an independent advocate to support and represent a person in the local authority-led care, and support needs assessment or safeguarding enquiry if the person has substantial difficulty in being involved in the process, and if they do not have an appropriate person to support them.\n\nThe committee pointed out that after the person's needs are established and support planned to meet these needs, many people experience difficulties with ongoing support. Because the needs assessment process can be challenging, the committee agreed that the person's support needs should be reviewed as needed, when their situation changes or if they request it, but not based on standard review periods.\n\n## How the recommendations might affect services\n\nIdentifying immediate risk of harm to self or others reinforces a statutory and professional duty, and does not represent a change in practice.\n\nA comprehensive assessment of health and social care and support needs involves a multidisciplinary approach, can be time-consuming and needs collaboration between professionals from different agencies. This should be happening across all services. However, practice is variable and these recommendations may represent a change in practice and result in a resource impact for some services.\n\nHospital admissions are good opportunities to provide a comprehensive and holistic assessment of safeguarding, physical and mental health, drug and alcohol treatment needs, and social care needs for people experiencing homelessness. This does not often happen in current practice and the committee thought that this was a missed opportunity to assess the person's comprehensive needs and start integrated care. The recommendations in this area may mean that services will need to plan for more tests, procedures and practitioner time. This could prolong a hospital stay, although discharge to the community would likely be safer and future admissions could be avoided. Such a proactive approach could have benefits in the long term, such as preventing people from getting into crisis because of unidentified needs, and reducing morbidity and mortality, and associated homelessness costs.\n\nAs a result of the recommendations, more people experiencing homelessness who may benefit from high levels of support may have an assessment of social care needs and go on to engage with services. But an appropriate assessment of the health and social care needs of some of the most marginalised people in society will ensure timely and appropriate care and support for them, with a potential for reduced morbidity, mortality and associated public sector costs.\n\nReturn to recommendations\n\n# Intermediate care\n\nRecommendation 1.7.1\n\n## Why the committee made the recommendation\n\nIntermediate care is a multidisciplinary service that helps people to be as independent as possible and provides support and rehabilitation to people at risk of hospital admission or who have been in hospital. Evidence from several economic studies suggested that it is cost effective and potentially cost saving. The committee agreed that providing such services would help avoid hospital admissions and ensure safe and timely discharge from hospital and transition to the community. Intermediate care can also prevent or shorten expensive inpatient care and provide appropriate care and support to people in need of more intense support than otherwise provided in the community.\n\n## How the recommendation might affect services\n\nIntermediate care, including step-down and step-up care, would represent a change in practice because this service is currently rare for people experiencing homelessness. This would need some funding but there is evidence that intermediate care represents value for money. Furthermore, considering the immense human and societal costs of homelessness, providing care that can support recovery and prevent repeat homelessness is likely to be beneficial to society overall. Intermediate care can be delivered in the community, such as in suitable hostels, or in designated facilities.\n\nReturn to recommendation\n\n# Transitions between different settings\n\nRecommendations 1.8.1 to 1.8.4\n\n## Why the committee made the recommendations\n\nThe committee discussed that people experiencing homelessness can be vulnerable during transition periods. However, testimony by expert witnesses also highlighted that these can also be opportunities for engagement and intervention. The committee agreed that transition periods can be a chance to build foundations for lasting support in the community.\n\nThe committee noted that a phased, focused and person-centred approach to transitions is currently unusual. Often the person is discharged or moves between services, settings or areas without thorough planning, follow up or coordination. For example, sometimes the person's homeless status and related needs are identified only at the point of discharge from hospital into the community. Identifying needs and collaboration between professionals and agencies is therefore essential.\n\nEffectiveness evidence comparing 'critical time intervention' (time-limited intensive support during a transition period) with usual care among people experiencing homelessness, including discharge from psychiatric inpatient care and moving from a homeless shelter to the community, showed benefits in terms of mental health service use, housing status and reduced psychiatric re-hospitalisation, although no difference in quality of life was reported. Despite some methodological limitations and mixed results in the evidence, the committee agreed that the general approach and key principles of critical time intervention should form the basis of recommendations on support for key transitions. This is because any transition between settings can be challenging, with a risk of people falling through the gaps, but with appropriate support, it can also be an opportunity for improved engagement and recovery.\n\nThe 'critical time intervention' model includes establishing a trusting and enduring relationship, and a gradual decrease in the intensity of support over a fixed period of time. The time period in the studies was 9\xa0months, but the committee agreed that the length of time needed for intense support during transition would depend on the circumstances and needs of the person. The committee agreed that, to make successful transitions, it is fundamental to start support before the move and continue it during and after transition. This needs an effective and coordinated handover across teams and practitioners. Good qualitative evidence highlighted that staff from all types of services recognised that most care is provided in silos with minimal coordination between agencies and providers. The findings emphasised the need for a more coordinated approach with appropriate information sharing. Good-quality evidence from qualitative studies also emphasised the importance of information sharing between practitioners so that people do not have to repeatedly give the same information. A trusting relationship is also more likely when support is from a single person throughout, or a coordinated team, reducing the need to repeat life stories and any associated trauma. Critical time interventions are seen as a holistic approach to support. The committee wished to reflect this, emphasising the need to link people with other services and the wider community, according to their needs and preferences.\n\nIrregular discharge (self-discharge against medical advice) represents a missed opportunity for services to engage with a person experiencing homelessness and to start integrated care. A common cause of self-discharge is when people experiencing homelessness have a history of problem opioid use and do not have access to the right dose of methadone according to their treatment plan in the community, so they self-discharge to address their withdrawal symptoms.\n\nFor some people with drug and alcohol treatment needs, a hospital admission is an opportunity to detox. If people experiencing homelessness return to the streets without appropriate support after detox, they have an increased risk of overdose and a risk that any care plans will fail. It is important that there are procedures to minimise self-discharges and prevent discharges to the street so that risks can be reduced, and discharges are as safe as possible. Reviewing incidents of self-discharge or discharge to the street can improve procedures and care in the future. The Department of Health and Social Care's Hospital discharge and community support: policy and operating model refers to the King's College London's support tool and briefing notes on transforming out-of-hospital care for people who are homeless, which outlines how safe and timely transfers of care can be delivered.\n\nThe committee also highlighted other NICE guidelines that cover important transition periods that may be applicable to people experiencing homelessness.\n\n## How the recommendations might affect services\n\nThere is wide variation in the support provided during transitions between settings. The recommendations should increase sustained support and lead to a more coordinated response to needs. This in turn could lead to reduced re-attendance after leaving hospital or breakdown of tenancy, and reduced morbidity and mortality.\n\nProcedures to review cases when a person experiencing homelessness has self-discharged or has been discharged to the street may be a change in practice for some hospitals. But, by learning from these situations and improving practice, there would be an opportunity to prevent irregular discharge in the future and improve outcomes for patients. Having a dedicated homelessness multidisciplinary team or designated homelessness lead working with the discharge team can help strengthen links to community services where people get methadone to ensure they continue to receive the right dose in hospitals. Enhanced connections with social services and local authorities will help link people experiencing homelessness to the right support. This may need additional resources, but reductions in morbidity, mortality and associated costs should offset additional costs in the long run. There was evidence that effective hospital discharge represents value for money.\n\nReturn to recommendations\n\n# Housing with health and social care support\n\nRecommendations 1.9.1 to 1.9.5\n\n## Why the committee made the recommendations\n\nAccess to suitable accommodation is a key determinant of health and social care outcomes. The committee discussed, based on their knowledge and experience, that there are various aspects of accommodation that can either hinder or help a person's recovery process and their engagement with health and social care. These might include practical and logistical considerations, such as the distance to health or social care services, accessibility, aids, and appropriate storage for medication.\n\nThere was good effectiveness evidence from the Housing First trials that people are more likely to stay housed if their accommodation has wraparound health and social care support. There was also evidence that this approach could be cost effective. The committee's experience of health and social care services designed to support housing was positive, and tenancy sustainment was commonly achieved through this wraparound approach. The committee agreed, based on their knowledge and experience, that the level of support depends on the person's needs, with some people needing specialist onsite support. These could be people with high levels of need or severe and multiple disadvantage who are vulnerable to abuse and exploitation, young people who have no experience of independent living, people who have experienced domestic abuse, or people with particular care needs who need support in everyday life because of premature aging, acquired brain injury or disability.\n\nThe committee discussed the lack of evidence on how to improve needs-based wraparound support for people with severe and multiple disadvantage and premature frailty, particularly those who have experience of rough sleeping. The committee made a research recommendation on the structural and systems factors in health and social care that could help or hinder commissioning and delivery of wraparound support integrated with housing and they agreed that research in this area should consider inequalities and collect data that enable the impact on different groups to be studied. The equality impact assessment provides further information on equalities considerations for this guideline.\n\nMoving into independent accommodation may seem like a positive transition, but based on the committee's experience, this can be one of the most difficult times for people who may have a history of traumatic experiences, have severe and multiple disadvantage, feel profoundly unsafe or have low self-confidence. Such a transition often causes the person to reflect on what has happened to them, which can be triggering and cause re-experiencing of trauma. It can lead to relapses in recovery, including problems with drug or alcohol use. Furthermore, people living in temporary accommodation or on the streets can form bonds with their peers that provide mutual support and a sense of belonging. This may be replaced by a feeling of isolation and loneliness when moving into independent accommodation. Effectiveness evidence on 'critical time interventions' showed that time-limited intense support, gradually lowered over time during transition periods, did not sustain all benefits over time, so the committee agreed that emotional and practical support should be provided for as long as is needed in this situation.\n\nThe committee also agreed that an assessment of the risks that could jeopardise the person's recovery, alongside recognition of their strengths, can help recovery, inform appropriate support needs and help people to stay in housing.\n\n## How the recommendations might affect services\n\nThere is variation in current availability and provision of health and social care support associated with housing. The recommendations aim to reduce variation in practice.\n\nThe Housing First model has been used in England to some extent and there is evidence that it represents value for money, but the associated wraparound support is variable and sometimes lacking. To provide wraparound care and support, better collaboration is needed between housing, health and social care services. Services may need to reorganise existing resources, including improving communication between agencies and services and allowing more practitioner time.\n\nLocal authorities should already have a range of housing options for differing support needs, although in some areas, accommodation with onsite support might be limited.\n\nAdditional costs of providing wraparound support with accommodation, according to needs, are likely to be offset by improved health and social care engagement and outcomes, sustained tenancy, reduced use of expensive emergency services and a reduced return to homelessness and associated costs.\n\nRisk assessment at the start of residency is a low-cost intervention that can potentially mitigate significant harmful outcomes.\n\nReturn to recommendations\n\n# Safeguarding\n\nRecommendations 1.10.1 to 1.10.7\n\n## Why the committee made the recommendations\n\nNo effectiveness evidence was identified on the role of adult social work, and safeguarding in particular, in an integrated response to the needs of people experiencing homelessness. The recommendations on safeguarding are based on testimony by experts who were invited by the committee to speak about the role of social work and adult safeguarding.\n\nThe experts highlighted the importance of understanding the person's backstory and historical context that led to the current situation, recognising the link between homelessness and self-neglect, the impact of trauma and how risk-taking can be a coping strategy. Because of the value of having a trusting relationship with the person experiencing homelessness, the experts emphasised the importance of having a single key person as a safeguarding lead in an integrated service model.\n\nSection 42 of the Care Act 2014 requires local authorities to make a safeguarding enquiry if an adult with care and support needs is experiencing or at risk of abuse or neglect. The committee agreed that a social worker within a homelessness multidisciplinary team would often be best placed to lead on these enquiries for people experiencing homelessness because of their professional expertise on the assessment and related legal duties and powers.\n\nThe experts suggested that safeguarding issues related to homeless populations have historically not been widely considered by Safeguarding Adults Boards. The committee agreed that having a homelessness lead in the Safeguarding Adults Boards could enhance learning and improve practice. The committee also agreed that Safeguarding Adults Boards have an important role in promoting understanding and best practice within local agencies related to safeguarding people experiencing homelessness, including through their statutory strategic plan and annual report and learning from Safeguarding Adults Reviews. By analysing and interrogating safeguarding notifications related to homelessness, the Safeguarding Adults Boards can also enhance their understanding of the appropriateness of local safeguarding arrangements.\n\nFinally, the experts highlighted the need for health and social care staff to understand the legal duties and powers related to safeguarding people experiencing homelessness, so that their welfare could be protected, concerns could be identified and addressed early, and harm mitigated.\n\n## How the recommendations might affect services\n\nThere are legal duties for safeguarding under the Care Act 2014 and the recommendations in this area only highlight the existing safeguarding responsibilities of service managers and local authorities. Teams involved in active safeguarding cases should already have legal literacy around safeguarding relevant legislation and the intersection of homelessness and multiple disadvantages, but may need more training.\n\nCurrently, based on the committee's experience, people experiencing homelessness often fall through the gaps, and safeguarding concerns are not identified and safeguarding notifications are not made. There may be a resource impact for services with practices that are sub-optimal and not aligned with legislation. Safeguarding will ensure that appropriate support plans are in place to manage the risks identified. For example, a person might be supported to move to more suitable accommodation.\n\nReturn to recommendations\n\n# Long-term support\n\nRecommendations 1.11.1 to 1.11.6\n\n## Why the committee made the recommendations\n\nPeople experiencing homelessness often need support due to severe and multiple disadvantage, including intersecting physical and mental health needs, psychological trauma, drug and alcohol treatment needs, and social care needs. The committee agreed that sustained effort and commitment from services is needed to support their recovery journey, which may often be non-linear.\n\nGood-quality evidence from qualitative studies showed that people experiencing homelessness often experience a lack of consistency and continuity from health and social care services. There was also good qualitative evidence that ongoing, sustained support, and a service provider's patience and continued attempts to offer support, can improve the person's engagement when they might otherwise be resistant to support. Conversely, discontinuity or interruption of care could lead to disengagement with services.\n\nThere was plenty of good-quality evidence from qualitative studies emphasising the importance of a trusting and respectful relationship between the person experiencing homelessness and the person supporting them. The evidence showed that continuity of care enabled people to form a relationship with their care provider. The committee agreed, based on their experience, that a trusting relationship is rarely built through a short-term contact but usually needs consistent and sustained contact from 1\xa0main lead or a small team of people who are part of integrated services across agencies.\n\nGood qualitative evidence suggested that people experiencing homelessness often prioritise their immediate needs over receiving care. The committee discussed that addressing immediate needs can be an opportunity to build long-term engagement with services.\n\nFrom their knowledge and experience, the committee were aware that people experiencing homelessness did not always follow a linear recovery journey and can encounter a relapse or crisis. Therefore, the committee thought it was important that services were flexible in allowing people to easily re-engage with services so that their situation would not escalate or deteriorate further.\n\nPremature ageing and frailty is common in people experiencing severe and multiple disadvantage and homelessness, and the committee discussed that improvements in their wellbeing can be made if long-term care and support plans take this into account.\n\nThe committee also recognised that not all people will recover and risk of premature death is higher in people experiencing homelessness compared with the general population. Palliative care has often not been available for people experiencing homelessness and those who are approaching the end of their lives may remain in for example hostel accommodation without provision of appropriate end of life care that supports the person's preferences.\n\n## How the recommendations might affect services\n\nThe recovery journey for some people can take a long time, and services need to be persistent, invest in building trust, and recognise that the process will often not be linear. Currently, long-term continued support is quite rare, and funding of services is often not aligned with such an approach. For example, tenancy sustainment teams are often underfunded and only offer time-limited support of varying quality. Offering long-term support could cost more because it may, for example, need lower caseloads, although for many people, the intensity and frequency of support will likely lessen over time. But the value of investing in systems that facilitate longer-term support and sustained care and engagement is likely to outweigh additional costs through, for example, reduced homelessness and morbidity and mortality, and associated public sector costs. Investing in longer-term support will likely help prevent people from returning to homelessness and needing more acute support. Services may need more capacity initially, but longer-term provision of timely help can stabilise people and prevent a crisis, which will be more detrimental for the person and more costly to services.\n\nCurrently, people experiencing homelessness have limited access to palliative care services. This should be improved with the introduction of homelessness multidisciplinary teams, coordinated care and improved access to specialist services, including palliative care. Palliative care services already exist, and should become more accessible to people experiencing homelessness.\n\nReturn to recommendations\n\n# Staff support and development\n\nRecommendations 1.12.1 to 1.12.3\n\n## Why the committee made the recommendations\n\nGood qualitative evidence showed that healthcare professionals felt ill-equipped and had insufficient knowledge of social determinants of health and homelessness, and the associated health needs for complicated health problems such as addiction and mental health problems. The evidence also showed that people experiencing homelessness felt that service providers did not understand the practicalities of being homeless and their specific needs. The committee discussed that further training and support was needed to strengthen the capacity of health and social care providers to address people's severe and multiple disadvantage and diverse needs.\n\nThe qualitative evidence also showed that training would raise awareness and improve provider knowledge in this area, and improve sensitivity and understanding for this population, so that care providers overcome preconceived ideas and judgemental behaviour. Good qualitative evidence showed that most people experiencing homelessness reported experience of discrimination on some level, with many recounting some form of prejudiced behaviour from service providers. The committee discussed that health and care providers should be trained to consider people's preferences rather than making assumptions about their needs and care solely based on their behaviour or appearance, for example. Furthermore, the committee discussed the importance of practitioners understanding and responding to the intersectionality of multiple disadvantages that people experiencing homelessness may face because of their characteristics.\n\nLimited evidence from qualitative studies among service providers also showed that some lack awareness of the impact that trauma has on a young person's life and how it may manifest in their behaviour. The evidence suggested that providers who do not operate from a trauma-informed care approach may inadvertently serve as a barrier.\n\nExperts also highlighted the importance of health and social care professionals' legal literacy and understanding of their duties and powers in relation to homelessness, mental capacity and safeguarding.\n\nThe committee were aware that there are various existing training and materials that organisations could use, such as e-learning for healthcare resources on tackling homelessness, free online training modules by the Faculty for Homeless and Inclusion Health and Public Health England's guidance on homelessness: applying 'All Our Health' and further resources in Health Education England's inclusion health education mapping and review.\n\nExperts highlighted the importance of staff support and supervision, which enables reflection on experiences and practices to enable continuous learning for staff and development of both the staff and practices. The committee agreed that reflective practice and supervision can increase staff motivation and wellbeing, quality of care and services.\n\n## How the recommendations might affect services\n\nCurrently, there is variation in training opportunities for health and social care staff who encounter people experiencing homelessness. Most statutory agencies regularly train their staff, but training on some issues relevant to homelessness, such as legal duties and powers, is not common practice for all services. This extra training could be delivered alongside existing staff training programmes in a variety of low-cost ways, for example, by remotely using pre-recorded sessions, and could coincide within existing training. Because of existing training and materials, there is no expected significant resource impact.\n\nTraining to understand the needs of people experiencing homelessness may mean that more people access specialist homelessness services. Training and ongoing support will facilitate joined-up and more connected services, for example, between specialist services and mainstream services, and ensure a holistic approach and a framework of support. Improved knowledge and understanding will improve access and care for people experiencing homelessness. Practitioners will be better placed to give information about available health and social care services, and enable services to meet people's needs before their problems escalate. For example, most people could be legally housed by local authorities and councils if more professionals had a better understanding of homelessness law and guidance.\n\nThe recommendations encourage services to include these elements in their training more consistently. They can also influence the development of professional competencies for trainees and future practitioners.\n\nReturn to recommendations"}
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https://www.nice.org.uk/guidance/ng214
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This guideline covers providing integrated health and social care services for people experiencing homelessness. It aims to improve access to and engagement with health and social care, and ensure care is coordinated across different services.
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39f84fba8c1a3ec30e44e7680509d10bc9e4aed0
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nice
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Dostarlimab for previously treated advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency
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Dostarlimab for previously treated advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency
Evidence-based recommendations on dostarlimab (Jemperli) for treating advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency in adults who have had platinum-based chemotherapy.
# Recommendations
Dostarlimab is recommended for use within the Cancer Drugs Fund as an option for treating advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency in adults who have had platinum-based chemotherapy. It is recommended only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect treatment with dostarlimab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There is no standard treatment for previously treated advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency. People are usually offered further chemotherapy, which has limited effectiveness, so there is an unmet need for an effective treatment for this population.
Clinical trial evidence suggests that dostarlimab increases the time until the cancer gets worse and how long people live. However, this is uncertain because the trial is ongoing and dostarlimab has not been directly compared with other treatment options. Indirect comparisons of dostarlimab with other treatments are highly uncertain because of differences between the included studies.
Dostarlimab has the potential to be cost effective, but more long-term evidence is needed to address the clinical uncertainties. So, dostarlimab cannot be recommended for routine use in the NHS.
More data from the dostarlimab trial would help address uncertainties about its clinical effectiveness. Dostarlimab is therefore recommended for use in the Cancer Drugs Fund so that more data can be collected.# Information about dostarlimab
# Marketing authorisation indication
Dostarlimab (Jemperli) is indicated as 'monotherapy for the treatment of adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer (EC) that has progressed on or following prior treatment with a platinum-containing regimen'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for dostarlimab.
# Price
The list price of dostarlimab is £5,887.33 per 500 mg vial. The company has a commercial arrangement. This makes dostarlimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition and current treatment
## Chemotherapy is standard of care for previously treated advanced or recurrent endometrial cancer with high MSI or MMR deficiency
Clinical experts explained that there are different subtypes of endometrial cancer and that endometrioid carcinoma is the most common. People with advanced or recurrent endometrial cancer who have already had platinum-based chemotherapy have an extremely poor prognosis. Advanced or recurrent endometrial cancer is also associated with a range of debilitating symptoms including deteriorating physical functioning and health-related quality of life. Around 23% of people with endometrial cancer have the subtype with high microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency biomarkers. Most people with advanced or recurrent endometrial cancer with high MSI or MMR deficiency that has progressed during or after treatment with a platinum-containing regimen will have further lines of chemotherapy. There is no standard care for second-line treatment. People usually have either paclitaxel or doxorubicin, or combination chemotherapy. A small number may have hormone therapy. The committee concluded that there is a range of different treatment options available to people after having platinum-based chemotherapy.
## People with the condition have a poor prognosis
The company evidence submission described a range of studies that showed poor prognosis for people with advanced or recurrent endometrial cancer after platinum-based chemotherapy. The clinical experts also noted recently reported results from the KEYNOTE‑775 trial that were not referred to in either the company's evidence submission or the ERG's report. This trial compared pembrolizumab plus lenvatinib with paclitaxel or doxorubicin monotherapy in people who have advanced endometrial cancer with MMR deficiency and who have had platinum-based chemotherapy. The committee heard that for people in the chemotherapy arm, median progression-free survival was 3.7 months and median overall survival was 8.6 months. The committee agreed that KEYNOTE‑775 was a useful source of comparator data for this population (see section 3.7). It concluded that people with the condition have a poor prognosis with current clinical management.
## There is high unmet need for people who have had previous treatment
The patient experts explained that existing treatments for previously treated advanced or recurrent endometrial cancer have limited effectiveness. Chemotherapy can also have considerable adverse effects that impact quality of life, including fatigue, pain, nausea, hair loss and itching. The clinical and patient experts explained that dostarlimab is associated with fewer serious adverse events than chemotherapy and would therefore offer a considerable improvement in quality of life. The patient experts emphasised that quality of life is very important to people with advanced or recurrent endometrial cancer because of their poor prognosis. Standard chemotherapy can take up to a day to be administered in hospital whereas dostarlimab takes approximately 30 minutes, which is much less burdensome for people having treatment. The patient experts noted that people with the condition would welcome more effective and targeted treatments that extend survival and improve quality of life, but also those with a lower treatment burden than standard chemotherapy. The committee agreed that the second-line treatment options provide limited survival benefit and are associated with adverse events that negatively impact quality of life. The committee concluded that people with previously treated advanced or recurrent endometrial cancer have high unmet clinical need.
# Clinical evidence
## The main clinical evidence comes from a single-arm study
Clinical-effectiveness evidence for dostarlimab came from the GARNET trial, an ongoing phase 1, open-label, single-arm, multicentre study of the efficacy and safety of dostarlimab. GARNET includes 129 people with recurrent or advanced endometrial cancer with high MSI or MMR deficiency who have progressed during or after platinum-based chemotherapy. The primary endpoints are objective response rate and duration of response. Secondary endpoints include progression-free survival, overall survival, health-related quality of life and safety. The results of GARNET are confidential and cannot be reported here. The company consider that dostarlimab shows a good objective response rate, and improves progression-free and overall survival in people who have a poor prognosis. The committee was aware that paclitaxel monotherapy is the only second-line chemotherapy treatment that has consistently shown a response rate of more than 20%, less than half the objective response rate shown by dostarlimab. However, the committee noted that this evidence was not from people with the MMR deficiency or high MSI biomarkers, that is, the subpopulation of interest. Clinical and patient experts noted that dostarlimab appears to be well tolerated and associated with a manageable adverse event profile similar to other currently licensed anti-programmed cell death ligand 1 (PD‑L1) treatments. Adverse events related to treatment were generally low grade, and discontinuation because of treatment-related adverse events was uncommon. The committee concluded that data from GARNET is very immature. It also concluded that the lack of a biomarker-matched comparator arm makes it difficult to compare dostarlimab with current treatments for this specific subpopulation of people with endometrial cancer.
## The real-world evidence subgroup from registry data is not a robust comparator for GARNET
The company's systematic literature review of comparator treatments identified some observational studies, but patient characteristics and Kaplan–Meier survival data were poorly reported in these studies. The studies were therefore not suitable for robust indirect treatment comparisons. The company identified a real-world evidence (RWE) cohort from retrospective linked patient-level health data from 2013 to 2018, available through the National Cancer Registry Analysis System (NCRAS). A subgroup of registry patients was identified as 'GARNET-like'. They had advanced or recurrent endometrial cancer that progressed after 1 platinum-based doublet chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The company considered that this subgroup matched the inclusion criteria of people in GARNET, although information on high MSI or MMR deficiency status was not available. Registry patients had a wide range of chemotherapy regimens. The company considered the RWE study to be the primary evidence to evaluate the comparative efficacy of dostarlimab. This was because of its large sample size, the close alignment to the patient characteristics in GARNET, and the real-world representation of current clinical management for this population. The ERG agreed that using the RWE is a pragmatic approach to resolving the lack of comparative data in the existing literature. However, it raised concerns about how generalisable the subgroup of people identified in the RWE as 'GARNET-like' are to people in GARNET, because:
There was no information on biomarkers in the NCRAS dataset, so it was uncertain how many of the subgroup could be expected to have endometrial cancer with high MSI or MMR deficiency.
Although people with an ECOG performance status of 2 or more were excluded from the RWE subgroup, there was no status recorded for almost half of the people included.
There were considerable differences in histology between GARNET and the RWE study. This included a much higher proportion of people with endometrioid disease in GARNET, which is associated with a more favourable prognosis than other histological subtypes.
People in GARNET had more prior lines of treatment than the RWE subgroup. This is because GARNET included people who had 1 or more previous treatments, but people in the RWE subgroup only had 1 treatment.Clinical experts explained that the differences in ECOG performance status would not cause substantial bias because they represent a relatively small difference between patient prognoses at this stage in the treatment pathway. They noted that differences in the number of lines of previous therapy was likely to be a key prognostic factor to consider when matching the 2 populations. The committee noted the ERG opinion that differences between the GARNET and RWE subgroup would cause any indirect treatment comparison to be highly uncertain. The committee agreed that the RWE represents a pragmatic approach to the problem of inadequate comparator studies. However, any indirect treatment comparisons using the RWE could not be robust. This is because of concerns over matching the 2 populations and the unknown prevalence of high MSI or MMR deficiency in the RWE subgroup. The committee also noted that there is often a discrepancy between evidence from clinical trials compared with RWE, which can have lower observed efficacy for a wide range of reasons. The clinical experts also noted that randomised trial data, when available, was considered preferable to RWE. This was particularly relevant because the trial and RWE were not matched for several factors, including MMR deficiency and MSI status. The committee concluded that evidence from the RWE subgroup was not a robust comparator for GARNET.
## The company's naive comparison suggests dostarlimab improves survival, but this is highly uncertain
The company's naive comparison with the GARNET-like subgroup from the RWE registry predicted that dostarlimab has better progression-free survival and overall survival outcomes than current care in the UK. This data is academic in confidence and cannot be reported here. The committee concluded that endometrial cancer with high MSI or MMR deficiency is more likely to respond to immunotherapy than the treatments used in current clinical management. However, the benefit of dostarlimab remained highly uncertain because of the limited follow up and lack of a comparator arm in GARNET.
## Evidence from KEYNOTE-775 is a more relevant comparator
The committee recalled that the clinical experts had described the recent reporting of KEYNOTE‑775 (see section 3.2). This trial compared pembrolizumab plus lenvatinib with paclitaxel or doxorubicin monotherapy in people who have advanced endometrial cancer with MMR deficiency and who have had platinum-based chemotherapy. The committee discussed whether the chemotherapy arm of KEYNOTE‑775 represents the most relevant comparator data for dostarlimab, because the evidence for dostarlimab came from a single-arm trial (see section 3.4). The clinical experts emphasised that the KEYNOTE‑775 population is biomarker-matched to people in the dostarlimab trial. They also emphasised that KEYNOTE‑775 is a randomised controlled trial rather than a real-world registry. It would therefore be a more reliable comparator for the dostarlimab single-arm trial. The committee agreed with the clinical experts and concluded that KEYNOTE‑775 may provide a better source of comparative data for the cost-effectiveness analyses of dostarlimab.
# Indirect treatment comparisons
## Matching-adjusted indirect treatment comparisons suggest that dostarlimab improves survival, but these are highly uncertain
To investigate the impact of any remaining differences between the 2 populations, the company also did a matching-adjusted indirect comparison (MAIC) of overall survival between GARNET and the UK RWE subgroup. The company did a targeted literature review to identify a range of prognostic variables typically associated with survival in people with endometrial cancer, which were validated by a panel of clinical experts. Cox regression models were also used to investigate the prognostic value of each potential matching variable. Based on these results, 2 MAIC scenarios were constructed:
Scenario 1, based on the prognostic variables identified by clinical expert opinion, including histology (non-endometrioid and unknown versus endometrioid) and the number of lines of prior platinum-based therapy for advanced or recurrent disease (0 or 1 versus 2 or more).
Scenario 2, based on the matching variables found to be statistically significant based on regression analyses, including ethnicity (black, other and unknown versus white), stage at diagnosis (stage 3 or 4 versus stage 1 or 2), histology (non-endometrioid and unknown versus endometrioid) and prior surgery (yes versus no).The results are marked as academic in confidence and cannot be reported here. Both matching scenarios showed that the median overall survival, as well as the percentage of people alive at months 6, 12 and 18, was greater with dostarlimab than current clinical management. The hazard ratios for overall survival showed that dostarlimab statistically significantly reduced the risk of death compared with current clinical management. The company considered that the similarity of the overall survival results between the unadjusted GARNET population and both matched scenarios showed minimal differences between the GARNET and RWE GARNET-like populations. However, the ERG considered that systematic differences remained between the 2 cohorts because of the methodological issues associated with data collection, case definition and selection. This particularly included the complicated screening processes used to identify the final RWE subgroup. The ERG noted that these systematic biases are difficult to recognise and quantify, and cannot be adjusted for by statistical methods. The committee agreed with the ERG about the limitations of the MAIC scenarios and the validity of the results. The committee also recalled its reservations about whether RWE would be an adequate proxy for a control arm of a randomised controlled trial comparing dostarlimab with conventional care in this population. The company also did a series of MAICs comparing GARNET with individual studies of some comparator chemotherapy treatments identified in the literature. This was to provide additional evidence to support the results from the primary MAICs between GARNET and the RWE study. However, the ERG cautioned that these MAICs were also severely limited because the studies had small sample sizes, and patient characteristics and prognostic variables were poorly reported. In particular, the lack of data on previous anticancer treatments was a key limitation because this is an important prognostic variable, based on clinical expert opinion. The ERG suggested that analyses from a more homogeneous subgroup, such as people with endometrioid disease, would help mitigate these concerns. The committee agreed that the company's MAICs (scenarios 1 and 2) could not be considered a robust source of evidence because of the high levels of uncertainty in matching the cohorts. The committee concluded that better data was needed to inform a robust analysis of comparative efficacy between dostarlimab and comparator treatments.
## Exploratory analysis is also uncertain, but the overall evidence suggests that dostarlimab is more effective than current care
At the technical engagement stage, the company provided an additional MAIC analysis that was based on more homogenous cohorts of people with the endometrioid subtype from GARNET and the RWE study. This was provided to explore the effect of closer population matching on the comparative efficacy of dostarlimab. The company considered the similar hazard ratios for the endometrioid-only cohorts and MAICs show only minor imbalances between the full RWE subgroup and GARNET populations. However, the ERG considered it more likely that the MAICs had not adequately adjusted for the remaining imbalances between the 2 endometrioid cohorts. While the endometrioid subgroup data mitigated one of the major differences between GARNET and RWE, the ERG noted that substantial differences in patient characteristics remained, even within this more homogeneous subgroup of patients. Key differences included ECOG performance status, International Federation of Gynaecology and Obstetrics stage, disease grade, number of prior platinum-based therapies for advanced or recurrent disease, and prior surgery for advanced or recurrent endometrial cancer. The net effect of excluding people who do not have the endometrioid subtype was a smaller estimated survival advantage for dostarlimab compared with comparator treatments. The ERG explained that while the endometrioid-only analysis may have removed histological type as a source of uncertainty, the comparisons still likely had a substantial degree of uncertainty. The MAIC for this subgroup did not adequately address these issues. Therefore, the relative effectiveness of dostarlimab estimated from the endometrioid-only subgroup is still associated with a high level of uncertainty and may be over-estimated. The committee agreed with the ERG that the endometrioid-only subgroup supplementary analysis had reduced some bias but was still highly uncertain because of remaining differences between the 2 populations (see section 3.5). The committee noted that the endometrioid-only MAIC suggested that closer matching resulted in reduced comparative efficacy of dostarlimab. It also noted that this further underlines the need for better evidence to produce more robust conclusions about the comparative effectiveness of dostarlimab. The committee concluded that dostarlimab had a biologically plausible reason for being more effective than conventional care, and the analyses presented tend to support this. However, the magnitude of any benefit remained highly uncertain because of the single-arm trial and major shortcomings in the comparator evidence.
# Economic model
## The company's model is appropriate for decision making
The company used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for endometrial cancer.
# Survival extrapolation
## There is high uncertainty in the extrapolation of overall survival because of the immaturity of trial data
The company independently fitted parametric models to dostarlimab (GARNET) and standard of care (the GARNET-like RWE cohort) in the base case cost-effectiveness analysis. It considered independent parametric models to be a more robust approach because of differences in the mechanisms of action between dostarlimab and the different chemotherapy options that are current clinical management. The company noted that treatment response to immunotherapy differs from the response to chemotherapy, including the possibility of a delayed response and longer-term treatment benefits after treatment discontinuation. The company's process for selecting the most appropriate curve for overall survival for dostarlimab was to:
explore the visual fit of parametric models by presenting them superimposed onto the Kaplan–Meier analysis
adjust the parametric model for the waning of treatment effect and so it does not exceed the overall survival of the general population
select an adjusted parametric model that best reflects and conforms to the predictions of the company's clinical expert advisory panel.The overall survival extrapolations appeared to provide a good fit to the observed Kaplan–Meier data for the duration of the data collection in the trial. The company selected the generalised gamma extrapolation for overall survival with dostarlimab beyond the trial data because it gives the most clinically plausible long-term extrapolations and is more closely aligned with the clinical expert feedback. The lognormal model was considered to give the next most clinically plausible long-term extrapolations after the generalised gamma model, and it also had the lowest sum of Akaike and Bayesian information criteria. However, the company asserted that the lognormal model is not clinically plausible. This is because when treatment waning was applied, the lognormal curve substantially underestimated the predicted numbers of people alive at 5, 10, 15 and 20 years compared with the clinical expert estimates. The ERG explained its concerns about relying on clinical experts' opinions on the expected overall survival for people having dostarlimab. It explained that the clinical predictions should probably be regarded as informed speculation because of the widely varying estimates from individual clinicians. It is possible that consulting more, or different, clinicians could result in a considerably different mean estimate. The ERG explained that it considered the company's preferred generalised gamma curve to be overly optimistic because it predicted survivors well beyond 30 years, which does not seem clinically plausible. The ERG preferred the Weibull curve because the company expert responses could be biased by the elicitation methods used, and therefore too high to assess how reasonable the adjusted curves were. The company did not accept the ERG's preference for the Weibull curve. It suggested that the shape of the hazard function produced by that model was inappropriate for the treatment effect associated with immunotherapies such as dostarlimab. But the ERG further explained that all models under consideration were associated with substantial uncertainty because of the lack of data. The visual fit of all models to the Kaplan–Meier data was relatively poor because the plot did not reach a median, exhibited several changing trajectories and had a long flat tail. The clinical experts explained that the Weibull curve preferred by the ERG appeared to be somewhat pessimistic. This is because it predicted lower overall survival than might be expected from immunotherapies in other clinical indications, which can have a prolonged treatment effect and a shallowing curve over time. Defining exactly where plateauing of the curve begins and how long it is maintained is uncertain, but this is very difficult to predict with any certainty given the limited duration of follow up in the trial. The ERG thought that longer-term overall survival was uncertain because the trial follow up was too short and there are not enough participants. It also thought that there were too few overall survival events relative to the number of participants to accurately predict future survival. The committee noted that longer follow up could partially mitigate this problem. The ERG also explained that after technical engagement, the company reconsidered its preferred treatment waning effect. Implementing this in the model substantially reduced the differences in results between the company's preferred generalised gamma model and the ERG's preferred Weibull model. But the ERG still considered that the generalised gamma was likely to be over optimistic. The ERG noted that the lognormal curve represented a middle value between the generalised gamma and the Weibull curve. But ultimately, the considerable uncertainties meant that there was not a strong case for selecting one extrapolation in preference to another. The committee noted the ERG's concerns over the relative plausibility of the models and concluded that the immaturity of the data limits selecting the most appropriate extrapolation for overall survival for dostarlimab.
# Key assumptions in the economic model
## The effect of treatment waning is uncertain, but the ERG's more conservative approach is currently preferred
The committee noted that the implementation of treatment waning in the economic model was closely related to the issue of extrapolating survival appropriately (see section 3.11). The company adjusted its implementation of treatment waning in the model after ERG feedback at technical engagement, but the ERG explained that it did not agree with this adjusted implementation. The values preferred by the company and the ERG are confidential and cannot be reported here. The ERG expressed its concern that there was little evidence to support the assumptions used by the company, particularly for the maintenance of full treatment effect for an extended duration beyond treatment discontinuation. The clinical experts explained that there is a broad clinical consensus that there is some retention of the full benefits from immunotherapy after stopping treatment. But, they noted that there is no good evidence on when waning of this benefit is likely to start. The company evidence submission referenced previous technology appraisals for other immunotherapies with the same mechanism of action as dostarlimab, such as nivolumab and pembrolizumab. In these, NICE had previously accepted a treatment effect duration of between 3 to 5 years when people stop having the immunotherapy after 2 years. However, the ERG maintained that there is no evidence to support that this will also be the case in this population. It preferred the waning of treatment effect to begin immediately at treatment discontinuation, with declining effect over a longer period of time until the chance of dying is the same between dostarlimab and current clinical management. The committee noted how the type of waning approach substantially impacts how the parametric overall survival models extrapolate survival in the economic model (see section 3.11) so recalled that this shows how choice of waning method is driving the overall survival model in the economic analysis. The committee acknowledged the high degree of uncertainty because of the lack of data to support the maintenance of full treatment effect after stopping treatment. Implementing the ERG's preferred treatment waning assumptions in the model would increase the company's corrected base case incremental cost-effectiveness ratio (ICER) from £38,363 to £43,028 per quality-adjusted life year (QALY) gained for dostarlimab compared with current clinical management. The committee concluded that the more conservative approach preferred by the ERG is favoured, given the immaturity of the data and high degree of uncertainty, although this could be mitigated with longer trial follow up.
## The percentage of people on treatment at key time points is uncertain
GARNET did not contain a stopping rule for dostarlimab. To obtain estimates of time to treatment discontinuation (TTD), the company presented a panel of clinical experts with the number remaining at risk instead of the Kaplan–Meier TTD curve. This resulted in a range of estimates for the percentage of people expected to remain on treatment at a specific timepoint in the economic model. These values and the timepoint are confidential and cannot be reported here. The ERG explained that the modelled TTD curve bears no resemblance to the numbers remaining on treatment that were presented to the experts. The ERG further explained that by presenting the number remaining at risk, data cut-off is effectively treated as a discontinuation event, and this incorrect assumption would seriously bias the presentation and experts' estimates. Unbiased overall survival and progression-free survival estimates adjusted for the TTD and treatment stopping rules would usually require consideration of the TTD and stopping rules. The ERG also questioned why the TTD and stopping rules elicitation exercise was done after the overall survival and progression-free survival elicitation exercise. The ERG suggested that while the range of TTD estimates could be considered as a likely minimum for the proportion of people remaining on treatment at that timepoint, they should not be used as averages. The ERG preferred a more conservative value that was towards the upper end of the range provided by the company's elicitation exercise. Implementing this value in the model would increase the company's corrected base case ICER for dostarlimab compared with current clinical management from £38,363 to £41,354 per QALY gained. The committee noted the ERG's view that the company TTD and stopping rules elicitation exercise was poorly constructed, and that its results are unreliable. The committee concluded that the more conservative value preferred by the ERG is appropriate given the high degree of uncertainty.
# End of life
## Dostarlimab meets the end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It recalled that KEYNOTE‑775 showed poor life expectancy for people with previously treated recurrent or advanced endometrial cancer with high MSI or MMR deficiency (see section 3.2). The committee noted that overall survival was immature in GARNET but has been modelled by the company and ERG. Both the company and ERG agree that dostarlimab appears to meet the end of life criteria for people with recurrent or advanced endometrial cancer that has progressed during or after platinum-based chemotherapy. However, the ERG cautioned that there is uncertainty around the survival estimates because GARNET's data is immature and there are many issues with comparator data and longer-term outcomes beyond 2 years. The committee concluded that dostarlimab likely meets the end of life criteria.
# Results of the cost-effectiveness analysis
## Dostarlimab is not recommended for routine use in the NHS
The committee noted that the company's base case ICER for dostarlimab compared with current clinical management increased to £38,363 per QALY when model errors identified by the ERG were corrected in the economic model. Although this ICER falls within the range that NICE considers to be cost effective for treatments at the end of life, it does not take into account the committee's preferences for amendments to the company model. Given the immaturity of GARNET data, uncertainty about long-term survival, absence of a matched trial population for current clinical management and reliance on a different real-world population, the committee agreed with the ERG's more conservative preferences. This included the ERG's modelling of both treatment waning and treatment discontinuation for dostarlimab. For extrapolation of overall survival, the committee agreed with the ERG that there is not enough evidence to prefer either the Weibull or generalised gamma curves. It also agreed that the true survival of people having dostarlimab lies within a wide range of possibilities. Using the ERG's preferred assumptions but with the company's choice of generalised gamma for overall survival for dostarlimab gave an ICER of £49,454 per QALY gained. The same assumptions with the ERG's alternative choice of the Weibull curve for overall survival for dostarlimab gave an ICER of £61,306 per QALY gained. The committee however noted that the choice of overall survival extrapolation was dependent on having confidence in the overall treatment comparison between dostarlimab and the comparator treatments. The committee agreed that the data from GARNET was too immature. It also agreed there was too much uncertainty in the MAICs to be confident about the robustness of any of the ICERs produced by the company's economic model. The committee concluded that dostarlimab could not be recommended for routine commissioning.
# Cancer Drugs Fund
## Dostarlimab is recommended for use in the Cancer Drugs Fund
Having concluded that dostarlimab could not be recommended for routine use, the committee then considered if it could be recommended for treating advanced or recurrent endometrial cancer with high MSI or MMR deficiency after platinum-based chemotherapy within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):
The company expressed an interest in dostarlimab being considered for funding through the Cancer Drugs Fund.
The committee noted that GARNET is still ongoing, with the next data cut expected in early 2022, and agreed that additional survival data is needed to reach a decision on the cost effectiveness of dostarlimab.
Clinical evidence from KEYNOTE‑775 (see section 3.2) would provide a better source comparator data for future cost-effectiveness analyses of dostarlimab. This is because it would overcome many of the problems associated with matching the GARNET and the RWE study populations that impacted the robustness of the company's indirect treatment comparisons.The committee considered that further data collection in the Cancer Drugs Fund could address some of the uncertainty in the company's estimates. It recalled that using the ERG's preferred assumptions but with the company's choice of generalised gamma for overall survival for dostarlimab gave a plausibly cost effective estimate of £49,454 per QALY gained. The committee concluded that dostarlimab met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended dostarlimab for use within the Cancer Drugs Fund as an option for people with advanced or recurrent endometrial cancer with high MSI or MMR deficiency after platinum-based chemotherapy, if the conditions in the managed access agreement are followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions as set out in section 3.12 and section 3.13, unless new evidence indicates otherwise.
# Innovation
## Some benefits of dostarlimab have not been captured in the QALY
The company considered dostarlimab to be an innovative treatment. The clinical experts agreed that this treatment represents a step change for people who have advanced or recurrent endometrial cancer with high MSI or MMR deficiency and who have few effective options after platinum-based chemotherapy. The benefits for people having treatment includes 1 factor not captured in the QALY estimate, which is the added value of a treatment that needs a shorter hospital visit than chemotherapy.
# Other factors
No equality or social value judgement issues were identified.# Recommendations for data collection
Proposals for further data collection in the Cancer Drugs Fund include further evidence on:
-verall survival
progression-free survival
time to treatment discontinuation, and
the comparative effectiveness.
|
{'Recommendations': 'Dostarlimab is recommended for use within the Cancer Drugs Fund as an option for treating advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency in adults who have had platinum-based chemotherapy. It is recommended only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect treatment with dostarlimab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for previously treated advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency. People are usually offered further chemotherapy, which has limited effectiveness, so there is an unmet need for an effective treatment for this population.\n\nClinical trial evidence suggests that dostarlimab increases the time until the cancer gets worse and how long people live. However, this is uncertain because the trial is ongoing and dostarlimab has not been directly compared with other treatment options. Indirect comparisons of dostarlimab with other treatments are highly uncertain because of differences between the included studies.\n\nDostarlimab has the potential to be cost effective, but more long-term evidence is needed to address the clinical uncertainties. So, dostarlimab cannot be recommended for routine use in the NHS.\n\nMore data from the dostarlimab trial would help address uncertainties about its clinical effectiveness. Dostarlimab is therefore recommended for use in the Cancer Drugs Fund so that more data can be collected.', 'Information about dostarlimab': "# Marketing authorisation indication\n\nDostarlimab (Jemperli) is indicated as 'monotherapy for the treatment of adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer (EC) that has progressed on or following prior treatment with a platinum-containing regimen'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for dostarlimab.\n\n# Price\n\nThe list price of dostarlimab is £5,887.33 per 500\xa0mg vial. The company has a commercial arrangement. This makes dostarlimab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition and current treatment\n\n## Chemotherapy is standard of care for previously treated advanced or recurrent endometrial cancer with high MSI or MMR deficiency\n\nClinical experts explained that there are different subtypes of endometrial cancer and that endometrioid carcinoma is the most common. People with advanced or recurrent endometrial cancer who have already had platinum-based chemotherapy have an extremely poor prognosis. Advanced or recurrent endometrial cancer is also associated with a range of debilitating symptoms including deteriorating physical functioning and health-related quality of life. Around 23% of people with endometrial cancer have the subtype with high microsatellite instability (MSI) or DNA mismatch repair (MMR) deficiency biomarkers. Most people with advanced or recurrent endometrial cancer with high MSI or MMR deficiency that has progressed during or after treatment with a platinum-containing regimen will have further lines of chemotherapy. There is no standard care for second-line treatment. People usually have either paclitaxel or doxorubicin, or combination chemotherapy. A small number may have hormone therapy. The committee concluded that there is a range of different treatment options available to people after having platinum-based chemotherapy.\n\n## People with the condition have a poor prognosis\n\nThe company evidence submission described a range of studies that showed poor prognosis for people with advanced or recurrent endometrial cancer after platinum-based chemotherapy. The clinical experts also noted recently reported results from the KEYNOTE‑775 trial that were not referred to in either the company's evidence submission or the ERG's report. This trial compared pembrolizumab plus lenvatinib with paclitaxel or doxorubicin monotherapy in people who have advanced endometrial cancer with MMR deficiency and who have had platinum-based chemotherapy. The committee heard that for people in the chemotherapy arm, median progression-free survival was 3.7\xa0months and median overall survival was 8.6\xa0months. The committee agreed that KEYNOTE‑775 was a useful source of comparator data for this population (see section\xa03.7). It concluded that people with the condition have a poor prognosis with current clinical management.\n\n## There is high unmet need for people who have had previous treatment\n\nThe patient experts explained that existing treatments for previously treated advanced or recurrent endometrial cancer have limited effectiveness. Chemotherapy can also have considerable adverse effects that impact quality of life, including fatigue, pain, nausea, hair loss and itching. The clinical and patient experts explained that dostarlimab is associated with fewer serious adverse events than chemotherapy and would therefore offer a considerable improvement in quality of life. The patient experts emphasised that quality of life is very important to people with advanced or recurrent endometrial cancer because of their poor prognosis. Standard chemotherapy can take up to a day to be administered in hospital whereas dostarlimab takes approximately 30\xa0minutes, which is much less burdensome for people having treatment. The patient experts noted that people with the condition would welcome more effective and targeted treatments that extend survival and improve quality of life, but also those with a lower treatment burden than standard chemotherapy. The committee agreed that the second-line treatment options provide limited survival benefit and are associated with adverse events that negatively impact quality of life. The committee concluded that people with previously treated advanced or recurrent endometrial cancer have high unmet clinical need.\n\n# Clinical evidence\n\n## The main clinical evidence comes from a single-arm study\n\nClinical-effectiveness evidence for dostarlimab came from the GARNET trial, an ongoing phase\xa01, open-label, single-arm, multicentre study of the efficacy and safety of dostarlimab. GARNET includes 129\xa0people with recurrent or advanced endometrial cancer with high MSI or MMR deficiency who have progressed during or after platinum-based chemotherapy. The primary endpoints are objective response rate and duration of response. Secondary endpoints include progression-free survival, overall survival, health-related quality of life and safety. The results of GARNET are confidential and cannot be reported here. The company consider that dostarlimab shows a good objective response rate, and improves progression-free and overall survival in people who have a poor prognosis. The committee was aware that paclitaxel monotherapy is the only second-line chemotherapy treatment that has consistently shown a response rate of more than 20%, less than half the objective response rate shown by dostarlimab. However, the committee noted that this evidence was not from people with the MMR deficiency or high MSI biomarkers, that is, the subpopulation of interest. Clinical and patient experts noted that dostarlimab appears to be well tolerated and associated with a manageable adverse event profile similar to other currently licensed anti-programmed cell death ligand\xa01 (PD‑L1) treatments. Adverse events related to treatment were generally low grade, and discontinuation because of treatment-related adverse events was uncommon. The committee concluded that data from GARNET is very immature. It also concluded that the lack of a biomarker-matched comparator arm makes it difficult to compare dostarlimab with current treatments for this specific subpopulation of people with endometrial cancer.\n\n## The real-world evidence subgroup from registry data is not a robust comparator for GARNET\n\nThe company's systematic literature review of comparator treatments identified some observational studies, but patient characteristics and Kaplan–Meier survival data were poorly reported in these studies. The studies were therefore not suitable for robust indirect treatment comparisons. The company identified a real-world evidence (RWE) cohort from retrospective linked patient-level health data from 2013 to 2018, available through the National Cancer Registry Analysis System (NCRAS). A subgroup of registry patients was identified as 'GARNET-like'. They had advanced or recurrent endometrial cancer that progressed after 1 platinum-based doublet chemotherapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The company considered that this subgroup matched the inclusion criteria of people in GARNET, although information on high MSI or MMR deficiency status was not available. Registry patients had a wide range of chemotherapy regimens. The company considered the RWE study to be the primary evidence to evaluate the comparative efficacy of dostarlimab. This was because of its large sample size, the close alignment to the patient characteristics in GARNET, and the real-world representation of current clinical management for this population. The ERG agreed that using the RWE is a pragmatic approach to resolving the lack of comparative data in the existing literature. However, it raised concerns about how generalisable the subgroup of people identified in the RWE as 'GARNET-like' are to people in GARNET, because:\n\nThere was no information on biomarkers in the NCRAS dataset, so it was uncertain how many of the subgroup could be expected to have endometrial cancer with high MSI or MMR deficiency.\n\nAlthough people with an ECOG performance status of 2 or more were excluded from the RWE subgroup, there was no status recorded for almost half of the people included.\n\nThere were considerable differences in histology between GARNET and the RWE study. This included a much higher proportion of people with endometrioid disease in GARNET, which is associated with a more favourable prognosis than other histological subtypes.\n\nPeople in GARNET had more prior lines of treatment than the RWE subgroup. This is because GARNET included people who had 1 or more previous treatments, but people in the RWE subgroup only had 1\xa0treatment.Clinical experts explained that the differences in ECOG performance status would not cause substantial bias because they represent a relatively small difference between patient prognoses at this stage in the treatment pathway. They noted that differences in the number of lines of previous therapy was likely to be a key prognostic factor to consider when matching the 2\xa0populations. The committee noted the ERG opinion that differences between the GARNET and RWE subgroup would cause any indirect treatment comparison to be highly uncertain. The committee agreed that the RWE represents a pragmatic approach to the problem of inadequate comparator studies. However, any indirect treatment comparisons using the RWE could not be robust. This is because of concerns over matching the 2\xa0populations and the unknown prevalence of high MSI or MMR deficiency in the RWE subgroup. The committee also noted that there is often a discrepancy between evidence from clinical trials compared with RWE, which can have lower observed efficacy for a wide range of reasons. The clinical experts also noted that randomised trial data, when available, was considered preferable to RWE. This was particularly relevant because the trial and RWE were not matched for several factors, including MMR deficiency and MSI status. The committee concluded that evidence from the RWE subgroup was not a robust comparator for GARNET.\n\n## The company's naive comparison suggests dostarlimab improves survival, but this is highly uncertain\n\nThe company's naive comparison with the GARNET-like subgroup from the RWE registry predicted that dostarlimab has better progression-free survival and overall survival outcomes than current care in the UK. This data is academic in confidence and cannot be reported here. The committee concluded that endometrial cancer with high MSI or MMR deficiency is more likely to respond to immunotherapy than the treatments used in current clinical management. However, the benefit of dostarlimab remained highly uncertain because of the limited follow up and lack of a comparator arm in GARNET.\n\n## Evidence from KEYNOTE-775 is a more relevant comparator\n\nThe committee recalled that the clinical experts had described the recent reporting of KEYNOTE‑775 (see section\xa03.2). This trial compared pembrolizumab plus lenvatinib with paclitaxel or doxorubicin monotherapy in people who have advanced endometrial cancer with MMR deficiency and who have had platinum-based chemotherapy. The committee discussed whether the chemotherapy arm of KEYNOTE‑775 represents the most relevant comparator data for dostarlimab, because the evidence for dostarlimab came from a single-arm trial (see section\xa03.4). The clinical experts emphasised that the KEYNOTE‑775 population is biomarker-matched to people in the dostarlimab trial. They also emphasised that KEYNOTE‑775 is a randomised controlled trial rather than a real-world registry. It would therefore be a more reliable comparator for the dostarlimab single-arm trial. The committee agreed with the clinical experts and concluded that KEYNOTE‑775 may provide a better source of comparative data for the cost-effectiveness analyses of dostarlimab.\n\n# Indirect treatment comparisons\n\n## Matching-adjusted indirect treatment comparisons suggest that dostarlimab improves survival, but these are highly uncertain\n\nTo investigate the impact of any remaining differences between the 2\xa0populations, the company also did a matching-adjusted indirect comparison (MAIC) of overall survival between GARNET and the UK RWE subgroup. The company did a targeted literature review to identify a range of prognostic variables typically associated with survival in people with endometrial cancer, which were validated by a panel of clinical experts. Cox regression models were also used to investigate the prognostic value of each potential matching variable. Based on these results, 2\xa0MAIC scenarios were constructed:\n\nScenario 1, based on the prognostic variables identified by clinical expert opinion, including histology (non-endometrioid and unknown versus endometrioid) and the number of lines of prior platinum-based therapy for advanced or recurrent disease (0 or 1 versus 2 or more).\n\nScenario 2, based on the matching variables found to be statistically significant based on regression analyses, including ethnicity (black, other and unknown versus white), stage at diagnosis (stage 3 or 4 versus stage 1 or 2), histology (non-endometrioid and unknown versus endometrioid) and prior surgery (yes versus no).The results are marked as academic in confidence and cannot be reported here. Both matching scenarios showed that the median overall survival, as well as the percentage of people alive at months\xa06,\xa012 and\xa018, was greater with dostarlimab than current clinical management. The hazard ratios for overall survival showed that dostarlimab statistically significantly reduced the risk of death compared with current clinical management. The company considered that the similarity of the overall survival results between the unadjusted GARNET population and both matched scenarios showed minimal differences between the GARNET and RWE GARNET-like populations. However, the ERG considered that systematic differences remained between the 2\xa0cohorts because of the methodological issues associated with data collection, case definition and selection. This particularly included the complicated screening processes used to identify the final RWE subgroup. The ERG noted that these systematic biases are difficult to recognise and quantify, and cannot be adjusted for by statistical methods. The committee agreed with the ERG about the limitations of the MAIC scenarios and the validity of the results. The committee also recalled its reservations about whether RWE would be an adequate proxy for a control arm of a randomised controlled trial comparing dostarlimab with conventional care in this population. The company also did a series of MAICs comparing GARNET with individual studies of some comparator chemotherapy treatments identified in the literature. This was to provide additional evidence to support the results from the primary MAICs between GARNET and the RWE study. However, the ERG cautioned that these MAICs were also severely limited because the studies had small sample sizes, and patient characteristics and prognostic variables were poorly reported. In particular, the lack of data on previous anticancer treatments was a key limitation because this is an important prognostic variable, based on clinical expert opinion. The ERG suggested that analyses from a more homogeneous subgroup, such as people with endometrioid disease, would help mitigate these concerns. The committee agreed that the company's MAICs (scenarios\xa01 and\xa02) could not be considered a robust source of evidence because of the high levels of uncertainty in matching the cohorts. The committee concluded that better data was needed to inform a robust analysis of comparative efficacy between dostarlimab and comparator treatments.\n\n## Exploratory analysis is also uncertain, but the overall evidence suggests that dostarlimab is more effective than current care\n\nAt the technical engagement stage, the company provided an additional MAIC analysis that was based on more homogenous cohorts of people with the endometrioid subtype from GARNET and the RWE study. This was provided to explore the effect of closer population matching on the comparative efficacy of dostarlimab. The company considered the similar hazard ratios for the endometrioid-only cohorts and MAICs show only minor imbalances between the full RWE subgroup and GARNET populations. However, the ERG considered it more likely that the MAICs had not adequately adjusted for the remaining imbalances between the 2\xa0endometrioid cohorts. While the endometrioid subgroup data mitigated one of the major differences between GARNET and RWE, the ERG noted that substantial differences in patient characteristics remained, even within this more homogeneous subgroup of patients. Key differences included ECOG performance status, International Federation of Gynaecology and Obstetrics stage, disease grade, number of prior platinum-based therapies for advanced or recurrent disease, and prior surgery for advanced or recurrent endometrial cancer. The net effect of excluding people who do not have the endometrioid subtype was a smaller estimated survival advantage for dostarlimab compared with comparator treatments. The ERG explained that while the endometrioid-only analysis may have removed histological type as a source of uncertainty, the comparisons still likely had a substantial degree of uncertainty. The MAIC for this subgroup did not adequately address these issues. Therefore, the relative effectiveness of dostarlimab estimated from the endometrioid-only subgroup is still associated with a high level of uncertainty and may be over-estimated. The committee agreed with the ERG that the endometrioid-only subgroup supplementary analysis had reduced some bias but was still highly uncertain because of remaining differences between the 2\xa0populations (see section\xa03.5). The committee noted that the endometrioid-only MAIC suggested that closer matching resulted in reduced comparative efficacy of dostarlimab. It also noted that this further underlines the need for better evidence to produce more robust conclusions about the comparative effectiveness of dostarlimab. The committee concluded that dostarlimab had a biologically plausible reason for being more effective than conventional care, and the analyses presented tend to support this. However, the magnitude of any benefit remained highly uncertain because of the single-arm trial and major shortcomings in the comparator evidence.\n\n# Economic model\n\n## The company's model is appropriate for decision making\n\nThe company used a partitioned-survival economic model that included 3\xa0health states: pre-progression, post-progression and death. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for endometrial cancer.\n\n# Survival extrapolation\n\n## There is high uncertainty in the extrapolation of overall survival because of the immaturity of trial data\n\nThe company independently fitted parametric models to dostarlimab (GARNET) and standard of care (the GARNET-like RWE cohort) in the base case cost-effectiveness analysis. It considered independent parametric models to be a more robust approach because of differences in the mechanisms of action between dostarlimab and the different chemotherapy options that are current clinical management. The company noted that treatment response to immunotherapy differs from the response to chemotherapy, including the possibility of a delayed response and longer-term treatment benefits after treatment discontinuation. The company's process for selecting the most appropriate curve for overall survival for dostarlimab was to:\n\nexplore the visual fit of parametric models by presenting them superimposed onto the Kaplan–Meier analysis\n\nadjust the parametric model for the waning of treatment effect and so it does not exceed the overall survival of the general population\n\nselect an adjusted parametric model that best reflects and conforms to the predictions of the company's clinical expert advisory panel.The overall survival extrapolations appeared to provide a good fit to the observed Kaplan–Meier data for the duration of the data collection in the trial. The company selected the generalised gamma extrapolation for overall survival with dostarlimab beyond the trial data because it gives the most clinically plausible long-term extrapolations and is more closely aligned with the clinical expert feedback. The lognormal model was considered to give the next most clinically plausible long-term extrapolations after the generalised gamma model, and it also had the lowest sum of Akaike and Bayesian information criteria. However, the company asserted that the lognormal model is not clinically plausible. This is because when treatment waning was applied, the lognormal curve substantially underestimated the predicted numbers of people alive at 5, 10, 15 and 20\xa0years compared with the clinical expert estimates. The ERG explained its concerns about relying on clinical experts' opinions on the expected overall survival for people having dostarlimab. It explained that the clinical predictions should probably be regarded as informed speculation because of the widely varying estimates from individual clinicians. It is possible that consulting more, or different, clinicians could result in a considerably different mean estimate. The ERG explained that it considered the company's preferred generalised gamma curve to be overly optimistic because it predicted survivors well beyond 30\xa0years, which does not seem clinically plausible. The ERG preferred the Weibull curve because the company expert responses could be biased by the elicitation methods used, and therefore too high to assess how reasonable the adjusted curves were. The company did not accept the ERG's preference for the Weibull curve. It suggested that the shape of the hazard function produced by that model was inappropriate for the treatment effect associated with immunotherapies such as dostarlimab. But the ERG further explained that all models under consideration were associated with substantial uncertainty because of the lack of data. The visual fit of all models to the Kaplan–Meier data was relatively poor because the plot did not reach a median, exhibited several changing trajectories and had a long flat tail. The clinical experts explained that the Weibull curve preferred by the ERG appeared to be somewhat pessimistic. This is because it predicted lower overall survival than might be expected from immunotherapies in other clinical indications, which can have a prolonged treatment effect and a shallowing curve over time. Defining exactly where plateauing of the curve begins and how long it is maintained is uncertain, but this is very difficult to predict with any certainty given the limited duration of follow up in the trial. The ERG thought that longer-term overall survival was uncertain because the trial follow up was too short and there are not enough participants. It also thought that there were too few overall survival events relative to the number of participants to accurately predict future survival. The committee noted that longer follow up could partially mitigate this problem. The ERG also explained that after technical engagement, the company reconsidered its preferred treatment waning effect. Implementing this in the model substantially reduced the differences in results between the company's preferred generalised gamma model and the ERG's preferred Weibull model. But the ERG still considered that the generalised gamma was likely to be over optimistic. The ERG noted that the lognormal curve represented a middle value between the generalised gamma and the Weibull curve. But ultimately, the considerable uncertainties meant that there was not a strong case for selecting one extrapolation in preference to another. The committee noted the ERG's concerns over the relative plausibility of the models and concluded that the immaturity of the data limits selecting the most appropriate extrapolation for overall survival for dostarlimab.\n\n# Key assumptions in the economic model\n\n## The effect of treatment waning is uncertain, but the ERG's more conservative approach is currently preferred\n\nThe committee noted that the implementation of treatment waning in the economic model was closely related to the issue of extrapolating survival appropriately (see section\xa03.11). The company adjusted its implementation of treatment waning in the model after ERG feedback at technical engagement, but the ERG explained that it did not agree with this adjusted implementation. The values preferred by the company and the ERG are confidential and cannot be reported here. The ERG expressed its concern that there was little evidence to support the assumptions used by the company, particularly for the maintenance of full treatment effect for an extended duration beyond treatment discontinuation. The clinical experts explained that there is a broad clinical consensus that there is some retention of the full benefits from immunotherapy after stopping treatment. But, they noted that there is no good evidence on when waning of this benefit is likely to start. The company evidence submission referenced previous technology appraisals for other immunotherapies with the same mechanism of action as dostarlimab, such as nivolumab and pembrolizumab. In these, NICE had previously accepted a treatment effect duration of between 3 to 5\xa0years when people stop having the immunotherapy after 2\xa0years. However, the ERG maintained that there is no evidence to support that this will also be the case in this population. It preferred the waning of treatment effect to begin immediately at treatment discontinuation, with declining effect over a longer period of time until the chance of dying is the same between dostarlimab and current clinical management. The committee noted how the type of waning approach substantially impacts how the parametric overall survival models extrapolate survival in the economic model (see section\xa03.11) so recalled that this shows how choice of waning method is driving the overall survival model in the economic analysis. The committee acknowledged the high degree of uncertainty because of the lack of data to support the maintenance of full treatment effect after stopping treatment. Implementing the ERG's preferred treatment waning assumptions in the model would increase the company's corrected base case incremental cost-effectiveness ratio (ICER) from £38,363 to £43,028 per quality-adjusted life year (QALY) gained for dostarlimab compared with current clinical management. The committee concluded that the more conservative approach preferred by the ERG is favoured, given the immaturity of the data and high degree of uncertainty, although this could be mitigated with longer trial follow up.\n\n## The percentage of people on treatment at key time points is uncertain\n\nGARNET did not contain a stopping rule for dostarlimab. To obtain estimates of time to treatment discontinuation (TTD), the company presented a panel of clinical experts with the number remaining at risk instead of the Kaplan–Meier TTD curve. This resulted in a range of estimates for the percentage of people expected to remain on treatment at a specific timepoint in the economic model. These values and the timepoint are confidential and cannot be reported here. The ERG explained that the modelled TTD curve bears no resemblance to the numbers remaining on treatment that were presented to the experts. The ERG further explained that by presenting the number remaining at risk, data cut-off is effectively treated as a discontinuation event, and this incorrect assumption would seriously bias the presentation and experts' estimates. Unbiased overall survival and progression-free survival estimates adjusted for the TTD and treatment stopping rules would usually require consideration of the TTD and stopping rules. The ERG also questioned why the TTD and stopping rules elicitation exercise was done after the overall survival and progression-free survival elicitation exercise. The ERG suggested that while the range of TTD estimates could be considered as a likely minimum for the proportion of people remaining on treatment at that timepoint, they should not be used as averages. The ERG preferred a more conservative value that was towards the upper end of the range provided by the company's elicitation exercise. Implementing this value in the model would increase the company's corrected base case ICER for dostarlimab compared with current clinical management from £38,363 to £41,354 per QALY gained. The committee noted the ERG's view that the company TTD and stopping rules elicitation exercise was poorly constructed, and that its results are unreliable. The committee concluded that the more conservative value preferred by the ERG is appropriate given the high degree of uncertainty.\n\n# End of life\n\n## Dostarlimab meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It recalled that KEYNOTE‑775 showed poor life expectancy for people with previously treated recurrent or advanced endometrial cancer with high MSI or MMR deficiency (see section\xa03.2). The committee noted that overall survival was immature in GARNET but has been modelled by the company and ERG. Both the company and ERG agree that dostarlimab appears to meet the end of life criteria for people with recurrent or advanced endometrial cancer that has progressed during or after platinum-based chemotherapy. However, the ERG cautioned that there is uncertainty around the survival estimates because GARNET's data is immature and there are many issues with comparator data and longer-term outcomes beyond 2\xa0years. The committee concluded that dostarlimab likely meets the end of life criteria.\n\n# Results of the cost-effectiveness analysis\n\n## Dostarlimab is not recommended for routine use in the NHS\n\nThe committee noted that the company's base case ICER for dostarlimab compared with current clinical management increased to £38,363 per QALY when model errors identified by the ERG were corrected in the economic model. Although this ICER falls within the range that NICE considers to be cost effective for treatments at the end of life, it does not take into account the committee's preferences for amendments to the company model. Given the immaturity of GARNET data, uncertainty about long-term survival, absence of a matched trial population for current clinical management and reliance on a different real-world population, the committee agreed with the ERG's more conservative preferences. This included the ERG's modelling of both treatment waning and treatment discontinuation for dostarlimab. For extrapolation of overall survival, the committee agreed with the ERG that there is not enough evidence to prefer either the Weibull or generalised gamma curves. It also agreed that the true survival of people having dostarlimab lies within a wide range of possibilities. Using the ERG's preferred assumptions but with the company's choice of generalised gamma for overall survival for dostarlimab gave an ICER of £49,454 per QALY gained. The same assumptions with the ERG's alternative choice of the Weibull curve for overall survival for dostarlimab gave an ICER of £61,306 per QALY gained. The committee however noted that the choice of overall survival extrapolation was dependent on having confidence in the overall treatment comparison between dostarlimab and the comparator treatments. The committee agreed that the data from GARNET was too immature. It also agreed there was too much uncertainty in the MAICs to be confident about the robustness of any of the ICERs produced by the company's economic model. The committee concluded that dostarlimab could not be recommended for routine commissioning.\n\n# Cancer Drugs Fund\n\n## Dostarlimab is recommended for use in the Cancer Drugs Fund\n\nHaving concluded that dostarlimab could not be recommended for routine use, the committee then considered if it could be recommended for treating advanced or recurrent endometrial cancer with high MSI or MMR deficiency after platinum-based chemotherapy within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):\n\nThe company expressed an interest in dostarlimab being considered for funding through the Cancer Drugs Fund.\n\nThe committee noted that GARNET is still ongoing, with the next data cut expected in early 2022, and agreed that additional survival data is needed to reach a decision on the cost effectiveness of dostarlimab.\n\nClinical evidence from KEYNOTE‑775 (see section\xa03.2) would provide a better source comparator data for future cost-effectiveness analyses of dostarlimab. This is because it would overcome many of the problems associated with matching the GARNET and the RWE study populations that impacted the robustness of the company's indirect treatment comparisons.The committee considered that further data collection in the Cancer Drugs Fund could address some of the uncertainty in the company's estimates. It recalled that using the ERG's preferred assumptions but with the company's choice of generalised gamma for overall survival for dostarlimab gave a plausibly cost effective estimate of £49,454 per QALY gained. The committee concluded that dostarlimab met the criteria to be considered for inclusion in the Cancer Drugs Fund. It recommended dostarlimab for use within the Cancer Drugs Fund as an option for people with advanced or recurrent endometrial cancer with high MSI or MMR deficiency after platinum-based chemotherapy, if the conditions in the managed access agreement are followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions as set out in section\xa03.12 and section\xa03.13, unless new evidence indicates otherwise.\n\n# Innovation\n\n## Some benefits of dostarlimab have not been captured in the QALY\n\nThe company considered dostarlimab to be an innovative treatment. The clinical experts agreed that this treatment represents a step change for people who have advanced or recurrent endometrial cancer with high MSI or MMR deficiency and who have few effective options after platinum-based chemotherapy. The benefits for people having treatment includes 1\xa0factor not captured in the QALY estimate, which is the added value of a treatment that needs a shorter hospital visit than chemotherapy.\n\n# Other factors\n\nNo equality or social value judgement issues were identified.", 'Recommendations for data collection': 'Proposals for further data collection in the Cancer Drugs Fund include further evidence on:\n\noverall survival\n\nprogression-free survival\n\ntime to treatment discontinuation, and\n\nthe comparative effectiveness.'}
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https://www.nice.org.uk/guidance/ta779
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Evidence-based recommendations on dostarlimab (Jemperli) for treating advanced or recurrent endometrial cancer with high microsatellite instability or mismatch repair deficiency in adults who have had platinum-based chemotherapy.
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09e99207f7ec4279ec6ab479d05ef7baa1c5149c
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nice
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Otitis media (acute): antimicrobial prescribing
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Otitis media (acute): antimicrobial prescribing
This guideline sets out an antimicrobial prescribing strategy for acute otitis media (ear infection). It aims to limit antibiotic use and reduce antimicrobial resistance. Acute otitis media can be caused by viruses or bacteria. It lasts for about a week, and most children get better in 3 days without antibiotics. Serious complications are rare.
# Recommendations
# Managing acute otitis media
## All children and young people with acute otitis media
Be aware that:
acute otitis media is a self-limiting infection that mainly affects children
acute otitis media can be caused by viruses and bacteria, and it is difficult to distinguish between these (both are often present at the same time)
symptoms last for about 3 days, but can last for up to 1 week
most children and young people get better within 3 days without antibiotics
complications such as mastoiditis are rare.
Assess and manage children under 5 who present with fever as outlined in the NICE guideline on fever in under 5s.
Give advice about the usual course of acute otitis media (about 3 days, can be up to 1 week).
Offer regular doses of paracetamol or ibuprofen for pain. Use the right dose for the age or weight of the child at the right time, and use maximum doses for severe pain.
Consider eardrops containing an anaesthetic and an analgesic for pain (see recommendation 1.2.1 for choice of treatment) if:
an immediate oral antibiotic prescription is not given (see recommendations 1.1.8 to 1.1.14), and
there is no eardrum perforation or otorrhoea.Review treatment if symptoms do not improve within 7 days or worsen at any time.
Explain that evidence suggests decongestants and antihistamines do not help symptoms.
Reassess at any time if symptoms worsen rapidly or significantly, taking account of:
alternative diagnoses, such as otitis media with effusion (glue ear)
any symptoms or signs suggesting a more serious illness or condition
previous antibiotic use, which may lead to resistant organisms.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on non-antimicrobial treatments.
Full details of the evidence and the committee's discussion are in the evidence review.
## Children and young people who may be less likely to benefit from antibiotics (those not covered by recommendations 1.1.11 to 1.1.14)
Consider no antibiotic prescription or a back-up antibiotic prescription (see recommendation 1.2.1 for choice of treatment), taking account of:
evidence that antibiotics make little difference to symptoms (no improvement in pain at 24 hours, and after that the number of children improving is similar to the number with adverse effects)
evidence that antibiotics make little difference to the development of common complications (such as short-term hearing loss , perforated eardrum or recurrent infection)
evidence that acute complications such as mastoiditis are rare with or without antibiotics
possible adverse effects of antibiotics, particularly diarrhoea and nausea.
When no antibiotic prescription is given, give advice about:
an antibiotic not being needed
seeking medical help if symptoms worsen rapidly or significantly, do not start to improve after 3 days, or the child or young person becomes systemically very unwell.
When a back-up antibiotic prescription is given, give advice about:
an antibiotic not being needed immediately
using the back-up prescription if symptoms do not start to improve within 3 days or if they worsen rapidly or significantly at any time
seeking medical help if symptoms worsen rapidly or significantly, or the child or young person becomes systemically very unwell.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on no antibiotic and back-up antibiotics.
Full details of the evidence and the committee's discussion are in the evidence review.
## Children and young people who may be more likely to benefit from antibiotics (those of any age with otorrhoea or those under 2 years with infection in both ears)
Consider no antibiotic prescription with advice (see recommendation 1.1.9), a back-up antibiotic prescription with advice (see recommendation 1.1.10) or an immediate antibiotic prescription (see recommendation 1.2.1 for choice of treatment), taking account of:
evidence that acute complications such as mastoiditis are rare with or without antibiotics
possible adverse effects of antibiotics, particularly diarrhoea and nausea.
When an immediate antibiotic prescription is given, give advice about seeking medical help if symptoms worsen rapidly or significantly, or the child or young person becomes systemically very unwell.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on no antibiotic, back-up antibiotics and choice of antibiotic.
Full details of the evidence and the committee's discussion are in the evidence review.
## Children and young people who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high risk of complications
Offer an immediate antibiotic prescription (see recommendation 1.2.1 for choice of treatment) with advice (see recommendation 1.1.12).
Refer children and young people to hospital if they have acute otitis media associated with:
a severe systemic infection (see the NICE guideline on sepsis)
acute complications, including mastoiditis, meningitis, intracranial abscess, sinus thrombosis or facial nerve paralysis.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on choice of antibiotic.
Full details of the evidence and the committee's discussion are in the evidence review.
# Choice of treatment
Follow table 1 when prescribing treatment for children and young people with acute otitis media.
Treatment
Choice, dosage and course length
Eardrops containing an anaesthetic and an analgesic
Phenazone 40 mg/g with lidocaine 10 mg/g:
Apply 4 drops two or three times a day for up to 7 days
Use only if an immediate oral antibiotic prescription is not given, and there is no eardrum perforation or otorrhoea
First-choice oral antibiotic
Amoxicillin:
month to 11 months, 125 mg three times a day for 5 to 7 days
year to 4 years, 250 mg three times a day for 5 to 7 days
years to 17 years, 500 mg three times a day for 5 to 7 days
Alternative first choice for penicillin allergy or intolerance (for people who are not pregnant)
Clarithromycin:
month to 11 years:
under 8 kg, 7.5 mg/kg twice a day for 5 to 7 days
kg to 11 kg, 62.5 mg twice a day for 5 to 7 days
kg to 19 kg, 125 mg twice a day for 5 to 7 days
kg to 29 kg, 187.5 mg twice a day for 5 to 7 days
kg to 40 kg, 250 mg twice a day for 5 to 7 days
years to 17 years, 250 mg to 500 mg twice a day for 5 to 7 days
Alternative first choice for penicillin allergy in pregnancy
Erythromycin:
years to 17 years, 250 mg to 500 mg four times a day or 500 mg to 1,000 mg twice a day for 5 to 7 days
Erythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.
Second-choice oral antibiotic (worsening symptoms on first choice taken for at least 2 to 3 days)
Co-amoxiclav:
month to 11 months, 0.25 ml/kg of 125/31 suspension three times a day for 5 to 7 days
year to 5 years, 5 ml of 125/31 suspension three times a day or 0.25 ml/kg of 125/31 suspension three times a day for 5 to 7 days
years to 11 years, 5 ml of 250/62 suspension three times a day or 0.15 ml/kg of 250/62 suspension three times a day for 5 to 7 days
years to 17 years, 250/125 mg or 500/125 mg three times a day for 5 to 7 days
Alternative second choice for penicillin allergy or intolerance
Consult local microbiologist
See the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment.
The age bands apply to children of average size. In practice, the prescriber will use the age bands along with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age. Doses given are by mouth using immediate-release medicines, unless otherwise stated.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on choice of antibiotic and antibiotic course length.
Full details of the evidence and the committee's discussion are in the evidence review.# Summary of the evidence
The recommendations in this guideline are based on the evidence identified, which was for children and young people under 18 years.
# Non‑antimicrobial treatments
## Oral analgesia (paracetamol and ibuprofen)
Paracetamol and ibuprofen were both more effective than placebo in reducing pain at 48 hours in children with acute otitis media (number needed to treat 6 to 7 for no pain at 48 hours; low to moderate quality evidence). This was based on a systematic review of randomised controlled trials (RCTs; Sjoukes et al. 2016). There were no significant differences in fever at 48 hours with paracetamol or ibuprofen compared with placebo (very low quality evidence).
No significant differences were found between paracetamol and ibuprofen for pain or fever at various time points (very low to low quality evidence). Furthermore, using ibuprofen and paracetamol in combination was no more effective than paracetamol alone, although this was based on very small numbers of children (very low to low quality evidence; Sjoukes et al. 2016).
Adverse events for paracetamol and ibuprofen were not significantly different from placebo (very low to low quality evidence). However, this should be interpreted cautiously because of the small number of children and the infrequent occurrence of adverse events (Sjoukes et al. 2016).
## Eardrops containing an anaesthetic and an analgesic
Eardrops containing an anaesthetic and an analgesic statistically significantly increased the proportion of children with a 50% and a 25% reduction in pain compared with placebo (NNT 5 for 50% pain reduction 10 minutes after having eardrops; low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Foxlee et al. 2011). These children were aged 3 years and over without eardrum perforation and were also having oral analgesia.
Eardrops containing an anaesthetic and an analgesic statistically significantly reduced antibiotic consumption at day 8 compared with usual care (no or delayed antibiotic prescription; 2.6% compared with 29.0%; moderate quality evidence). There was also a statistically significant reduction in parent‑reported pain scores at day 2 (low quality evidence). This was based on an RCT in children aged 1 to 10 years who did not need immediate antibiotics (Hay et al. 2019). Most children (88%) were also having oral analgesia.
No adverse effects were seen with eardrops containing an anaesthetic and an analgesic, but this was based on very small numbers of children (very low to low quality evidence; Foxlee et al. 2011, Hay et al. 2019).
## Decongestants and antihistamines
Overall, decongestants and antihistamines, used alone or in combination, did not improve clinical outcomes in children with acute otitis media who were taking antibiotics (used in 14 out of 15 RCTs; very low to low quality evidence). This was based on a systematic review and meta-analysis of RCTs (Coleman et al. 2008). There was a reduction in the rate of persistent acute otitis media at 2 weeks with a combination of decongestant plus antihistamine compared with placebo (NNT 11 ; low quality evidence). However, a subgroup analysis of higher quality studies found no benefit with treatment.
Adverse effects (excluding drowsiness and hyperactivity) were significantly increased with decongestants, but not with antihistamines or a combination of decongestant plus antihistamine, compared with placebo (very low quality evidence). However, there is considerable uncertainty about these results (Coleman et al. 2008).
# Oral corticosteroids
Oral prednisolone taken for 5 days did not improve any clinical outcomes in children aged 3 months to 6 years with acute otitis media who were at risk of recurrence (at least 2 previous episodes of acute otitis media), compared with placebo (very low quality evidence). Outcomes included treatment failure during the first 2 weeks, duration of effusion and recurrence. This was based on a small RCT (Chonmaitree et al. 2003).
Adverse effects or discontinuations because of adverse effects did not appear to be significantly different between prednisolone and placebo, although the study was very small and full data were not reported (low quality evidence; Chonmaitree et al. 2003).
Systemic effects (mineralocorticoid and glucocorticoid) may occur with oral corticosteroids, including a range of psychological or behavioural effects (particularly in children; Drug Safety Update on inhaled and intranasal corticosteroids).
## Committee discussion on non-antimicrobial treatments
The committee discussed the importance of managing a child's pain and felt that for parents this is the main priority. They agreed that paracetamol or ibuprofen needs to be taken at the right time and at the right dose, with maximum doses being used for severe pain.
Based on evidence and their experience, the committee agreed that paracetamol or ibuprofen should be offered for pain associated with acute otitis media. Parents or carers could be advised to buy paracetamol or ibuprofen over the counter in line with local policies on the prescribing of such medicines.
Based on evidence, the committee agreed that eardrops containing an anaesthetic and an analgesic (in addition to oral analgesics) may reduce antibiotic consumption and relieve pain in children who did not need immediate antibiotics.
They recognised that these eardrops should not be used in children with eardrum perforation or otorrhoea. They discussed the rare adverse effect of methemoglobinemia (associated with topical anaesthetics in very young children). They noted that the age of the children varied in the studies (from 1 year), but that there is no age-based restriction for using the licensed preparation (phenazone with lidocaine eardrops).
They were aware that there is currently only 1 licensed preparation (a prescription only medicine), which was not the preparation used in the studies. However, the committee were content that a class effect would be seen.
There is no direct evidence to support the use of eardrops containing an anaesthetic and an analgesic in children who need immediate antibiotics. The committee agreed that it is uncertain whether these eardrops would provide additional benefit when used with oral analgesia in children having immediate antibiotics. Therefore, they recommended their use only for children who do not need an immediate oral antibiotic.
The committee agreed that evidence does not support using decongestants or antihistamines to help symptoms of acute otitis media.
The committee agreed, based on the evidence, not to make a recommendation on the use of oral corticosteroids to manage acute otitis media in children.
# No antibiotic
Acute otitis media is a self-limiting infection of the middle ear. It can be caused by viruses or bacteria, and both are often present at the same time. In most children acute otitis media resolves without treatment.
The most common bacterial causes of acute otitis media are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes (the Canadian Paediatric Society's position statement, 2016).
More common complications of acute otitis media are recurrence of infection, hearing loss (which is usually temporary) and perforated eardrum. However, antibiotics make little difference to the rates of these (see efficacy of antibiotics).
Acute complications of acute otitis media (such as mastoiditis, meningitis, intracranial abscess, sinus thrombosis and facial nerve paralysis) are rare. The incidence of mastoiditis after otitis media is 1.8 per 10,000 episodes after antibiotics compared with 3.8 per 10,000 episodes without antibiotics. This gives a NNT of 4,831 to prevent 1 child from developing mastoiditis (Thompson et al. 2009).
## Efficacy of antibiotics
Antibiotics did not significantly reduce pain at 24 hours compared with placebo in children with acute otitis media; around 60% of children in both groups had no pain (high quality evidence). Antibiotics did significantly reduce pain at 2 to 3 days, but the absolute difference was small; 88% of children had no pain in the antibiotic group compared with 84% in the placebo group (NNT 24 ; moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Venekamp et al. 2015).
Antibiotics significantly reduced the number of children with abnormal tympanometry findings (a surrogate measure for hearing loss) compared with placebo at 2 to 4 weeks, but not at 6 to 8 weeks or 3 months. However, the absolute difference was small; at 2 to 4 weeks, 39% of children had abnormal tympanometry findings with antibiotics compared with 48% with placebo (NNT 12 ; low quality evidence; Venekamp et al. 2015).
Antibiotics significantly reduced the number of children with eardrum perforation. However, again the absolute benefits were small with 5% of children having a perforation in the placebo group compared with 2% in the antibiotic group (NNT 33 ; moderate quality evidence; Venekamp et al. 2015).
Antibiotics did not reduce the number of children with late recurrence of acute otitis media (which was common in both groups: 18% of children taking antibiotics compared with 20% of children taking placebo, moderate quality evidence; Venekamp et al. 2015).
Antibiotics seem to be more beneficial in 2 pre-defined groups of children, based on subgroup analyses of intervention studies comparing antibiotics with placebo. Firstly, children under 2 years with bilateral acute otitis media, where the NNT was 4 for symptom resolution (low quality evidence). Secondly, children with acute otitis media and otorrhoea (discharge following eardrum perforation), where the NNT was 3 for symptom resolution (moderate quality evidence). This was based on a meta-analysis of individual patient data from RCTs (Rovers et al. 2006). However, the literature search was not designed specifically to identify prognostic evidence.
No systematic reviews or RCTs of topical antibiotics were identified.
## Safety of antibiotics
Allergic reactions to penicillins occur in 1 to 10% of people and anaphylactic reactions occur in less than 0.05%. People with a history of atopic allergy (for example, asthma, eczema and hay fever) have a higher risk of anaphylactic reactions to penicillins. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin). See the NICE guideline on drug allergy for more information.
Antibiotic-associated diarrhoea occurs in 2 to 25% of people taking antibiotics, depending on the antibiotic used (NICE Clinical Knowledge Summary on diarrhoea – antibiotic associated).
Adverse events (vomiting, diarrhoea or rash) were significantly increased in children with acute otitis media taking antibiotics compared with those taking placebo (moderate quality evidence). The number needed to harm (NNH) was 13 (range 9 to 25). This was based on a systematic review and meta-analysis of RCTs (Venekamp et al. 2015).
See the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines.
Acute otitis media can be caused by viral or bacterial infections, both of which are usually self-limiting and do not routinely need antibiotics.
Based on evidence, the committee agreed that antibiotics make little difference to ear pain or to the rates of more common complications, such as recurrence of infection. The small increased risk of perforation was noted, but 33 children (range 20 to 100) would need to be treated with antibiotics to avoid 1 child experiencing perforation. Antibiotics also made little difference to short-term hearing loss as assessed by the surrogate marker of tympanometry.
More serious complications of acute otitis media, such as mastoiditis, are rare and the NNT with antibiotics to prevent 1 child from developing mastoiditis is approximately 5,000.
The committee acknowledged the recommendation in the NICE guideline on respiratory tract infections (self-limiting): prescribing antibiotics for no antibiotic or a back-up antibiotic prescription for most children with acute otitis media.
# Back-up antibiotics
A back-up antibiotic prescription or watchful waiting was as effective as immediate antibiotics in children with acute otitis media for reducing pain at 3 to 7 days (moderate quality evidence). There were also no significant differences between groups for abnormal tympanometry findings (a surrogate measure for hearing loss), eardrum perforation or recurrence of infection (very low to moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Venekamp et al. 2015).
A back-up antibiotic prescription was compared with no antibiotics and immediate antibiotics in a systematic review of RCTs (Spurling et al. 2013). In 1 RCT there was no significant difference between back-up antibiotics and no antibiotics for pain or fever on day 3 (very low to low quality evidence). In 1 RCT there was no significant difference between back-up antibiotics and immediate antibiotics for pain on day 3 (moderate quality evidence).
Immediate antibiotics were associated with a significantly increased risk of adverse events (vomiting, diarrhoea or rash) compared with back-up antibiotics or watchful waiting (NNH 8 ; moderate quality evidence; Venekamp et al. 2015).
The incidence of vomiting or rash was not significantly different with back‑up antibiotics compared with immediate antibiotics (very low quality evidence), but there was significantly less diarrhoea with back‑up antibiotics (NNH 8 ; data pooled by NICE; high quality evidence; Spurling et al. 2013). No safety data were available on back‑up antibiotics compared with no antibiotics.
## Committee discussion on back-up antibiotics
Based on evidence, the committee agreed that no antibiotic prescription or a back-up antibiotic prescription could be considered for most children with acute otitis media.
The committee discussed that acute otitis media could have a viral or a bacterial cause, and distinguishing between these is difficult. However, both are usually self-limiting and do not routinely need antibiotics. The committee discussed that a back-up antibiotic prescription may be preferred over no antibiotic in some children, but that prescribers need to weigh up the small clinical benefits from antibiotics against their potential to cause adverse effects.
The committee agreed that a back-up antibiotic prescription could be used if symptoms significantly worsen or do not improve within 3 days (by which time most self-limiting infections would be starting to resolve), or if they worsen rapidly or significantly at any time.
The committee acknowledged the recommendations in the previous NICE guideline on upper respiratory tract infections that, for acute otitis media, a no antibiotic prescribing strategy or a back-up antibiotic prescribing strategy should be agreed, but that depending on clinical assessment of severity, immediate antibiotics can also be considered for children under 2 years with infection in both ears or children of any age with otorrhoea (discharge following perforation of the eardrum). For these subgroups the committee agreed that an immediate antibiotic prescription could also be considered as an option, because antibiotics may be more likely to be beneficial in these subgroups. The committee discussed that an immediate antibiotic may be preferred over no antibiotic or a back-up antibiotic prescription in some children based on clinical judgement.
The committee agreed that immediate antibiotics are important for children who are systemically very unwell, have symptoms or signs of a more serious illness, or are at high risk of serious complications because of pre-existing comorbidity. This includes children with significant heart, lung, renal, liver or neuromuscular disease, immunosuppression, cystic fibrosis, and young children who were born prematurely.
# Choice of antibiotic
There were no major differences in treatment success between classes of antibiotics, including penicillins, cephalosporins and macrolides for treating uncomplicated acute otitis media in children. There was no difference in treatment success between ampicillin or amoxicillin compared with ceftriaxone; co‑amoxiclav compared with ceftriaxone; co‑amoxiclav compared with azithromycin; or cefaclor compared with azithromycin (low to moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Shekelle et al. 2010).
Co‑amoxiclav was associated with significantly more adverse events than a cephalosporin (very low to moderate quality evidence) or azithromycin (moderate quality evidence; Shekelle et al. 2010).
Shekelle et al. 2010 also considered evidence for treating recurrent or persistent acute otitis media in children. None of the studies found a significant benefit in treatment success for any particular antibiotic (moderate quality evidence). There were 5 individual RCTs that compared different antibiotic treatments: co‑amoxiclav compared with gatifloxacin (2 RCTs), co‑amoxiclav compared with levofloxacin (1 RCT), co‑amoxiclav compared with azithromycin (1 RCT), and cefaclor compared with cefuroxime (1 RCT).
## Committee discussion on choice of antibiotic
Based on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance.
The committee discussed that, if an antibiotic is needed to treat an infection that is not life-threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. For infections that are not life-threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective.
Based on evidence, their experience and resistance data, the committee agreed to recommend amoxicillin as the first choice because this is current practice for antibiotic treatment in children with acute otitis media, and the risk of resistance is acceptable. The dosage of 125 mg to 500 mg three times a day (based on age) is the usual dose, and was similar to that used in studies in the evidence review. The committee discussed that phenoxymethylpenicillin has a lower risk of resistance than amoxicillin, and microbiologically would be expected to be equivalent. However, medicines adherence is particularly important for children, and acute otitis media most commonly presents in young children. Amoxicillin has a three times a day dosage rather than four times a day for phenoxymethylpenicillin, and the liquid formulation is more palatable.
Based on evidence, their experience and resistance data, the committee agreed to recommend clarithromycin as the alternative first-choice antibiotic for use in penicillin allergy or amoxicillin intolerance. In pregnancy, erythromycin was recommended if there is true penicillin allergy. The doses recommended (based on weight and age) are the usual doses for children, and were similar to those used in studies in the evidence review. The committee discussed that there was evidence for another macrolide, azithromycin. However, they agreed not to recommend this because clarithromycin or erythromycin are current practice, and azithromycin should be reserved for more serious infections.
The committee discussed the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
Based on evidence, their experience and resistance data, the committee agreed to recommend co‑amoxiclav as the second-choice antibiotic for use if symptoms worsen on a first-choice antibiotic taken for at least 2 to 3 days. This broad-spectrum treatment combines a penicillin (amoxicillin) with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone. People who do not respond to amoxicillin may be more likely to have an infection that is resistant to it. The dosage of 0.25 ml/kg of 125/31 suspension to 250/125 mg or 500/125 mg three times a day (based on weight and age) is the usual dose for children, and was similar to that used in studies in the evidence review.
# Antibiotic course length
A short course of antibiotics (more than 48 hours but less than 7 days) was associated with significantly higher treatment failure at 8 to 19 days, or 1 month or less, compared with a long course (7 days or longer). Treatment failure (defined as a lack of clinical resolution, relapse or recurrence of acute otitis media within 1 month of starting treatment) occurred in 18.0% of the short-course group compared with 14.4% of the long-course group at 8 to 19 days (NNT 28 ; very low quality evidence), and in 20.5% of the short-course group compared with 17.5% of the long-course group at 1 month or less (NNT 34 ; low quality evidence). However, there was no difference in treatment failure between short and long courses at other time points. This was based on a systematic review and meta‑analysis of RCTs (Kozyrskyj et al. 2010).
There were significantly fewer gastrointestinal adverse events with a short course of antibiotics (more than 48 hours but less than 7 days) compared with a long course (7 days or longer; very low quality evidence). However, this result was based on the reported odds ratio and was not statistically significant when the relative risk was calculated (Kozyrskyj et al. 2010).
## Committee discussions on antibiotic course length
The committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed to minimise the risk of antimicrobial resistance.
Based on evidence, their experience and resistance data, the committee agreed that a 5‑ to 7‑day course of all the recommended antibiotics was sufficient to treat acute otitis media in children. This takes into account both the evidence for clinical effectiveness and the evidence for safety and tolerability of antibiotics, and minimises the risk of resistance. Studies on the use of specific antibiotics to treat acute otitis media sometimes had longer course lengths than 7 days.
The committee noted that no studies were identified that directly compared a 5‑day course of antibiotics with a 7‑day course.
Based on evidence, the committee recognised that more children may have treatment failure with an antibiotic course of less than 7 days compared with a course of 7 days or more. However, the absolute difference is small. At 8 to 19 days, 82% of children taking antibiotics for less than 7 days were better, compared with 86% of those taking antibiotics for 7 days or more. They agreed that, if a decision to prescribe an antibiotic is made, a 5‑day course may be sufficient for many children, reserving 7‑day courses for those with a clinical assessment of more severe or recurrent infection.
# Antibiotic dose frequency
Once or twice daily dosing of amoxicillin or co‑amoxiclav was as effective as three times a day dosing for clinical cure rates at the end of antibiotic treatment (high quality evidence). The duration of treatment was 10 days in most studies, and the dose of amoxicillin or co‑amoxiclav varied. There were no significant differences in the rates of recurrence (very low to low quality evidence), adverse effects (very low to low quality evidence) and adherence (high quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Thanaviratananich et al. 2013).
## Committee discussions on antibiotic dose frequency
The committee discussed the evidence for once or twice daily dosing of amoxicillin and co‑amoxiclav, but it is unknown if this would have a detrimental effect on the risk of resistance to these antibiotics. The evidence supporting once or twice daily dosing is for different doses and longer treatment durations. This goes against the general principle of antimicrobial stewardship to prescribe the shortest course that is effective.
The committee agreed that, when prescribing amoxicillin or co‑amoxiclav, a dosing frequency of three times a day should be prescribed, as is current practice.
See the full evidence review for more information.# Other considerations
# Medicines adherence
Medicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (see the NICE guideline on medicines adherence).
# Resource implications
Respiratory tract infections, including acute otitis media, are a common reason for consultations in primary care, and therefore are a common reason for potential antibiotic prescribing.
There is potential for resource savings if no antibiotic or a back-up antibiotic prescription is used. There was significantly lower antibiotic use with back‑up antibiotics compared with immediate antibiotics, both when the back‑up antibiotic prescription was given at the time of consultation (38% compared with 87%; moderate quality evidence) and when the prescription had to be collected on a separate visit (24% compared with 87%; high quality evidence). There was no significant difference between groups in re‑consultation rates (low quality evidence). This was based on a systematic review of RCTs (Spurling et al. 2013).
Recommended antibiotics are all available as generic formulations. Eardrops containing an anaesthetic and an analgesic (Otigo eardrops) are a prescription only medicine. See the Drug Tariff for costs.
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{'Recommendations': "# Managing acute otitis media\n\n## All children and young people with acute otitis media\n\nBe aware that:\n\nacute otitis media is a self-limiting infection that mainly affects children\n\nacute otitis media can be caused by viruses and bacteria, and it is difficult to distinguish between these (both are often present at the same time)\n\nsymptoms last for about 3\xa0days, but can last for up to 1\xa0week\n\nmost children and young people get better within 3\xa0days without antibiotics\n\ncomplications such as mastoiditis are rare. \n\nAssess and manage children under\xa05 who present with fever as outlined in the NICE guideline on fever in under\xa05s. \n\nGive advice about the usual course of acute otitis media (about 3\xa0days, can be up to 1\xa0week). \n\nOffer regular doses of paracetamol or ibuprofen for pain. Use the right dose for the age or weight of the child at the right time, and use maximum doses for severe pain. \n\nConsider eardrops containing an anaesthetic and an analgesic for pain (see recommendation 1.2.1 for choice of treatment) if:\n\nan immediate oral antibiotic prescription is not given (see recommendations 1.1.8 to 1.1.14), and\n\nthere is no eardrum perforation or otorrhoea.Review treatment if symptoms do not improve within 7\xa0days or worsen at any time. \n\nExplain that evidence suggests decongestants and antihistamines do not help symptoms. \n\nReassess at any time if symptoms worsen rapidly or significantly, taking account of:\n\nalternative diagnoses, such as otitis media with effusion (glue ear)\n\nany symptoms or signs suggesting a more serious illness or condition\n\nprevious antibiotic use, which may lead to resistant organisms. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on non-antimicrobial treatments.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n## Children and young people who may be less likely to benefit from antibiotics (those not covered by recommendations\xa01.1.11 to\xa01.1.14)\n\nConsider no antibiotic prescription or a back-up antibiotic prescription (see recommendation 1.2.1 for choice of treatment), taking account of:\n\nevidence that antibiotics make little difference to symptoms (no improvement in pain at 24\xa0hours, and after that the number of children improving is similar to the number with adverse effects)\n\nevidence that antibiotics make little difference to the development of common complications (such as short-term hearing loss [measured by tympanometry], perforated eardrum or recurrent infection)\n\nevidence that acute complications such as mastoiditis are rare with or without antibiotics\n\npossible adverse effects of antibiotics, particularly diarrhoea and nausea. \n\nWhen no antibiotic prescription is given, give advice about:\n\nan antibiotic not being needed\n\nseeking medical help if symptoms worsen rapidly or significantly, do not start to improve after 3\xa0days, or the child or young person becomes systemically very unwell. \n\nWhen a back-up antibiotic prescription is given, give advice about:\n\nan antibiotic not being needed immediately\n\nusing the back-up prescription if symptoms do not start to improve within 3\xa0days or if they worsen rapidly or significantly at any time\n\nseeking medical help if symptoms worsen rapidly or significantly, or the child or young person becomes systemically very unwell. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on no antibiotic and back-up antibiotics.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n## Children and young people who may be more likely to benefit from antibiotics (those of any age with otorrhoea or those under 2\xa0years with infection in both ears)\n\nConsider no antibiotic prescription with advice (see recommendation\xa01.1.9), a back-up antibiotic prescription with advice (see recommendation\xa01.1.10) or an immediate antibiotic prescription (see recommendation 1.2.1 for choice of treatment), taking account of:\n\nevidence that acute complications such as mastoiditis are rare with or without antibiotics\n\npossible adverse effects of antibiotics, particularly diarrhoea and nausea. \n\nWhen an immediate antibiotic prescription is given, give advice about seeking medical help if symptoms worsen rapidly or significantly, or the child or young person becomes systemically very unwell. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on no antibiotic, back-up antibiotics and choice of antibiotic.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n## Children and young people who are systemically very unwell, have symptoms and signs of a more serious illness or condition, or are at high risk of complications\n\nOffer an immediate antibiotic prescription (see recommendation 1.2.1 for choice of treatment) with advice (see recommendation\xa01.1.12). \n\nRefer children and young people to hospital if they have acute otitis media associated with:\n\na severe systemic infection (see the NICE guideline on sepsis)\n\nacute complications, including mastoiditis, meningitis, intracranial abscess, sinus thrombosis or facial nerve paralysis. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on choice of antibiotic.\n\nFull details of the evidence and the committee's discussion are in the evidence review.\n\n# Choice of treatment\n\nFollow table\xa01 when prescribing treatment for children and young people with acute otitis media. [2018, amended 2022]\n\nTreatment\n\nChoice, dosage and course length\n\nEardrops containing an anaesthetic and an analgesic\n\nPhenazone 40\xa0mg/g with lidocaine 10\xa0mg/g:\n\nApply 4\xa0drops two or three times a day for up to 7\xa0days\n\nUse only if an immediate oral antibiotic prescription is not given, and there is no eardrum perforation or otorrhoea\n\nFirst-choice oral antibiotic\n\nAmoxicillin:\n\nmonth to 11\xa0months, 125\xa0mg three times a day for 5\xa0to 7\xa0days\n\nyear to 4\xa0years, 250\xa0mg three times a day for 5\xa0to 7\xa0days\n\nyears to 17\xa0years, 500\xa0mg three times a day for 5\xa0to 7\xa0days\n\nAlternative first choice for penicillin allergy or intolerance (for people who are not pregnant)\n\nClarithromycin:\n\nmonth to 11\xa0years:\n\nunder 8\xa0kg, 7.5\xa0mg/kg twice a day for 5\xa0to 7\xa0days\n\nkg to 11\xa0kg, 62.5\xa0mg twice a day for 5\xa0to 7\xa0days\n\nkg to 19\xa0kg, 125\xa0mg twice a day for 5\xa0to 7\xa0days\n\nkg to 29\xa0kg, 187.5\xa0mg twice a day for 5\xa0to 7\xa0days\n\nkg to 40\xa0kg, 250\xa0mg twice a day for 5\xa0to 7\xa0days\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg twice a day for 5\xa0to 7\xa0days\n\nAlternative first choice for penicillin allergy in pregnancy\n\nErythromycin:\n\nyears to 17\xa0years, 250\xa0mg to 500\xa0mg four times a day or 500\xa0mg to 1,000\xa0mg twice a day for 5\xa0to 7\xa0days\n\nErythromycin is preferred if a macrolide is needed in pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. See the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy.\n\nSecond-choice oral antibiotic (worsening symptoms on first choice taken for at least 2\xa0to 3\xa0days)\n\nCo-amoxiclav:\n\nmonth to 11\xa0months, 0.25\xa0ml/kg of 125/31 suspension three times a day for 5\xa0to 7\xa0days\n\nyear to 5\xa0years, 5\xa0ml of 125/31 suspension three times a day or 0.25\xa0ml/kg of 125/31 suspension three times a day for 5\xa0to 7\xa0days\n\nyears to 11\xa0years, 5\xa0ml of 250/62 suspension three times a day or 0.15\xa0ml/kg of 250/62 suspension three times a day for 5\xa0to 7\xa0days\n\nyears to 17\xa0years, 250/125\xa0mg or 500/125\xa0mg three times a day for 5\xa0to 7\xa0days\n\nAlternative second choice for penicillin allergy or intolerance\n\nConsult local microbiologist\n\nSee the BNF for children for appropriate use and dosing in specific populations, for example, hepatic impairment and renal impairment.\n\nThe age bands apply to children of average size. In practice, the prescriber will use the age bands along with other factors such as the severity of the condition and the child's size in relation to the average size of children of the same age. Doses given are by mouth using immediate-release medicines, unless otherwise stated. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the evidence and committee discussion on choice of antibiotic and antibiotic course length.\n\nFull details of the evidence and the committee's discussion are in the evidence review.", 'Summary of the evidence': "The recommendations in this guideline are based on the evidence identified, which was for children and young people under 18\xa0years. \n\n# Non‑antimicrobial treatments\n\n## Oral analgesia (paracetamol and ibuprofen)\n\nParacetamol and ibuprofen were both more effective than placebo in reducing pain at 48\xa0hours in children with acute otitis media (number needed to treat [NNT] 6\xa0to\xa07 [range 4\xa0to\xa027] for no pain at 48\xa0hours; low to moderate quality evidence). This was based on a systematic review of randomised controlled trials (RCTs; Sjoukes et al.\xa02016). There were no significant differences in fever at 48\xa0hours with paracetamol or ibuprofen compared with placebo (very low quality evidence). \n\nNo significant differences were found between paracetamol and ibuprofen for pain or fever at various time points (very low to low quality evidence). Furthermore, using ibuprofen and paracetamol in combination was no more effective than paracetamol alone, although this was based on very small numbers of children (very low to low quality evidence; Sjoukes et al.\xa02016). \n\nAdverse events for paracetamol and ibuprofen were not significantly different from placebo (very low to low quality evidence). However, this should be interpreted cautiously because of the small number of children and the infrequent occurrence of adverse events (Sjoukes et al.\xa02016). \n\n## Eardrops containing an anaesthetic and an analgesic\n\nEardrops containing an anaesthetic and an analgesic statistically significantly increased the proportion of children with a 50% and a 25% reduction in pain compared with placebo (NNT\xa05 [range 3\xa0to\xa016] for 50% pain reduction 10\xa0minutes after having eardrops; low quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Foxlee et al.\xa02011). These children were aged 3\xa0years and over without eardrum perforation and were also having oral analgesia. \n\nEardrops containing an anaesthetic and an analgesic statistically significantly reduced antibiotic consumption at day\xa08 compared with usual care (no or delayed antibiotic prescription; 2.6% compared with 29.0%; moderate quality evidence). There was also a statistically significant reduction in parent‑reported pain scores at day\xa02 (low quality evidence). This was based on an RCT in children aged 1\xa0to 10\xa0years who did not need immediate antibiotics (Hay et al. 2019). Most children (88%) were also having oral analgesia. \n\nNo adverse effects were seen with eardrops containing an anaesthetic and an analgesic, but this was based on very small numbers of children (very low to low quality evidence; Foxlee et al.\xa02011, Hay et al. 2019). [2018, amended 2022]\n\n## Decongestants and antihistamines\n\nOverall, decongestants and antihistamines, used alone or in combination, did not improve clinical outcomes in children with acute otitis media who were taking antibiotics (used in 14\xa0out of 15\xa0RCTs; very low to low quality evidence). This was based on a systematic review and meta-analysis of RCTs (Coleman et al.\xa02008). There was a reduction in the rate of persistent acute otitis media at 2\xa0weeks with a combination of decongestant plus antihistamine compared with placebo (NNT\xa011 [range 6\xa0to\xa0104]; low quality evidence). However, a subgroup analysis of higher quality studies found no benefit with treatment. \n\nAdverse effects (excluding drowsiness and hyperactivity) were significantly increased with decongestants, but not with antihistamines or a combination of decongestant plus antihistamine, compared with placebo (very low quality evidence). However, there is considerable uncertainty about these results (Coleman et al.\xa02008). \n\n# Oral corticosteroids\n\nOral prednisolone taken for 5\xa0days did not improve any clinical outcomes in children aged 3\xa0months to 6\xa0years with acute otitis media who were at risk of recurrence (at least 2\xa0previous episodes of acute otitis media), compared with placebo (very low quality evidence). Outcomes included treatment failure during the first 2\xa0weeks, duration of effusion and recurrence. This was based on a small RCT (Chonmaitree et al.\xa02003). \n\nAdverse effects or discontinuations because of adverse effects did not appear to be significantly different between prednisolone and placebo, although the study was very small and full data were not reported (low quality evidence; Chonmaitree et al.\xa02003). \n\nSystemic effects (mineralocorticoid and glucocorticoid) may occur with oral corticosteroids, including a range of psychological or behavioural effects (particularly in children; Drug Safety Update on inhaled and intranasal corticosteroids). \n\n## Committee discussion on non-antimicrobial treatments\n\nThe committee discussed the importance of managing a child's pain and felt that for parents this is the main priority. They agreed that paracetamol or ibuprofen needs to be taken at the right time and at the right dose, with maximum doses being used for severe pain. \n\nBased on evidence and their experience, the committee agreed that paracetamol or ibuprofen should be offered for pain associated with acute otitis media. Parents or carers could be advised to buy paracetamol or ibuprofen over the counter in line with local policies on the prescribing of such medicines. \n\nBased on evidence, the committee agreed that eardrops containing an anaesthetic and an analgesic (in addition to oral analgesics) may reduce antibiotic consumption and relieve pain in children who did not need immediate antibiotics. \n\nThey recognised that these eardrops should not be used in children with eardrum perforation or otorrhoea. They discussed the rare adverse effect of methemoglobinemia (associated with topical anaesthetics in very young children). They noted that the age of the children varied in the studies (from 1\xa0year), but that there is no age-based restriction for using the licensed preparation (phenazone with lidocaine [Otigo] eardrops). \n\nThey were aware that there is currently only 1\xa0licensed preparation (a prescription only medicine), which was not the preparation used in the studies. However, the committee were content that a class effect would be seen. \n\nThere is no direct evidence to support the use of eardrops containing an anaesthetic and an analgesic in children who need immediate antibiotics. The committee agreed that it is uncertain whether these eardrops would provide additional benefit when used with oral analgesia in children having immediate antibiotics. Therefore, they recommended their use only for children who do not need an immediate oral antibiotic. \n\nThe committee agreed that evidence does not support using decongestants or antihistamines to help symptoms of acute otitis media. \n\nThe committee agreed, based on the evidence, not to make a recommendation on the use of oral corticosteroids to manage acute otitis media in children. \n\n# No antibiotic\n\nAcute otitis media is a self-limiting infection of the middle ear. It can be caused by viruses or bacteria, and both are often present at the same time. In most children acute otitis media resolves without treatment. \n\nThe most common bacterial causes of acute otitis media are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes (the Canadian Paediatric Society's position statement, 2016). \n\nMore common complications of acute otitis media are recurrence of infection, hearing loss (which is usually temporary) and perforated eardrum. However, antibiotics make little difference to the rates of these (see efficacy of antibiotics). \n\nAcute complications of acute otitis media (such as mastoiditis, meningitis, intracranial abscess, sinus thrombosis and facial nerve paralysis) are rare. The incidence of mastoiditis after otitis media is 1.8\xa0per 10,000\xa0episodes after antibiotics compared with 3.8\xa0per 10,000\xa0episodes without antibiotics. This gives a NNT of\xa04,831 to prevent 1\xa0child from developing mastoiditis (Thompson et al.\xa02009). \n\n## Efficacy of antibiotics\n\nAntibiotics did not significantly reduce pain at 24\xa0hours compared with placebo in children with acute otitis media; around 60% of children in both groups had no pain (high quality evidence). Antibiotics did significantly reduce pain at 2\xa0to\xa03\xa0days, but the absolute difference was small; 88% of children had no pain in the antibiotic group compared with 84% in the placebo group (NNT\xa024 [range 15\xa0to\xa070]; moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Venekamp et al.\xa02015). \n\nAntibiotics significantly reduced the number of children with abnormal tympanometry findings (a surrogate measure for hearing loss) compared with placebo at 2\xa0to\xa04\xa0weeks, but not at 6\xa0to\xa08\xa0weeks or 3\xa0months. However, the absolute difference was small; at 2\xa0to 4\xa0weeks, 39% of children had abnormal tympanometry findings with antibiotics compared with 48% with placebo (NNT\xa012 [range 18\xa0to\xa021]; low quality evidence; Venekamp et al.\xa02015). \n\nAntibiotics significantly reduced the number of children with eardrum perforation. However, again the absolute benefits were small with 5% of children having a perforation in the placebo group compared with 2% in the antibiotic group (NNT\xa033 [range 20\xa0to\xa0100]; moderate quality evidence; Venekamp et al.\xa02015). \n\nAntibiotics did not reduce the number of children with late recurrence of acute otitis media (which was common in both groups: 18% of children taking antibiotics compared with 20% of children taking placebo, moderate quality evidence; Venekamp et al.\xa02015). \n\nAntibiotics seem to be more beneficial in 2\xa0pre-defined groups of children, based on subgroup analyses of intervention studies comparing antibiotics with placebo. Firstly, children under 2\xa0years with bilateral acute otitis media, where the NNT was 4\xa0for symptom resolution (low quality evidence). Secondly, children with acute otitis media and otorrhoea (discharge following eardrum perforation), where the NNT was 3\xa0for symptom resolution (moderate quality evidence). This was based on a meta-analysis of individual patient data from RCTs (Rovers et al.\xa02006). However, the literature search was not designed specifically to identify prognostic evidence. \n\nNo systematic reviews or RCTs of topical antibiotics were identified. \n\n## Safety of antibiotics\n\nAllergic reactions to penicillins occur in 1\xa0to\xa010% of people and anaphylactic reactions occur in less than\xa00.05%. People with a history of atopic allergy (for example, asthma, eczema and hay fever) have a higher risk of anaphylactic reactions to penicillins. People with a history of immediate hypersensitivity to penicillins may also react to cephalosporins and other beta‑lactam antibiotics (BNF information on phenoxymethylpenicillin). See the NICE guideline on drug allergy for more information. \n\nAntibiotic-associated diarrhoea occurs in 2\xa0to\xa025% of people taking antibiotics, depending on the antibiotic used (NICE Clinical Knowledge Summary on diarrhoea – antibiotic associated). \n\nAdverse events (vomiting, diarrhoea or rash) were significantly increased in children with acute otitis media taking antibiotics compared with those taking placebo (moderate quality evidence). The number needed to harm (NNH) was\xa013 (range 9\xa0to\xa025). This was based on a systematic review and meta-analysis of RCTs (Venekamp et al.\xa02015). \n\nSee the summaries of product characteristics for information on contraindications, cautions and adverse effects of individual medicines. \n\nAcute otitis media can be caused by viral or bacterial infections, both of which are usually self-limiting and do not routinely need antibiotics. \n\nBased on evidence, the committee agreed that antibiotics make little difference to ear pain or to the rates of more common complications, such as recurrence of infection. The small increased risk of perforation was noted, but 33\xa0children (range 20\xa0to\xa0100) would need to be treated with antibiotics to avoid 1\xa0child experiencing perforation. Antibiotics also made little difference to short-term hearing loss as assessed by the surrogate marker of tympanometry. \n\nMore serious complications of acute otitis media, such as mastoiditis, are rare and the NNT with antibiotics to prevent 1\xa0child from developing mastoiditis is approximately 5,000. \n\nThe committee acknowledged the recommendation in the NICE guideline on respiratory tract infections (self-limiting): prescribing antibiotics for no antibiotic or a back-up antibiotic prescription for most children with acute otitis media. \n\n# Back-up antibiotics\n\nA back-up antibiotic prescription or watchful waiting was as effective as immediate antibiotics in children with acute otitis media for reducing pain at 3\xa0to\xa07\xa0days (moderate quality evidence). There were also no significant differences between groups for abnormal tympanometry findings (a surrogate measure for hearing loss), eardrum perforation or recurrence of infection (very low to moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Venekamp et al.\xa02015). \n\nA back-up antibiotic prescription was compared with no antibiotics and immediate antibiotics in a systematic review of RCTs (Spurling et al.\xa02013). In 1\xa0RCT there was no significant difference between back-up antibiotics and no antibiotics for pain or fever on day\xa03 (very low to low quality evidence). In 1\xa0RCT there was no significant difference between back-up antibiotics and immediate antibiotics for pain on day\xa03 (moderate quality evidence). \n\nImmediate antibiotics were associated with a significantly increased risk of adverse events (vomiting, diarrhoea or rash) compared with back-up antibiotics or watchful waiting (NNH\xa08 [range 5\xa0to\xa019]; moderate quality evidence; Venekamp et al.\xa02015).\n\nThe incidence of vomiting or rash was not significantly different with back‑up antibiotics compared with immediate antibiotics (very low quality evidence), but there was significantly less diarrhoea with back‑up antibiotics (NNH\xa08 [range 5\xa0to\xa015]; data pooled by NICE; high quality evidence; Spurling et al.\xa02013). No safety data were available on back‑up antibiotics compared with no antibiotics.\n\n## Committee discussion on back-up antibiotics\n\nBased on evidence, the committee agreed that no antibiotic prescription or a back-up antibiotic prescription could be considered for most children with acute otitis media.\n\nThe committee discussed that acute otitis media could have a viral or a bacterial cause, and distinguishing between these is difficult. However, both are usually self-limiting and do not routinely need antibiotics. The committee discussed that a back-up antibiotic prescription may be preferred over no antibiotic in some children, but that prescribers need to weigh up the small clinical benefits from antibiotics against their potential to cause adverse effects.\n\nThe committee agreed that a back-up antibiotic prescription could be used if symptoms significantly worsen or do not improve within 3\xa0days (by which time most self-limiting infections would be starting to resolve), or if they worsen rapidly or significantly at any time.\n\nThe committee acknowledged the recommendations in the previous NICE guideline on upper respiratory tract infections that, for acute otitis media, a no antibiotic prescribing strategy or a back-up antibiotic prescribing strategy should be agreed, but that depending on clinical assessment of severity, immediate antibiotics can also be considered for children under 2\xa0years with infection in both ears or children of any age with otorrhoea (discharge following perforation of the eardrum). For these subgroups the committee agreed that an immediate antibiotic prescription could also be considered as an option, because antibiotics may be more likely to be beneficial in these subgroups. The committee discussed that an immediate antibiotic may be preferred over no antibiotic or a back-up antibiotic prescription in some children based on clinical judgement.\n\nThe committee agreed that immediate antibiotics are important for children who are systemically very unwell, have symptoms or signs of a more serious illness, or are at high risk of serious complications because of pre-existing comorbidity. This includes children with significant heart, lung, renal, liver or neuromuscular disease, immunosuppression, cystic fibrosis, and young children who were born prematurely.\n\n# Choice of antibiotic\n\nThere were no major differences in treatment success between classes of antibiotics, including penicillins, cephalosporins and macrolides for treating uncomplicated acute otitis media in children. There was no difference in treatment success between ampicillin or amoxicillin compared with ceftriaxone; co‑amoxiclav compared with ceftriaxone; co‑amoxiclav compared with azithromycin; or cefaclor compared with azithromycin (low to moderate quality evidence). This was based on a systematic review and meta-analysis of RCTs (Shekelle et al.\xa02010).\n\nCo‑amoxiclav was associated with significantly more adverse events than a cephalosporin (very low to moderate quality evidence) or azithromycin (moderate quality evidence; Shekelle et al.\xa02010).\n\nShekelle et al.\xa02010 also considered evidence for treating recurrent or persistent acute otitis media in children. None of the studies found a significant benefit in treatment success for any particular antibiotic (moderate quality evidence). There were 5\xa0individual RCTs that compared different antibiotic treatments: co‑amoxiclav compared with gatifloxacin (2\xa0RCTs), co‑amoxiclav compared with levofloxacin (1\xa0RCT), co‑amoxiclav compared with azithromycin (1\xa0RCT), and cefaclor compared with cefuroxime (1\xa0RCT).\n\n## Committee discussion on choice of antibiotic\n\nBased on evidence of no major differences in clinical effectiveness between classes of antibiotics, the committee agreed that the choice of antibiotic should largely be driven by minimising the risk of resistance.\n\nThe committee discussed that, if an antibiotic is needed to treat an infection that is not life-threatening, a narrow-spectrum antibiotic should generally be first choice. Indiscriminate use of broad-spectrum antibiotics creates a selective advantage for bacteria resistant even to these 'last-line' broad-spectrum agents, and also kills normal commensal flora leaving people susceptible to antibiotic-resistant harmful bacteria such as Clostridium difficile. For infections that are not life-threatening, broad-spectrum antibiotics need to be reserved for second-choice treatment when narrow-spectrum antibiotics are ineffective.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend amoxicillin as the first choice because this is current practice for antibiotic treatment in children with acute otitis media, and the risk of resistance is acceptable. The dosage of 125\xa0mg to 500\xa0mg three times a day (based on age) is the usual dose, and was similar to that used in studies in the evidence review. The committee discussed that phenoxymethylpenicillin has a lower risk of resistance than amoxicillin, and microbiologically would be expected to be equivalent. However, medicines adherence is particularly important for children, and acute otitis media most commonly presents in young children. Amoxicillin has a three times a day dosage rather than four times a day for phenoxymethylpenicillin, and the liquid formulation is more palatable.\n\nBased on evidence, their experience and resistance data, the committee agreed to recommend clarithromycin as the alternative first-choice antibiotic for use in penicillin allergy or amoxicillin intolerance. In pregnancy, erythromycin was recommended if there is true penicillin allergy. The doses recommended (based on weight and age) are the usual doses for children, and were similar to those used in studies in the evidence review. The committee discussed that there was evidence for another macrolide, azithromycin. However, they agreed not to recommend this because clarithromycin or erythromycin are current practice, and azithromycin should be reserved for more serious infections.\n\nThe committee discussed the Medicines and Healthcare products Regulatory Agency (MHRA) Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides. \n\nBased on evidence, their experience and resistance data, the committee agreed to recommend co‑amoxiclav as the second-choice antibiotic for use if symptoms worsen on a first-choice antibiotic taken for at least 2\xa0to\xa03\xa0days. This broad-spectrum treatment combines a penicillin (amoxicillin) with a beta-lactamase inhibitor, making it active against beta-lactamase-producing bacteria that are resistant to amoxicillin alone. People who do not respond to amoxicillin may be more likely to have an infection that is resistant to it. The dosage of 0.25\xa0ml/kg of 125/31\xa0suspension to 250/125\xa0mg or 500/125\xa0mg three times a day (based on weight and age) is the usual dose for children, and was similar to that used in studies in the evidence review. \n\n# Antibiotic course length\n\nA short course of antibiotics (more than 48\xa0hours but less than 7\xa0days) was associated with significantly higher treatment failure at 8\xa0to\xa019\xa0days, or 1\xa0month or less, compared with a long course (7\xa0days or longer). Treatment failure (defined as a lack of clinical resolution, relapse or recurrence of acute otitis media within 1\xa0month of starting treatment) occurred in 18.0% of the short-course group compared with 14.4% of the long-course group at 8\xa0to\xa019\xa0days (NNT\xa028 [range 17\xa0to\xa077]; very low quality evidence), and in 20.5% of the short-course group compared with 17.5% of the long-course group at 1\xa0month or less (NNT\xa034 [range 20\xa0to\xa0124]; low quality evidence). However, there was no difference in treatment failure between short and long courses at other time points. This was based on a systematic review and meta‑analysis of RCTs (Kozyrskyj et al.\xa02010). \n\nThere were significantly fewer gastrointestinal adverse events with a short course of antibiotics (more than 48\xa0hours but less than 7\xa0days) compared with a long course (7\xa0days or longer; very low quality evidence). However, this result was based on the reported odds ratio and was not statistically significant when the relative risk was calculated (Kozyrskyj et al.\xa02010). \n\n## Committee discussions on antibiotic course length\n\nThe committee agreed that, when an antibiotic is appropriate, the shortest course that is likely to be effective should be prescribed to minimise the risk of antimicrobial resistance. \n\nBased on evidence, their experience and resistance data, the committee agreed that a 5‑ to 7‑day course of all the recommended antibiotics was sufficient to treat acute otitis media in children. This takes into account both the evidence for clinical effectiveness and the evidence for safety and tolerability of antibiotics, and minimises the risk of resistance. Studies on the use of specific antibiotics to treat acute otitis media sometimes had longer course lengths than 7\xa0days. \n\nThe committee noted that no studies were identified that directly compared a 5‑day course of antibiotics with a 7‑day course. \n\nBased on evidence, the committee recognised that more children may have treatment failure with an antibiotic course of less than 7\xa0days compared with a course of 7\xa0days or more. However, the absolute difference is small. At 8\xa0to\xa019\xa0days, 82% of children taking antibiotics for less than 7\xa0days were better, compared with 86% of those taking antibiotics for 7\xa0days or more. They agreed that, if a decision to prescribe an antibiotic is made, a 5‑day course may be sufficient for many children, reserving 7‑day courses for those with a clinical assessment of more severe or recurrent infection. \n\n# Antibiotic dose frequency\n\nOnce or twice daily dosing of amoxicillin or co‑amoxiclav was as effective as three times a day dosing for clinical cure rates at the end of antibiotic treatment (high quality evidence). The duration of treatment was 10\xa0days in most studies, and the dose of amoxicillin or co‑amoxiclav varied. There were no significant differences in the rates of recurrence (very low to low quality evidence), adverse effects (very low to low quality evidence) and adherence (high quality evidence). This was based on a systematic review and meta‑analysis of RCTs (Thanaviratananich et al.\xa02013). \n\n## Committee discussions on antibiotic dose frequency\n\nThe committee discussed the evidence for once or twice daily dosing of amoxicillin and co‑amoxiclav, but it is unknown if this would have a detrimental effect on the risk of resistance to these antibiotics. The evidence supporting once or twice daily dosing is for different doses and longer treatment durations. This goes against the general principle of antimicrobial stewardship to prescribe the shortest course that is effective. \n\nThe committee agreed that, when prescribing amoxicillin or co‑amoxiclav, a dosing frequency of three times a day should be prescribed, as is current practice. \n\nSee the full evidence review for more information.", 'Other considerations': '# Medicines adherence\n\nMedicines adherence may be a problem for some people with medicines that require frequent dosing (for example, some antibiotics) or longer treatment duration (see the NICE guideline on medicines adherence). \n\n# Resource implications\n\nRespiratory tract infections, including acute otitis media, are a common reason for consultations in primary care, and therefore are a common reason for potential antibiotic prescribing. \n\nThere is potential for resource savings if no antibiotic or a back-up antibiotic prescription is used. There was significantly lower antibiotic use with back‑up antibiotics compared with immediate antibiotics, both when the back‑up antibiotic prescription was given at the time of consultation (38% compared with 87%; moderate quality evidence) and when the prescription had to be collected on a separate visit (24% compared with 87%; high quality evidence). There was no significant difference between groups in re‑consultation rates (low quality evidence). This was based on a systematic review of RCTs (Spurling et al.\xa02013). \n\nRecommended antibiotics are all available as generic formulations. Eardrops containing an anaesthetic and an analgesic (Otigo eardrops) are a prescription only medicine. See the Drug Tariff for costs. '}
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https://www.nice.org.uk/guidance/ng91
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This guideline sets out an antimicrobial prescribing strategy for acute otitis media (ear infection). It aims to limit antibiotic use and reduce antimicrobial resistance. Acute otitis media can be caused by viruses or bacteria. It lasts for about a week, and most children get better in 3 days without antibiotics. Serious complications are rare.
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500038dab18f3bf0a16f0d982248e71a167bf24f
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nice
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Percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis
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Percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis
Evidence-based recommendations on percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis. This involves inserting a tube called a stent into or across the cystic duct. The aim is to allow bile to flow through the tube, bypassing the blockage and preventing further obstruction.
# Recommendations
Evidence on the safety and efficacy of percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis is inadequate in quality and quantity. But because patients would otherwise need permanent external drainage, the procedure can be considered for this condition, as long as special arrangements for clinical governance, consent, and audit or research are in place. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wanting to do percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by a multidisciplinary team.
This procedure should only be done in specialist centres by clinicians with specific training and experience in this procedure.
Further research should report details of patient selection, the procedure undertaken, the type of stent used and whether the patient is later able to have definitive surgery.# The condition, current treatments and procedure
# The condition
Acute calculous cholecystitis is inflammation of the gallbladder caused by a gallstone or biliary sludge that blocks the cystic duct. The blockage in the cystic duct causes bile to build up in the gallbladder, increasing the pressure inside it and causing it to become inflamed. Symptoms include pain, fever, nausea and vomiting.
# Current treatments
Treatments include intravenous fluids, medicines (analgesics and antibiotics), endoscopic or percutaneous biliary drainage, and surgery (laparoscopic or open cholecystectomy). NICE's guideline on gallstone disease recommends offering early laparoscopic cholecystectomy (to be carried out within 1 week of diagnosis) to patients with acute cholecystitis.
# The procedure
This procedure places a stent via a cholecystostomy tract into the cystic duct to provide antegrade gallbladder drainage and prevent further obstructive episodes of cholecystitis. This procedure is suitable for patients who otherwise need long-term external drainage.
Before the procedure, a percutaneous cholecystostomy and drainage is done to resolve the acute episode. This procedure is usually done using conscious sedation. The cholecystostomy drain is used for cholangiography to confirm cystic duct obstruction. Under fluoroscopic guidance, a guidewire and catheter are passed through the cholecystostomy tract, through the cystic duct and into the duodenum. A stent is then inserted and placed in or across the cystic duct.
After the procedure, an external gallbladder drain is usually left in situ for a few days to ensure that there is good antegrade drainage of bile into the duodenum. The external drain can then be removed after a satisfactory cholangiogram.
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{'Recommendations': "Evidence on the safety and efficacy of percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis is inadequate in quality and quantity. But because patients would otherwise need permanent external drainage, the procedure can be considered for this condition, as long as special arrangements for clinical governance, consent, and audit or research are in place. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team.\n\nThis procedure should only be done in specialist centres by clinicians with specific training and experience in this procedure.\n\nFurther research should report details of patient selection, the procedure undertaken, the type of stent used and whether the patient is later able to have definitive surgery.", 'The condition, current treatments and procedure': "# The condition\n\nAcute calculous cholecystitis is inflammation of the gallbladder caused by a gallstone or biliary sludge that blocks the cystic duct. The blockage in the cystic duct causes bile to build up in the gallbladder, increasing the pressure inside it and causing it to become inflamed. Symptoms include pain, fever, nausea and vomiting.\n\n# Current treatments\n\nTreatments include intravenous fluids, medicines (analgesics and antibiotics), endoscopic or percutaneous biliary drainage, and surgery (laparoscopic or open cholecystectomy). NICE's guideline on gallstone disease recommends offering early laparoscopic cholecystectomy (to be carried out within 1\xa0week of diagnosis) to patients with acute cholecystitis.\n\n# The procedure\n\nThis procedure places a stent via a cholecystostomy tract into the cystic duct to provide antegrade gallbladder drainage and prevent further obstructive episodes of cholecystitis. This procedure is suitable for patients who otherwise need long-term external drainage.\n\nBefore the procedure, a percutaneous cholecystostomy and drainage is done to resolve the acute episode. This procedure is usually done using conscious sedation. The cholecystostomy drain is used for cholangiography to confirm cystic duct obstruction. Under fluoroscopic guidance, a guidewire and catheter are passed through the cholecystostomy tract, through the cystic duct and into the duodenum. A stent is then inserted and placed in or across the cystic duct.\n\nAfter the procedure, an external gallbladder drain is usually left in situ for a few days to ensure that there is good antegrade drainage of bile into the duodenum. The external drain can then be removed after a satisfactory cholangiogram."}
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https://www.nice.org.uk/guidance/ipg720
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Evidence-based recommendations on percutaneous insertion of a cystic duct stent after cholecystostomy for acute calculous cholecystitis. This involves inserting a tube called a stent into or across the cystic duct. The aim is to allow bile to flow through the tube, bypassing the blockage and preventing further obstruction.
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10613711c2ed2c24d90cbe692371a82e50e0da7f
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nice
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Empagliflozin for treating chronic heart failure with reduced ejection fraction
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Empagliflozin for treating chronic heart failure with reduced ejection fraction
Evidence-based recommendations on empagliflozin (Jardiance) for treating chronic heart failure with reduced ejection fraction in adults.
# Recommendations
Empagliflozin is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction in adults, only if it is used as an add-on to optimised standard care with:
an angiotensin-converting enzyme (ACE) inhibitor or angiotensin 2 receptor blocker (ARB), with a beta blocker and, if tolerated, a mineralocorticoid receptor antagonist (MRA), or
sacubitril valsartan with a beta blocker and, if tolerated, an MRA.
Start empagliflozin for treating symptomatic heart failure with reduced ejection fraction on the advice of a heart failure specialist. Monitoring should be done by the most appropriate healthcare professional.
This recommendation is not intended to affect treatment with empagliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with heart failure with reduced ejection fraction may have symptoms that are not controlled well enough despite being on the most appropriate (optimised) standard care. Standard care includes an ACE inhibitor or an ARB, with a beta blocker and, if tolerated, an MRA. Then, if symptoms continue on this, people may be offered sacubitril valsartan with a beta blocker and, if tolerated, an MRA.
Evidence from a clinical trial shows that empagliflozin plus standard care reduces the risk of dying from cardiovascular causes compared with placebo plus standard care. It also shows that it reduces the likelihood of hospitalisation for heart failure. There are no trials directly comparing empagliflozin with the most appropriate comparator, dapagliflozin. However, an indirect comparison suggests that empagliflozin is likely to be similar to dapagliflozin in reducing the risk of dying and the likelihood of hospitalisations for heart failure.
The cost-effectiveness estimates for empagliflozin are within what NICE normally considers an acceptable use of NHS resources. So empagliflozin is recommended.
Increased monitoring or changes to other medicines being taken may be needed for treating heart failure with empagliflozin. So, it should only be started on advice from a heart failure specialist.# Information about empagliflozin
# Marketing authorisation indication
Empagliflozin (Jardiance, Boehringer Ingelheim) has a marketing authorisation 'in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of 10 mg or 25 mg empagliflozin is £36.59 per 28‑tablet pack (excluding VAT; BNF online, accessed November 2021). The annual treatment cost is £476.98. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by Boehringer Ingelheim, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## People with chronic heart failure with reduced ejection fraction would welcome a new treatment option
Heart failure with reduced ejection fraction is a chronic condition that affects survival and quality of life. The patient experts highlighted the psychological effects of a diagnosis. They explained that breathlessness, extreme fatigue and fluid accumulation in particular can be debilitating. Clinical expert submissions to NICE confirmed that heart failure with reduced ejection fraction is associated with high rates of death and hospitalisation. They also stated that there is an unmet need for new treatment options. Current treatments aim to manage symptoms and stabilise the disease to prevent further decline in quality of life and to keep people alive longer. The clinical experts explained that, despite optimising therapies, many people still have symptoms, including breathlessness. The patient experts said that they would welcome a new treatment option, especially if it could be used early in the treatment pathway. The committee concluded that there is an unmet need for a new treatment option for symptomatic chronic heart failure with reduced ejection fraction. It also concluded that people with the condition and healthcare professionals would welcome a new treatment option.
# The treatment pathway
## People should be optimised on standard care before having a sodium-glucose co-transporter 2 (SGLT2) inhibitor
NICE's guideline on diagnosing and managing chronic heart failure in adults recommends a range of drug treatments for newly diagnosed heart failure with reduced ejection fraction. These are separated into first-line and specialist treatments. First-line treatments include angiotensin-converting enzyme (ACE) inhibitors, or angiotensin 2 receptor blockers (ARBs) when an ACE inhibitor is not tolerated. Beta blockers can also be offered and a mineralocorticoid receptor antagonist (MRA) can be offered if appropriate and tolerated. The company's submission had suggested that empagliflozin should be positioned as an add-on to first-line treatment in people with heart failure with reduced ejection fraction who may or may not have comorbidities. The committee understood that this is narrower than the marketing authorisation, which does not specify use as an add-on treatment for heart failure with reduced ejection fraction. The clinical experts said the company's positioning was now in line with the European Society of Cardiology guidelines on the diagnosis and treatment of acute and chronic heart failure. These guidelines recommend that empagliflozin or dapagliflozin (another SGLT2 inhibitor) could be started earlier in the care pathway for heart failure with reduced ejection fraction. The committee noted this was not directly in line with NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction. This recommends that dapagliflozin is used after standard care is optimised. The committee noted that there are a range of treatments for heart failure with reduced ejection fraction. It concluded that empagliflozin was an appropriate treatment that should be used as an add-on to optimised standard care.
## Dapagliflozin is the most appropriate comparator for this appraisal
The final scope for this appraisal listed 2 comparators: individually optimised standard care without empagliflozin, and dapagliflozin as an add-on to standard care. The company stated that individually optimised standard care was the most relevant comparator. That is, people should have the most appropriate treatments used for standard care before starting treatment with empagliflozin. This was because most people with heart failure with reduced ejection fraction in England and Wales would have at least one of these treatment options. It did not consider dapagliflozin to be a relevant comparator because it considered that this was not standard care in the NHS. It cited recent market data suggesting that dapagliflozin is used by very few people with heart failure alone, and is most frequently used by people with heart failure and type 2 diabetes. The committee noted that NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction had only been published in February 2021 so there had been a relatively short period of time to consider uptake. The clinical experts stated uptake had increased widely since publication of the guidance and that it would now be considered as standard care. The committee considered whether empagliflozin and dapagliflozin would likely be used interchangeably in the same place in the treatment pathway for chronic heart failure with reduced ejection fraction. The clinical experts said that the European Society of Cardiology guidelines on the diagnosis and treatment of acute and chronic heart failure did not distinguish between the 2 SGLT2 inhibitors. For this reason, they would also consider that empagliflozin and dapagliflozin would be used in the same groups of people. They further noted that it would be unlikely that someone who is not eligible for treatment with dapagliflozin would be eligible for treatment with empagliflozin. This was because the technologies are considered to work in the same way. The committee concluded that dapagliflozin was the most appropriate comparator for this appraisal.
# Clinical evidence
## EMPEROR-Reduced is the key trial and is broadly generalisable to NHS clinical practice
EMPEROR-Reduced was a double-blind randomised clinical trial comparing empagliflozin plus standard care with placebo plus standard care. Standard care could include medical therapy with an ACE inhibitor, an ARB, a beta blocker or an MRA. The trial included people aged at least 18 who had had a diagnosis of chronic heart failure for at least 3 months. They had moderate to severe heart failure with reduced ejection fraction. This was defined by a left ventricular ejection fraction of 40% or less based on the New York Heart Association functional class 2 to 4. The clinical experts said that the trial findings were generalisable to NHS clinical practice. However, they highlighted several differences between the population in EMPEROR-Reduced and people having treatment in the NHS:
The average age in the intention-to-treat population was 67 years, while the average in the NHS at diagnosis is 77 years.
The proportion of women (24%) was smaller than would be expected in the NHS.
The proportion of people using an ACE inhibitor or ARB was lower than would be expected in the NHS.The ERG stated that the characteristics of people in EMPEROR-Reduced, may not reflect that of the population in the NHS. The clinical experts agreed this might be an issue of how people are recruited to take part in clinical trials. People who are older and who might have more comorbidities would be less likely to be involved in a clinical trial so they might be under-represented. The committee noted EMPEROR-Reduced was not powered to show any difference in subgroups by age. The clinical experts said there would be no apparent reason why relative treatment effects would be different between subgroups of younger and older ages. The committee concluded that data from the intention-to-treat population in EMPEROR-Reduced was broadly generalisable to NHS clinical practice.
## Empagliflozin plus standard care compared with placebo plus standard care is clinically effective
The primary efficacy outcome in EMPEROR-Reduced was a composite of cardiovascular death and hospitalisation for heart failure. Intention-to-treat analyses showed that empagliflozin plus standard care reduced the incidence of the primary outcome by 25.0% compared with placebo plus standard care (hazard ratio 0.75; 95% confidence interval 0.65 to 0.86; p<0.0001). At a median follow up of 16 months, results showed that 19.4% of people having empagliflozin plus standard care had an event compared with 24.7% in the placebo group. The committee concluded that empagliflozin is clinically effective compared with placebo and that it reduces the risk of cardiovascular events when added to standard care.
# Indirect treatment comparison
## The indirect treatment comparison shows that clinical outcomes between empagliflozin and dapagliflozin are similar
There were no trials directly comparing empagliflozin with dapagliflozin so the company presented an indirect treatment comparison using the Bucher method. This compared the results from EMPEROR-Reduced with those from DAPA‑HF. DAPA‑HF was a phase 3 multinational double-blind randomised controlled trial. It compared dapagliflozin plus standard care with placebo plus standard care in people with stable symptoms of heart failure with reduced ejection fraction. The company supported the indirect comparison with the results from a published pooled meta-analysis reported by Zannad et al. (2020). This pooled data for dapagliflozin and empagliflozin to create class effect estimates for SGLT2 inhibitors compared with placebo. The ERG broadly agreed that the results from the meta-analyses suggested there was a statistically significant benefit with SGLT2 inhibitors compared with placebo for all outcomes. However, the ERG noted that the results of the meta-analysis were only based on 1 trial of empagliflozin and 1 trial of dapagliflozin. It therefore considered the Bucher comparison was a more appropriate method of assessing the comparative efficacy of empagliflozin compared with dapagliflozin. The results of the indirect treatment comparison suggested there was no difference between empagliflozin and dapagliflozin in any of the outcomes (all results are confidential and cannot be reported here). However, the results suggested a trend towards possible differences in cardiovascular deaths, all-cause mortality and renal function. The committee was aware that the ERG had explored this uncertainty in the cost–utility analysis (see section 3.8). The committee noted that there were some baseline differences in the Bucher indirect treatment comparison between people in EMPEROR-Reduced and DAPA‑HF. People in EMPEROR-Reduced may have had a more severe renal impairment than people in DAPA‑HF. This meant that people in EMPEROR-Reduced may have been more likely to have a hospitalisation for heart failure or mortality event compared with those in DAPA‑HF. The committee acknowledged the limitations of the comparison but agreed it was appropriate for decision making. The committee concluded that the results of the Bucher indirect treatment comparison showed that the clinical outcomes between empagliflozin and dapagliflozin are similar.
# The company's economic model
## The company's model is suitable for decision making
The company modelled cost effectiveness using a state transition model with 5 states (4 based on symptom severity plus 1 for death). It captured disease severity using the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS). This is a disease-specific measure of quality of life. People transitioned through quartiles based on KCCQ‑CSS (0 to 100, with high scores indicating lower symptom burden), and a specific utility and cost associated with each state. The committee considered whether the KCCQ is an appropriate measure to capture quality-of-life outcomes. It noted that there may be some inconsistencies in how the size of effect translates from trial data to modelled quality-of-life effects. The clinical experts explained that the KCCQ is a well-validated comprehensive quality-of-life and symptom questionnaire for heart failure. The ERG stated that it was satisfied with the company's choice of KCCQ‑CSS states in the model. The committee concluded that the company's model structure was appropriate for decision making.
# Cost-effectiveness estimates
## Empagliflozin is recommended as an option for treating chronic heart failure with reduced ejection fraction
The company considered that a cost-comparison was the most appropriate way to estimate the cost effectiveness of empagliflozin compared with dapagliflozin. This was based on an assumption of equivalent effectiveness between empagliflozin and dapagliflozin. It noted that both drugs had the same list price, dosing frequency and method of administration, and that available evidence suggested the treatments were clinically equivalent. The ERG suggested that a cost–utility analysis may have been more appropriate. This was because the company's assumption of equal effectiveness was based on only 2 trials and ignored potential uncertainty (see section 3.6). After technical engagement, the company provided a cost–utility analysis to help with decision making. However, it argued that this type of analysis would amplify any uncertainty in the results of the indirect treatment comparison. The company's base-case cost–utility analysis assumed there was no survival benefit with empagliflozin over dapagliflozin. However, it assumed that taking empagliflozin would lead to improvements in renal function and reduced hospitalisations for heart failure. This was based on the results of the Bucher indirect treatment comparison (see section 3.6). The company's probabilistic and deterministic cost-effectiveness estimates suggested that empagliflozin dominated dapagliflozin (meaning it was less costly and at least equally effective). The ERG did additional scenario analyses to show the effect of adding the different outcomes included in the Bucher indirect treatment comparison. These scenarios included the following assumptions:
equal effectiveness in all outcomes
survival benefit for dapagliflozin
survival benefit for dapagliflozin and a reduction in hospitalisations for heart failure for empagliflozin
survival benefit for dapagliflozin, a reduction in hospitalisations for heart failure and an improvement in renal function for empagliflozin.For the assumption of equal effectiveness, the results showed no difference in total costs or quality-adjusted life years between the 2 treatments. The results for the other scenarios included in the ERG's analyses were in the south-west quadrant of the cost-effectiveness plane. This means that empagliflozin was estimated to be less costly and less effective than dapagliflozin (the exact results are academic in confidence and cannot be reported here). The committee understood that the ERG's scenarios were exploratory only. It also agreed that they were uncertain. This was because they were based on the results of the Bucher indirect treatment comparison, which showed no overall difference between the 2 treatments. The committee considered its earlier conclusion that dapagliflozin was the most appropriate comparator (see section 3.3) based on:
its comparable mechanism of action
its use in a comparable place in the treatment pathway
the results of the indirect treatment comparison, which showed no difference between the 2 treatments.The committee was satisfied that empagliflozin is similarly effective to dapagliflozin and that its costs are identical. It concluded to recommend empagliflozin as an option for treating symptomatic chronic heart failure with reduced ejection fraction.
## Empagliflozin is not a step-change in treatment but does provide choice for people with heart failure with reduced ejection fraction
The committee recalled that people with heart failure with reduced ejection fraction have a poor prognosis and that there is an unmet need for treatment options (see section 3.1). It noted that empagliflozin is not the first drug of its class to gain regulatory approval for use in heart failure. So, it could not be considered a step-change in treatment. However, the committee concluded that it could be considered a relevant addition to current treatments and increase clinical choice.
# Other factors
## No equalities considerations were identified
The committee noted that the meta-analysis by Zannad et al. (2020; see section 3.6) suggested that SGLT2 inhibitors were most effective in people with a black or Asian family background. It noted that EMPEROR-Reduced mainly included people with a white family background. The committee noted that neither EMPEROR-Reduced or DAPA‑HF was powered to show difference between subgroups of different ages or people from a different family background. The clinical experts said that there is no reason to restrict empagliflozin use in adults based on age or family background. The committee noted that its recommendations applied to all people regardless of family background. It recognised that there were no ongoing clinical trials or data collection to validate the possibility of differences in treatment effect because of family background. But it considered that there may be the potential to explore this issue further in future research.
## A heart failure specialist should advise on starting empagliflozin and the most appropriate healthcare professional should monitor treatment
NICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team should work in collaboration with the primary care team to start new medicines that need specialist supervision. The committee noted that people taking empagliflozin for heart failure who also have diabetes might need adjustments in their diabetes medication for safety reasons because of an increased risk of ketoacidosis. The committee considered that risk factors should be identified, and some increased monitoring may be needed for treating heart failure with empagliflozin. So, it considered that a heart failure specialist was the most appropriate clinician to advise on starting treatment. The committee also noted that the summary of product characteristics states an assessment of renal function is recommended before starting empagliflozin and this should be done periodically during treatment. So, the committee considered that monitoring should be done by the most appropriate healthcare professional. The committee further noted that NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction included recommendations on who should advise on starting treatment and appropriate monitoring. The committee concluded that a heart failure specialist should advise on starting empagliflozin and monitoring should be done by the most appropriate healthcare professional.
|
{'Recommendations': 'Empagliflozin is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction in adults, only if it is used as an add-on to optimised standard care with:\n\nan angiotensin-converting enzyme (ACE) inhibitor or angiotensin\xa02 receptor blocker (ARB), with a beta blocker and, if tolerated, a mineralocorticoid receptor antagonist (MRA), or\n\nsacubitril valsartan with a beta blocker and, if tolerated, an MRA.\n\nStart empagliflozin for treating symptomatic heart failure with reduced ejection fraction on the advice of a heart failure specialist. Monitoring should be done by the most appropriate healthcare professional.\n\nThis recommendation is not intended to affect treatment with empagliflozin that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with heart failure with reduced ejection fraction may have symptoms that are not controlled well enough despite being on the most appropriate (optimised) standard care. Standard care includes an ACE inhibitor or an ARB, with a beta blocker and, if tolerated, an MRA. Then, if symptoms continue on this, people may be offered sacubitril valsartan with a beta blocker and, if tolerated, an MRA.\n\nEvidence from a clinical trial shows that empagliflozin plus standard care reduces the risk of dying from cardiovascular causes compared with placebo plus standard care. It also shows that it reduces the likelihood of hospitalisation for heart failure. There are no trials directly comparing empagliflozin with the most appropriate comparator, dapagliflozin. However, an indirect comparison suggests that empagliflozin is likely to be similar to dapagliflozin in reducing the risk of dying and the likelihood of hospitalisations for heart failure.\n\nThe cost-effectiveness estimates for empagliflozin are within what NICE normally considers an acceptable use of NHS resources. So empagliflozin is recommended.\n\nIncreased monitoring or changes to other medicines being taken may be needed for treating heart failure with empagliflozin. So, it should only be started on advice from a heart failure specialist.', 'Information about empagliflozin': "# Marketing authorisation indication\n\nEmpagliflozin (Jardiance, Boehringer Ingelheim) has a marketing authorisation 'in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of 10\xa0mg or 25\xa0mg empagliflozin is £36.59 per 28‑tablet pack (excluding VAT; BNF online, accessed November\xa02021). The annual treatment cost is £476.98. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Boehringer Ingelheim, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## People with chronic heart failure with reduced ejection fraction would welcome a new treatment option\n\nHeart failure with reduced ejection fraction is a chronic condition that affects survival and quality of life. The patient experts highlighted the psychological effects of a diagnosis. They explained that breathlessness, extreme fatigue and fluid accumulation in particular can be debilitating. Clinical expert submissions to NICE confirmed that heart failure with reduced ejection fraction is associated with high rates of death and hospitalisation. They also stated that there is an unmet need for new treatment options. Current treatments aim to manage symptoms and stabilise the disease to prevent further decline in quality of life and to keep people alive longer. The clinical experts explained that, despite optimising therapies, many people still have symptoms, including breathlessness. The patient experts said that they would welcome a new treatment option, especially if it could be used early in the treatment pathway. The committee concluded that there is an unmet need for a new treatment option for symptomatic chronic heart failure with reduced ejection fraction. It also concluded that people with the condition and healthcare professionals would welcome a new treatment option.\n\n# The treatment pathway\n\n## People should be optimised on standard care before having a sodium-glucose co-transporter\xa02 (SGLT2) inhibitor\n\nNICE's guideline on diagnosing and managing chronic heart failure in adults recommends a range of drug treatments for newly diagnosed heart failure with reduced ejection fraction. These are separated into first-line and specialist treatments. First-line treatments include angiotensin-converting enzyme (ACE) inhibitors, or angiotensin\xa02 receptor blockers (ARBs) when an ACE inhibitor is not tolerated. Beta blockers can also be offered and a mineralocorticoid receptor antagonist (MRA) can be offered if appropriate and tolerated. The company's submission had suggested that empagliflozin should be positioned as an add-on to first-line treatment in people with heart failure with reduced ejection fraction who may or may not have comorbidities. The committee understood that this is narrower than the marketing authorisation, which does not specify use as an add-on treatment for heart failure with reduced ejection fraction. The clinical experts said the company's positioning was now in line with the European Society of Cardiology guidelines on the diagnosis and treatment of acute and chronic heart failure. These guidelines recommend that empagliflozin or dapagliflozin (another SGLT2 inhibitor) could be started earlier in the care pathway for heart failure with reduced ejection fraction. The committee noted this was not directly in line with NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction. This recommends that dapagliflozin is used after standard care is optimised. The committee noted that there are a range of treatments for heart failure with reduced ejection fraction. It concluded that empagliflozin was an appropriate treatment that should be used as an add-on to optimised standard care.\n\n## Dapagliflozin is the most appropriate comparator for this appraisal\n\nThe final scope for this appraisal listed 2\xa0comparators: individually optimised standard care without empagliflozin, and dapagliflozin as an add-on to standard care. The company stated that individually optimised standard care was the most relevant comparator. That is, people should have the most appropriate treatments used for standard care before starting treatment with empagliflozin. This was because most people with heart failure with reduced ejection fraction in England and Wales would have at least one of these treatment options. It did not consider dapagliflozin to be a relevant comparator because it considered that this was not standard care in the NHS. It cited recent market data suggesting that dapagliflozin is used by very few people with heart failure alone, and is most frequently used by people with heart failure and type\xa02 diabetes. The committee noted that NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction had only been published in February\xa02021 so there had been a relatively short period of time to consider uptake. The clinical experts stated uptake had increased widely since publication of the guidance and that it would now be considered as standard care. The committee considered whether empagliflozin and dapagliflozin would likely be used interchangeably in the same place in the treatment pathway for chronic heart failure with reduced ejection fraction. The clinical experts said that the European Society of Cardiology guidelines on the diagnosis and treatment of acute and chronic heart failure did not distinguish between the 2\xa0SGLT2 inhibitors. For this reason, they would also consider that empagliflozin and dapagliflozin would be used in the same groups of people. They further noted that it would be unlikely that someone who is not eligible for treatment with dapagliflozin would be eligible for treatment with empagliflozin. This was because the technologies are considered to work in the same way. The committee concluded that dapagliflozin was the most appropriate comparator for this appraisal.\n\n# Clinical evidence\n\n## EMPEROR-Reduced is the key trial and is broadly generalisable to NHS clinical practice\n\nEMPEROR-Reduced was a double-blind randomised clinical trial comparing empagliflozin plus standard care with placebo plus standard care. Standard care could include medical therapy with an ACE inhibitor, an ARB, a beta blocker or an MRA. The trial included people aged at least 18 who had had a diagnosis of chronic heart failure for at least 3\xa0months. They had moderate to severe heart failure with reduced ejection fraction. This was defined by a left ventricular ejection fraction of 40% or less based on the New York Heart Association functional class 2\xa0to\xa04. The clinical experts said that the trial findings were generalisable to NHS clinical practice. However, they highlighted several differences between the population in EMPEROR-Reduced and people having treatment in the NHS:\n\nThe average age in the intention-to-treat population was 67\xa0years, while the average in the NHS at diagnosis is 77\xa0years.\n\nThe proportion of women (24%) was smaller than would be expected in the NHS.\n\nThe proportion of people using an ACE inhibitor or ARB was lower than would be expected in the NHS.The ERG stated that the characteristics of people in EMPEROR-Reduced, may not reflect that of the population in the NHS. The clinical experts agreed this might be an issue of how people are recruited to take part in clinical trials. People who are older and who might have more comorbidities would be less likely to be involved in a clinical trial so they might be under-represented. The committee noted EMPEROR-Reduced was not powered to show any difference in subgroups by age. The clinical experts said there would be no apparent reason why relative treatment effects would be different between subgroups of younger and older ages. The committee concluded that data from the intention-to-treat population in EMPEROR-Reduced was broadly generalisable to NHS clinical practice.\n\n## Empagliflozin plus standard care compared with placebo plus standard care is clinically effective\n\nThe primary efficacy outcome in EMPEROR-Reduced was a composite of cardiovascular death and hospitalisation for heart failure. Intention-to-treat analyses showed that empagliflozin plus standard care reduced the incidence of the primary outcome by 25.0% compared with placebo plus standard care (hazard ratio [HR] 0.75; 95% confidence interval [CI] 0.65 to 0.86; p<0.0001). At a median follow up of 16\xa0months, results showed that 19.4% of people having empagliflozin plus standard care had an event compared with 24.7% in the placebo group. The committee concluded that empagliflozin is clinically effective compared with placebo and that it reduces the risk of cardiovascular events when added to standard care.\n\n# Indirect treatment comparison\n\n## The indirect treatment comparison shows that clinical outcomes between empagliflozin and dapagliflozin are similar\n\nThere were no trials directly comparing empagliflozin with dapagliflozin so the company presented an indirect treatment comparison using the Bucher method. This compared the results from EMPEROR-Reduced with those from DAPA‑HF. DAPA‑HF was a phase\xa03 multinational double-blind randomised controlled trial. It compared dapagliflozin plus standard care with placebo plus standard care in people with stable symptoms of heart failure with reduced ejection fraction. The company supported the indirect comparison with the results from a published pooled meta-analysis reported by Zannad et al. (2020). This pooled data for dapagliflozin and empagliflozin to create class effect estimates for SGLT2 inhibitors compared with placebo. The ERG broadly agreed that the results from the meta-analyses suggested there was a statistically significant benefit with SGLT2 inhibitors compared with placebo for all outcomes. However, the ERG noted that the results of the meta-analysis were only based on 1\xa0trial of empagliflozin and 1\xa0trial of dapagliflozin. It therefore considered the Bucher comparison was a more appropriate method of assessing the comparative efficacy of empagliflozin compared with dapagliflozin. The results of the indirect treatment comparison suggested there was no difference between empagliflozin and dapagliflozin in any of the outcomes (all results are confidential and cannot be reported here). However, the results suggested a trend towards possible differences in cardiovascular deaths, all-cause mortality and renal function. The committee was aware that the ERG had explored this uncertainty in the cost–utility analysis (see section\xa03.8). The committee noted that there were some baseline differences in the Bucher indirect treatment comparison between people in EMPEROR-Reduced and DAPA‑HF. People in EMPEROR-Reduced may have had a more severe renal impairment than people in DAPA‑HF. This meant that people in EMPEROR-Reduced may have been more likely to have a hospitalisation for heart failure or mortality event compared with those in DAPA‑HF. The committee acknowledged the limitations of the comparison but agreed it was appropriate for decision making. The committee concluded that the results of the Bucher indirect treatment comparison showed that the clinical outcomes between empagliflozin and dapagliflozin are similar.\n\n# The company's economic model\n\n## The company's model is suitable for decision making\n\nThe company modelled cost effectiveness using a state transition model with 5\xa0states (4\xa0based on symptom severity plus 1\xa0for death). It captured disease severity using the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS). This is a disease-specific measure of quality of life. People transitioned through quartiles based on KCCQ‑CSS (0\xa0to\xa0100, with high scores indicating lower symptom burden), and a specific utility and cost associated with each state. The committee considered whether the KCCQ is an appropriate measure to capture quality-of-life outcomes. It noted that there may be some inconsistencies in how the size of effect translates from trial data to modelled quality-of-life effects. The clinical experts explained that the KCCQ is a well-validated comprehensive quality-of-life and symptom questionnaire for heart failure. The ERG stated that it was satisfied with the company's choice of KCCQ‑CSS states in the model. The committee concluded that the company's model structure was appropriate for decision making.\n\n# Cost-effectiveness estimates\n\n## Empagliflozin is recommended as an option for treating chronic heart failure with reduced ejection fraction\n\nThe company considered that a cost-comparison was the most appropriate way to estimate the cost effectiveness of empagliflozin compared with dapagliflozin. This was based on an assumption of equivalent effectiveness between empagliflozin and dapagliflozin. It noted that both drugs had the same list price, dosing frequency and method of administration, and that available evidence suggested the treatments were clinically equivalent. The ERG suggested that a cost–utility analysis may have been more appropriate. This was because the company's assumption of equal effectiveness was based on only 2\xa0trials and ignored potential uncertainty (see section\xa03.6). After technical engagement, the company provided a cost–utility analysis to help with decision making. However, it argued that this type of analysis would amplify any uncertainty in the results of the indirect treatment comparison. The company's base-case cost–utility analysis assumed there was no survival benefit with empagliflozin over dapagliflozin. However, it assumed that taking empagliflozin would lead to improvements in renal function and reduced hospitalisations for heart failure. This was based on the results of the Bucher indirect treatment comparison (see section\xa03.6). The company's probabilistic and deterministic cost-effectiveness estimates suggested that empagliflozin dominated dapagliflozin (meaning it was less costly and at least equally effective). The ERG did additional scenario analyses to show the effect of adding the different outcomes included in the Bucher indirect treatment comparison. These scenarios included the following assumptions:\n\nequal effectiveness in all outcomes\n\nsurvival benefit for dapagliflozin\n\nsurvival benefit for dapagliflozin and a reduction in hospitalisations for heart failure for empagliflozin\n\nsurvival benefit for dapagliflozin, a reduction in hospitalisations for heart failure and an improvement in renal function for empagliflozin.For the assumption of equal effectiveness, the results showed no difference in total costs or quality-adjusted life years between the 2\xa0treatments. The results for the other scenarios included in the ERG's analyses were in the south-west quadrant of the cost-effectiveness plane. This means that empagliflozin was estimated to be less costly and less effective than dapagliflozin (the exact results are academic in confidence and cannot be reported here). The committee understood that the ERG's scenarios were exploratory only. It also agreed that they were uncertain. This was because they were based on the results of the Bucher indirect treatment comparison, which showed no overall difference between the 2\xa0treatments. The committee considered its earlier conclusion that dapagliflozin was the most appropriate comparator (see section\xa03.3) based on:\n\nits comparable mechanism of action\n\nits use in a comparable place in the treatment pathway\n\nthe results of the indirect treatment comparison, which showed no difference between the 2\xa0treatments.The committee was satisfied that empagliflozin is similarly effective to dapagliflozin and that its costs are identical. It concluded to recommend empagliflozin as an option for treating symptomatic chronic heart failure with reduced ejection fraction.\n\n## Empagliflozin is not a step-change in treatment but does provide choice for people with heart failure with reduced ejection fraction\n\nThe committee recalled that people with heart failure with reduced ejection fraction have a poor prognosis and that there is an unmet need for treatment options (see section\xa03.1). It noted that empagliflozin is not the first drug of its class to gain regulatory approval for use in heart failure. So, it could not be considered a step-change in treatment. However, the committee concluded that it could be considered a relevant addition to current treatments and increase clinical choice.\n\n# Other factors\n\n## No equalities considerations were identified\n\nThe committee noted that the meta-analysis by Zannad et al. (2020; see section\xa03.6) suggested that SGLT2 inhibitors were most effective in people with a black or Asian family background. It noted that EMPEROR-Reduced mainly included people with a white family background. The committee noted that neither EMPEROR-Reduced or DAPA‑HF was powered to show difference between subgroups of different ages or people from a different family background. The clinical experts said that there is no reason to restrict empagliflozin use in adults based on age or family background. The committee noted that its recommendations applied to all people regardless of family background. It recognised that there were no ongoing clinical trials or data collection to validate the possibility of differences in treatment effect because of family background. But it considered that there may be the potential to explore this issue further in future research.\n\n## A heart failure specialist should advise on starting empagliflozin and the most appropriate healthcare professional should monitor treatment\n\nNICE's guideline on chronic heart failure in adults: diagnosis and management recommends that a specialist heart failure multidisciplinary team should work in collaboration with the primary care team to start new medicines that need specialist supervision. The committee noted that people taking empagliflozin for heart failure who also have diabetes might need adjustments in their diabetes medication for safety reasons because of an increased risk of ketoacidosis. The committee considered that risk factors should be identified, and some increased monitoring may be needed for treating heart failure with empagliflozin. So, it considered that a heart failure specialist was the most appropriate clinician to advise on starting treatment. The committee also noted that the summary of product characteristics states an assessment of renal function is recommended before starting empagliflozin and this should be done periodically during treatment. So, the committee considered that monitoring should be done by the most appropriate healthcare professional. The committee further noted that NICE's technology appraisal guidance on dapagliflozin for treating chronic heart failure with reduced ejection fraction included recommendations on who should advise on starting treatment and appropriate monitoring. The committee concluded that a heart failure specialist should advise on starting empagliflozin and monitoring should be done by the most appropriate healthcare professional."}
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https://www.nice.org.uk/guidance/ta773
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Evidence-based recommendations on empagliflozin (Jardiance) for treating chronic heart failure with reduced ejection fraction in adults.
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Dapagliflozin for treating chronic kidney disease
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Dapagliflozin for treating chronic kidney disease
Evidence-based recommendations on dapagliflozin (Forxiga) for chronic kidney disease in adults.
# Recommendations
Dapagliflozin is recommended as an option for treating chronic kidney disease (CKD) in adults. It is recommended only if:
it is an add-on to optimised standard care including the highest tolerated licensed dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), unless these are contraindicated, and
people have an estimated glomerular filtration rate (eGFR) of 25 ml/min/1.73 m2 to 75 ml/min/1.73 m2 at the start of treatment and:
have type 2 diabetes or
have a urine albumin-to-creatinine ratio (uACR) of 22.6 mg/mmol or more.
This recommendation is not intended to affect treatment with dapagliflozin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Management of CKD aims to slow disease progression. Standard care is lifestyle and dietary changes, and usually ACE inhibitors or ARBs. Dapagliflozin is an oral treatment for CKD. The company proposes that dapagliflozin would be used as an add-on to optimised standard care with ACE inhibitors or ARBs, which is narrower than its marketing authorisation.
Clinical trial evidence suggests that dapagliflozin plus standard care is more effective than standard care alone. The main clinical trial only included people with an eGFR of 25 ml/min/1.73 m2 to 75 ml/min/1.73 m2 and a uACR of 22.6 mg/mmol to 565 mg/mmol. Evidence is available for dapagliflozin from a different clinical trial for people with CKD and type 2 diabetes and with a uACR of less than 22.6 mg/mmol. There is no clinical trial evidence available for dapagliflozin in people with CKD without type 2 diabetes and with a uACR of less than 22.6 mg/mmol.
For the groups for which there is good enough clinical evidence, the cost-effectiveness estimates are within the range that NICE considers an acceptable use of NHS resources. So, dapagliflozin is recommended for these groups as an add-on to optimised standard care including ACE inhibitors or ARBs.# Information about dapagliflozin
# Marketing authorisation indication
Dapagliflozin (Forxiga, AstraZeneca) is indicated for 'treating chronic kidney disease (CKD) in adults'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for dapagliflozin.
# Price
The list price of dapagliflozin is £36.59 for a 28‑pack of 10 mg tablets, giving a yearly cost of £477.30. Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:
the uncertainty around the target patient population and the effectiveness of dapagliflozin in people excluded from the DAPA‑CKD trial (issue 1, see ERG report page 12)
concerns about the company's overall modelling approach and overall survival predictions (issue 2, see ERG report page 13).
# The condition
## Chronic kidney disease can have substantial effects on quality of life
Chronic kidney disease (CKD) is a complex progressive disorder with loss of nephrons causing kidney function to decline over time. This can eventually lead to end-stage renal disease and death. CKD happens because of systemic disease affecting the kidney, such as type 2 diabetes, hypertension or cardiovascular disease, or from primary kidney disease such as glomerulonephritis. Conditions such as type 2 diabetes, hypertension and cardiovascular disease can also be caused by CKD. CKD varies in severity and the NICE guideline on chronic kidney disease: assessment and management (NG203) recommends classifying CKD in adults using a combination of glomerular filtration rate (GFR) and albumin-to-creatinine ratio (ACR). GFR is a measure of kidney function, estimated using a creatinine blood test (eGFR). eGFR is categorised from G1 (eGFR of more than 90 ml/min/1.73 m2), defined as no reduction in kidney function, to G5 (eGFR of less than 15 ml/min/1.73 m2), defined as kidney failure. ACR is a marker of kidney damage, measured using a urine sample (uACR). uACR is categorised from A1 (uACR of less than 3 mg/mmol), defined as normal or mild damage, to A3 (uACR of more than 30 mg/mmol), defined as severe damage. Around 1.9 million adults in the UK have CKD with an eGFR category of G3a to G5, and it is likely there are many more undiagnosed. Patient experts highlighted that CKD can have huge implications on a person's quality of life. They explained that CKD affects mental health and emotional wellbeing, capacity to stay in work and the ability to maintain relationships. People with CKD must spend a significant amount of time in hospital, especially when having dialysis treatment. The committee noted the additional support people need with daily activities and treatment, and the impact of this on carers. It concluded that CKD represents a significant burden for people and can substantially affect both physical and psychological aspects of quality of life.
# Treatment pathway and comparator
## There is an unmet need for more effective treatments for CKD and a new treatment option would be welcomed
The patient and clinical experts highlighted that CKD is incurable with limited pharmacological options for delaying progression. The clinical experts explained that the main aims of treatment are to prevent disease progression and reduce cardiovascular morbidity and mortality. They explained that the current treatment pathway for CKD is not particularly well defined, and the evidence is rapidly changing. However, there is a general alignment of treatment practice with NG203. The guideline recommends lifestyle advice including dietary interventions for adults with CKD. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are standard pharmacological management for CKD, but these only slow disease progression. Patient experts reiterated that preventing disease progression and delaying the need for a kidney transplant are particularly important for people with CKD. The committee noted that with current best practice CKD can often still progress to end-stage renal disease. It concluded that there is an unmet need for more effective therapies for treating CKD, and that patients and clinicians would welcome a new treatment option.
## Dapagliflozin would be used as an add-on to optimised standard care, including an ACE inhibitor or ARB
In its original submission the company positioned dapagliflozin for people having optimised standard care, which may or may not have included an ACE inhibitor or ARB. The ERG highlighted that this was inconsistent with the main source of clinical evidence for dapagliflozin in treating CKD, the DAPA‑CKD trial (see section 3.7). This is because 97% of people in DAPA‑CKD were either having an optimised ACE inhibitor or ARB. In response to technical engagement the company updated its positioning to people who were having an optimised ACE inhibitor or ARB. The committee was aware that NICE's guideline on type 2 diabetes in adults: management (NG28) recommends sodium-glucose cotransporter‑2 (SGLT2) inhibitors for people with CKD and type 2 diabetes who are having an optimised ACE inhibitor or ARB. It is considered best practice to offer an ACE inhibitor or ARB at an optimised dose before prescribing an SGLT2 inhibitor. The clinical experts agreed that although dapagliflozin would likely have some benefit for people not having an ACE inhibitor or ARB, it should be used as an add-on to these treatments. They explained that most people would already be having an ACE inhibitor or ARB and would likely continue having these until needing dialysis. The committee concluded that dapagliflozin would be used as an add-on to optimised standard care, including an ACE inhibitor or ARB at the highest tolerated licensed dose, unless these are contraindicated.
## Standard care is an appropriate comparator for dapagliflozin
In its submission the company compared dapagliflozin plus standard care with standard care alone. The company represented standard care using the placebo arm of DAPA‑CKD (see section 3.7). This comprised of background therapies including ACE inhibitors or ARBs, statins and antiplatelets. The ERG agreed with the company's description of how CKD is currently managed in the UK. The committee concluded that standard care is an appropriate comparator for dapagliflozin.
## Canagliflozin is a relevant comparator in people with diabetic kidney disease
Canagliflozin is another SGLT2 inhibitor with a marketing authorisation for type 2 diabetes. The company did not consider canagliflozin a relevant comparator for dapagliflozin in CKD, because it noted that canagliflozin is not widely used for treating CKD with type 2 diabetes in the UK. However, the company did an indirect treatment comparison of dapagliflozin and canagliflozin in people with CKD and type 2 diabetes (see section 3.11). The clinical experts noted that canagliflozin is being increasingly used by nephrologists, but acknowledged that the guidelines supporting the use of SGLT2 inhibitors in people with CKD were relatively new. NG28 recommends offering an SGLT2 inhibitor to adults with CKD and type 2 diabetes, in addition to an ACE inhibitor or ARB, if their ACR is more than 30 mg/mmol and they meet the criteria in the marketing authorisation. NG28 also recommends considering an SGLT2 inhibitor for adults with CKD and type 2 diabetes, in addition to an ACE inhibitor or ARB, if their ACR is between 3 mg/mmol and 30 mg/mmol and they meet the criteria in the marketing authorisation. The committee noted that the comparator in the NICE scope was established clinical management without dapagliflozin. The committee considered that, since canagliflozin was recommended in NG28 and is being used to some extent in clinical practice, it represents established clinical practice for people with CKD and type 2 diabetes. In response to consultation the company reiterated that the uptake of canagliflozin has been slow in UK clinical practice for people having treatment for CKD. It also noted that canagliflozin has a marketing authorisation for treating diabetic kidney disease (CKD caused by type 2 diabetes). This is a subgroup of people with CKD and type 2 diabetes. The ERG explained that it is reasonable to include canagliflozin as a comparator for the subgroup of people with comorbid type 2 diabetes, when the licensed indications for both treatments overlap. The committee concluded that canagliflozin is a relevant comparator in people with diabetic kidney disease.
## It is appropriate to make recommendations for dapagliflozin based on uACR levels
In its updated economic model, the company split the population into subgroups based on uACR level and type 2 diabetes status (see section 3.14). NG203 recommends measuring proteinuria with uACR in adults with an eGFR of less than 60 ml/min/1.73 m2, or in adults with an eGFR of more than 60 ml/min/1.73 m2 if there is a strong suspicion of CKD. The clinical experts explained that uACR testing is not done consistently in clinical practice. They noted that although the test is simple to do, there is some hesitancy about doing urine tests, particularly when there may be a delay before getting the results. The committee heard from a patient expert who explained that they would not hesitate to provide a urine sample, particularly if this ensured they had the best treatment. The clinical experts added that urine protein-to-creatinine ratio (uPCR) tests are widely done, but it is difficult to map the results of uACR and uPCR tests to each other accurately. They explained that in their experience, uACR is no more difficult to measure than uPCR, but would need a change in practice. During consultation, the company highlighted that making recommendations based on uACR levels would risk people not having access to dapagliflozin because of a lack of testing, particularly those without type 2 diabetes. A consultee also advised that the prevalence of proteinuria testing differs by age and ethnicity. The committee acknowledged that uACR testing is not currently implemented consistently in the NHS. If this did not change, limiting dapagliflozin to subgroups based on uACR levels may negatively affect patient access. However, uACR testing is easy to do, has value in identifying people with CKD who are likely to benefit from dapagliflozin, and is recommended in NG203. Therefore, the committee concluded that the current low levels of uACR testing should not prevent it from being included as a criterion in recommendations for dapagliflozin.
# Clinical-effectiveness evidence
## DAPA-CKD suggests that dapagliflozin is more effective than standard care, but the evidence does not cover the full marketing authorisation
The main clinical evidence for dapagliflozin in the company submission came from DAPA‑CKD. This was a randomised, double-blind trial in adults with CKD, with or without type 2 diabetes. DAPA‑CKD compared dapagliflozin plus standard care (n=2,152) with placebo plus standard care (n=2,152) over a median follow-up period of 2.4 years. DAPA‑CKD included people with an eGFR of 25 ml/min/1.73 m2 to 75 ml/min/1.73 m2 and a uACR of 22.6 mg/mmol to 565 mg/mmol. People's disease had to be stable on a maximum tolerated dose of an ACE inhibitor or ARB for at least 4 weeks before screening, unless medically contraindicated. The trial did not include people with CKD who had type 1 diabetes or who had an organ transplant. The primary outcome in DAPA‑CKD was a composite outcome of a sustained eGFR decline of 50% or more, end-stage renal disease or death from renal or cardiovascular causes. Results showed that the primary composite outcome occurred in 9.2% of people having dapagliflozin, compared with 14.5% of people having placebo (hazard ratio 0.61, 95% confidence interval 0.51 to 0.72). Clinical advice to the ERG suggested that the management of CKD in DAPA‑CKD was broadly generalisable to UK clinical practice. However, the ERG highlighted that DAPA‑CKD did not give clinical efficacy evidence for some groups of people with CKD who would be included in the marketing authorisation for dapagliflozin. These included people:
not having optimised ACE inhibitors or ARBs
with a uACR of less than 22.6 mg/mmol
with an eGFR of less than 25 ml/min/1.73 m2 or more than 75 ml/min/1.73 m2
who had an organ transplant.The clinical experts considered that there would likely be benefits in starting dapagliflozin in people with an eGFR of between 15 ml/min/1.73 m2 and 25 ml/min/1.73 m2, despite the lack of clinical evidence. However, one expert noted the uncertainty in this population, as well as concerns with the impact of a transient decrease in eGFR associated with SGLT2 inhibitors at lower eGFR levels. The committee concluded that the results from DAPA‑CKD suggest that dapagliflozin plus standard care is more effective than standard care alone. But, it noted that DAPA‑CKD tested dapagliflozin only in an enriched population with greater potential to benefit from treatment. The results may therefore not necessarily be transferrable to the groups of people with CKD excluded from DAPA‑CKD.
## DECLARE-TIMI-58 and DAPA-HF provide evidence for some people excluded from DAPA-CKD, but evidence gaps remain
The company presented additional clinical evidence from 2 randomised controlled trials, DECLARE‑TIMI‑58 (n=17,160) and DAPA‑HF (n=4,744). This was to provide renal outcome data across a broader population. DECLARE‑TIMI‑58 included people with type 2 diabetes who had, or were at high risk of, cardiovascular events, and who had a creatinine clearance of 60 ml/min/1.73 m2 or more. However, 7.4% of people (n=1,265) had an eGFR of less than 60 ml/min/1.73 m2. Inclusion in DECLARE‑TIMI‑58 was not restricted based on uACR level, so the trial is likely to have enrolled people across a wide range of uACR levels. DAPA‑HF included people with heart failure with reduced ejection fraction, regardless of whether they had comorbid type 2 diabetes. People in DAPA‑HF had to have an eGFR of 30 ml/min/1.73 m2 or more, and uACR was not measured. Both DECLARE‑TIMI‑58 and DAFA‑HF included some people with comorbid CKD (34.8% and 40.7%, respectively). Neither study included people with type 1 diabetes or who had an organ transplant. Results from DECLARE‑TIMI‑58 and DAPA‑HF suggested that dapagliflozin plus standard care is more effective than standard care alone across the broad CKD population, regardless of uACR and eGFR levels. DECLARE‑TIMI‑58 showed that the dapagliflozin treatment effect was consistent between people with a uACR of less than 22.6 mg/mmol and those with a uACR of 22.6 mg/mmol or higher for the following end points: the co-primary end point of hospitalisation for heart failure or cardiovascular death, and the renal end point without cardiovascular death (eGFR decline of 40% or more, end-stage renal disease, or death from renal causes). However, the ERG highlighted that there remained some subgroups of people with CKD for which there was no clinical trial evidence for dapagliflozin. These included:
people without type 2 diabetes and with a uACR of less than 22.6 mg/mmol
people who had an organ transplant.The ERG also noted that the data from DAPA‑HF was not used in the company's economic model. The committee concluded that DECLARE‑TIMI‑58 and DAPA‑HF showed that dapagliflozin was clinically effective in some subgroups of people with CKD outside of DAPA‑CKD. However, the size of benefit in subgroups outside DAPA‑CKD was uncertain, and important uncertainties and evidence gaps remained.
## There is a lack of evidence for dapagliflozin in people with CKD who have had an organ transplant
The company did not present evidence for dapagliflozin in people with CKD who have had an organ transplant. Clinical experts advised that there is a lack of evidence for using dapagliflozin in these people in general. The experts highlighted that further clinical trials are needed to establish the clinical effectiveness and safety of dapagliflozin in these people. A consultation comment highlighted that evidence should be developed on the benefits of dapagliflozin for people with kidney transplants. The committee concluded that there is a lack of evidence for dapagliflozin in people with CKD who have had an organ transplant, and there is need for further clinical trials in these people.
## The company's simulated outcomes analysis and real-world evidence does not robustly resolve the evidence gap for people with low uACR levels without type 2 diabetes
In response to technical engagement, to address the lack of clinical-effectiveness evidence for dapagliflozin in people without type 2 diabetes and with a uACR of less than 22.6 mg/mmol (see section 3.8), the company provided an additional analysis. This estimated outcomes for people with low uACR levels, split by whether or not they had type 2 diabetes. The company did a simulated treatment outcomes analysis using a Poisson model to fit an estimated yearly event rate conditional on uACR as the continuous variable from DAPA‑CKD, with a uACR range extended from 3.39 mg/mmol to 565 mg/mmol. The results are academic in confidence and cannot be reported here. The ERG explained that such an analysis only supported a hypothesis that dapagliflozin might work in this population. The company had extrapolated event rates to a population in which there was no actual clinical evidence of dapagliflozin efficacy. In response to consultation, the company provided real-world evidence to support the efficacy of dapagliflozin in people without type 2 diabetes and with a uACR of less than 22.6 mg/mmol. This came from a US study of 2 databases. The ERG noted that this analysis had several limitations. It was based on small sample sizes, used a surrogate end point and was based on observational data. The committee agreed that, in the absence of robust trial evidence, the company's simulated treatment outcomes analysis and real-world evidence did not resolve the evidence gap in people with low uACR levels without type 2 diabetes.
## Dapagliflozin and canagliflozin are likely to be equally effective in people with diabetic kidney disease, and the least costly option that meets individual patient needs should be used
Although it did not consider canagliflozin a relevant comparator (see section 3.5), the company presented an indirect comparison to estimate the efficacy of dapagliflozin compared with canagliflozin for people with CKD and type 2 diabetes. The company did an anchored matching-adjusted indirect comparison using data from the DAPA‑CKD and CREDENCE trials. CREDENCE was a randomised, double-blind trial of people with type 2 diabetes and albuminuric CKD (uACR of more than 33.9 mg/mmol) having canagliflozin or placebo. The results of the indirect comparison suggested equal efficacy between dapagliflozin and canagliflozin in people with CKD and type 2 diabetes. The ERG explained that the selection of covariates in the matching-adjusted indirect comparison was overly complex. It also highlighted that the assumption of proportional hazards (that is, the relative risk of an event is fixed irrespective of time) may not be satisfied. Therefore, the Cox proportional hazard model used by the company may not be appropriate. However, the ERG considered that despite the limitations with the indirect comparison, the overall conclusion of equal efficacy was reasonable. The clinical experts explained that there was likely to be a class effect for SGLT2 inhibitors in treating CKD. The committee considered the company's indirect comparison with canagliflozin acceptable for decision making, and that a conclusion of equal efficacy for dapagliflozin and canagliflozin in people with diabetic kidney disease was reasonable. It was not presented with any evidence suggesting a distinction between dapagliflozin and canagliflozin for people with diabetic kidney disease. It concluded that the least costly option of the 2 that meets individual patient needs should be used.
# Adverse events
## The adverse event profile of dapagliflozin for CKD is consistent with other licensed indications for dapagliflozin
The adverse event profile of dapagliflozin for treating CKD in the company submission was informed by evidence from DAPA‑CKD. Dapagliflozin was associated with fewer deaths resulting from adverse events. There were also fewer serious adverse events with dapagliflozin compared with placebo. However, dapagliflozin was associated with a higher rate of serious adverse events among people with type 2 diabetes compared with those without type 2 diabetes. Nobody experienced diabetic ketoacidosis with dapagliflozin, and people having dapagliflozin had lower rates of major hypoglycaemic events, renal events, amputations, fractures and symptoms of volume depletion compared with placebo. The ERG explained that the adverse event profile of dapagliflozin for CKD from DAPA‑CKD was generally consistent with other indications such as diabetes and heart failure. The committee noted this, and concluded that the adverse event profile of dapagliflozin in CKD is consistent with the other licensed indications for dapagliflozin.
# Economic model
## The company's economic model structure is appropriate
The company developed a de novo health economic model to assess the cost effectiveness of dapagliflozin plus standard care compared with standard care alone for people with CKD. The model used a cohort-level state transition approach with 6 health states defined according to CKD stages 1 to 5 (including stages G3a and G3b), with additional states for dialysis, kidney transplant and death. It used a lifetime horizon and a cycle length of 1 month. A yearly discount rate of 3.5% was applied to costs and outcomes. Clinical Practice Research Datalink (CPRD) data informed patient baseline characteristics. CPRD is a real-world research service that collects patient data from a network of general practices across the UK. It links this to a range of other health-related data to provide a longitudinal, representative UK population health dataset. Some event risks in the model (mortality, hospitalisation for heart failure, and acute kidney injury) were also adjusted to match the CPRD data. However, the probabilities of transitioning between CKD stages were not similarly adjusted. The ERG and its clinical advisers considered the company's overall model structure to be reasonable, but noted concerns about the overall survival predictions (see section 3.17). The company assumed that dapagliflozin would not need any additional appointments or tests beyond those already associated with managing CKD. The committee was uncertain whether this would be the case, particularly for people without type 2 diabetes. Therefore, the costs for dapagliflozin may have been underestimated in the model for these people. However, the committee concluded that the company's overall model structure was appropriate.
## Given the differences in available evidence, the 3 subgroups should be considered separately during decision making
To address ERG concerns at technical engagement about the lack of clinical evidence in some groups of people with CKD (see section 3.7), the company provided an updated economic model. The updated model included a revised patient population having optimised ACE inhibitors or ARBs, and the CPRD population used by the company to adjust the model was updated to reflect this. Also, the model used data from a subgroup of people with CKD from DECLARE‑TIMI‑58. The company presented a weighted economic analysis for the following subgroups according to their prevalence in the updated CPRD dataset:
Subgroup 1: uACR of 22.6 mg/mmol or more, with or without type 2 diabetes.
Subgroup 2: uACR of less than 22.6 mg/mmol, with type 2 diabetes.
Subgroup 3: uACR of less than 22.6 mg/mmol, without type 2 diabetes.The updated model re-estimated patient characteristics, mortality risks and transient event risks for each subgroup based on the relevant CPRD dataset. The ERG highlighted that subgroup 1 most closely reflected the DAPA‑CKD population and that DECLARE‑TIMI‑58 also provided clinical evidence for subgroup 2, but there was no direct clinical evidence in subgroup 3. The company's updated model assumed that the CKD stage transition probabilities in subgroup 3 were the same as in subgroup 2. It also assumed that the overall survival model was the same in all 3 subgroups, except a non-type 2 diabetes adjustment factor was applied for subgroup 3. The ERG did not consider the company's weighted analysis to be appropriate, given the differences in the availability and strength of the evidence for each subgroup. Subgroup 1 was closest to DAPA‑CKD but represented a small proportion of the overall weighted economic analysis, with most of the quality-adjusted life years (QALYs) and costs in the model informed by subgroups 2 and 3. The committee was concerned that subgroup 3 accounted for around one third of the company's weighted population in the cost-effectiveness analyses updated after consultation (see section 3.15), in which there is no direct clinical evidence for dapagliflozin. It agreed with the ERG that the 3 subgroups should be considered separately in decision making.
## The company's updated CPRD adjustment is uncertain, but this is unlikely to have a large effect on the cost-effectiveness estimates for subgroup 2
The company updated its model in response to consultation to use a CPRD dataset that included people with an eGFR of 25 ml/min/1.73 m2 to 75 ml/min/1.73 m2 having optimised ACE inhibitors or ARBs, with or without a diagnosis of CKD. This was intended to better reflect the population in the preliminary recommendations in the appraisal consultation document. However, clinical advice to the ERG suggested that the new CPRD dataset would include a large proportion of people who do not have CKD. The committee also heard that in the post-consultation model, the CPRD dataset for subgroup 2 and 3 was not stratified by type 2 diabetes status to reflect the population more accurately in each of these subgroups. Instead, the company used a single CPRD dataset in which around two thirds of people had type 2 diabetes and one third did not. The company noted that for subgroup 2, the cost-effectiveness estimate for dapagliflozin plus standard care compared with standard care alone was similar regardless of whether the CPRD adjustment was applied. The committee also noted that the cost-effectiveness estimates for dapagliflozin in subgroup 2 were similar based on both the technical engagement and post-consultation models. This suggested that the uncertainties around the CPRD adjustment had little effect on the cost-effectiveness results in this subgroup. However, there were much greater differences between the cost-effectiveness results in subgroup 3 depending on whether the CPRD adjustment was applied, suggesting greater uncertainty. The committee concluded that the updated CPRD adjustment was uncertain because the dataset likely included people without CKD who would not have dapagliflozin, and because it had not been stratified by type 2 diabetes status for subgroups 2 and 3. But, this did not have a large effect on the cost-effectiveness estimates for subgroup 2.
## The mean age in the model should reflect the same CPRD datasets as those used to inform the other patient characteristics
In its technical engagement model the company used a mean (average) age of 64 years from a separate CPRD dataset. This included people with an eGFR of less than 90 ml/min/1.73 m2 who were taking ACE inhibitors or ARBs but did not need to have a formal diagnosis of CKD. This was lower than the mean ages from the CPRD datasets used to adjust the 3 subgroups in the model, which ranged from around 74 to 78 years. The company noted that clinician input supported using the lower mean age, as did registry data. However, the ERG explained that the company's approach was inconsistent. This was because all other baseline characteristics and event risk adjustments in the model were based on subgroup-specific CPRD datasets all needing a formal CKD diagnosis. Therefore, it was inappropriate to include a mix of patient characteristics from separate groups of people from different CPRD datasets. The ERG preferred to use the subgroup-specific CPRD datasets informing the baseline characteristics and event risk adjustments for each subgroup in the model, for which the mean ages were higher than the company's approach. The clinical experts noted that although there was uncertainty about what the mean age of people was in clinical practice, it was likely to be higher than that used by the company. They explained that although the mean age of people with CKD seen in secondary care was likely to be closer to the company's estimate, this may not fully represent those who would have dapagliflozin in clinical practice because people having treatment in primary care may be older. The committee considered that the mean age estimate from the separate CPRD dataset was inappropriate because it was likely that many people in this dataset did not have CKD. Also, applying a lower age estimate in a dataset with characteristics and risks estimated from an older population was inappropriate. This is because younger people do not have the same characteristics and risks as older people. In response to consultation, the company updated the mean ages in its model so that they were based on the same CPRD datasets as the other baseline characteristics. The weighted mean age in the company's updated model (around 73 years) was higher than the estimate used in its technical engagement model. The committee recalled that there were some uncertainties with the new CPRD dataset (see section 3.15). But, because the company's updated model used the CPRD data consistently, the committee considered that the revised mean age was more appropriate.
## Despite limitations in the company's approach to overall survival modelling, its impact on decision making is likely to be small
The company modelled the treatment effect of dapagliflozin on overall survival through 2 mechanisms:
Directly, by applying a treatment-related hazard ratio for overall survival to each CKD state from a multivariable survival model to each state-specific overall survival model except transplant.
Indirectly, by applying transition matrices that lead to slower disease progression for people having dapagliflozin plus standard care compared with standard care alone.The ERG highlighted that when the adjustment to the CPRD dataset (see section 3.13) was removed, the company's model overestimated overall survival compared with the data from DAPA‑CKD. The ERG was uncertain about the cause of this, but it may have been because:
The company had included a post-randomisation covariate (CKD stage), which can lead to problems in determining causality.
The company estimated state-specific mortality risks using a 'mean of covariates' approach, which has been shown to lead to bias when estimating survival distributions.However, the ERG noted that even if the issues identified in the company's approach to overall survival modelling were resolved, the incremental cost-effectiveness ratio for dapagliflozin compared with standard care would likely remain below £20,000 per QALY gained in the DAPA‑CKD population. The committee concluded that despite the limitations with the company's approach to overall survival modelling, its impact on decision making was likely to be small.
# Cost-effectiveness estimates
## Dapagliflozin is cost effective in the population represented in DAPA-CKD
The committee recalled that it would consider the company's 3 subgroups separately in decision making (see section 3.14). It considered the cost effectiveness of dapagliflozin plus standard care compared with standard care alone in subgroup 1 (people with a uACR of 22.6 mg/mmol or more, with or without type 2 diabetes). In the company's updated model in response to consultation, dapagliflozin plus standard care dominated standard care in this subgroup (that is, it was more effective and less costly than standard care). However, the committee recalled that the evidence was weaker for dapagliflozin outside of the eGFR levels in DAPA‑CKD. It also noted that dapagliflozin was likely to have a large impact on NHS resources given the size of the patient population (see section 3.1), and so it needed to see robust clinical and cost-effectiveness evidence. It concluded that the cost-effectiveness estimate for dapagliflozin in subgroup 1 was an acceptable use of NHS resources. The recommended population should be limited to the eGFR and uACR levels included in DAPA‑CKD (see section 3.7) to match the available evidence.
## Dapagliflozin is cost effective for people with a uACR of less than 22.6 mg/mmol and type 2 diabetes
The committee considered the cost effectiveness of dapagliflozin plus standard care compared with standard care alone in subgroup 2 (people with a uACR of less than 22.6 mg/mmol and type 2 diabetes). In the company's updated model in response to consultation, the incremental cost-effectiveness ratio (ICER) for dapagliflozin plus standard care compared with standard care in this subgroup was around £6,000 per QALY gained. The recommendations in NG28 state that for people with type 2 diabetes and CKD, in addition to an ARB or an ACE inhibitor, an SGLT2 inhibitor should be considered if their ACR is 3 mg/mmol to 30 mg/mmol and offered if their ACR is higher than 30 mg/mmol (see section 3.5). Although the committee was aware of this broader context, it was mindful that its remit was to appraise the clinical and cost effectiveness of dapagliflozin. It consequently focused its decision making on the evidence provided for this technology appraisal. It recalled that DECLARE‑TIMI‑58 provided evidence for the treatment effect of dapagliflozin in people with CKD and type 2 diabetes with a uACR of less than 22.6 mg/mmol (see section 3.8). The committee also understood that the company had used this evidence to inform the cost-effectiveness estimate of dapagliflozin in subgroup 2 in its updated model (see section 3.14). The committee noted that the ICER in this subgroup was comfortably within what NICE considers an acceptable use of NHS resources. In response to consultation, the company provided further subgroup analysis of subgroup 2. It divided subgroup 2 into people with a uACR of less than 3 mg/mmol, and people with a uACR of 3 mg/mmol to 22 mg/mmol. The ICERs for both these subgroups were similar to the ICER for subgroup 2 as a whole (around £6,000 per QALY gained). The committee therefore concluded that dapagliflozin can be recommended for people with CKD with a uACR of less than 22.6 mg/mmol and type 2 diabetes.
## Dapagliflozin cannot be recommended in people with a uACR of less than 22.6 mg/mmol who do not have type 2 diabetes
The committee considered the cost effectiveness of dapagliflozin plus standard care compared with standard care alone in subgroup 3 (people with a uACR of less than 22.6 mg/mmol without type 2 diabetes). In the company's updated model in response to consultation, the ICER for dapagliflozin plus standard care compared with standard care in this subgroup was around £17,000 per QALY gained. There was no direct clinical evidence informing subgroup 3 in the company's model (see section 3.8), and there was uncertainty around the CPRD adjustment in this subgroup (see section 3.15). This generated considerable uncertainty in the plausibility of the cost-effectiveness estimates for this population. The committee noted a stakeholder's comment that the benefits of dapagliflozin in preventing decline in renal function should be weighed against the potential consequences of overprescribing and drug interactions, particularly in people with milder disease. It also understood from the company at the second appraisal committee meeting that subgroup 3 is likely to comprise more of the CKD population than the CPRD data suggests. Therefore, the committee considered that the consequence of decision error was likely to be higher for this subgroup. It concluded that dapagliflozin cannot be recommended for the population in subgroup 3.
# Innovation
## Dapagliflozin is an innovative treatment for CKD, but all relevant benefits are reflected in the cost-effectiveness estimates
The company considered dapagliflozin to be innovative because it addresses a significant unmet need in CKD, which is associated with a significant clinical and economic burden and for which standard care is inadequate for many people. The patient and clinical experts highlighted the lack of effective pharmacological management for CKD and the importance of slowing down disease progression. Patient experts felt that dapagliflozin offers a step change for treating CKD, because its ability to delay disease progression offers real hope. Clinical experts highlighted that the benefits of dapagliflozin are distinct from a blood glucose reduction alone, and that reducing progression to end-stage renal disease will increase quality of life. The committee acknowledged the new benefits offered by dapagliflozin and other SGLT2 inhibitors as additional treatment options for CKD. However, it concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY measurements.
# Equalities considerations
## There are no equalities issues relevant to the recommendations
No equalities issues were raised during scoping stage. During technical engagement, patient and clinical expert submissions highlighted that CKD disproportionally affects people from Black, Asian, and minority ethnic groups and lower socioeconomic backgrounds. People from these groups are also more likely to have CKD that progresses quicker to kidney failure and to die earlier. During consultation, a consultee also highlighted that use of ACE inhibitors or ARBs differs by ethnicity and socioeconomic status. However, the committee did not consider these to be equality issues that could be resolved by this appraisal. No other potential equality issues were raised. The committee concluded that there were no equalities issues relevant to the recommendation.
|
{'Recommendations': 'Dapagliflozin is recommended as an option for treating chronic kidney disease (CKD) in adults. It is recommended only if:\n\nit is an add-on to optimised standard care including the highest tolerated licensed dose of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), unless these are contraindicated, and\n\npeople have an estimated glomerular filtration rate (eGFR) of 25\xa0ml/min/1.73\xa0m2 to 75\xa0ml/min/1.73\xa0m2 at the start of treatment and:\n\n\n\nhave type\xa02 diabetes or\n\nhave a urine albumin-to-creatinine ratio (uACR) of 22.6\xa0mg/mmol or more.\n\n\n\nThis recommendation is not intended to affect treatment with dapagliflozin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nManagement of CKD aims to slow disease progression. Standard care is lifestyle and dietary changes, and usually ACE inhibitors or ARBs. Dapagliflozin is an oral treatment for CKD. The company proposes that dapagliflozin would be used as an add-on to optimised standard care with ACE inhibitors or ARBs, which is narrower than its marketing authorisation.\n\nClinical trial evidence suggests that dapagliflozin plus standard care is more effective than standard care alone. The main clinical trial only included people with an eGFR of 25\xa0ml/min/1.73\xa0m2 to 75\xa0ml/min/1.73\xa0m2 and a uACR of 22.6\xa0mg/mmol to 565\xa0mg/mmol. Evidence is available for dapagliflozin from a different clinical trial for people with CKD and type\xa02 diabetes and with a uACR of less than 22.6\xa0mg/mmol. There is no clinical trial evidence available for dapagliflozin in people with CKD without type\xa02 diabetes and with a uACR of less than 22.6\xa0mg/mmol.\n\nFor the groups for which there is good enough clinical evidence, the cost-effectiveness estimates are within the range that NICE considers an acceptable use of NHS resources. So, dapagliflozin is recommended for these groups as an add-on to optimised standard care including ACE inhibitors or ARBs.', 'Information about dapagliflozin': "# Marketing authorisation indication\n\nDapagliflozin (Forxiga, AstraZeneca) is indicated for 'treating chronic kidney disease (CKD) in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for dapagliflozin.\n\n# Price\n\nThe list price of dapagliflozin is £36.59 for a 28‑pack of 10\xa0mg tablets, giving a yearly cost of £477.30. Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:\n\nthe uncertainty around the target patient population and the effectiveness of dapagliflozin in people excluded from the DAPA‑CKD trial (issue\xa01, see ERG report page\xa012)\n\nconcerns about the company's overall modelling approach and overall survival predictions (issue\xa02, see ERG report page\xa013).\n\n# The condition\n\n## Chronic kidney disease can have substantial effects on quality of life\n\nChronic kidney disease (CKD) is a complex progressive disorder with loss of nephrons causing kidney function to decline over time. This can eventually lead to end-stage renal disease and death. CKD happens because of systemic disease affecting the kidney, such as type\xa02 diabetes, hypertension or cardiovascular disease, or from primary kidney disease such as glomerulonephritis. Conditions such as type\xa02 diabetes, hypertension and cardiovascular disease can also be caused by CKD. CKD varies in severity and the NICE guideline on chronic kidney disease: assessment and management (NG203) recommends classifying CKD in adults using a combination of glomerular filtration rate (GFR) and albumin-to-creatinine ratio (ACR). GFR is a measure of kidney function, estimated using a creatinine blood test (eGFR). eGFR is categorised from G1 (eGFR of more than 90\xa0ml/min/1.73\xa0m2), defined as no reduction in kidney function, to G5 (eGFR of less than 15\xa0ml/min/1.73\xa0m2), defined as kidney failure. ACR is a marker of kidney damage, measured using a urine sample (uACR). uACR is categorised from A1 (uACR of less than 3\xa0mg/mmol), defined as normal or mild damage, to A3 (uACR of more than 30\xa0mg/mmol), defined as severe damage. Around 1.9\xa0million adults in the UK have CKD with an eGFR category of G3a to G5, and it is likely there are many more undiagnosed. Patient experts highlighted that CKD can have huge implications on a person's quality of life. They explained that CKD affects mental health and emotional wellbeing, capacity to stay in work and the ability to maintain relationships. People with CKD must spend a significant amount of time in hospital, especially when having dialysis treatment. The committee noted the additional support people need with daily activities and treatment, and the impact of this on carers. It concluded that CKD represents a significant burden for people and can substantially affect both physical and psychological aspects of quality of life.\n\n# Treatment pathway and comparator\n\n## There is an unmet need for more effective treatments for CKD and a new treatment option would be welcomed\n\nThe patient and clinical experts highlighted that CKD is incurable with limited pharmacological options for delaying progression. The clinical experts explained that the main aims of treatment are to prevent disease progression and reduce cardiovascular morbidity and mortality. They explained that the current treatment pathway for CKD is not particularly well defined, and the evidence is rapidly changing. However, there is a general alignment of treatment practice with NG203. The guideline recommends lifestyle advice including dietary interventions for adults with CKD. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) are standard pharmacological management for CKD, but these only slow disease progression. Patient experts reiterated that preventing disease progression and delaying the need for a kidney transplant are particularly important for people with CKD. The committee noted that with current best practice CKD can often still progress to end-stage renal disease. It concluded that there is an unmet need for more effective therapies for treating CKD, and that patients and clinicians would welcome a new treatment option.\n\n## Dapagliflozin would be used as an add-on to optimised standard care, including an ACE inhibitor or ARB\n\nIn its original submission the company positioned dapagliflozin for people having optimised standard care, which may or may not have included an ACE inhibitor or ARB. The ERG highlighted that this was inconsistent with the main source of clinical evidence for dapagliflozin in treating CKD, the DAPA‑CKD trial (see section\xa03.7). This is because 97% of people in DAPA‑CKD were either having an optimised ACE inhibitor or ARB. In response to technical engagement the company updated its positioning to people who were having an optimised ACE inhibitor or ARB. The committee was aware that NICE's guideline on type\xa02 diabetes in adults: management (NG28) recommends sodium-glucose cotransporter‑2 (SGLT2) inhibitors for people with CKD and type\xa02 diabetes who are having an optimised ACE inhibitor or ARB. It is considered best practice to offer an ACE inhibitor or ARB at an optimised dose before prescribing an SGLT2 inhibitor. The clinical experts agreed that although dapagliflozin would likely have some benefit for people not having an ACE inhibitor or ARB, it should be used as an add-on to these treatments. They explained that most people would already be having an ACE inhibitor or ARB and would likely continue having these until needing dialysis. The committee concluded that dapagliflozin would be used as an add-on to optimised standard care, including an ACE inhibitor or ARB at the highest tolerated licensed dose, unless these are contraindicated.\n\n## Standard care is an appropriate comparator for dapagliflozin\n\nIn its submission the company compared dapagliflozin plus standard care with standard care alone. The company represented standard care using the placebo arm of DAPA‑CKD (see section\xa03.7). This comprised of background therapies including ACE inhibitors or ARBs, statins and antiplatelets. The ERG agreed with the company's description of how CKD is currently managed in the UK. The committee concluded that standard care is an appropriate comparator for dapagliflozin.\n\n## Canagliflozin is a relevant comparator in people with diabetic kidney disease\n\nCanagliflozin is another SGLT2 inhibitor with a marketing authorisation for type\xa02 diabetes. The company did not consider canagliflozin a relevant comparator for dapagliflozin in CKD, because it noted that canagliflozin is not widely used for treating CKD with type\xa02 diabetes in the UK. However, the company did an indirect treatment comparison of dapagliflozin and canagliflozin in people with CKD and type\xa02 diabetes (see section\xa03.11). The clinical experts noted that canagliflozin is being increasingly used by nephrologists, but acknowledged that the guidelines supporting the use of SGLT2 inhibitors in people with CKD were relatively new. NG28 recommends offering an SGLT2 inhibitor to adults with CKD and type\xa02 diabetes, in addition to an ACE inhibitor or ARB, if their ACR is more than 30\xa0mg/mmol and they meet the criteria in the marketing authorisation. NG28 also recommends considering an SGLT2 inhibitor for adults with CKD and type\xa02 diabetes, in addition to an ACE inhibitor or ARB, if their ACR is between 3\xa0mg/mmol and 30\xa0mg/mmol and they meet the criteria in the marketing authorisation. The committee noted that the comparator in the NICE scope was established clinical management without dapagliflozin. The committee considered that, since canagliflozin was recommended in NG28 and is being used to some extent in clinical practice, it represents established clinical practice for people with CKD and type\xa02 diabetes. In response to consultation the company reiterated that the uptake of canagliflozin has been slow in UK clinical practice for people having treatment for CKD. It also noted that canagliflozin has a marketing authorisation for treating diabetic kidney disease (CKD caused by type\xa02 diabetes). This is a subgroup of people with CKD and type\xa02 diabetes. The ERG explained that it is reasonable to include canagliflozin as a comparator for the subgroup of people with comorbid type\xa02 diabetes, when the licensed indications for both treatments overlap. The committee concluded that canagliflozin is a relevant comparator in people with diabetic kidney disease.\n\n## It is appropriate to make recommendations for dapagliflozin based on uACR levels\n\nIn its updated economic model, the company split the population into subgroups based on uACR level and type\xa02 diabetes status (see section\xa03.14). NG203 recommends measuring proteinuria with uACR in adults with an eGFR of less than 60\xa0ml/min/1.73\xa0m2, or in adults with an eGFR of more than 60\xa0ml/min/1.73\xa0m2 if there is a strong suspicion of CKD. The clinical experts explained that uACR testing is not done consistently in clinical practice. They noted that although the test is simple to do, there is some hesitancy about doing urine tests, particularly when there may be a delay before getting the results. The committee heard from a patient expert who explained that they would not hesitate to provide a urine sample, particularly if this ensured they had the best treatment. The clinical experts added that urine protein-to-creatinine ratio (uPCR) tests are widely done, but it is difficult to map the results of uACR and uPCR tests to each other accurately. They explained that in their experience, uACR is no more difficult to measure than uPCR, but would need a change in practice. During consultation, the company highlighted that making recommendations based on uACR levels would risk people not having access to dapagliflozin because of a lack of testing, particularly those without type\xa02 diabetes. A consultee also advised that the prevalence of proteinuria testing differs by age and ethnicity. The committee acknowledged that uACR testing is not currently implemented consistently in the NHS. If this did not change, limiting dapagliflozin to subgroups based on uACR levels may negatively affect patient access. However, uACR testing is easy to do, has value in identifying people with CKD who are likely to benefit from dapagliflozin, and is recommended in NG203. Therefore, the committee concluded that the current low levels of uACR testing should not prevent it from being included as a criterion in recommendations for dapagliflozin.\n\n# Clinical-effectiveness evidence\n\n## DAPA-CKD suggests that dapagliflozin is more effective than standard care, but the evidence does not cover the full marketing authorisation\n\nThe main clinical evidence for dapagliflozin in the company submission came from DAPA‑CKD. This was a randomised, double-blind trial in adults with CKD, with or without type\xa02 diabetes. DAPA‑CKD compared dapagliflozin plus standard care (n=2,152) with placebo plus standard care (n=2,152) over a median follow-up period of 2.4\xa0years. DAPA‑CKD included people with an eGFR of 25\xa0ml/min/1.73\xa0m2 to 75\xa0ml/min/1.73\xa0m2 and a uACR of 22.6\xa0mg/mmol to\xa0565 mg/mmol. People's disease had to be stable on a maximum tolerated dose of an ACE inhibitor or ARB for at least 4\xa0weeks before screening, unless medically contraindicated. The trial did not include people with CKD who had type\xa01 diabetes or who had an organ transplant. The primary outcome in DAPA‑CKD was a composite outcome of a sustained eGFR decline of 50% or more, end-stage renal disease or death from renal or cardiovascular causes. Results showed that the primary composite outcome occurred in 9.2% of people having dapagliflozin, compared with 14.5% of people having placebo (hazard ratio [HR]\xa00.61, 95% confidence interval [CI] 0.51 to 0.72). Clinical advice to the ERG suggested that the management of CKD in DAPA‑CKD was broadly generalisable to UK clinical practice. However, the ERG highlighted that DAPA‑CKD did not give clinical efficacy evidence for some groups of people with CKD who would be included in the marketing authorisation for dapagliflozin. These included people:\n\nnot having optimised ACE inhibitors or ARBs\n\nwith a uACR of less than 22.6\xa0mg/mmol\n\nwith an eGFR of less than 25\xa0ml/min/1.73\xa0m2 or more than 75\xa0ml/min/1.73\xa0m2\n\nwho had an organ transplant.The clinical experts considered that there would likely be benefits in starting dapagliflozin in people with an eGFR of between 15\xa0ml/min/1.73\xa0m2 and 25\xa0ml/min/1.73\xa0m2, despite the lack of clinical evidence. However, one expert noted the uncertainty in this population, as well as concerns with the impact of a transient decrease in eGFR associated with SGLT2 inhibitors at lower eGFR levels. The committee concluded that the results from DAPA‑CKD suggest that dapagliflozin plus standard care is more effective than standard care alone. But, it noted that DAPA‑CKD tested dapagliflozin only in an enriched population with greater potential to benefit from treatment. The results may therefore not necessarily be transferrable to the groups of people with CKD excluded from DAPA‑CKD.\n\n## DECLARE-TIMI-58 and DAPA-HF provide evidence for some people excluded from DAPA-CKD, but evidence gaps remain\n\nThe company presented additional clinical evidence from 2\xa0randomised controlled trials, DECLARE‑TIMI‑58 (n=17,160) and DAPA‑HF (n=4,744). This was to provide renal outcome data across a broader population. DECLARE‑TIMI‑58 included people with type\xa02 diabetes who had, or were at high risk of, cardiovascular events, and who had a creatinine clearance of 60\xa0ml/min/1.73\xa0m2 or more. However, 7.4% of people (n=1,265) had an eGFR of less than 60\xa0ml/min/1.73\xa0m2. Inclusion in DECLARE‑TIMI‑58 was not restricted based on uACR level, so the trial is likely to have enrolled people across a wide range of uACR levels. DAPA‑HF included people with heart failure with reduced ejection fraction, regardless of whether they had comorbid type\xa02 diabetes. People in DAPA‑HF had to have an eGFR of 30\xa0ml/min/1.73\xa0m2 or more, and uACR was not measured. Both DECLARE‑TIMI‑58 and DAFA‑HF included some people with comorbid CKD (34.8% and 40.7%, respectively). Neither study included people with type\xa01 diabetes or who had an organ transplant. Results from DECLARE‑TIMI‑58 and DAPA‑HF suggested that dapagliflozin plus standard care is more effective than standard care alone across the broad CKD population, regardless of uACR and eGFR levels. DECLARE‑TIMI‑58 showed that the dapagliflozin treatment effect was consistent between people with a uACR of less than 22.6\xa0mg/mmol and those with a uACR of 22.6\xa0mg/mmol or higher for the following end points: the co-primary end point of hospitalisation for heart failure or cardiovascular death, and the renal end point without cardiovascular death (eGFR decline of 40% or more, end-stage renal disease, or death from renal causes). However, the ERG highlighted that there remained some subgroups of people with CKD for which there was no clinical trial evidence for dapagliflozin. These included:\n\npeople without type\xa02 diabetes and with a uACR of less than 22.6\xa0mg/mmol\n\npeople who had an organ transplant.The ERG also noted that the data from DAPA‑HF was not used in the company's economic model. The committee concluded that DECLARE‑TIMI‑58 and DAPA‑HF showed that dapagliflozin was clinically effective in some subgroups of people with CKD outside of DAPA‑CKD. However, the size of benefit in subgroups outside DAPA‑CKD was uncertain, and important uncertainties and evidence gaps remained.\n\n## There is a lack of evidence for dapagliflozin in people with CKD who have had an organ transplant\n\nThe company did not present evidence for dapagliflozin in people with CKD who have had an organ transplant. Clinical experts advised that there is a lack of evidence for using dapagliflozin in these people in general. The experts highlighted that further clinical trials are needed to establish the clinical effectiveness and safety of dapagliflozin in these people. A consultation comment highlighted that evidence should be developed on the benefits of dapagliflozin for people with kidney transplants. The committee concluded that there is a lack of evidence for dapagliflozin in people with CKD who have had an organ transplant, and there is need for further clinical trials in these people.\n\n## The company's simulated outcomes analysis and real-world evidence does not robustly resolve the evidence gap for people with low uACR levels without type\xa02 diabetes\n\nIn response to technical engagement, to address the lack of clinical-effectiveness evidence for dapagliflozin in people without type\xa02 diabetes and with a uACR of less than 22.6\xa0mg/mmol (see section\xa03.8), the company provided an additional analysis. This estimated outcomes for people with low uACR levels, split by whether or not they had type\xa02 diabetes. The company did a simulated treatment outcomes analysis using a Poisson model to fit an estimated yearly event rate conditional on uACR as the continuous variable from DAPA‑CKD, with a uACR range extended from 3.39\xa0mg/mmol to 565\xa0mg/mmol. The results are academic in confidence and cannot be reported here. The ERG explained that such an analysis only supported a hypothesis that dapagliflozin might work in this population. The company had extrapolated event rates to a population in which there was no actual clinical evidence of dapagliflozin efficacy. In response to consultation, the company provided real-world evidence to support the efficacy of dapagliflozin in people without type\xa02 diabetes and with a uACR of less than 22.6\xa0mg/mmol. This came from a US study of 2\xa0databases. The ERG noted that this analysis had several limitations. It was based on small sample sizes, used a surrogate end point and was based on observational data. The committee agreed that, in the absence of robust trial evidence, the company's simulated treatment outcomes analysis and real-world evidence did not resolve the evidence gap in people with low uACR levels without type\xa02 diabetes.\n\n## Dapagliflozin and canagliflozin are likely to be equally effective in people with diabetic kidney disease, and the least costly option that meets individual patient needs should be used\n\nAlthough it did not consider canagliflozin a relevant comparator (see section\xa03.5), the company presented an indirect comparison to estimate the efficacy of dapagliflozin compared with canagliflozin for people with CKD and type\xa02 diabetes. The company did an anchored matching-adjusted indirect comparison using data from the DAPA‑CKD and CREDENCE trials. CREDENCE was a randomised, double-blind trial of people with type\xa02 diabetes and albuminuric CKD (uACR of more than 33.9\xa0mg/mmol) having canagliflozin or placebo. The results of the indirect comparison suggested equal efficacy between dapagliflozin and canagliflozin in people with CKD and type\xa02 diabetes. The ERG explained that the selection of covariates in the matching-adjusted indirect comparison was overly complex. It also highlighted that the assumption of proportional hazards (that is, the relative risk of an event is fixed irrespective of time) may not be satisfied. Therefore, the Cox proportional hazard model used by the company may not be appropriate. However, the ERG considered that despite the limitations with the indirect comparison, the overall conclusion of equal efficacy was reasonable. The clinical experts explained that there was likely to be a class effect for SGLT2 inhibitors in treating CKD. The committee considered the company's indirect comparison with canagliflozin acceptable for decision making, and that a conclusion of equal efficacy for dapagliflozin and canagliflozin in people with diabetic kidney disease was reasonable. It was not presented with any evidence suggesting a distinction between dapagliflozin and canagliflozin for people with diabetic kidney disease. It concluded that the least costly option of the 2 that meets individual patient needs should be used.\n\n# Adverse events\n\n## The adverse event profile of dapagliflozin for CKD is consistent with other licensed indications for dapagliflozin\n\nThe adverse event profile of dapagliflozin for treating CKD in the company submission was informed by evidence from DAPA‑CKD. Dapagliflozin was associated with fewer deaths resulting from adverse events. There were also fewer serious adverse events with dapagliflozin compared with placebo. However, dapagliflozin was associated with a higher rate of serious adverse events among people with type\xa02 diabetes compared with those without type\xa02 diabetes. Nobody experienced diabetic ketoacidosis with dapagliflozin, and people having dapagliflozin had lower rates of major hypoglycaemic events, renal events, amputations, fractures and symptoms of volume depletion compared with placebo. The ERG explained that the adverse event profile of dapagliflozin for CKD from DAPA‑CKD was generally consistent with other indications such as diabetes and heart failure. The committee noted this, and concluded that the adverse event profile of dapagliflozin in CKD is consistent with the other licensed indications for dapagliflozin.\n\n# Economic model\n\n## The company's economic model structure is appropriate\n\nThe company developed a de novo health economic model to assess the cost effectiveness of dapagliflozin plus standard care compared with standard care alone for people with CKD. The model used a cohort-level state transition approach with 6\xa0health states defined according to CKD stages\xa01 to 5 (including stages G3a and G3b), with additional states for dialysis, kidney transplant and death. It used a lifetime horizon and a cycle length of 1\xa0month. A yearly discount rate of 3.5% was applied to costs and outcomes. Clinical Practice Research Datalink (CPRD) data informed patient baseline characteristics. CPRD is a real-world research service that collects patient data from a network of general practices across the UK. It links this to a range of other health-related data to provide a longitudinal, representative UK population health dataset. Some event risks in the model (mortality, hospitalisation for heart failure, and acute kidney injury) were also adjusted to match the CPRD data. However, the probabilities of transitioning between CKD stages were not similarly adjusted. The ERG and its clinical advisers considered the company's overall model structure to be reasonable, but noted concerns about the overall survival predictions (see section\xa03.17). The company assumed that dapagliflozin would not need any additional appointments or tests beyond those already associated with managing CKD. The committee was uncertain whether this would be the case, particularly for people without type\xa02 diabetes. Therefore, the costs for dapagliflozin may have been underestimated in the model for these people. However, the committee concluded that the company's overall model structure was appropriate.\n\n## Given the differences in available evidence, the 3\xa0subgroups should be considered separately during decision making\n\nTo address ERG concerns at technical engagement about the lack of clinical evidence in some groups of people with CKD (see section\xa03.7), the company provided an updated economic model. The updated model included a revised patient population having optimised ACE inhibitors or ARBs, and the CPRD population used by the company to adjust the model was updated to reflect this. Also, the model used data from a subgroup of people with CKD from DECLARE‑TIMI‑58. The company presented a weighted economic analysis for the following subgroups according to their prevalence in the updated CPRD dataset:\n\nSubgroup 1: uACR of 22.6\xa0mg/mmol or more, with or without type\xa02 diabetes.\n\nSubgroup 2: uACR of less than 22.6\xa0mg/mmol, with type\xa02 diabetes.\n\nSubgroup 3: uACR of less than 22.6\xa0mg/mmol, without type\xa02 diabetes.The updated model re-estimated patient characteristics, mortality risks and transient event risks for each subgroup based on the relevant CPRD dataset. The ERG highlighted that subgroup\xa01 most closely reflected the DAPA‑CKD population and that DECLARE‑TIMI‑58 also provided clinical evidence for subgroup\xa02, but there was no direct clinical evidence in subgroup\xa03. The company's updated model assumed that the CKD stage transition probabilities in subgroup\xa03 were the same as in subgroup\xa02. It also assumed that the overall survival model was the same in all 3\xa0subgroups, except a non-type\xa02 diabetes adjustment factor was applied for subgroup\xa03. The ERG did not consider the company's weighted analysis to be appropriate, given the differences in the availability and strength of the evidence for each subgroup. Subgroup\xa01 was closest to DAPA‑CKD but represented a small proportion of the overall weighted economic analysis, with most of the quality-adjusted life years (QALYs) and costs in the model informed by subgroups\xa02 and\xa03. The committee was concerned that subgroup\xa03 accounted for around one third of the company's weighted population in the cost-effectiveness analyses updated after consultation (see section\xa03.15), in which there is no direct clinical evidence for dapagliflozin. It agreed with the ERG that the 3\xa0subgroups should be considered separately in decision making.\n\n## The company's updated CPRD adjustment is uncertain, but this is unlikely to have a large effect on the cost-effectiveness estimates for subgroup\xa02\n\nThe company updated its model in response to consultation to use a CPRD dataset that included people with an eGFR of 25\xa0ml/min/1.73\xa0m2 to 75\xa0ml/min/1.73\xa0m2 having optimised ACE inhibitors or ARBs, with or without a diagnosis of CKD. This was intended to better reflect the population in the preliminary recommendations in the appraisal consultation document. However, clinical advice to the ERG suggested that the new CPRD dataset would include a large proportion of people who do not have CKD. The committee also heard that in the post-consultation model, the CPRD dataset for subgroup\xa02\xa0and 3 was not stratified by type\xa02 diabetes status to reflect the population more accurately in each of these subgroups. Instead, the company used a single CPRD dataset in which around two thirds of people had type\xa02 diabetes and one third did not. The company noted that for subgroup\xa02, the cost-effectiveness estimate for dapagliflozin plus standard care compared with standard care alone was similar regardless of whether the CPRD adjustment was applied. The committee also noted that the cost-effectiveness estimates for dapagliflozin in subgroup\xa02 were similar based on both the technical engagement and post-consultation models. This suggested that the uncertainties around the CPRD adjustment had little effect on the cost-effectiveness results in this subgroup. However, there were much greater differences between the cost-effectiveness results in subgroup\xa03 depending on whether the CPRD adjustment was applied, suggesting greater uncertainty. The committee concluded that the updated CPRD adjustment was uncertain because the dataset likely included people without CKD who would not have dapagliflozin, and because it had not been stratified by type\xa02 diabetes status for subgroups\xa02 and\xa03. But, this did not have a large effect on the cost-effectiveness estimates for subgroup\xa02.\n\n## The mean age in the model should reflect the same CPRD datasets as those used to inform the other patient characteristics\n\nIn its technical engagement model the company used a mean (average) age of 64\xa0years from a separate CPRD dataset. This included people with an eGFR of less than 90\xa0ml/min/1.73\xa0m2 who were taking ACE inhibitors or ARBs but did not need to have a formal diagnosis of CKD. This was lower than the mean ages from the CPRD datasets used to adjust the 3\xa0subgroups in the model, which ranged from around 74 to 78\xa0years. The company noted that clinician input supported using the lower mean age, as did registry data. However, the ERG explained that the company's approach was inconsistent. This was because all other baseline characteristics and event risk adjustments in the model were based on subgroup-specific CPRD datasets all needing a formal CKD diagnosis. Therefore, it was inappropriate to include a mix of patient characteristics from separate groups of people from different CPRD datasets. The ERG preferred to use the subgroup-specific CPRD datasets informing the baseline characteristics and event risk adjustments for each subgroup in the model, for which the mean ages were higher than the company's approach. The clinical experts noted that although there was uncertainty about what the mean age of people was in clinical practice, it was likely to be higher than that used by the company. They explained that although the mean age of people with CKD seen in secondary care was likely to be closer to the company's estimate, this may not fully represent those who would have dapagliflozin in clinical practice because people having treatment in primary care may be older. The committee considered that the mean age estimate from the separate CPRD dataset was inappropriate because it was likely that many people in this dataset did not have CKD. Also, applying a lower age estimate in a dataset with characteristics and risks estimated from an older population was inappropriate. This is because younger people do not have the same characteristics and risks as older people. In response to consultation, the company updated the mean ages in its model so that they were based on the same CPRD datasets as the other baseline characteristics. The weighted mean age in the company's updated model (around 73\xa0years) was higher than the estimate used in its technical engagement model. The committee recalled that there were some uncertainties with the new CPRD dataset (see section\xa03.15). But, because the company's updated model used the CPRD data consistently, the committee considered that the revised mean age was more appropriate.\n\n## Despite limitations in the company's approach to overall survival modelling, its impact on decision making is likely to be small\n\nThe company modelled the treatment effect of dapagliflozin on overall survival through 2\xa0mechanisms:\n\nDirectly, by applying a treatment-related hazard ratio for overall survival to each CKD state from a multivariable survival model to each state-specific overall survival model except transplant.\n\nIndirectly, by applying transition matrices that lead to slower disease progression for people having dapagliflozin plus standard care compared with standard care alone.The ERG highlighted that when the adjustment to the CPRD dataset (see section\xa03.13) was removed, the company's model overestimated overall survival compared with the data from DAPA‑CKD. The ERG was uncertain about the cause of this, but it may have been because:\n\nThe company had included a post-randomisation covariate (CKD stage), which can lead to problems in determining causality.\n\nThe company estimated state-specific mortality risks using a 'mean of covariates' approach, which has been shown to lead to bias when estimating survival distributions.However, the ERG noted that even if the issues identified in the company's approach to overall survival modelling were resolved, the incremental cost-effectiveness ratio for dapagliflozin compared with standard care would likely remain below £20,000 per QALY gained in the DAPA‑CKD population. The committee concluded that despite the limitations with the company's approach to overall survival modelling, its impact on decision making was likely to be small.\n\n# Cost-effectiveness estimates\n\n## Dapagliflozin is cost effective in the population represented in DAPA-CKD\n\nThe committee recalled that it would consider the company's 3\xa0subgroups separately in decision making (see section\xa03.14). It considered the cost effectiveness of dapagliflozin plus standard care compared with standard care alone in subgroup\xa01 (people with a uACR of 22.6\xa0mg/mmol or more, with or without type\xa02 diabetes). In the company's updated model in response to consultation, dapagliflozin plus standard care dominated standard care in this subgroup (that is, it was more effective and less costly than standard care). However, the committee recalled that the evidence was weaker for dapagliflozin outside of the eGFR levels in DAPA‑CKD. It also noted that dapagliflozin was likely to have a large impact on NHS resources given the size of the patient population (see section\xa03.1), and so it needed to see robust clinical and cost-effectiveness evidence. It concluded that the cost-effectiveness estimate for dapagliflozin in subgroup\xa01 was an acceptable use of NHS resources. The recommended population should be limited to the eGFR and uACR levels included in DAPA‑CKD (see section\xa03.7) to match the available evidence.\n\n## Dapagliflozin is cost effective for people with a uACR of less than 22.6\xa0mg/mmol and type\xa02 diabetes\n\nThe committee considered the cost effectiveness of dapagliflozin plus standard care compared with standard care alone in subgroup\xa02 (people with a uACR of less than 22.6\xa0mg/mmol and type\xa02 diabetes). In the company's updated model in response to consultation, the incremental cost-effectiveness ratio (ICER) for dapagliflozin plus standard care compared with standard care in this subgroup was around £6,000 per QALY gained. The recommendations in NG28 state that for people with type\xa02 diabetes and CKD, in addition to an ARB or an ACE inhibitor, an SGLT2 inhibitor should be considered if their ACR is 3\xa0mg/mmol to 30\xa0mg/mmol and offered if their ACR is higher than 30\xa0mg/mmol (see section\xa03.5). Although the committee was aware of this broader context, it was mindful that its remit was to appraise the clinical and cost effectiveness of dapagliflozin. It consequently focused its decision making on the evidence provided for this technology appraisal. It recalled that DECLARE‑TIMI‑58 provided evidence for the treatment effect of dapagliflozin in people with CKD and type\xa02 diabetes with a uACR of less than 22.6\xa0mg/mmol (see section\xa03.8). The committee also understood that the company had used this evidence to inform the cost-effectiveness estimate of dapagliflozin in subgroup\xa02 in its updated model (see section\xa03.14). The committee noted that the ICER in this subgroup was comfortably within what NICE considers an acceptable use of NHS resources. In response to consultation, the company provided further subgroup analysis of subgroup\xa02. It divided subgroup\xa02 into people with a uACR of less than 3\xa0mg/mmol, and people with a uACR of 3\xa0mg/mmol to 22\xa0mg/mmol. The ICERs for both these subgroups were similar to the ICER for subgroup\xa02 as a whole (around £6,000 per QALY gained). The committee therefore concluded that dapagliflozin can be recommended for people with CKD with a uACR of less than 22.6\xa0mg/mmol and type\xa02 diabetes.\n\n## Dapagliflozin cannot be recommended in people with a uACR of less than 22.6\xa0mg/mmol who do not have type\xa02 diabetes\n\nThe committee considered the cost effectiveness of dapagliflozin plus standard care compared with standard care alone in subgroup\xa03 (people with a uACR of less than 22.6\xa0mg/mmol without type\xa02 diabetes). In the company's updated model in response to consultation, the ICER for dapagliflozin plus standard care compared with standard care in this subgroup was around £17,000 per QALY gained. There was no direct clinical evidence informing subgroup\xa03 in the company's model (see section\xa03.8), and there was uncertainty around the CPRD adjustment in this subgroup (see section\xa03.15). This generated considerable uncertainty in the plausibility of the cost-effectiveness estimates for this population. The committee noted a stakeholder's comment that the benefits of dapagliflozin in preventing decline in renal function should be weighed against the potential consequences of overprescribing and drug interactions, particularly in people with milder disease. It also understood from the company at the second appraisal committee meeting that subgroup\xa03 is likely to comprise more of the CKD population than the CPRD data suggests. Therefore, the committee considered that the consequence of decision error was likely to be higher for this subgroup. It concluded that dapagliflozin cannot be recommended for the population in subgroup\xa03.\n\n# Innovation\n\n## Dapagliflozin is an innovative treatment for CKD, but all relevant benefits are reflected in the cost-effectiveness estimates\n\nThe company considered dapagliflozin to be innovative because it addresses a significant unmet need in CKD, which is associated with a significant clinical and economic burden and for which standard care is inadequate for many people. The patient and clinical experts highlighted the lack of effective pharmacological management for CKD and the importance of slowing down disease progression. Patient experts felt that dapagliflozin offers a step change for treating CKD, because its ability to delay disease progression offers real hope. Clinical experts highlighted that the benefits of dapagliflozin are distinct from a blood glucose reduction alone, and that reducing progression to end-stage renal disease will increase quality of life. The committee acknowledged the new benefits offered by dapagliflozin and other SGLT2 inhibitors as additional treatment options for CKD. However, it concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY measurements.\n\n# Equalities considerations\n\n## There are no equalities issues relevant to the recommendations\n\nNo equalities issues were raised during scoping stage. During technical engagement, patient and clinical expert submissions highlighted that CKD disproportionally affects people from Black, Asian, and minority ethnic groups and lower socioeconomic backgrounds. People from these groups are also more likely to have CKD that progresses quicker to kidney failure and to die earlier. During consultation, a consultee also highlighted that use of ACE inhibitors or ARBs differs by ethnicity and socioeconomic status. However, the committee did not consider these to be equality issues that could be resolved by this appraisal. No other potential equality issues were raised. The committee concluded that there were no equalities issues relevant to the recommendation."}
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https://www.nice.org.uk/guidance/ta775
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Evidence-based recommendations on dapagliflozin (Forxiga) for chronic kidney disease in adults.
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dc4e7df246b247c751bba847105ea3819df445cf
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nice
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Pitolisant hydrochloride for treating excessive daytime sleepiness caused by obstructive sleep apnoea
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Pitolisant hydrochloride for treating excessive daytime sleepiness caused by obstructive sleep apnoea
Evidence-based recommendations on pitolisant hydrochloride for treating excessive daytime sleepiness caused by obstructive sleep apnoea in adults.
# Recommendations
Pitolisant hydrochloride is not recommended, within its marketing authorisation, to improve wakefulness and reduce excessive daytime sleepiness in adults with obstructive sleep apnoea whose sleepiness has not been satisfactorily treated by primary obstructive sleep apnoea therapy such as continuous positive airway pressure (CPAP), or who cannot tolerate it.
This recommendation is not intended to affect treatment with pitolisant hydrochloride that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Excessive daytime sleepiness caused by obstructive sleep apnoea is usually treated with primary obstructive sleep apnoea therapy such as CPAP or mandibular advancement devices.
Clinical trial evidence suggests that pitolisant hydrochloride reduces excessive daytime sleepiness, with and without CPAP. But there is uncertainty about the evidence because of the way the trials were done. It is also uncertain how much pitolisant hydrochloride improves quality of life because of how it was measured in the trials.
Because of the uncertainty in the clinical evidence and economic model, the cost-effectiveness estimates are also uncertain. They are also likely to be higher than what NICE normally considers an acceptable use of NHS resources. So pitolisant hydrochloride is not recommended.# Information about pitolisant hydrochloride
# Marketing authorisation indication
Pitolisant hydrochloride (Ozawade, Bioprojet Pharma) is indicated 'to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients with obstructive sleep apnoea (OSA) whose EDS has not been satisfactorily treated by, or who have not tolerated, OSA primary therapy, such as continuous positive airway pressure (CPAP)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for pitolisant hydrochloride.
# Price
The list price of pitolisant hydrochloride is £138 for a 30‑pack of 4.5‑mg or 18‑mg tablets (excluding VAT; company submission).# Committee discussion
The appraisal committee considered evidence submitted by Bioprojet Pharma, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## Excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life
The patient expert explained that obstructive sleep apnoea can affect people's physical and mental wellbeing. Excessive daytime sleepiness affects daily life including education, employment, maintaining a social life and the ability to drive. Symptoms of sleep apnoea such as snoring can disrupt a partner's sleep, affecting their own quality of life. The patient expert said that a better understanding of the condition among GPs could improve consistency in arriving at a diagnosis sooner. The clinical experts noted that obstructive sleep apnoea can be associated with high blood pressure, heart disease and stroke. The committee concluded that excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life.
## Pitolisant hydrochloride would typically be offered with CPAP, but some people cannot tolerate CPAP
The clinical experts advised that most people with excessive daytime sleepiness caused by obstructive sleep apnoea are referred to sleep clinics. Initial treatment includes lifestyle advice about weight loss. For people with mild symptomatic obstructive sleep apnoea, mandibular advancement devices are considered. For adults with moderate or severe obstructive sleep apnoea, NICE's technology appraisal guidance on continuous positive airway pressure (CPAP) recommends it for treating obstructive sleep apnoea. The patient expert explained that CPAP is usually well tolerated but some people may need to adjust to sleeping with a mask that is connected to a small machine. The clinical experts explained that some people cannot tolerate CPAP because they feel claustrophobic wearing a mask, which can be exacerbated by certain mental health issues. People with neurodegenerative conditions may also not tolerate CPAP, and some people have anatomical variations that make CPAP unsuitable for them. The clinical and patient experts also explained that some people using CPAP will have residual excessive daytime sleepiness. They noted that pitolisant hydrochloride is a potential treatment option that would be welcome for improving excessive sleepiness, although it does not treat the underlying causes of obstructive sleep apnoea. The committee concluded that because pitolisant hydrochloride does not treat underlying airway obstruction, it would likely be used in addition to CPAP, but it acknowledged that some people cannot tolerate CPAP.
## Mandibular advancement device availability varies across the country
The clinical experts explained that people who decline CPAP or cannot tolerate it may be offered a mandibular advancement device, which helps prevent the airway closing. They highlighted that this varies in practice because the devices are not available at every sleep clinic. About 20% of people who do not have CPAP might be offered a mandibular advancement device. However, because mandibular advancement devices are now recommended in NICE's guideline on obstructive sleep apnoea, they may be used more frequently. The company stated that mandibular advancement devices are generally used earlier in the treatment pathway than CPAP, so someone who declines CPAP is likely to have already been offered a mandibular advancement device. The committee concluded that because of the uncertainty around availability of mandibular advancement devices, it was appropriate to not consider them in this appraisal.
## Pitolisant hydrochloride is likely to be prescribed in secondary care
The clinical experts highlighted that pitolisant hydrochloride would likely be prescribed in specialist sleep clinics (secondary care) because of the need to monitor adherence to CPAP. They highlighted that additional monitoring would be needed if pitolisant hydrochloride were recommended. They were uncertain if prescribing could move to primary care in the future. The committee concluded that pitolisant hydrochloride is likely to be prescribed in secondary care.
# Clinical evidence
## Pitolisant hydrochloride improves excessive daytime sleepiness, with and without CPAP
HAROSA 1 and HAROSA 2 were randomised trials of people having either pitolisant hydrochloride plus standard care (including lifestyle changes and CPAP optimisation for CPAP users) or placebo plus standard care, for a 12‑week double-blind period. After 12 weeks, everyone in the trial was offered pitolisant hydrochloride for 40 weeks (the open-label phase). In HAROSA 1, people had been using nasal CPAP therapy for at least 3 months and had excessive daytime sleepiness before starting the trial. HAROSA 2 included only people who had not used CPAP and had excessive daytime sleepiness. The primary outcome of the trials was reduction in Epworth Sleepiness Scale (ESS) score. ESS scores of 10 or less indicate normal daytime sleepiness, and scores of 11 to 24 indicate excessive daytime sleepiness. The results showed a reduction in mean ESS scores from baseline to week 12 for the pitolisant hydrochloride group in both trials. In people who used CPAP, the mean ESS score reduced by 5.52 points in the pitolisant hydrochloride group. In people who had not used CPAP, the mean ESS score reduced by 6.30 points in the pitolisant hydrochloride group. In terms of quality of life, people in HAROSA 1 reported no statistically significant difference in EQ‑5D or visual analogue scale score during the double-blind phase of the trial. However, there was an improvement in the pain and discomfort dimension of the EQ‑5D in HAROSA 2. The clinical experts explained that an ESS reduction of 2 or more points could be considered clinically relevant, but noted that there is no clinical consensus about this because it will vary between individuals. The committee concluded that pitolisant hydrochloride improves excessive daytime sleepiness, with or without CPAP.
## The HAROSA trials are broadly generalisable to NHS practice but may exclude some people who might be eligible for pitolisant hydrochloride
The HAROSA trials had a criterion that stated people with psychiatric illness could be excluded. The company clarified that people with depression were only excluded if the investigating clinician felt that it would make study participation challenging for them, rather than for any particular concern about comorbid conditions. A Beck Depression Inventory (13‑item short form) score of less than 16 was an inclusion criterion, meaning that people with mild (score 5 to 7) and moderate (score 8 to 15) depression were included in the HAROSA trials. The company stated that the trials included people with depression and anxiety. There were 18% of people in HAROSA 1 and 5% in HAROSA 2 who had a pre-existing psychiatric illness. The committee noted that the company's submission stated that about half of people with severe excessive daytime sleepiness have coexisting depression. The clinical experts estimated that about half of people referred to sleep clinics might have antidepressant therapy of some kind. The committee accepted that some people with depression were included in the trials, but the proportions were lower than might be expected in the NHS. This might affect the generalisability of the trial data. The effect of this on the clinical-effectiveness estimates was unknown. The committee concluded that the HAROSA trials were broadly generalisable for decision making, but may under-represent people with psychiatric illness.
## Adherence to CPAP is unlikely to be affected by treatment with pitolisant hydrochloride
The patient expert explained that some people with excessive daytime sleepiness may prefer to manage their symptoms with medicine, rather than using CPAP. So they might use CPAP less often when taking pitolisant hydrochloride, which could lead to a reduction in the combined benefits of CPAP and pitolisant hydrochloride. The clinical experts said that most sleep clinics can remotely monitor CPAP use. Some people, such as heavy goods vehicle drivers, regularly have their CPAP use monitored remotely. The clinical experts stated that people having pitolisant hydrochloride alongside CPAP may have their use monitored more frequently than in current practice. The committee concluded that CPAP use is unlikely to be affected by treatment with pitolisant hydrochloride, because of regular monitoring. In response to consultation, the patient expert reiterated concerns that people having pitolisant hydrochloride in addition to CPAP may use their CPAP machine less often. The committee acknowledged concerns about reduced CPAP adherence, but concluded that it had not seen evidence to change its original conclusion that pitolisant hydrochloride use is unlikely to affect CPAP use.
## A trial of pitolisant hydrochloride for narcolepsy had a follow-up period long enough to understand its side effects
The clinical experts had experience using pitolisant hydrochloride with people who have narcolepsy. They commented that they could rapidly see the benefits as well as the side effects of the treatment. The company provided data from HARMONY, a study of people taking pitolisant hydrochloride for narcolepsy for 1 year or more. The ERG cautioned that the effectiveness of pitolisant hydrochloride in HARMONY does not directly correlate to effectiveness in obstructive sleep apnoea because the cause of sleepiness is different. The committee concluded that the HARMONY follow-up period was long enough for decision making about the side effects of pitolisant hydrochloride.
# The economic model
## The company's new model is acceptable for decision making but has limitations
The company's original model was based on a model developed by McDaid et al. (2007) for NICE's technology appraisal guidance on CPAP for treating obstructive sleep apnoea. The model in that appraisal included a method of mapping ESS scores to EQ‑5D utility values (from now, the McDaid approach). The ERG noted that pitolisant hydrochloride and CPAP treat different aspects of the condition, so following the CPAP model may not be the best approach for evaluating pitolisant hydrochloride. However, it stated that the relevant consequences of the comparisons could be adequately assessed using this model, although it may be more complicated than necessary. It corrected some aspects of the company's model, which had a small effect on the company's base-case incremental cost-effectiveness ratio (ICER). But the committee was interested in a model that considered people with a disease response and those without, separately, and explored placebo adjustments (see section 3.11). Restructuring the model in this way, and adjusting for a placebo effect, might reveal greater differences between the 2 groups. In response to consultation, the company submitted a new model similar to the one used in NICE's technology appraisal guidance on solriamfetol for treating excessive daytime sleepiness caused by obstructive sleep apnoea. The new model included a decision tree for the first 52 weeks of treatment followed by a Markov model with 3 health states: 'responder', 'non-responder' and 'death'. Movement through the model was based on disease response. The company assumed that people who had standard care could be considered 'responders'. The model adjusted for the Hawthorne effect using a centring approach. The ERG agreed that the new model was consistent with the committee's comments from the first meeting about response status and adjustment for a placebo effect. However, it noted several limitations, including:
no explanation of how baseline utility values were derived
errors in the formulas used to map ESS scores to EQ‑5D utility values using the McDaid approach, which resulted in overestimated values
uncertainty around the response transition probabilities informed by stopping treatment
it did not include probabilistic sensitivity analyses, so the probability that pitolisant hydrochloride is cost effective is unknown.The committee questioned the company's approach of assigning utility values based on both response status and treatment group. It acknowledged the limitations of the new model but concluded that it was acceptable for decision making.
## There is no direct evidence that pitolisant hydrochloride reduces cardiovascular events
The company's original model assumed that a reduction in ESS score was related to a reduction in cardiovascular disease risk (that is, people could move into the post-coronary heart disease state if they had an acute cardiovascular event and survived). The original modelling also assumed that pitolisant hydrochloride lowers the risk of cardiovascular events, which are more prevalent in people with excessive daytime sleepiness caused by obstructive sleep apnoea. The committee noted that the company did not explain the biological mechanism by which pitolisant hydrochloride may reduce cardiovascular events. The clinical experts explained that because of the lack of long-term clinical trials in obstructive sleep apnoea, they rely on markers for cardiovascular risk such as blood pressure. They stated that there is evidence that people using CPAP have reduced blood pressure along with their daytime sleepiness. But they noted that there was no direct evidence to validate this assumption in the economic model. The ERG agreed that it had not seen evidence that a reduction in ESS score with pitolisant hydrochloride would lead to a reduction in cardiovascular events. It was unaware of any reasonable mechanism by which a wakefulness drug would reduce cardiovascular risk, rather than this being a result of treating the underlying cause of excessive sleepiness (obstructive sleep apnoea). The committee noted that the HAROSA trials showed no changes in people's blood pressure levels. In the absence of evidence of changes in cardiovascular markers, the committee agreed with the ERG. It concluded that there was no direct evidence of a clinical or biological mechanism by which pitolisant hydrochloride affects cardiovascular events. In response to consultation, the company provided a new model that did not include a potential effect of pitolisant hydrochloride on the risk of cardiovascular events (see section 3.9). The committee noted this was consistent with its conclusion at the first committee meeting.
## Adjusting for the Hawthorne effect is the most appropriate approach to adjust for the placebo effect
The ESS score improved from baseline to week 12 in the placebo group in both HAROSA trials. The clinical experts suggested this could be because of potential observation bias from the Hawthorne effect (that is, people reported an improvement in ESS scores because they have more frequent contact with trial investigators than they would with clinicians in clinical practice). The committee noted the potential causes of such an effect and discussed ways to adjust for it. One way might be to remove the improvement in ESS scores observed in the placebo group from both the placebo and the pitolisant hydrochloride groups in the model (sometimes referred to as a centring approach). At its first meeting, the committee concluded that approaches to account for the placebo effect shown in the HAROSA trials should be explored to understand its effect on the cost-effectiveness results. In response to consultation, the company submitted a new model that adjusted for the placebo effect using a centring approach, under the assumption that placebo group improvements were a result of the Hawthorne effect. The ERG provided additional scenarios that assumed:
a true placebo effect (adjusted for by removing the treatment effect for placebo for comparator group, but keeping it in the pitolisant group)
a regression to the mean effect (no adjustment based on the assumption that the trial may have captured extreme ESS scores that would trend towards the mean over time) or
an equal contribution from the 3 proposed effects.The ERG noted that the regression to the mean model would only be appropriate if it was evident that people's ESS scores fluctuated over time. The clinical experts explained that there is limited long-term ESS score data for people who are having treatment for excessive daytime sleepiness. The experts added that in clinical practice, they observe some fluctuation in people's ESS scores. The committee noted that it had not seen evidence of how much people's ESS scores fluctuated over time. It concluded that adjusting for the Hawthorne effect by removing the treatment effect for placebo from the comparator and pitolisant hydrochloride groups was the most appropriate approach to adjust for the placebo effect.
## The EQ-5D utility values from both the trials and the McDaid mapping approach are relevant for consideration
The company stated that the EQ‑5D questionnaires may not adequately capture quality-of-life benefits in people with obstructive sleep apnoea. It explained that because EQ‑5D is a generic instrument, it is not designed to specifically measure changes in quality of life for people with excessive daytime sleepiness caused by obstructive sleep apnoea. It also noted that the EQ‑5D does not have a sleep domain, which means improvements in sleep or daytime wakefulness are unlikely to be captured. So the company's submission mapped ESS scores from the trials to the EQ‑5D (the McDaid approach) rather than using values derived directly from the trials. The company stated that this was consistent with the approach used in NICE's technology appraisal guidance on CPAP for treating obstructive sleep apnoea. Clinical experts agreed with the company that the EQ‑5D may not capture changes in excessive daytime sleepiness. The ERG commented that it is possible that a modest decrease in excessive sleepiness does not significantly impact health-related quality of life. The committee was concerned that if the EQ‑5D does not capture quality-of-life benefits adequately in this population, the ESS scores should not be mapped to the EQ‑5D, because it will remain insensitive. The committee also noted that the McDaid report stated that the EQ‑5D could capture the health effects of sleepiness through its impact on usual activities or anxiety and depression. After technical engagement, the company provided an analysis of mean difference by treatment group using individual patient data from EQ‑5D data in the trials. These are academic in confidence and cannot be presented here. The committee considered it uncertain whether the EQ‑5D captures quality-of-life benefits in people with obstructive sleep apnoea. In response to consultation, the company presented evidence from a commissioned study to support the position that the EQ‑5D is not sensitive to changes in quality of life for this population. The study investigated 3 metrics that are derivable from the EQ‑5D: EQ‑INDEX (sum score of the 5 dimensions), EQ‑Visual Analogue Scale (EQ‑VAS), and z‑score (composite of EQ‑INDEX and EQ‑VAS) in the pitolisant hydrochloride HAROSA trials. The study showed that there was no significant difference in EQ‑INDEX for people who had pitolisant hydrochloride and people who had placebo. It also found that the EQ‑VAS appeared better correlated with clinical outcomes than the EQ‑INDEX. Typically, the larger the EQ‑INDEX, or sum of the individual dimensions, the more severe or frequent the problems. However, the study standardised the EQ‑INDEX to a 0 to 100 scale and reversed the direction to align with the EQ‑VAS, where larger values represent higher reported health. The ERG explained that because the EQ‑INDEX was standardised and reversed, it was unknown what the results would have been if EQ‑5D utilities based on the UK value set were used. The ERG explained that the study did not provide evidence that EQ‑5D utility values are insensitive to changes in quality of life for this population because the EQ‑INDEX is not the same as EQ‑5D utility values. The company commented that using the EQ‑VAS was not an acceptable option within the NICE reference case. The committee was aware that NICE's guide to the methods of technology appraisal states that "in some circumstances the EQ‑5D may not be the most appropriate. To make a case that the EQ‑5D is inappropriate, qualitative empirical evidence on the lack of content validity for the EQ‑5D should be provided, demonstrating that key dimensions of health are missing. This should be supported by evidence that shows that EQ‑5D performs poorly on tests of construct validity and responsiveness in a particular patient population. This evidence should be derived from a synthesis of peer-reviewed literature. In these circumstances alternative health-related quality of life measures may be used and must be accompanied by a carefully detailed account of the methods used to generate the data, their validity, and how these methods affect the utility values." The committee concluded that both EQ‑5D utility values from the trials and the McDaid approach were relevant for consideration.
## An average of the 2 sources of utility values should be used to inform the economic model
The ERG provided additional scenarios that used an average of 2 sources (the trial EQ‑5D utility values and ESS scores mapped to the EQ‑5D using the McDaid approach). The ERG explored 2 methods for averaging the HAROSA and McDaid utilities. The first method averaged the EQ‑5D utilities directly from HAROSA with the utilities from McDaid. This approach assumed no relationship between ESS score and EQ‑5D in HAROSA. The second method averaged the coefficient of change in ESS score and change in EQ‑5D from HAROSA and McDaid. The committee recognised that both methods used novel techniques of determining a utility value using 2 different types of evidence (EQ‑5D directly elicited from the trials, and the McDaid mapping approach). However, it understood that the first method took account of any differences in the models used to calculate the utility values (such as covariates). The committee noted the company's approach of assigning utility values was based on both response status and treatment group. It did not consider this approach to be appropriate because there was no evidence provided for a treatment-related difference in quality of life that was not associated with ESS. It agreed that health state utility values based on response status and independent of treatment group would have been preferred. The committee recalled its preference from the first committee meeting for trial EQ‑5D values. But it acknowledged that ESS scores mapped using McDaid were also relevant because this was another source of evidence for the change in quality of life associated with ESS. On balance, the committee concluded that the most appropriate source of utility values was uncertain. It agreed that the average of the 2 sources of utility values, using the ERG's first method, should be used to inform the economic model.
## A utility decrement for road traffic accidents is not acceptable
The ERG explained that it agreed to keep the road traffic accidents utility in the original model, on the basis that people taking pitolisant hydrochloride would be more alert when driving. But it noted the utility values for people in slight road traffic accidents appeared too low. So the ERG assumed that people who experienced a slight road traffic accident had a disutility equal to the most severe other event in the model (stroke). It stated that there is no direct evidence to show that pitolisant hydrochloride would reduce the incidence of road traffic accidents because this was not measured in the HAROSA trials. It also stated that the model assumed that people with excessive daytime sleepiness who take pitolisant hydrochloride and drive have the same risk of a road traffic accident as the general population driving in the UK, which is not a plausible assumption. The committee concluded that people with obstructive sleep apnoea and excessive daytime sleepiness must not drive until their symptoms are under control. So it agreed not to include a utility decrement for road traffic accidents.
# Cost-effectiveness estimates
## Pitolisant hydrochloride is not a cost-effective use of NHS resources
The committee considered the cost-effectiveness estimates for pitolisant hydrochloride with and without CPAP, plus standard care, compared with standard care alone. The company provided cost-effectiveness estimates for 2 populations in line with the marketing authorisation. The company's base case adjusted for the Hawthorne effect (using a centring approach) and used utility values derived from ESS scores mapped to EQ‑5D using the McDaid approach. For people who have residual excessive daytime sleepiness despite using CPAP, the company's deterministic ICER for pitolisant hydrochloride plus CPAP and standard care, compared with CPAP plus standard care alone, was estimated to be £32,430 per quality-adjusted life year (QALY) gained. For people who declined or could not tolerate CPAP, the ICER for pitolisant hydrochloride plus standard care compared with standard care alone was estimated to be £28,431 per QALY gained. The committee preferred the scenario presented by the ERG, which used the average of 2 sources of utility values: the trial EQ‑5D utility values and ESS scores mapped to the EQ‑5D using the McDaid approach. For people with residual excessive daytime sleepiness despite CPAP, this increased the ICER to £53,287 per QALY gained. For people who declined or could not tolerate CPAP, the ICER was estimated to be £50,348 per QALY gained. The committee concluded that the most plausible ICER is likely to be above what NICE considers a cost-effective use of NHS resources.
# Other factors
## People who find CPAP difficult to use are considered in the decision making
The clinical expert noted that some people with mental health or neurodegenerative conditions may find it challenging to use CPAP regularly, making it difficult to control excessive daytime sleepiness caused by obstructive sleep apnoea. The marketing authorisation for pitolisant hydrochloride includes people with obstructive sleep apnoea whose excessive daytime sleepiness has not been satisfactorily treated by primary obstructive sleep apnoea therapy, such as CPAP. The committee agreed with the clinical experts that people who find CPAP difficult may be disadvantaged and this was taken into account in its decision making.
# Conclusion
## Pitolisant hydrochloride is not recommended for treating excessive daytime sleepiness caused by obstructive sleep apnoea
The committee recognised that excessive daytime sleepiness caused by obstructive sleep apnoea is a debilitating condition that negatively affects many aspects of daily life. It acknowledged that pitolisant hydrochloride with standard care was more effective than standard care alone in reducing excessive daytime sleepiness, as measured by the ESS. The committee noted uncertainty around the utility values used in the model and the placebo effect adjustment. The committee considered that the most plausible cost-effectiveness estimates for pitolisant hydrochloride were above the range that NICE usually considers an acceptable use of NHS resources. Therefore, it did not recommend pitolisant hydrochloride for routine commissioning in the NHS.
|
{'Recommendations': 'Pitolisant hydrochloride is not recommended, within its marketing authorisation, to improve wakefulness and reduce excessive daytime sleepiness in adults with obstructive sleep apnoea whose sleepiness has not been satisfactorily treated by primary obstructive sleep apnoea therapy such as continuous positive airway pressure (CPAP), or who cannot tolerate it.\n\nThis recommendation is not intended to affect treatment with pitolisant hydrochloride that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nExcessive daytime sleepiness caused by obstructive sleep apnoea is usually treated with primary obstructive sleep apnoea therapy such as CPAP or mandibular advancement devices.\n\nClinical trial evidence suggests that pitolisant hydrochloride reduces excessive daytime sleepiness, with and without CPAP. But there is uncertainty about the evidence because of the way the trials were done. It is also uncertain how much pitolisant hydrochloride improves quality of life because of how it was measured in the trials.\n\nBecause of the uncertainty in the clinical evidence and economic model, the cost-effectiveness estimates are also uncertain. They are also likely to be higher than what NICE normally considers an acceptable use of NHS resources. So pitolisant hydrochloride is not recommended.', 'Information about pitolisant hydrochloride': "# Marketing authorisation indication\n\nPitolisant hydrochloride (Ozawade, Bioprojet Pharma) is indicated 'to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients with obstructive sleep apnoea (OSA) whose EDS has not been satisfactorily treated by, or who have not tolerated, OSA primary therapy, such as continuous positive airway pressure (CPAP)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pitolisant hydrochloride.\n\n# Price\n\nThe list price of pitolisant hydrochloride is £138 for a 30‑pack of 4.5‑mg or 18‑mg tablets (excluding VAT; company submission).", 'Committee discussion': 'The appraisal committee considered evidence submitted by Bioprojet Pharma, a review of this submission by the evidence review group (ERG), NICE\'s technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life\n\nThe patient expert explained that obstructive sleep apnoea can affect people\'s physical and mental wellbeing. Excessive daytime sleepiness affects daily life including education, employment, maintaining a social life and the ability to drive. Symptoms of sleep apnoea such as snoring can disrupt a partner\'s sleep, affecting their own quality of life. The patient expert said that a better understanding of the condition among GPs could improve consistency in arriving at a diagnosis sooner. The clinical experts noted that obstructive sleep apnoea can be associated with high blood pressure, heart disease and stroke. The committee concluded that excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life.\n\n## Pitolisant hydrochloride would typically be offered with CPAP, but some people cannot tolerate CPAP\n\nThe clinical experts advised that most people with excessive daytime sleepiness caused by obstructive sleep apnoea are referred to sleep clinics. Initial treatment includes lifestyle advice about weight loss. For people with mild symptomatic obstructive sleep apnoea, mandibular advancement devices are considered. For adults with moderate or severe obstructive sleep apnoea, NICE\'s technology appraisal guidance on continuous positive airway pressure (CPAP) recommends it for treating obstructive sleep apnoea. The patient expert explained that CPAP is usually well tolerated but some people may need to adjust to sleeping with a mask that is connected to a small machine. The clinical experts explained that some people cannot tolerate CPAP because they feel claustrophobic wearing a mask, which can be exacerbated by certain mental health issues. People with neurodegenerative conditions may also not tolerate CPAP, and some people have anatomical variations that make CPAP unsuitable for them. The clinical and patient experts also explained that some people using CPAP will have residual excessive daytime sleepiness. They noted that pitolisant hydrochloride is a potential treatment option that would be welcome for improving excessive sleepiness, although it does not treat the underlying causes of obstructive sleep apnoea. The committee concluded that because pitolisant hydrochloride does not treat underlying airway obstruction, it would likely be used in addition to CPAP, but it acknowledged that some people cannot tolerate CPAP.\n\n## Mandibular advancement device availability varies across the country\n\nThe clinical experts explained that people who decline CPAP or cannot tolerate it may be offered a mandibular advancement device, which helps prevent the airway closing. They highlighted that this varies in practice because the devices are not available at every sleep clinic. About 20% of people who do not have CPAP might be offered a mandibular advancement device. However, because mandibular advancement devices are now recommended in NICE\'s guideline on obstructive sleep apnoea, they may be used more frequently. The company stated that mandibular advancement devices are generally used earlier in the treatment pathway than CPAP, so someone who declines CPAP is likely to have already been offered a mandibular advancement device. The committee concluded that because of the uncertainty around availability of mandibular advancement devices, it was appropriate to not consider them in this appraisal.\n\n## Pitolisant hydrochloride is likely to be prescribed in secondary care\n\nThe clinical experts highlighted that pitolisant hydrochloride would likely be prescribed in specialist sleep clinics (secondary care) because of the need to monitor adherence to CPAP. They highlighted that additional monitoring would be needed if pitolisant hydrochloride were recommended. They were uncertain if prescribing could move to primary care in the future. The committee concluded that pitolisant hydrochloride is likely to be prescribed in secondary care.\n\n# Clinical evidence\n\n## Pitolisant hydrochloride improves excessive daytime sleepiness, with and without CPAP\n\nHAROSA\xa01 and HAROSA\xa02 were randomised trials of people having either pitolisant hydrochloride plus standard care (including lifestyle changes and CPAP optimisation for CPAP users) or placebo plus standard care, for a 12‑week double-blind period. After 12\xa0weeks, everyone in the trial was offered pitolisant hydrochloride for 40\xa0weeks (the open-label phase). In HAROSA\xa01, people had been using nasal CPAP therapy for at least 3\xa0months and had excessive daytime sleepiness before starting the trial. HAROSA\xa02 included only people who had not used CPAP and had excessive daytime sleepiness. The primary outcome of the trials was reduction in Epworth Sleepiness Scale (ESS) score. ESS scores of 10\xa0or less indicate normal daytime sleepiness, and scores of 11\xa0to\xa024 indicate excessive daytime sleepiness. The results showed a reduction in mean ESS scores from baseline to week\xa012 for the pitolisant hydrochloride group in both trials. In people who used CPAP, the mean ESS score reduced by 5.52\xa0points in the pitolisant hydrochloride group. In people who had not used CPAP, the mean ESS score reduced by 6.30\xa0points in the pitolisant hydrochloride group. In terms of quality of life, people in HAROSA\xa01 reported no statistically significant difference in EQ‑5D or visual analogue scale score during the double-blind phase of the trial. However, there was an improvement in the pain and discomfort dimension of the EQ‑5D in HAROSA\xa02. The clinical experts explained that an ESS reduction of 2\xa0or more points could be considered clinically relevant, but noted that there is no clinical consensus about this because it will vary between individuals. The committee concluded that pitolisant hydrochloride improves excessive daytime sleepiness, with or without CPAP.\n\n## The HAROSA trials are broadly generalisable to NHS practice but may exclude some people who might be eligible for pitolisant hydrochloride\n\nThe HAROSA trials had a criterion that stated people with psychiatric illness could be excluded. The company clarified that people with depression were only excluded if the investigating clinician felt that it would make study participation challenging for them, rather than for any particular concern about comorbid conditions. A Beck Depression Inventory (13‑item short form) score of less than\xa016 was an inclusion criterion, meaning that people with mild (score 5\xa0to\xa07) and moderate (score 8\xa0to\xa015) depression were included in the HAROSA trials. The company stated that the trials included people with depression and anxiety. There were 18% of people in HAROSA\xa01 and 5% in HAROSA\xa02 who had a pre-existing psychiatric illness. The committee noted that the company\'s submission stated that about half of people with severe excessive daytime sleepiness have coexisting depression. The clinical experts estimated that about half of people referred to sleep clinics might have antidepressant therapy of some kind. The committee accepted that some people with depression were included in the trials, but the proportions were lower than might be expected in the NHS. This might affect the generalisability of the trial data. The effect of this on the clinical-effectiveness estimates was unknown. The committee concluded that the HAROSA trials were broadly generalisable for decision making, but may under-represent people with psychiatric illness.\n\n## Adherence to CPAP is unlikely to be affected by treatment with pitolisant hydrochloride\n\nThe patient expert explained that some people with excessive daytime sleepiness may prefer to manage their symptoms with medicine, rather than using CPAP. So they might use CPAP less often when taking pitolisant hydrochloride, which could lead to a reduction in the combined benefits of CPAP and pitolisant hydrochloride. The clinical experts said that most sleep clinics can remotely monitor CPAP use. Some people, such as heavy goods vehicle drivers, regularly have their CPAP use monitored remotely. The clinical experts stated that people having pitolisant hydrochloride alongside CPAP may have their use monitored more frequently than in current practice. The committee concluded that CPAP use is unlikely to be affected by treatment with pitolisant hydrochloride, because of regular monitoring. In response to consultation, the patient expert reiterated concerns that people having pitolisant hydrochloride in addition to CPAP may use their CPAP machine less often. The committee acknowledged concerns about reduced CPAP adherence, but concluded that it had not seen evidence to change its original conclusion that pitolisant hydrochloride use is unlikely to affect CPAP use.\n\n## A trial of pitolisant hydrochloride for narcolepsy had a follow-up period long enough to understand its side effects\n\nThe clinical experts had experience using pitolisant hydrochloride with people who have narcolepsy. They commented that they could rapidly see the benefits as well as the side effects of the treatment. The company provided data from HARMONY, a study of people taking pitolisant hydrochloride for narcolepsy for 1\xa0year or more. The ERG cautioned that the effectiveness of pitolisant hydrochloride in HARMONY does not directly correlate to effectiveness in obstructive sleep apnoea because the cause of sleepiness is different. The committee concluded that the HARMONY follow-up period was long enough for decision making about the side effects of pitolisant hydrochloride.\n\n# The economic model\n\n## The company\'s new model is acceptable for decision making but has limitations\n\nThe company\'s original model was based on a model developed by McDaid et al. (2007) for NICE\'s technology appraisal guidance on CPAP for treating obstructive sleep apnoea. The model in that appraisal included a method of mapping ESS scores to EQ‑5D utility values (from now, the McDaid approach). The ERG noted that pitolisant hydrochloride and CPAP treat different aspects of the condition, so following the CPAP model may not be the best approach for evaluating pitolisant hydrochloride. However, it stated that the relevant consequences of the comparisons could be adequately assessed using this model, although it may be more complicated than necessary. It corrected some aspects of the company\'s model, which had a small effect on the company\'s base-case incremental cost-effectiveness ratio (ICER). But the committee was interested in a model that considered people with a disease response and those without, separately, and explored placebo adjustments (see section\xa03.11). Restructuring the model in this way, and adjusting for a placebo effect, might reveal greater differences between the 2\xa0groups. In response to consultation, the company submitted a new model similar to the one used in NICE\'s technology appraisal guidance on solriamfetol for treating excessive daytime sleepiness caused by obstructive sleep apnoea. The new model included a decision tree for the first 52\xa0weeks of treatment followed by a Markov model with 3\xa0health states: \'responder\', \'non-responder\' and \'death\'. Movement through the model was based on disease response. The company assumed that people who had standard care could be considered \'responders\'. The model adjusted for the Hawthorne effect using a centring approach. The ERG agreed that the new model was consistent with the committee\'s comments from the first meeting about response status and adjustment for a placebo effect. However, it noted several limitations, including:\n\nno explanation of how baseline utility values were derived\n\nerrors in the formulas used to map ESS scores to EQ‑5D utility values using the McDaid approach, which resulted in overestimated values\n\nuncertainty around the response transition probabilities informed by stopping treatment\n\nit did not include probabilistic sensitivity analyses, so the probability that pitolisant hydrochloride is cost effective is unknown.The committee questioned the company\'s approach of assigning utility values based on both response status and treatment group. It acknowledged the limitations of the new model but concluded that it was acceptable for decision making.\n\n## There is no direct evidence that pitolisant hydrochloride reduces cardiovascular events\n\nThe company\'s original model assumed that a reduction in ESS score was related to a reduction in cardiovascular disease risk (that is, people could move into the post-coronary heart disease state if they had an acute cardiovascular event and survived). The original modelling also assumed that pitolisant hydrochloride lowers the risk of cardiovascular events, which are more prevalent in people with excessive daytime sleepiness caused by obstructive sleep apnoea. The committee noted that the company did not explain the biological mechanism by which pitolisant hydrochloride may reduce cardiovascular events. The clinical experts explained that because of the lack of long-term clinical trials in obstructive sleep apnoea, they rely on markers for cardiovascular risk such as blood pressure. They stated that there is evidence that people using CPAP have reduced blood pressure along with their daytime sleepiness. But they noted that there was no direct evidence to validate this assumption in the economic model. The ERG agreed that it had not seen evidence that a reduction in ESS score with pitolisant hydrochloride would lead to a reduction in cardiovascular events. It was unaware of any reasonable mechanism by which a wakefulness drug would reduce cardiovascular risk, rather than this being a result of treating the underlying cause of excessive sleepiness (obstructive sleep apnoea). The committee noted that the HAROSA trials showed no changes in people\'s blood pressure levels. In the absence of evidence of changes in cardiovascular markers, the committee agreed with the ERG. It concluded that there was no direct evidence of a clinical or biological mechanism by which pitolisant hydrochloride affects cardiovascular events. In response to consultation, the company provided a new model that did not include a potential effect of pitolisant hydrochloride on the risk of cardiovascular events (see section\xa03.9). The committee noted this was consistent with its conclusion at the first committee meeting.\n\n## Adjusting for the Hawthorne effect is the most appropriate approach to adjust for the placebo effect\n\nThe ESS score improved from baseline to week\xa012 in the placebo group in both HAROSA trials. The clinical experts suggested this could be because of potential observation bias from the Hawthorne effect (that is, people reported an improvement in ESS scores because they have more frequent contact with trial investigators than they would with clinicians in clinical practice). The committee noted the potential causes of such an effect and discussed ways to adjust for it. One way might be to remove the improvement in ESS scores observed in the placebo group from both the placebo and the pitolisant hydrochloride groups in the model (sometimes referred to as a centring approach). At its first meeting, the committee concluded that approaches to account for the placebo effect shown in the HAROSA trials should be explored to understand its effect on the cost-effectiveness results. In response to consultation, the company submitted a new model that adjusted for the placebo effect using a centring approach, under the assumption that placebo group improvements were a result of the Hawthorne effect. The ERG provided additional scenarios that assumed:\n\na true placebo effect (adjusted for by removing the treatment effect for placebo for comparator group, but keeping it in the pitolisant group)\n\na regression to the mean effect (no adjustment based on the assumption that the trial may have captured extreme ESS scores that would trend towards the mean over time) or\n\nan equal contribution from the 3\xa0proposed effects.The ERG noted that the regression to the mean model would only be appropriate if it was evident that people\'s ESS scores fluctuated over time. The clinical experts explained that there is limited long-term ESS score data for people who are having treatment for excessive daytime sleepiness. The experts added that in clinical practice, they observe some fluctuation in people\'s ESS scores. The committee noted that it had not seen evidence of how much people\'s ESS scores fluctuated over time. It concluded that adjusting for the Hawthorne effect by removing the treatment effect for placebo from the comparator and pitolisant hydrochloride groups was the most appropriate approach to adjust for the placebo effect.\n\n## The EQ-5D utility values from both the trials and the McDaid mapping approach are relevant for consideration\n\nThe company stated that the EQ‑5D questionnaires may not adequately capture quality-of-life benefits in people with obstructive sleep apnoea. It explained that because EQ‑5D is a generic instrument, it is not designed to specifically measure changes in quality of life for people with excessive daytime sleepiness caused by obstructive sleep apnoea. It also noted that the EQ‑5D does not have a sleep domain, which means improvements in sleep or daytime wakefulness are unlikely to be captured. So the company\'s submission mapped ESS scores from the trials to the EQ‑5D (the McDaid approach) rather than using values derived directly from the trials. The company stated that this was consistent with the approach used in NICE\'s technology appraisal guidance on CPAP for treating obstructive sleep apnoea. Clinical experts agreed with the company that the EQ‑5D may not capture changes in excessive daytime sleepiness. The ERG commented that it is possible that a modest decrease in excessive sleepiness does not significantly impact health-related quality of life. The committee was concerned that if the EQ‑5D does not capture quality-of-life benefits adequately in this population, the ESS scores should not be mapped to the EQ‑5D, because it will remain insensitive. The committee also noted that the McDaid report stated that the EQ‑5D could capture the health effects of sleepiness through its impact on usual activities or anxiety and depression. After technical engagement, the company provided an analysis of mean difference by treatment group using individual patient data from EQ‑5D data in the trials. These are academic in confidence and cannot be presented here. The committee considered it uncertain whether the EQ‑5D captures quality-of-life benefits in people with obstructive sleep apnoea. In response to consultation, the company presented evidence from a commissioned study to support the position that the EQ‑5D is not sensitive to changes in quality of life for this population. The study investigated 3\xa0metrics that are derivable from the EQ‑5D: EQ‑INDEX (sum score of the 5\xa0dimensions), EQ‑Visual Analogue Scale (EQ‑VAS), and z‑score (composite of EQ‑INDEX and EQ‑VAS) in the pitolisant hydrochloride HAROSA trials. The study showed that there was no significant difference in EQ‑INDEX for people who had pitolisant hydrochloride and people who had placebo. It also found that the EQ‑VAS appeared better correlated with clinical outcomes than the EQ‑INDEX. Typically, the larger the EQ‑INDEX, or sum of the individual dimensions, the more severe or frequent the problems. However, the study standardised the EQ‑INDEX to a 0\xa0to\xa0100 scale and reversed the direction to align with the EQ‑VAS, where larger values represent higher reported health. The ERG explained that because the EQ‑INDEX was standardised and reversed, it was unknown what the results would have been if EQ‑5D utilities based on the UK value set were used. The ERG explained that the study did not provide evidence that EQ‑5D utility values are insensitive to changes in quality of life for this population because the EQ‑INDEX is not the same as EQ‑5D utility values. The company commented that using the EQ‑VAS was not an acceptable option within the NICE reference case. The committee was aware that NICE\'s guide to the methods of technology appraisal states that "in some circumstances the EQ‑5D may not be the most appropriate. To make a case that the EQ‑5D is inappropriate, qualitative empirical evidence on the lack of content validity for the EQ‑5D should be provided, demonstrating that key dimensions of health are missing. This should be supported by evidence that shows that EQ‑5D performs poorly on tests of construct validity and responsiveness in a particular patient population. This evidence should be derived from a synthesis of peer-reviewed literature. In these circumstances alternative health-related quality of life measures may be used and must be accompanied by a carefully detailed account of the methods used to generate the data, their validity, and how these methods affect the utility values." The committee concluded that both EQ‑5D utility values from the trials and the McDaid approach were relevant for consideration.\n\n## An average of the 2\xa0sources of utility values should be used to inform the economic model\n\nThe ERG provided additional scenarios that used an average of 2\xa0sources (the trial EQ‑5D utility values and ESS scores mapped to the EQ‑5D using the McDaid approach). The ERG explored 2\xa0methods for averaging the HAROSA and McDaid utilities. The first method averaged the EQ‑5D utilities directly from HAROSA with the utilities from McDaid. This approach assumed no relationship between ESS score and EQ‑5D in HAROSA. The second method averaged the coefficient of change in ESS score and change in EQ‑5D from HAROSA and McDaid. The committee recognised that both methods used novel techniques of determining a utility value using 2\xa0different types of evidence (EQ‑5D directly elicited from the trials, and the McDaid mapping approach). However, it understood that the first method took account of any differences in the models used to calculate the utility values (such as covariates). The committee noted the company\'s approach of assigning utility values was based on both response status and treatment group. It did not consider this approach to be appropriate because there was no evidence provided for a treatment-related difference in quality of life that was not associated with ESS. It agreed that health state utility values based on response status and independent of treatment group would have been preferred. The committee recalled its preference from the first committee meeting for trial EQ‑5D values. But it acknowledged that ESS scores mapped using McDaid were also relevant because this was another source of evidence for the change in quality of life associated with ESS. On balance, the committee concluded that the most appropriate source of utility values was uncertain. It agreed that the average of the 2\xa0sources of utility values, using the ERG\'s first method, should be used to inform the economic model.\n\n## A utility decrement for road traffic accidents is not acceptable\n\nThe ERG explained that it agreed to keep the road traffic accidents utility in the original model, on the basis that people taking pitolisant hydrochloride would be more alert when driving. But it noted the utility values for people in slight road traffic accidents appeared too low. So the ERG assumed that people who experienced a slight road traffic accident had a disutility equal to the most severe other event in the model (stroke). It stated that there is no direct evidence to show that pitolisant hydrochloride would reduce the incidence of road traffic accidents because this was not measured in the HAROSA trials. It also stated that the model assumed that people with excessive daytime sleepiness who take pitolisant hydrochloride and drive have the same risk of a road traffic accident as the general population driving in the UK, which is not a plausible assumption. The committee concluded that people with obstructive sleep apnoea and excessive daytime sleepiness must not drive until their symptoms are under control. So it agreed not to include a utility decrement for road traffic accidents.\n\n# Cost-effectiveness estimates\n\n## Pitolisant hydrochloride is not a cost-effective use of NHS resources\n\nThe committee considered the cost-effectiveness estimates for pitolisant hydrochloride with and without CPAP, plus standard care, compared with standard care alone. The company provided cost-effectiveness estimates for 2\xa0populations in line with the marketing authorisation. The company\'s base case adjusted for the Hawthorne effect (using a centring approach) and used utility values derived from ESS scores mapped to EQ‑5D using the McDaid approach. For people who have residual excessive daytime sleepiness despite using CPAP, the company\'s deterministic ICER for pitolisant hydrochloride plus CPAP and standard care, compared with CPAP plus standard care alone, was estimated to be £32,430 per quality-adjusted life year (QALY) gained. For people who declined or could not tolerate CPAP, the ICER for pitolisant hydrochloride plus standard care compared with standard care alone was estimated to be £28,431 per QALY gained. The committee preferred the scenario presented by the ERG, which used the average of 2\xa0sources of utility values: the trial EQ‑5D utility values and ESS scores mapped to the EQ‑5D using the McDaid approach. For people with residual excessive daytime sleepiness despite CPAP, this increased the ICER to £53,287 per QALY gained. For people who declined or could not tolerate CPAP, the ICER was estimated to be £50,348 per QALY gained. The committee concluded that the most plausible ICER is likely to be above what NICE considers a cost-effective use of NHS resources.\n\n# Other factors\n\n## People who find CPAP difficult to use are considered in the decision making\n\nThe clinical expert noted that some people with mental health or neurodegenerative conditions may find it challenging to use CPAP regularly, making it difficult to control excessive daytime sleepiness caused by obstructive sleep apnoea. The marketing authorisation for pitolisant hydrochloride includes people with obstructive sleep apnoea whose excessive daytime sleepiness has not been satisfactorily treated by primary obstructive sleep apnoea therapy, such as CPAP. The committee agreed with the clinical experts that people who find CPAP difficult may be disadvantaged and this was taken into account in its decision making.\n\n# Conclusion\n\n## Pitolisant hydrochloride is not recommended for treating excessive daytime sleepiness caused by obstructive sleep apnoea\n\nThe committee recognised that excessive daytime sleepiness caused by obstructive sleep apnoea is a debilitating condition that negatively affects many aspects of daily life. It acknowledged that pitolisant hydrochloride with standard care was more effective than standard care alone in reducing excessive daytime sleepiness, as measured by the ESS. The committee noted uncertainty around the utility values used in the model and the placebo effect adjustment. The committee considered that the most plausible cost-effectiveness estimates for pitolisant hydrochloride were above the range that NICE usually considers an acceptable use of NHS resources. Therefore, it did not recommend pitolisant hydrochloride for routine commissioning in the NHS.'}
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https://www.nice.org.uk/guidance/ta776
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Evidence-based recommendations on pitolisant hydrochloride for treating excessive daytime sleepiness caused by obstructive sleep apnoea in adults.
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dcbc038c3fc4f15c8dde810f95c3a16cc3b0d88c
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nice
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Solriamfetol for treating excessive daytime sleepiness caused by obstructive sleep apnoea
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Solriamfetol for treating excessive daytime sleepiness caused by obstructive sleep apnoea
Evidence-based recommendations on solriamfetol (Sunosi) for treating excessive daytime sleepiness caused by obstructive sleep apnoea in adults.
# Recommendations
Solriamfetol is not recommended, within its marketing authorisation, to improve wakefulness and reduce excessive daytime sleepiness in adults with obstructive sleep apnoea whose sleepiness has not been satisfactorily treated by primary obstructive sleep apnoea therapy, such as continuous positive airway pressure (CPAP).
This recommendation is not intended to affect treatment with solriamfetol that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Excessive daytime sleepiness caused by obstructive sleep apnoea is usually first treated with a primary obstructive sleep apnoea therapy such as CPAP (standard care).
Clinical trial evidence shows that solriamfetol alone and when added to standard care reduces excessive daytime sleepiness compared with standard care alone.
The trial evidence does not show an improvement in quality of life. This may be because of how it was measured in the trials. It is likely that reducing excessive daytime sleepiness translates into improved quality of life, but it is uncertain by how much.
There are also concerns about how the trial data has been used in the economic model. Therefore, the cost-effectiveness estimates for solriamfetol compared with standard care alone are uncertain. They are also likely to be higher than what NICE normally considers an acceptable use of NHS resources. So, solriamfetol is not recommended.# Information about solriamfetol
# Marketing authorisation indication
Solriamfetol (Sunosi, Jazz Pharmaceuticals) is indicated 'to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients with obstructive sleep apnoea (OSA) whose EDS has not been satisfactorily treated by primary OSA therapy, such as continuous positive airway pressure (CPAP)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for solriamfetol.
# Price
The list price for solriamfetol is £177.52 for a 75‑mg 28‑day pack and £248.64 for a 150‑mg 28‑day pack (excluding VAT; BNF online accessed September 2021). The company has a commercial arrangement, which would have applied if the technology had been recommended.# Committee discussion
The appraisal committee considered evidence submitted by Jazz Pharmaceuticals, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage. It agreed that a subgroup of people with a baseline Epworth Sleepiness Scale (ESS) score of more than 12 should be used in the modelling (see the technical report, issue 2).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues: primary therapy adherence, treatment response, adjustment for the improvement in the control arm, health utility values, partner utilities, treatment discontinuation, adverse events and dosing splits (see the technical report, issues 1 to 9), which were outstanding after the technical engagement stage.
# The condition
## Excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life, but it is uncertain by how much
The patient expert explained that obstructive sleep apnoea can negatively affect people's physical and mental wellbeing. Because of excessive daytime sleepiness, aspects of daily life such as education, employment, maintaining a social life and the ability to drive, are all negatively affected. Symptoms of sleep apnoea such as snoring can disrupt partners' sleep, which may affect their quality of life as well. The clinical experts agreed that excessive daytime sleepiness negatively affects people's quality of life, but said it can be difficult to measure by how much. They also noted that obstructive sleep apnoea can be associated with an increased risk of high blood pressure or stroke. The committee concluded that excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life. However, it was uncertain how much reducing excessive daytime sleepiness would improve quality of life.
## CPAP is an appropriate comparator, but some people cannot tolerate it
The clinical experts said that most people with excessive daytime sleepiness caused by obstructive sleep apnoea are referred to sleep clinics. Initial treatment includes lifestyle advice about weight loss. Mandibular devices are considered for people with mild symptomatic obstructive sleep apnoea. NICE's technology appraisal guidance on continuous positive airway pressure (CPAP) for obstructive sleep apnoea/hypopnoea syndrome (from now, TA139) recommends CPAP for adults with moderate or severe obstructive sleep apnoea. The patient expert explained that CPAP is usually well tolerated but is associated with some inconvenience or discomfort. Wearing a face mask connected to the CPAP machine can also restrict sleeping. The clinical experts also said that some people cannot tolerate CPAP because they can feel claustrophobic wearing a mask, which can be exacerbated by certain mental health issues. People with neurodegenerative conditions may also not tolerate CPAP. The clinical and patient experts said that some people using CPAP will still have residual excessive daytime sleepiness. They noted that solriamfetol would be welcomed as another potential treatment option for this group. The committee concluded CPAP is an appropriate comparator. But some people cannot tolerate it, so a comparison with standard care without a primary obstructive sleep apnoea therapy was also important.
## Solriamfetol is likely to be limited to secondary care
Obstructive sleep apnoea is currently treated in sleep services commissioned by the relevant clinical commissioning group. The clinical experts noted that, if solriamfetol was recommended, the likely requirement for more monitoring of adherence to CPAP (see section 3.5) could put pressure on these services. In its evidence submission and economic model, the company assumed that solriamfetol would be administered in specialist sleep services only. The committee asked the clinical experts if there was a possibility that solriamfetol could be prescribed in primary care. The experts suggested that treatment would have to be started in the specialist sleep clinics but were uncertain if longer-term prescribing could move to primary care. In response to consultation, the company provided information from clinicians and pharmacists to support its claim that solriamfetol would be limited to secondary care. It noted that solriamfetol has a black triangle in its marketing authorisation, meaning additional monitoring is needed. This would likely severely limit the use of solriamfetol in primary care. The committee concluded that solriamfetol is likely to be limited to secondary care.
# Clinical evidence
## Solriamfetol reduces excessive daytime sleepiness
The main clinical-effectiveness evidence for solriamfetol came from TONES 3. This was a 12‑week, randomised, double-blind, placebo-controlled, multicentre trial. The intervention was solriamfetol in doses of 37.5 mg, 75 mg and 150 mg (also including an unlicensed 300 mg dose). In both the intervention and comparator groups, around 70% of patients were using a primary obstructive sleep apnoea therapy, defined as either a prior effective surgical intervention or CPAP, at the start of the trial. These people were classified as adherent. The co-primary outcome of the trial was change in the ESS score and Maintenance of Wakefulness Test (MWT) from baseline to week 12. The results showed a significant change in ESS score and MWT from baseline to week 12 across all 3 licensed solriamfetol doses. The committee concluded that solriamfetol reduces excessive daytime sleepiness.
## Solriamfetol is unlikely to affect adherence to a primary obstructive sleep apnoea therapy like CPAP
The patient expert and ERG said that some people with excessive daytime sleepiness may prefer to manage their symptoms with medicine instead of a primary therapy such as CPAP. This could lead to them using CPAP less and so a reduction in the combined benefits of CPAP and solriamfetol. The company included patient adherence to a primary therapy in its 3 trials (TONES 3, TONES 4 and TONES 5) as an exploratory end point. It also provided results from a peer-reviewed paper by Schweitzer et al. (2021), which showed no effect on primary therapy adherence in TONES 5 from baseline up to week 40. TONES 5 was an open-label trial assessing solriamfetol's long-term safety and efficacy for up to 52 weeks, and included patients who had completed another solriamfetol trial (including TONES 3). It included a 2‑week placebo-controlled randomised withdrawal phase. The ERG noted that the results of Schweitzer et al. were highly uncertain because of missing data and poor reporting. It said that the estimates were not reported separately for people classified as adherent or non-adherent at baseline. The clinical experts said that most sleep clinics can monitor CPAP machines remotely and that some people, such as heavy goods vehicle drivers, have their CPAP use monitored remotely regularly. The clinical experts acknowledged that, although people having solriamfetol alongside a primary therapy such as CPAP would have their use monitored, it may have to be more frequent. The committee noted the uncertainty in the TONES 5 data on adherence. It would have preferred to see more sensitivity analyses of the impact of missing data in Schweitzer et al., and a subgroup analysis stratified by adherence at baseline. In response to consultation, the company provided additional sensitivity analyses, which showed that people having solriamfetol would meet the standard definition of adherence, even in a 'worst case' scenario with respect to the missing data from Schweitzer et al. In these analyses, adherence was defined as CPAP use of 4 hours or more on 70% of nights. The committee concluded that adherence to a primary therapy like CPAP is unlikely to be affected by treatment with solriamfetol.
# The economic model
## The company's model of solriamfetol with and without standard care is suitable
TONES 3 included people who adhered to a primary obstructive sleep apnoea therapy (standard care) and people who did not (see section 3.4). In the economic model presented at the first committee meeting, the company assumed that everyone entering the model had either solriamfetol with standard care (for example, CPAP) or standard care without solriamfetol. It presented a cost-effectiveness scenario analysis that included people from TONES 3 who did not adhere to standard care. The ERG noted that the baseline ESS score for the non-adherent group was worse than the adherent group. This meant that the improvement in ESS score because of solriamfetol treatment was greater, resulting in a lower incremental cost-effectiveness ratio (ICER) if the non-adherent group data was used. The committee felt that the company had not properly explained its methods for modelling the non-adherent group, or why people were not using their primary therapy. The committee recalled that the marketing authorisation for solriamfetol includes people who previously used a primary therapy but stopped. The committee also recalled that people with mental health or neurodegenerative conditions may struggle to use CPAP regularly (see section 3.2). It considered that recommendations restricting solriamfetol only for use with CPAP could discriminate against this group. The committee concluded that it would like to see clinical- and cost-effectiveness evidence for people who were not using a primary therapy. In response to consultation, the company provided clinical and cost-effectiveness evidence for people who were not using a primary therapy at baseline in TONES 3. The committee noted that the cost-effectiveness results were similar for people using a primary therapy at baseline compared with people who were not. It concluded that the company's model of solriamfetol with and without standard care was suitable for decision making.
## Treatment response defined as an ESS score reduction of 2 points or more is appropriate
The clinical experts said that the definition of treatment response for obstructive sleep apnoea varies considerably in clinical practice. The company used the ESS in TONES 3 as a component of the co-primary end point (see section 3.4). The model it presented at the first committee meeting defined treatment response as an ESS score reduction of 3 or more points, based on clinical opinion. Advice to the ERG was that an ESS score reduction of 2 or more points was appropriate but clinicians would consider other factors when assessing treatment effectiveness. The clinical experts said that, although an ESS score reduction of 2 or more points may be appropriate, there is no consensus on what reduction can be considered clinically relevant and that it varies by individual. The ERG tested the ESS score reduction threshold in a scenario analysis, which showed that changing the threshold did not significantly affect the cost-effectiveness results. The committee acknowledged the uncertainty about the ESS but concluded that an ESS score reduction of 2 or more points was an appropriate criterion for treatment response. In response to consultation, the company updated its model to define treatment response as an ESS score reduction of 2 or more points. The committee accepted this for decision making.
## The company's Hawthorne effect scenario is an acceptable approach to account for the improvement in the control arm
In TONES 3, ESS score improved from baseline to week 12 in the control arm (placebo plus standard care). The company suggested that this was likely to be a 'true placebo' effect – that is, the effect would not continue in the real world for standard care plus placebo. However, the company acknowledged that the improvement in the TONES 3 control arm may also be because of observation bias – the Hawthorne effect (that is, patients reported an improvement in ESS score because they were being observed). Under this assumption, the size of treatment effect for both arms would be lower in the real world, but the relative difference between the arms would be maintained. The company adjusted for the Hawthorne effect by removing the improvement in ESS score observed in the control arm from both the standard care and solriamfetol with standard care groups in its model. However, the ERG considered that some of the improvement in the TONES 3 control arm could be because of regression to the mean. This is a tendency for extreme values to move closer to the mean when measures are repeated over time. The ERG preferred to use the raw unadjusted trial data for both the standard care and solriamfetol with standard care groups in the model, which it considered would reflect outcomes in clinical practice. During technical engagement and in response to consultation, the company presented evidence to suggest that the improvement in the TONES 3 control arm was unlikely to be because of regression to the mean. This included evidence from people transitioning from TONES 3 to TONES 5. Those who were already having solriamfetol showed a greater improvement in ESS score when treatment with solriamfetol was unblinded. The company also noted that the speed of improvement in the TONES 3 control arm was too fast to be regression to the mean, and that the baseline ESS scores in TONES 4 and TONES 5 were similar. This meant that neither baseline was a temporary extreme value, as would be expected with regression to the mean. The committee acknowledged that there may be some regression to the mean. In response to consultation, the company did sensitivity analyses, varying the relative contribution of each of the 3 potential mechanisms for the improvement in the TONES 3 control arm (regression to the mean, Hawthorne effect and true placebo). The company considered that assuming the control arm improvement was solely because of the Hawthorne effect, was conservative. This is because the true placebo effect may also be relevant due to the possible psychological benefit of having placebo in the trial, that is generalisable to routine practice. The ERG explained that there was not enough evidence to decide which mechanism was most relevant. It highlighted that there was uncertainty in the company's regression to the mean analyses. This was because the company assumed that people having solriamfetol whose symptoms did not respond to treatment had the same mean ESS score as the pooled standard care arm. The ERG was also concerned that attributing the control arm improvement to the true placebo effect would mean that the NHS would be paying for the benefit of placebo, if solriamfetol was recommended on this basis. The committee considered that the company's adjustment for the Hawthorne effect in its model was plausible. It felt that it was unlikely that regression to the mean was a major cause of the improvement in the TONES 3 control arm. It agreed with the ERG's concern about the true placebo effect. The committee concluded that it was reasonable to consider the 100% Hawthorne effect scenario in its decision making.
# Quality of life
## EQ-5D may have limitations in assessing quality of life for people with excessive daytime sleepiness
EQ‑5D data from TONES 3 showed that people having solriamfetol had no improvement in quality of life from baseline to week 12. The clinical experts explained it is likely that the reduction in ESS score in TONES 3 would have some impact on quality of life, but it is difficult to determine the extent of improvement using standard quality-of-life measures such as the EQ‑5D. Higher ESS scores mean more excessive daytime sleepiness. The company explained that the EQ‑5D is insensitive to changes in quality of life for people with excessive daytime sleepiness caused by obstructive sleep apnoea. This is because it does not include a sleep domain and is unable to measure the impact of obstructive sleep apnoea on interpersonal relationships. The company suggested that the EQ‑5D data collected in TONES 3 did not accurately reflect the substantial quality-of-life burden of the disease. It also noted that the EQ‑5D results were inconsistent with the other TONES 3 outcome measures. The committee concluded that the EQ‑5D may have limitations in assessing quality of life for people with excessive daytime sleepiness.
## Using the National Health and Wellness Survey may be biased
The company used a mapping algorithm to estimate EQ‑5D values based on ESS scores using data from the National Health and Wellness Survey (NHWS). The ERG considered that the company's mapping approach using NHWS was appropriate given the lack of alternative data. However, the committee was concerned that, if EQ‑5D is truly insensitive to changes in quality of life for people with this condition (see section 3.9), then mapping ESS scores to the EQ‑5D would not be appropriate and an alternative quality-of-life measure should be used. In response to consultation, the company said that it did not consider that the EQ‑5D or SF‑36 data collected in the TONES trials would accurately reflect the burden of obstructive sleep apnoea on quality of life. It continued to use the NHWS mapping algorithm as its base case and did not provide alternative SF‑6D utilities. In its second meeting, the committee noted several concerns with the company's NHWS mapping approach. It understood that the NHWS data was collected online from people who self-reported experience of obstructive sleep apnoea, narcolepsy, or both, rather than people who had necessarily been formally diagnosed. This may limit how relevant the NHWS data was to NHS clinical practice. The design of the NHWS also did not allow analysis of changes in ESS score or EQ‑5D over time, which may have given a more reliable measure of how change in ESS score predicts change in utility. The ERG highlighted that the NHWS algorithm may have omitted important predictive variables relating to quality of life. The committee was aware that similar mapping algorithms, based on longitudinal data that did not map change scores, have been used in NICE's technology appraisal guidance on nivolumab for advanced squamous non-small-cell lung cancer after chemotherapy and benralizumab for treating severe eosinophilic asthma. But, it noted that in the current appraisal, trial data and other sources for the mapping were available. The company said that the NHWS mapping algorithm used best methodological practice and that it should be considered as the base case. Despite this, the committee concluded that although the NHWS mapping approach might have advantages, it preferred a mapping based on the McDaid algorithm (see section 3.11) because it is likely to be less biased.
## TONES 3 and the McDaid algorithm are the most appropriate utility sources
The company provided a scenario using the mapping algorithm from TA139, reported in McDaid et al. (2009). This used individual patient data measured both before and after treatment from 3 studies of people with sleep apnoea who attended sleep clinics. The committee acknowledged uncertainty because the McDaid algorithm was based on a smaller sample size than the NHWS. However, it noted that McDaid had been accepted by the committee in TA139, and that McDaid did not share some of the limitations of the NHWS data (see section 3.10). But the committee agreed that mapping should be considered a second-best option compared with using the available trial data. The company provided analyses suggesting that the EQ‑5D data from TONES 3 was inappropriate to use because there was a 'ceiling effect'. A large proportion of patients in TONES 3 had a baseline utility of 1 (the maximum utility value). This meant there was minimal room for utility scores to improve during the trial. The company also provided an analysis simulating what the utility gain might have been had different baseline utility values (from other CPAP studies) been used. The ERG had concerns about the rationale for the ceiling effect because it was unclear why other CPAP studies that also used EQ‑5D would not have had a similar ceiling effect. It noted that the baseline utility in the studies provided by the company were also in a population who had not had CPAP and so did not necessarily align with the population for this appraisal. The company showed research (Feng et al. 2021) suggesting a large ceiling effect with EQ‑5D and that it does not include aspects of quality of life such as energy and wellbeing. It argued that studies in people who had not had CPAP were more appropriate, because symptoms would not have been satisfactorily managed by CPAP in people who would have solriamfetol. The company also noted that the baseline EQ‑5D values in TONES 3 did not reflect the high baseline ESS scores, and that the trial was not long enough to capture changes in quality of life. The committee considered that the McDaid mapping would have some of the same issues as the EQ‑5D data from TONES 3, because it still used the EQ‑5D. It felt that it had not been presented with enough evidence to disregard the EQ‑5D data from TONES 3. So the committee considered that evidence directly from TONES 3 was a relevant source for consideration, despite uncertainty about the utility gain associated with ESS and the general limitations of using EQ‑5D. The company preferred assigning utility values based on both response status and treatment group because it considered that patients who had placebo in the trial would not be considered to 'respond' in practice. The committee did not agree with this approach, because there was no evidence provided for a treatment-related difference in quality of life that was not associated with ESS score. It agreed that health state utility values based on response status and independent of treatment group were preferred. The committee concluded that the quality-of-life benefits for solriamfetol from TONES 3 or from the utilities mapped using McDaid were the most acceptable sources for consideration in its decision making.
## Averaging the utility values directly from TONES 3 and McDaid is appropriate
The committee considered that both TONES 3 and the McDaid algorithm provided equally plausible estimates of how much reducing excessive daytime sleepiness improves quality of life. It noted that the utility estimates differed widely, resulting in considerably different cost-effectiveness estimates depending on which utilities were used. The ERG explored 2 methods for averaging the TONES 3 and McDaid utilities. This would mean that reducing excessive daytime sleepiness would give some quality-of-life improvement in the model, though not as little as TONES 3 suggested or as much as McDaid alone suggested. The committee considered this approach would be the most appropriate way of producing an ICER for its decision making. The first method averaged the EQ‑5D utilities directly from TONES 3 with the utilities from McDaid. This approach assumed no relationship between ESS score and EQ‑5D in TONES 3. The second method averaged the coefficient of change in ESS score and change in EQ‑5D from TONES 3 and McDaid. The company considered that the methods used by the ERG were unconventional and lacked transparency. The company was also unclear why the 2 utility sources had been weighted equally in the ERG's analysis. The committee was not convinced there was enough evidence to prefer 1 source of utilities over the other. It recognised that both methods used novel techniques to determine a utility value between 2 different types of evidence. It noted that both methods had limitations, but the first method was preferable because it took into account any differences in the models used to calculate the utility values (such as covariates). The committee concluded that using the first method to average the utility values from TONES 3 and McDaid was appropriate.
## Partner utility values are an important consideration but there is not enough evidence to include them in the modelling
Paragraph 5.1.7 on perspective in NICE's guide to the methods of technology appraisal notes that the perspective on outcomes should include all direct health effects, whether for patients or for other people. The company included partner utility values as a scenario in its modelling. This was because of the substantial impact that symptoms of obstructive sleep apnoea and its treatment can have on partners. The clinical expert agreed that partner utility values should be considered because of the substantial impact on family members (see section 3.1). But the ERG was concerned about the methods the company used to estimate partner utility values because the time trade-off utility estimates may not be comparable to those from the EQ‑5D. In its first meeting, the committee considered that partner utility values are important, but it had not been presented with enough evidence to support their inclusion in the modelling. In response to consultation, the company did not provide additional evidence to support including partner utilities. So, the committee did not change its earlier conclusion.
## Hospitalisation costs for serious adverse events should be included in the modelling
The company model presented at the first committee meeting did not include any costs for serious adverse events. The company said this was because most adverse events in TONES 3 were mild or moderate in severity. For adverse events that led to treatment discontinuation, the company model included the cost of 1 GP consultation. The ERG highlighted that some of the serious adverse events related to solriamfetol in the 150 mg arm of TONES 5 led to hospitalisation. This included 1 stroke. The company argued that including the cost of stroke would not be appropriate because it can occur in the target patient population in the 'real world'. In its base case, the ERG included hospitalisation costs for serious adverse events in patients taking solriamfetol (including stroke). In response to consultation, the company provided scenario analyses using different hospitalisation costs, based on hospitalisation rates. Its revised base case used annualised hospitalisation rates from TONES 3 for both treatment arms. The ERG highlighted that the company base case included a higher rate of hospitalisation with standard care than with solriamfetol, which the ERG considered implausible. The ERG preferred to use hospitalisation rates from TONES 5. The committee was presented with 3 other scenarios:
Scenario 1: hospitalisation rates from TONES 5 irrespective of relationship to solriamfetol for the solriamfetol arm, with no hospitalisation costs for the standard care arm.
Scenario 2: hospitalisation rates from TONES 5 irrespective of relationship to solriamfetol for the solriamfetol arm, and hospitalisation rates based on Hospital Episode Statistics data for the standard care arm.
Scenario 3: treatment-related hospitalisation rates from TONES 5 for the solriamfetol arm, with no hospitalisation costs for the standard care arm.The committee agreed with the ERG that the company base case was implausible. It considered that in scenarios 1 and 2, the hospitalisation rates for the solriamfetol arm were implausibly high. So, the committee concluded that the hospitalisation costs presented in scenario 3 were acceptable for decision making (the exact hospitalisation rates are commercial in confidence and cannot be reported here).
## A dose split based on US prescribing data is acceptable
Solriamfetol is available in different doses, which vary in cost and effectiveness. The clinical experts explained that it is difficult to estimate the most likely dose split in NHS clinical practice. Results for the different solriamfetol doses were weighted, based on dose-splitting assumptions, to inform cost-effectiveness comparisons between solriamfetol and standard care. In the company's base case, it was assumed that the dose splits were 40%, 40% and 20% respectively for the 37.5 mg, 75 mg and 150 mg doses of solriamfetol. The ERG noted that this dose split was different to that reported in a US study of prescribing data, in which a greater proportion of patients had the 75 mg dose (the figures are commercial in confidence and cannot be reported here). The ERG preferred to use the dose split based on the US prescribing data, in the absence of UK-specific data on solriamfetol prescribing patterns. In response to consultation, the company updated its base case to include the ERG's preferred dose split. The ERG highlighted that the cost-effectiveness conclusions were not sensitive to dose-split assumptions. The committee concluded that the dose split based on US prescribing data was acceptable for decision making.
# Cost-effectiveness estimates
## Because of the uncertainty, an acceptable ICER is at the lower end of what NICE normally considers an acceptable use of NHS resources
NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, particularly around:
the adjustment for the improvement in the control arm (see section 3.8)
how the quality-of-life benefit of solriamfetol was measured (see sections 3.9 to 3.12).So, the committee agreed that, because of the high level of uncertainty in the analyses, an acceptable ICER would be at the lower end of the range that NICE normally considers an acceptable use of NHS resources.
## Solriamfetol alone and with standard care is not a cost-effective use of NHS resources
The committee considered the cost-effectiveness estimates for solriamfetol alone and with standard care compared with standard care alone. The cost-effectiveness results are commercial in confidence because they included the patient access scheme discount for solriamfetol. The committee preferred the following assumptions:
treatment response defined as an ESS score reduction of 2 or more points (see section 3.7)
applying the 100% Hawthorne effect scenario to account for the improvement in the control arm (see section 3.8)
utilities based on the average of the EQ‑5D data directly from TONES 3 and utilities mapped using McDaid (see section 3.12)
hospitalisation costs for solriamfetol included for treatment-related serious adverse events from TONES 5, with no hospitalisation costs for standard care (see section 3.14)
the ERG's preferred dose split, based on the US prescribing data (see section 3.15).The ERG provided scenarios based on the committee's preferred assumptions. These used subgroup data based on use of CPAP at baseline from TONES 3. For people who can use CPAP, the ICER for solriamfetol with standard care compared with standard care alone was above the range the committee considered acceptable (see section 3.16). For people who cannot use CPAP, the ICER for solriamfetol alone compared with standard care was also above this range.
# Conclusion
## Solriamfetol is not recommended for treating excessive daytime sleepiness caused by obstructive sleep apnoea
The committee recognised that excessive daytime sleepiness caused by obstructive sleep apnoea is a debilitating condition that negatively affects many aspects of daily life (see section 3.1). It acknowledged that solriamfetol alone and with standard care was more effective than standard care alone in reducing excessive daytime sleepiness, as measured by the ESS and MWT. It also acknowledged that partner utilities were not included in the modelling. But it recognised obstructive sleep apnoea may affect partners and took this into account in its decision making. However, the committee believed that substantial uncertainty remained in the company's analysis. It considered that the most plausible cost-effectiveness estimates for solriamfetol alone and with standard care compared with standard care alone were above the range considered an acceptable use of NHS resources, even after taking into account the other factors (see section 3.16). Therefore, it did not recommend solriamfetol for routine commissioning in the NHS.
|
{'Recommendations': 'Solriamfetol is not recommended, within its marketing authorisation, to improve wakefulness and reduce excessive daytime sleepiness in adults with obstructive sleep apnoea whose sleepiness has not been satisfactorily treated by primary obstructive sleep apnoea therapy, such as continuous positive airway pressure (CPAP).\n\nThis recommendation is not intended to affect treatment with solriamfetol that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nExcessive daytime sleepiness caused by obstructive sleep apnoea is usually first treated with a primary obstructive sleep apnoea therapy such as CPAP (standard care).\n\nClinical trial evidence shows that solriamfetol alone and when added to standard care reduces excessive daytime sleepiness compared with standard care alone.\n\nThe trial evidence does not show an improvement in quality of life. This may be because of how it was measured in the trials. It is likely that reducing excessive daytime sleepiness translates into improved quality of life, but it is uncertain by how much.\n\nThere are also concerns about how the trial data has been used in the economic model. Therefore, the cost-effectiveness estimates for solriamfetol compared with standard care alone are uncertain. They are also likely to be higher than what NICE normally considers an acceptable use of NHS resources. So, solriamfetol is not recommended.', 'Information about solriamfetol': "# Marketing authorisation indication\n\nSolriamfetol (Sunosi, Jazz Pharmaceuticals) is indicated 'to improve wakefulness and reduce excessive daytime sleepiness (EDS) in adult patients with obstructive sleep apnoea (OSA) whose EDS has not been satisfactorily treated by primary OSA therapy, such as continuous positive airway pressure (CPAP)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for solriamfetol.\n\n# Price\n\nThe list price for solriamfetol is £177.52 for a 75‑mg 28‑day pack and £248.64 for a 150‑mg 28‑day pack (excluding VAT; BNF online accessed September\xa02021). The company has a commercial arrangement, which would have applied if the technology had been recommended.", 'Committee discussion': "The appraisal committee considered evidence submitted by Jazz Pharmaceuticals, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage. It agreed that a subgroup of people with a baseline Epworth Sleepiness Scale (ESS) score of more than\xa012 should be used in the modelling (see the technical report, issue\xa02).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues: primary therapy adherence, treatment response, adjustment for the improvement in the control arm, health utility values, partner utilities, treatment discontinuation, adverse events and dosing splits (see the technical report, issues\xa01 to\xa09), which were outstanding after the technical engagement stage.\n\n# The condition\n\n## Excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life, but it is uncertain by how much\n\nThe patient expert explained that obstructive sleep apnoea can negatively affect people's physical and mental wellbeing. Because of excessive daytime sleepiness, aspects of daily life such as education, employment, maintaining a social life and the ability to drive, are all negatively affected. Symptoms of sleep apnoea such as snoring can disrupt partners' sleep, which may affect their quality of life as well. The clinical experts agreed that excessive daytime sleepiness negatively affects people's quality of life, but said it can be difficult to measure by how much. They also noted that obstructive sleep apnoea can be associated with an increased risk of high blood pressure or stroke. The committee concluded that excessive daytime sleepiness caused by obstructive sleep apnoea affects quality of life. However, it was uncertain how much reducing excessive daytime sleepiness would improve quality of life.\n\n## CPAP is an appropriate comparator, but some people cannot tolerate it\n\nThe clinical experts said that most people with excessive daytime sleepiness caused by obstructive sleep apnoea are referred to sleep clinics. Initial treatment includes lifestyle advice about weight loss. Mandibular devices are considered for people with mild symptomatic obstructive sleep apnoea. NICE's technology appraisal guidance on continuous positive airway pressure (CPAP) for obstructive sleep apnoea/hypopnoea syndrome (from now, TA139) recommends CPAP for adults with moderate or severe obstructive sleep apnoea. The patient expert explained that CPAP is usually well tolerated but is associated with some inconvenience or discomfort. Wearing a face mask connected to the CPAP machine can also restrict sleeping. The clinical experts also said that some people cannot tolerate CPAP because they can feel claustrophobic wearing a mask, which can be exacerbated by certain mental health issues. People with neurodegenerative conditions may also not tolerate CPAP. The clinical and patient experts said that some people using CPAP will still have residual excessive daytime sleepiness. They noted that solriamfetol would be welcomed as another potential treatment option for this group. The committee concluded CPAP is an appropriate comparator. But some people cannot tolerate it, so a comparison with standard care without a primary obstructive sleep apnoea therapy was also important.\n\n## Solriamfetol is likely to be limited to secondary care\n\nObstructive sleep apnoea is currently treated in sleep services commissioned by the relevant clinical commissioning group. The clinical experts noted that, if solriamfetol was recommended, the likely requirement for more monitoring of adherence to CPAP (see section\xa03.5) could put pressure on these services. In its evidence submission and economic model, the company assumed that solriamfetol would be administered in specialist sleep services only. The committee asked the clinical experts if there was a possibility that solriamfetol could be prescribed in primary care. The experts suggested that treatment would have to be started in the specialist sleep clinics but were uncertain if longer-term prescribing could move to primary care. In response to consultation, the company provided information from clinicians and pharmacists to support its claim that solriamfetol would be limited to secondary care. It noted that solriamfetol has a black triangle in its marketing authorisation, meaning additional monitoring is needed. This would likely severely limit the use of solriamfetol in primary care. The committee concluded that solriamfetol is likely to be limited to secondary care.\n\n# Clinical evidence\n\n## Solriamfetol reduces excessive daytime sleepiness\n\nThe main clinical-effectiveness evidence for solriamfetol came from TONES\xa03. This was a 12‑week, randomised, double-blind, placebo-controlled, multicentre trial. The intervention was solriamfetol in doses of 37.5\xa0mg, 75\xa0mg and 150\xa0mg (also including an unlicensed 300\xa0mg dose). In both the intervention and comparator groups, around 70% of patients were using a primary obstructive sleep apnoea therapy, defined as either a prior effective surgical intervention or CPAP, at the start of the trial. These people were classified as adherent. The co-primary outcome of the trial was change in the ESS score and Maintenance of Wakefulness Test (MWT) from baseline to week\xa012. The results showed a significant change in ESS score and MWT from baseline to week\xa012 across all 3\xa0licensed solriamfetol doses. The committee concluded that solriamfetol reduces excessive daytime sleepiness.\n\n## Solriamfetol is unlikely to affect adherence to a primary obstructive sleep apnoea therapy like CPAP\n\nThe patient expert and ERG said that some people with excessive daytime sleepiness may prefer to manage their symptoms with medicine instead of a primary therapy such as CPAP. This could lead to them using CPAP less and so a reduction in the combined benefits of CPAP and solriamfetol. The company included patient adherence to a primary therapy in its 3\xa0trials (TONES\xa03, TONES\xa04 and TONES\xa05) as an exploratory end point. It also provided results from a peer-reviewed paper by Schweitzer et al. (2021), which showed no effect on primary therapy adherence in TONES\xa05 from baseline up to week\xa040. TONES\xa05 was an open-label trial assessing solriamfetol's long-term safety and efficacy for up to 52\xa0weeks, and included patients who had completed another solriamfetol trial (including TONES\xa03). It included a 2‑week placebo-controlled randomised withdrawal phase. The ERG noted that the results of Schweitzer et al. were highly uncertain because of missing data and poor reporting. It said that the estimates were not reported separately for people classified as adherent or non-adherent at baseline. The clinical experts said that most sleep clinics can monitor CPAP machines remotely and that some people, such as heavy goods vehicle drivers, have their CPAP use monitored remotely regularly. The clinical experts acknowledged that, although people having solriamfetol alongside a primary therapy such as CPAP would have their use monitored, it may have to be more frequent. The committee noted the uncertainty in the TONES\xa05 data on adherence. It would have preferred to see more sensitivity analyses of the impact of missing data in Schweitzer et al., and a subgroup analysis stratified by adherence at baseline. In response to consultation, the company provided additional sensitivity analyses, which showed that people having solriamfetol would meet the standard definition of adherence, even in a 'worst case' scenario with respect to the missing data from Schweitzer et al. In these analyses, adherence was defined as CPAP use of 4\xa0hours or more on 70% of nights. The committee concluded that adherence to a primary therapy like CPAP is unlikely to be affected by treatment with solriamfetol.\n\n# The economic model\n\n## The company's model of solriamfetol with and without standard care is suitable\n\nTONES\xa03 included people who adhered to a primary obstructive sleep apnoea therapy (standard care) and people who did not (see section\xa03.4). In the economic model presented at the first committee meeting, the company assumed that everyone entering the model had either solriamfetol with standard care (for example, CPAP) or standard care without solriamfetol. It presented a cost-effectiveness scenario analysis that included people from TONES\xa03 who did not adhere to standard care. The ERG noted that the baseline ESS score for the non-adherent group was worse than the adherent group. This meant that the improvement in ESS score because of solriamfetol treatment was greater, resulting in a lower incremental cost-effectiveness ratio (ICER) if the non-adherent group data was used. The committee felt that the company had not properly explained its methods for modelling the non-adherent group, or why people were not using their primary therapy. The committee recalled that the marketing authorisation for solriamfetol includes people who previously used a primary therapy but stopped. The committee also recalled that people with mental health or neurodegenerative conditions may struggle to use CPAP regularly (see section\xa03.2). It considered that recommendations restricting solriamfetol only for use with CPAP could discriminate against this group. The committee concluded that it would like to see clinical- and cost-effectiveness evidence for people who were not using a primary therapy. In response to consultation, the company provided clinical and cost-effectiveness evidence for people who were not using a primary therapy at baseline in TONES\xa03. The committee noted that the cost-effectiveness results were similar for people using a primary therapy at baseline compared with people who were not. It concluded that the company's model of solriamfetol with and without standard care was suitable for decision making.\n\n## Treatment response defined as an ESS score reduction of 2\xa0points or more is appropriate\n\nThe clinical experts said that the definition of treatment response for obstructive sleep apnoea varies considerably in clinical practice. The company used the ESS in TONES\xa03 as a component of the co-primary end point (see section\xa03.4). The model it presented at the first committee meeting defined treatment response as an ESS score reduction of 3\xa0or more points, based on clinical opinion. Advice to the ERG was that an ESS score reduction of 2\xa0or more points was appropriate but clinicians would consider other factors when assessing treatment effectiveness. The clinical experts said that, although an ESS score reduction of 2\xa0or more points may be appropriate, there is no consensus on what reduction can be considered clinically relevant and that it varies by individual. The ERG tested the ESS score reduction threshold in a scenario analysis, which showed that changing the threshold did not significantly affect the cost-effectiveness results. The committee acknowledged the uncertainty about the ESS but concluded that an ESS score reduction of 2\xa0or more points was an appropriate criterion for treatment response. In response to consultation, the company updated its model to define treatment response as an ESS score reduction of 2\xa0or more points. The committee accepted this for decision making.\n\n## The company's Hawthorne effect scenario is an acceptable approach to account for the improvement in the control arm\n\nIn TONES\xa03, ESS score improved from baseline to week\xa012 in the control arm (placebo plus standard care). The company suggested that this was likely to be a 'true placebo' effect – that is, the effect would not continue in the real world for standard care plus placebo. However, the company acknowledged that the improvement in the TONES\xa03 control arm may also be because of observation bias – the Hawthorne effect (that is, patients reported an improvement in ESS score because they were being observed). Under this assumption, the size of treatment effect for both arms would be lower in the real world, but the relative difference between the arms would be maintained. The company adjusted for the Hawthorne effect by removing the improvement in ESS score observed in the control arm from both the standard care and solriamfetol with standard care groups in its model. However, the ERG considered that some of the improvement in the TONES\xa03 control arm could be because of regression to the mean. This is a tendency for extreme values to move closer to the mean when measures are repeated over time. The ERG preferred to use the raw unadjusted trial data for both the standard care and solriamfetol with standard care groups in the model, which it considered would reflect outcomes in clinical practice. During technical engagement and in response to consultation, the company presented evidence to suggest that the improvement in the TONES\xa03 control arm was unlikely to be because of regression to the mean. This included evidence from people transitioning from TONES\xa03 to TONES\xa05. Those who were already having solriamfetol showed a greater improvement in ESS score when treatment with solriamfetol was unblinded. The company also noted that the speed of improvement in the TONES\xa03 control arm was too fast to be regression to the mean, and that the baseline ESS scores in TONES\xa04 and TONES\xa05 were similar. This meant that neither baseline was a temporary extreme value, as would be expected with regression to the mean. The committee acknowledged that there may be some regression to the mean. In response to consultation, the company did sensitivity analyses, varying the relative contribution of each of the 3\xa0potential mechanisms for the improvement in the TONES\xa03 control arm (regression to the mean, Hawthorne effect and true placebo). The company considered that assuming the control arm improvement was solely because of the Hawthorne effect, was conservative. This is because the true placebo effect may also be relevant due to the possible psychological benefit of having placebo in the trial, that is generalisable to routine practice. The ERG explained that there was not enough evidence to decide which mechanism was most relevant. It highlighted that there was uncertainty in the company's regression to the mean analyses. This was because the company assumed that people having solriamfetol whose symptoms did not respond to treatment had the same mean ESS score as the pooled standard care arm. The ERG was also concerned that attributing the control arm improvement to the true placebo effect would mean that the NHS would be paying for the benefit of placebo, if solriamfetol was recommended on this basis. The committee considered that the company's adjustment for the Hawthorne effect in its model was plausible. It felt that it was unlikely that regression to the mean was a major cause of the improvement in the TONES\xa03 control arm. It agreed with the ERG's concern about the true placebo effect. The committee concluded that it was reasonable to consider the 100% Hawthorne effect scenario in its decision making.\n\n# Quality of life\n\n## EQ-5D may have limitations in assessing quality of life for people with excessive daytime sleepiness\n\nEQ‑5D data from TONES\xa03 showed that people having solriamfetol had no improvement in quality of life from baseline to week\xa012. The clinical experts explained it is likely that the reduction in ESS score in TONES\xa03 would have some impact on quality of life, but it is difficult to determine the extent of improvement using standard quality-of-life measures such as the EQ‑5D. Higher ESS scores mean more excessive daytime sleepiness. The company explained that the EQ‑5D is insensitive to changes in quality of life for people with excessive daytime sleepiness caused by obstructive sleep apnoea. This is because it does not include a sleep domain and is unable to measure the impact of obstructive sleep apnoea on interpersonal relationships. The company suggested that the EQ‑5D data collected in TONES\xa03 did not accurately reflect the substantial quality-of-life burden of the disease. It also noted that the EQ‑5D results were inconsistent with the other TONES\xa03 outcome measures. The committee concluded that the EQ‑5D may have limitations in assessing quality of life for people with excessive daytime sleepiness.\n\n## Using the National Health and Wellness Survey may be biased\n\nThe company used a mapping algorithm to estimate EQ‑5D values based on ESS scores using data from the National Health and Wellness Survey (NHWS). The ERG considered that the company's mapping approach using NHWS was appropriate given the lack of alternative data. However, the committee was concerned that, if EQ‑5D is truly insensitive to changes in quality of life for people with this condition (see section\xa03.9), then mapping ESS scores to the EQ‑5D would not be appropriate and an alternative quality-of-life measure should be used. In response to consultation, the company said that it did not consider that the EQ‑5D or SF‑36 data collected in the TONES trials would accurately reflect the burden of obstructive sleep apnoea on quality of life. It continued to use the NHWS mapping algorithm as its base case and did not provide alternative SF‑6D utilities. In its second meeting, the committee noted several concerns with the company's NHWS mapping approach. It understood that the NHWS data was collected online from people who self-reported experience of obstructive sleep apnoea, narcolepsy, or both, rather than people who had necessarily been formally diagnosed. This may limit how relevant the NHWS data was to NHS clinical practice. The design of the NHWS also did not allow analysis of changes in ESS score or EQ‑5D over time, which may have given a more reliable measure of how change in ESS score predicts change in utility. The ERG highlighted that the NHWS algorithm may have omitted important predictive variables relating to quality of life. The committee was aware that similar mapping algorithms, based on longitudinal data that did not map change scores, have been used in NICE's technology appraisal guidance on nivolumab for advanced squamous non-small-cell lung cancer after chemotherapy and benralizumab for treating severe eosinophilic asthma. But, it noted that in the current appraisal, trial data and other sources for the mapping were available. The company said that the NHWS mapping algorithm used best methodological practice and that it should be considered as the base case. Despite this, the committee concluded that although the NHWS mapping approach might have advantages, it preferred a mapping based on the McDaid algorithm (see section\xa03.11) because it is likely to be less biased.\n\n## TONES 3 and the McDaid algorithm are the most appropriate utility sources\n\nThe company provided a scenario using the mapping algorithm from TA139, reported in McDaid et al. (2009). This used individual patient data measured both before and after treatment from 3\xa0studies of people with sleep apnoea who attended sleep clinics. The committee acknowledged uncertainty because the McDaid algorithm was based on a smaller sample size than the NHWS. However, it noted that McDaid had been accepted by the committee in TA139, and that McDaid did not share some of the limitations of the NHWS data (see section\xa03.10). But the committee agreed that mapping should be considered a second-best option compared with using the available trial data. The company provided analyses suggesting that the EQ‑5D data from TONES\xa03 was inappropriate to use because there was a 'ceiling effect'. A large proportion of patients in TONES\xa03 had a baseline utility of\xa01 (the maximum utility value). This meant there was minimal room for utility scores to improve during the trial. The company also provided an analysis simulating what the utility gain might have been had different baseline utility values (from other CPAP studies) been used. The ERG had concerns about the rationale for the ceiling effect because it was unclear why other CPAP studies that also used EQ‑5D would not have had a similar ceiling effect. It noted that the baseline utility in the studies provided by the company were also in a population who had not had CPAP and so did not necessarily align with the population for this appraisal. The company showed research (Feng et al. 2021) suggesting a large ceiling effect with EQ‑5D and that it does not include aspects of quality of life such as energy and wellbeing. It argued that studies in people who had not had CPAP were more appropriate, because symptoms would not have been satisfactorily managed by CPAP in people who would have solriamfetol. The company also noted that the baseline EQ‑5D values in TONES\xa03 did not reflect the high baseline ESS scores, and that the trial was not long enough to capture changes in quality of life. The committee considered that the McDaid mapping would have some of the same issues as the EQ‑5D data from TONES\xa03, because it still used the EQ‑5D. It felt that it had not been presented with enough evidence to disregard the EQ‑5D data from TONES\xa03. So the committee considered that evidence directly from TONES\xa03 was a relevant source for consideration, despite uncertainty about the utility gain associated with ESS and the general limitations of using EQ‑5D. The company preferred assigning utility values based on both response status and treatment group because it considered that patients who had placebo in the trial would not be considered to 'respond' in practice. The committee did not agree with this approach, because there was no evidence provided for a treatment-related difference in quality of life that was not associated with ESS score. It agreed that health state utility values based on response status and independent of treatment group were preferred. The committee concluded that the quality-of-life benefits for solriamfetol from TONES\xa03 or from the utilities mapped using McDaid were the most acceptable sources for consideration in its decision making.\n\n## Averaging the utility values directly from TONES\xa03 and McDaid is appropriate\n\nThe committee considered that both TONES\xa03 and the McDaid algorithm provided equally plausible estimates of how much reducing excessive daytime sleepiness improves quality of life. It noted that the utility estimates differed widely, resulting in considerably different cost-effectiveness estimates depending on which utilities were used. The ERG explored 2\xa0methods for averaging the TONES\xa03 and McDaid utilities. This would mean that reducing excessive daytime sleepiness would give some quality-of-life improvement in the model, though not as little as TONES\xa03 suggested or as much as McDaid alone suggested. The committee considered this approach would be the most appropriate way of producing an ICER for its decision making. The first method averaged the EQ‑5D utilities directly from TONES\xa03 with the utilities from McDaid. This approach assumed no relationship between ESS score and EQ‑5D in TONES\xa03. The second method averaged the coefficient of change in ESS score and change in EQ‑5D from TONES\xa03 and McDaid. The company considered that the methods used by the ERG were unconventional and lacked transparency. The company was also unclear why the 2\xa0utility sources had been weighted equally in the ERG's analysis. The committee was not convinced there was enough evidence to prefer 1\xa0source of utilities over the other. It recognised that both methods used novel techniques to determine a utility value between 2\xa0different types of evidence. It noted that both methods had limitations, but the first method was preferable because it took into account any differences in the models used to calculate the utility values (such as covariates). The committee concluded that using the first method to average the utility values from TONES\xa03 and McDaid was appropriate.\n\n## Partner utility values are an important consideration but there is not enough evidence to include them in the modelling\n\nParagraph 5.1.7 on perspective in NICE's guide to the methods of technology appraisal notes that the perspective on outcomes should include all direct health effects, whether for patients or for other people. The company included partner utility values as a scenario in its modelling. This was because of the substantial impact that symptoms of obstructive sleep apnoea and its treatment can have on partners. The clinical expert agreed that partner utility values should be considered because of the substantial impact on family members (see\xa0section\xa03.1). But the ERG was concerned about the methods the company used to estimate partner utility values because the time trade-off utility estimates may not be comparable to those from the EQ‑5D. In its first meeting, the committee considered that partner utility values are important, but it had not been presented with enough evidence to support their inclusion in the modelling. In response to consultation, the company did not provide additional evidence to support including partner utilities. So, the committee did not change its earlier conclusion.\n\n## Hospitalisation costs for serious adverse events should be included in the modelling\n\nThe company model presented at the first committee meeting did not include any costs for serious adverse events. The company said this was because most adverse events in TONES\xa03 were mild or moderate in severity. For adverse events that led to treatment discontinuation, the company model included the cost of 1\xa0GP consultation. The ERG highlighted that some of the serious adverse events related to solriamfetol in the 150\xa0mg arm of TONES\xa05 led to hospitalisation. This included 1\xa0stroke. The company argued that including the cost of stroke would not be appropriate because it can occur in the target patient population in the 'real world'. In its base case, the ERG included hospitalisation costs for serious adverse events in patients taking solriamfetol (including stroke). In response to consultation, the company provided scenario analyses using different hospitalisation costs, based on hospitalisation rates. Its revised base case used annualised hospitalisation rates from TONES\xa03 for both treatment arms. The ERG highlighted that the company base case included a higher rate of hospitalisation with standard care than with solriamfetol, which the ERG considered implausible. The ERG preferred to use hospitalisation rates from TONES\xa05. The committee was presented with 3\xa0other scenarios:\n\nScenario 1: hospitalisation rates from TONES\xa05 irrespective of relationship to solriamfetol for the solriamfetol arm, with no hospitalisation costs for the standard care arm.\n\nScenario 2: hospitalisation rates from TONES\xa05 irrespective of relationship to solriamfetol for the solriamfetol arm, and hospitalisation rates based on Hospital Episode Statistics data for the standard care arm.\n\nScenario 3: treatment-related hospitalisation rates from TONES\xa05 for the solriamfetol arm, with no hospitalisation costs for the standard care arm.The committee agreed with the ERG that the company base case was implausible. It considered that in scenarios\xa01 and\xa02, the hospitalisation rates for the solriamfetol arm were implausibly high. So, the committee concluded that the hospitalisation costs presented in scenario\xa03 were acceptable for decision making (the exact hospitalisation rates are commercial in confidence and cannot be reported here).\n\n## A dose split based on US prescribing data is acceptable\n\nSolriamfetol is available in different doses, which vary in cost and effectiveness. The clinical experts explained that it is difficult to estimate the most likely dose split in NHS clinical practice. Results for the different solriamfetol doses were weighted, based on dose-splitting assumptions, to inform cost-effectiveness comparisons between solriamfetol and standard care. In the company's base case, it was assumed that the dose splits were 40%, 40% and 20% respectively for the 37.5\xa0mg, 75\xa0mg and 150\xa0mg doses of solriamfetol. The ERG noted that this dose split was different to that reported in a US study of prescribing data, in which a greater proportion of patients had the 75\xa0mg dose (the figures are commercial in confidence and cannot be reported here). The ERG preferred to use the dose split based on the US prescribing data, in the absence of UK-specific data on solriamfetol prescribing patterns. In response to consultation, the company updated its base case to include the ERG's preferred dose split. The ERG highlighted that the cost-effectiveness conclusions were not sensitive to dose-split assumptions. The committee concluded that the dose split based on US prescribing data was acceptable for decision making.\n\n# Cost-effectiveness estimates\n\n## Because of the uncertainty, an acceptable ICER is at the lower end of what NICE normally considers an acceptable use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, particularly around:\n\nthe adjustment for the improvement in the control arm (see section\xa03.8)\n\nhow the quality-of-life benefit of solriamfetol was measured (see sections\xa03.9\xa0to\xa03.12).So, the committee agreed that, because of the high level of uncertainty in the analyses, an acceptable ICER would be at the lower end of the range that NICE normally considers an acceptable use of NHS resources.\n\n## Solriamfetol alone and with standard care is not a cost-effective use of NHS resources\n\nThe committee considered the cost-effectiveness estimates for solriamfetol alone and with standard care compared with standard care alone. The cost-effectiveness results are commercial in confidence because they included the patient access scheme discount for solriamfetol. The committee preferred the following assumptions:\n\ntreatment response defined as an ESS score reduction of 2\xa0or more points (see section\xa03.7)\n\napplying the 100% Hawthorne effect scenario to account for the improvement in the control arm (see section\xa03.8)\n\nutilities based on the average of the EQ‑5D data directly from TONES\xa03 and utilities mapped using McDaid (see section\xa03.12)\n\nhospitalisation costs for solriamfetol included for treatment-related serious adverse events from TONES\xa05, with no hospitalisation costs for standard care (see section\xa03.14)\n\nthe ERG's preferred dose split, based on the US prescribing data (see section\xa03.15).The ERG provided scenarios based on the committee's preferred assumptions. These used subgroup data based on use of CPAP at baseline from TONES\xa03. For people who can use CPAP, the ICER for solriamfetol with standard care compared with standard care alone was above the range the committee considered acceptable (see section\xa03.16). For people who cannot use CPAP, the ICER for solriamfetol alone compared with standard care was also above this range.\n\n# Conclusion\n\n## Solriamfetol is not recommended for treating excessive daytime sleepiness caused by obstructive sleep apnoea\n\nThe committee recognised that excessive daytime sleepiness caused by obstructive sleep apnoea is a debilitating condition that negatively affects many aspects of daily life (see section\xa03.1). It acknowledged that solriamfetol alone and with standard care was more effective than standard care alone in reducing excessive daytime sleepiness, as measured by the ESS and MWT. It also acknowledged that partner utilities were not included in the modelling. But it recognised obstructive sleep apnoea may affect partners and took this into account in its decision making. However, the committee believed that substantial uncertainty remained in the company's analysis. It considered that the most plausible cost-effectiveness estimates for solriamfetol alone and with standard care compared with standard care alone were above the range considered an acceptable use of NHS resources, even after taking into account the other factors (see section\xa03.16). Therefore, it did not recommend solriamfetol for routine commissioning in the NHS."}
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https://www.nice.org.uk/guidance/ta777
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Evidence-based recommendations on solriamfetol (Sunosi) for treating excessive daytime sleepiness caused by obstructive sleep apnoea in adults.
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263b5b4db2b0d3e12366ee8216065352cba2f186
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nice
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Pegcetacoplan for treating paroxysmal nocturnal haemoglobinuria
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Pegcetacoplan for treating paroxysmal nocturnal haemoglobinuria
Evidence-based recommendations on pegcetacoplan (Aspaveli) for treating paroxysmal nocturnal haemoglobinuria in adults who have anaemia after at least 3 months of treatment with a C5 inhibitor.
# Recommendations
Pegcetacoplan is recommended, within its marketing authorisation, as an option for treating paroxysmal nocturnal haemoglobinuria (PNH) in adults who have anaemia after at least 3 months of treatment with a C5 inhibitor. It is recommended only if the company provides pegcetacoplan according to the commercial arrangement.
Why the committee made these recommendations
Current treatments for PNH include C5 inhibitors such as eculizumab and ravulizumab. Some people still experience anaemia and symptoms of PNH while having these treatments. Clinical trial evidence suggests that pegcetacoplan improves haemoglobin levels (a measure of anaemia) and haematological symptoms of PNH for people who have anaemia while taking eculizumab. Pegcetacoplan is likely to have the same clinical benefits for people who have anaemia while taking ravulizumab, because ravulizumab is very similar to eculizumab.
For adults with anaemia while having a C5 inhibitor, pegcetacoplan is more effective and costs less than ravulizumab and eculizumab. Therefore, it is recommended.# Information about pegcetacoplan
# Marketing authorisation indication
Pegcetacoplan (Aspaveli, Swedish Orphan Biovitrum) is indicated 'in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who are anaemic after treatment with a C5 inhibitor for at least 3 months'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of pegcetacoplan is £3,100.00 for a 1,080‑mg vial (excluding VAT; confirmed by company). The company has a commercial arrangement (simple discount patient access scheme). This makes pegcetacoplan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Swedish Orphan Biovitrum (Sobi), a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# New treatment option
## People with paroxysmal nocturnal haemoglobinuria would welcome pegcetacoplan as a new treatment option
Paroxysmal nocturnal haemoglobinuria (PNH) is a rare blood condition in which red blood cells are attacked by the body's immune system. The breakdown of red blood cells can happen within the blood vessels (intravascular haemolysis) or outside the blood vessels (extravascular haemolysis). This often results in anaemia, which needs blood transfusions, and severe symptoms of haemolysis. Current treatments for PNH include the C5 complement protein inhibitors eculizumab and ravulizumab. Submissions from the clinical and patient experts advised that people with PNH who are having these treatments often continue to experience anaemia because of extravascular haemolysis. This causes suboptimal disease control and the need for blood transfusions. The committee understood that because pegcetacoplan works by inhibiting the C3 complement protein rather than the C5 complement protein in the immune system, it would likely target both intravascular and extravascular haemolysis. This means it could offer benefits for people who continue to have anaemia while having C5 complement protein inhibitors that only target intravascular haemolysis. Patient expert statements described how current treatments can be inconvenient. This is because of frequent cannulation and because a healthcare professional is needed to administer the treatment by intravenous infusion at a person's home. The committee understood that pegcetacoplan is available as a subcutaneous infusion that can be self-administered and so would offer greater flexibility to people with PNH. The patient expert statements explained that, because pegcetacoplan is given more frequently than eculizumab and ravulizumab, this could be difficult for some people to manage and may increase the likelihood of injection site reactions. However, they considered these to be minor inconveniences compared with the benefits that pegcetacoplan offers. Patient expert statements also described how treatment with pegcetacoplan has resulted in fewer blood transfusions and improved fatigue levels and quality of life, including a positive effect on their mental wellbeing and ability to work. The committee concluded that people with PNH would welcome pegcetacoplan as a new treatment option.
# Treatment pathway
## The company's positioning of pegcetacoplan is appropriate
In England, PNH is managed by the PNH National Service. This consists of 2 centres and 8 outreach clinics, and a local haematologist through a shared care agreement. The severity of symptoms varies between people and over time, which means that not everyone with PNH needs treatment with eculizumab or ravulizumab. The indications for treatment with the current C5 inhibitors are included in the PNH National Service's indications for treatment with eculizumab and NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria. The committee considered that more people are likely to have ravulizumab in the future because of its lower treatment frequency compared with eculizumab. It discussed the company's positioning of pegcetacoplan for adults who have anaemia after at least 3 months of treatment with a C5 inhibitor. It recalled comments from the clinical and patient expert submissions that C5 inhibitors had significantly reduced the disease burden of PNH. However, some people still experience symptoms despite treatment because of extravascular haemolysis. The company's proposed positioning of pegcetacoplan would mean that it would only be offered to people if they still had anaemia after treatment with eculizumab or ravulizumab. The committee noted that the positioning was in line with the marketing authorisation and clinical trial evidence for pegcetacoplan. It was satisfied that this reflected how pegcetacoplan would likely be used in the NHS. Therefore, it concluded that the company's positioning of pegcetacoplan in the treatment pathway was appropriate.
# Clinical evidence
## Pegcetacoplan improves change from baseline in haemoglobin level at week 16 compared with eculizumab
The company submission included the PEGASUS open-label, active-comparator, randomised controlled trial that compared pegcetacoplan with eculizumab in adults who had haemoglobin levels of less than 105 g/litre despite treatment with eculizumab. People were randomised to have either pegcetacoplan or eculizumab. People randomised to the eculizumab arm continued to have it at their current dose that had been stable for at least 3 months before screening. The trial was done in 3 phases:
-week run-in period in which all patients had pegcetacoplan plus eculizumab (baseline was day 28 of the run-in period)
-week randomised controlled period in which patients were randomised to either pegcetacoplan or eculizumab monotherapy
-week open-label period in which all patients who completed the randomised controlled period had pegcetacoplan monotherapy (people who were randomised to have eculizumab completed another 4‑week run-in period before switching to pegcetacoplan monotherapy for the remaining 28 weeks).The primary outcome of the study was the change from baseline in haemoglobin level at week 16, which was statistically significantly higher in the pegcetacoplan arm compared with the eculizumab arm (least squares mean difference 38.4 g/litre, 95% confidence interval 23.3 to 53.4, p<0.0001). The committee concluded that pegcetacoplan improves the change from baseline in haemoglobin level at week 16 compared with eculizumab.
## The trial results are generalisable to clinical practice in England
The PEGASUS trial was done across 44 sites internationally including at a PNH specialist centre in England. The company considered the generalisability of the trial evidence with an advisory board, including UK clinical experts experienced in the treatment of PNH. The committee acknowledged opinion from both the company's and ERG's clinical experts that the PEGASUS trial results were generalisable to the population who would likely have pegcetacoplan in NHS clinical practice. The committee discussed the company's definition of anaemia in the PEGASUS trial, defined as a haemoglobin level of less than 105 g/litre. It noted comments from the ERG's clinical experts, which suggested that higher haemoglobin levels could also be considered as uncontrolled anaemia in some people with PNH. The company explained that the haemoglobin threshold had been selected based on clinical expert opinion and because it aligned with previous clinical trials in PNH, the published literature and haemoglobin levels observed in PNH registries. It highlighted that based on the literature, the median haemoglobin level of people enrolled in the international PNH Registry was 106 g/litre and in people referred to the UK PNH National Service was 109 g/litre, which are both similar to the threshold used in the PEGASUS trial. The committee considered that although there is some variation in clinical judgement, the company's definition of anaemia would include most people who would be considered to have anaemia after having treatment with eculizumab or ravulizumab in NHS clinical practice. It therefore concluded that the trial results were generalisable to clinical practice in England.
## The results of the company's indirect treatment comparison are not robust for decision making
The company did not identify any direct evidence comparing the clinical effectiveness of pegcetacoplan with ravulizumab. Therefore, it did an anchored matching-adjusted indirect comparison to compare the effectiveness of pegcetacoplan and ravulizumab in people who had previously had eculizumab. The company used individual patient data from the PEGASUS trial for pegcetacoplan and eculizumab and from Study 302 for ravulizumab and eculizumab, which was considered in NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria. The company identified key differences in the designs of the 2 trials that could not be adjusted to make them comparable. It also identified important differences in the trial eligibility criteria, which meant that it was not possible to accurately match the haemoglobin levels of patients between trials. Both the company and ERG considered that the results of the indirect comparison may be subject to bias because of these differences and because the effect of key effect modifiers (haemoglobin level and history of transfusions) could not be considered in the matching process. The committee concluded that the results of the company's indirect treatment comparison were not robust for decision making.
## The company's assumption of equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population is reasonable
There is no robust evidence comparing the treatment efficacy of pegcetacoplan and ravulizumab (see section 3.5). So, the company assumed equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population (people with anaemia despite treatment with eculizumab). The results from Study 302 showed that ravulizumab was non-inferior to eculizumab, with point estimates favouring ravulizumab for all primary and secondary endpoints, but these differences were not statistically significant. The committee noted that NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria concluded that ravulizumab and eculizumab were similarly effective and had a similar safety profile. The ERG considered that it was not possible to be certain from the available evidence that the efficacy of ravulizumab would be the same as eculizumab in the PEGASUS trial population. This is because of key differences between the PEGASUS trial and Study 302 (see section 3.5). The committee considered that ravulizumab is a re-engineered form of eculizumab and both technologies are biologically very similar with over 99% homology. It noted that the ERG's clinical experts considered that the efficacy of both treatments is likely to be equal in any population. Therefore, the committee concluded that the company's assumption of equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population was reasonable.
# Cost effectiveness
## The company's model is suitable for decision making
The company presented a cohort-level state transition model that reflected the evidence available from the PEGASUS trial and included 4 health states:
no transfusions needed and a haemoglobin level of less than 105 g/litre
no transfusions needed and a haemoglobin level of 105 g/litre or more
transfusions needed
death.Spontaneous remission was not modelled because the company considered that this would not be expected to vary by treatment. The company's clinical experts considered that extravascular breakthrough haemolysis results in a drop in haemoglobin level and blood transfusions, both of which are captured in the model health states. The model included a 4‑week cycle length with half-cycle correction, and outcomes were assessed over a lifetime time horizon. The committee noted that the company's model structure was different to the model presented in NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria, which had 8 states, based on breakthrough haemolysis in addition to a spontaneous remission and death state. It understood that the company considered that the ravulizumab model was not appropriate for capturing the benefits associated with pegcetacoplan, such as preventing extravascular haemolysis or improving fatigue. The committee discussed the company's summary of product characteristics for pegcetacoplan, which indicated that for the first 4 weeks of treatment, pegcetacoplan should be given in addition to a person's current dose of C5 inhibitor treatment. This is to reduce the risk of haemolysis from abruptly stopping treatment with either eculizumab or ravulizumab. It noted that the company's model assumed that there was no overlap of treatments and people started taking pegcetacoplan on its own without a concurrent C5 inhibitor. This was because the company's model had included data from the randomised controlled period, in which patients had either pegcetacoplan or eculizumab, and not the run-in period in which both treatments were given (see section 3.3). The company explained that, since the trial, it had consulted with clinical experts who considered that such an overlap of treatments would not likely happen in clinical practice. This is because people who switch from eculizumab or ravulizumab to pegcetacoplan will still experience an ongoing effect of C5 inhibition after stopping treatment and so having treatments concurrently is not needed. The committee considered that the company's assumption was reasonable and reflected how pegcetacoplan would likely be used in NHS clinical practice. It noted that the ERG considered that the company's model was well built, and the model structure reflects the PNH treatment pathway with 2 minor exceptions. The ERG considered that the proportion of people having a C5 inhibitor who were having chelation therapies at baseline in the model should be based on the PEGASUS clinical study report rather than the trial run-in period, as used in the company's base case. It also considered that the application of half-cycle corrections should start from cycle 1 rather than cycle 0 as in the company's model, but that implementing this change would have a negligible effect on the cost-effectiveness results. The committee considered the ERG's critique and that the company's model structure was validated by the company's advisory board. It concluded that the company's model was suitable for decision making.
## Pegcetacoplan is recommended as a cost-effective use of NHS resources
The committee considered the ERG's preferred modelling assumptions that included 2 minor revisions to the company's base case:
using chelation therapy proportions from the PEGASUS clinical study report (see section 3.7)
including adverse event costs.Using the confidential discounts for pegcetacoplan and ravulizumab, pegcetacoplan was more effective and less costly compared with both eculizumab and ravulizumab in the company and ERG base cases and in all scenario analyses presented by the company and ERG. Exact results are confidential and cannot be reported here. The committee noted that the total modelled costs were the least expensive for pegcetacoplan, partly because it is self-administered and reduces the need for blood transfusions. The committee concluded that pegcetacoplan, when compared with eculizumab and ravulizumab, was a cost-effective use of NHS resources. It therefore recommended pegcetacoplan as an option for treating PNH in adults.
# Other factors
## There are no equality issues relevant to the recommendations
The committee discussed the potential equality issues raised during scoping. It noted stakeholder comments that pegcetacoplan is given by a subcutaneous infusion and can be self-administered at home. This may have implications for people with physical or learning disabilities, particularly if they have manual dexterity issues. The company explained that if pegcetacoplan was recommended by the committee, it would provide a patient support programme that would identify and support people who may need additional help to take their subcutaneous infusions at home. The committee considered that this would help to reduce inequalities in access to pegcetacoplan treatment because of its method of administration. It noted stakeholder comments that age and pregnancy are protected characteristics and inequalities may arise if different recommendations are made for children and pregnant women. The committee discussed that children and pregnant women were excluded from the PEGASUS trial. It noted a comment from a clinical expert submission that pegcetacoplan should not be used in pregnancy. The committee considered the pegcetacoplan indication is currently limited to adults and it can only recommend a treatment within its marketing authorisation. The committee concluded that there were no equality issues relevant to the recommendations.
## The benefits of pegcetacoplan are captured in the cost-effectiveness analysis
The company considers pegcetacoplan to be innovative because it prevents both intravascular and extravascular haemolysis by targeting the complement cascade earlier than C5 inhibitors. The committee agreed that these are important benefits and recognised that pegcetacoplan will be the first C3 inhibitor licensed for PNH. It recalled patient expert statements highlighting that treatment with eculizumab and ravulizumab can be inconvenient for some people because of frequent cannulation and because a healthcare professional is needed to administer the intravenous infusion at a person's home. The committee recognised that pegcetacoplan is available as a subcutaneous infusion that can be self-administered and that this may offer benefits for some people compared with current treatments. However, it recalled patient expert statements that because pegcetacoplan is administered more frequently than existing treatments, it may be less convenient for other people. The committee considered that these potential advantages and disadvantages associated with pegcetacoplan's administration may have already been captured in the company's model. This is because the company modelled a disutility for eculizumab to reflect that it has more regular dosing than ravulizumab, and that it is an intravenous infusion whereas pegcetacoplan is a subcutaneous infusion. It assumed no disutility for ravulizumab and pegcetacoplan because they were both assumed to reduce the burden of administration compared with eculizumab. The committee concluded that the benefits of pegcetacoplan are captured in the cost-effectiveness analysis.
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{'Recommendations': 'Pegcetacoplan is recommended, within its marketing authorisation, as an option for treating paroxysmal nocturnal haemoglobinuria (PNH) in adults who have anaemia after at least 3\xa0months of treatment with a C5\xa0inhibitor. It is recommended only if the company provides pegcetacoplan according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatments for PNH include C5 inhibitors such as eculizumab and ravulizumab. Some people still experience anaemia and symptoms of PNH while having these treatments. Clinical trial evidence suggests that pegcetacoplan improves haemoglobin levels (a measure of anaemia) and haematological symptoms of PNH for people who have anaemia while taking eculizumab. Pegcetacoplan is likely to have the same clinical benefits for people who have anaemia while taking ravulizumab, because ravulizumab is very similar to eculizumab.\n\nFor adults with anaemia while having a C5 inhibitor, pegcetacoplan is more effective and costs less than ravulizumab and eculizumab. Therefore, it is recommended.', 'Information about pegcetacoplan': "# Marketing authorisation indication\n\nPegcetacoplan (Aspaveli, Swedish Orphan Biovitrum) is indicated 'in the treatment of adult patients with paroxysmal nocturnal haemoglobinuria (PNH) who are anaemic after treatment with a C5 inhibitor for at least 3\xa0months'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of pegcetacoplan is £3,100.00 for a 1,080‑mg vial (excluding VAT; confirmed by company). The company has a commercial arrangement (simple discount patient access scheme). This makes pegcetacoplan available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Swedish Orphan Biovitrum (Sobi), a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## People with paroxysmal nocturnal haemoglobinuria would welcome pegcetacoplan as a new treatment option\n\nParoxysmal nocturnal haemoglobinuria (PNH) is a rare blood condition in which red blood cells are attacked by the body's immune system. The breakdown of red blood cells can happen within the blood vessels (intravascular haemolysis) or outside the blood vessels (extravascular haemolysis). This often results in anaemia, which needs blood transfusions, and severe symptoms of haemolysis. Current treatments for PNH include the C5 complement protein inhibitors eculizumab and ravulizumab. Submissions from the clinical and patient experts advised that people with PNH who are having these treatments often continue to experience anaemia because of extravascular haemolysis. This causes suboptimal disease control and the need for blood transfusions. The committee understood that because pegcetacoplan works by inhibiting the C3 complement protein rather than the C5 complement protein in the immune system, it would likely target both intravascular and extravascular haemolysis. This means it could offer benefits for people who continue to have anaemia while having C5 complement protein inhibitors that only target intravascular haemolysis. Patient expert statements described how current treatments can be inconvenient. This is because of frequent cannulation and because a healthcare professional is needed to administer the treatment by intravenous infusion at a person's home. The committee understood that pegcetacoplan is available as a subcutaneous infusion that can be self-administered and so would offer greater flexibility to people with PNH. The patient expert statements explained that, because pegcetacoplan is given more frequently than eculizumab and ravulizumab, this could be difficult for some people to manage and may increase the likelihood of injection site reactions. However, they considered these to be minor inconveniences compared with the benefits that pegcetacoplan offers. Patient expert statements also described how treatment with pegcetacoplan has resulted in fewer blood transfusions and improved fatigue levels and quality of life, including a positive effect on their mental wellbeing and ability to work. The committee concluded that people with PNH would welcome pegcetacoplan as a new treatment option.\n\n# Treatment pathway\n\n## The company's positioning of pegcetacoplan is appropriate\n\nIn England, PNH is managed by the PNH National Service. This consists of 2\xa0centres and 8\xa0outreach clinics, and a local haematologist through a shared care agreement. The severity of symptoms varies between people and over time, which means that not everyone with PNH needs treatment with eculizumab or ravulizumab. The indications for treatment with the current C5\xa0inhibitors are included in the PNH National Service's indications for treatment with eculizumab and NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria. The committee considered that more people are likely to have ravulizumab in the future because of its lower treatment frequency compared with eculizumab. It discussed the company's positioning of pegcetacoplan for adults who have anaemia after at least 3\xa0months of treatment with a C5\xa0inhibitor. It recalled comments from the clinical and patient expert submissions that C5\xa0inhibitors had significantly reduced the disease burden of PNH. However, some people still experience symptoms despite treatment because of extravascular haemolysis. The company's proposed positioning of pegcetacoplan would mean that it would only be offered to people if they still had anaemia after treatment with eculizumab or ravulizumab. The committee noted that the positioning was in line with the marketing authorisation and clinical trial evidence for pegcetacoplan. It was satisfied that this reflected how pegcetacoplan would likely be used in the NHS. Therefore, it concluded that the company's positioning of pegcetacoplan in the treatment pathway was appropriate.\n\n# Clinical evidence\n\n## Pegcetacoplan improves change from baseline in haemoglobin level at week\xa016 compared with eculizumab\n\nThe company submission included the PEGASUS open-label, active-comparator, randomised controlled trial that compared pegcetacoplan with eculizumab in adults who had haemoglobin levels of less than 105\xa0g/litre despite treatment with eculizumab. People were randomised to have either pegcetacoplan or eculizumab. People randomised to the eculizumab arm continued to have it at their current dose that had been stable for at least 3\xa0months before screening. The trial was done in 3\xa0phases:\n\n-week run-in period in which all patients had pegcetacoplan plus eculizumab (baseline was day\xa028 of the run-in period)\n\n-week randomised controlled period in which patients were randomised to either pegcetacoplan or eculizumab monotherapy\n\n-week open-label period in which all patients who completed the randomised controlled period had pegcetacoplan monotherapy (people who were randomised to have eculizumab completed another 4‑week run-in period before switching to pegcetacoplan monotherapy for the remaining 28\xa0weeks).The primary outcome of the study was the change from baseline in haemoglobin level at week\xa016, which was statistically significantly higher in the pegcetacoplan arm compared with the eculizumab arm (least squares mean difference 38.4\xa0g/litre, 95% confidence interval [CI] 23.3 to 53.4, p<0.0001). The committee concluded that pegcetacoplan improves the change from baseline in haemoglobin level at week\xa016 compared with eculizumab.\n\n## The trial results are generalisable to clinical practice in England\n\nThe PEGASUS trial was done across 44\xa0sites internationally including at a PNH specialist centre in England. The company considered the generalisability of the trial evidence with an advisory board, including UK clinical experts experienced in the treatment of PNH. The committee acknowledged opinion from both the company's and ERG's clinical experts that the PEGASUS trial results were generalisable to the population who would likely have pegcetacoplan in NHS clinical practice. The committee discussed the company's definition of anaemia in the PEGASUS trial, defined as a haemoglobin level of less than 105\xa0g/litre. It noted comments from the ERG's clinical experts, which suggested that higher haemoglobin levels could also be considered as uncontrolled anaemia in some people with PNH. The company explained that the haemoglobin threshold had been selected based on clinical expert opinion and because it aligned with previous clinical trials in PNH, the published literature and haemoglobin levels observed in PNH registries. It highlighted that based on the literature, the median haemoglobin level of people enrolled in the international PNH Registry was 106\xa0g/litre and in people referred to the UK PNH National Service was 109\xa0g/litre, which are both similar to the threshold used in the PEGASUS trial. The committee considered that although there is some variation in clinical judgement, the company's definition of anaemia would include most people who would be considered to have anaemia after having treatment with eculizumab or ravulizumab in NHS clinical practice. It therefore concluded that the trial results were generalisable to clinical practice in England.\n\n## The results of the company's indirect treatment comparison are not robust for decision making\n\nThe company did not identify any direct evidence comparing the clinical effectiveness of pegcetacoplan with ravulizumab. Therefore, it did an anchored matching-adjusted indirect comparison to compare the effectiveness of pegcetacoplan and ravulizumab in people who had previously had eculizumab. The company used individual patient data from the PEGASUS trial for pegcetacoplan and eculizumab and from Study\xa0302 for ravulizumab and eculizumab, which was considered in NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria. The company identified key differences in the designs of the 2\xa0trials that could not be adjusted to make them comparable. It also identified important differences in the trial eligibility criteria, which meant that it was not possible to accurately match the haemoglobin levels of patients between trials. Both the company and ERG considered that the results of the indirect comparison may be subject to bias because of these differences and because the effect of key effect modifiers (haemoglobin level and history of transfusions) could not be considered in the matching process. The committee concluded that the results of the company's indirect treatment comparison were not robust for decision making.\n\n## The company's assumption of equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population is reasonable\n\nThere is no robust evidence comparing the treatment efficacy of pegcetacoplan and ravulizumab (see section\xa03.5). So, the company assumed equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population (people with anaemia despite treatment with eculizumab). The results from Study\xa0302 showed that ravulizumab was non-inferior to eculizumab, with point estimates favouring ravulizumab for all primary and secondary endpoints, but these differences were not statistically significant. The committee noted that NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria concluded that ravulizumab and eculizumab were similarly effective and had a similar safety profile. The ERG considered that it was not possible to be certain from the available evidence that the efficacy of ravulizumab would be the same as eculizumab in the PEGASUS trial population. This is because of key differences between the PEGASUS trial and Study\xa0302 (see section\xa03.5). The committee considered that ravulizumab is a re-engineered form of eculizumab and both technologies are biologically very similar with over 99% homology. It noted that the ERG's clinical experts considered that the efficacy of both treatments is likely to be equal in any population. Therefore, the committee concluded that the company's assumption of equal efficacy between ravulizumab and eculizumab in the PEGASUS trial population was reasonable.\n\n# Cost effectiveness\n\n## The company's model is suitable for decision making\n\nThe company presented a cohort-level state transition model that reflected the evidence available from the PEGASUS trial and included 4\xa0health states:\n\nno transfusions needed and a haemoglobin level of less than 105\xa0g/litre\n\nno transfusions needed and a haemoglobin level of 105\xa0g/litre or more\n\ntransfusions needed\n\ndeath.Spontaneous remission was not modelled because the company considered that this would not be expected to vary by treatment. The company's clinical experts considered that extravascular breakthrough haemolysis results in a drop in haemoglobin level and blood transfusions, both of which are captured in the model health states. The model included a 4‑week cycle length with half-cycle correction, and outcomes were assessed over a lifetime time horizon. The committee noted that the company's model structure was different to the model presented in NICE's technology appraisal guidance on ravulizumab for treating paroxysmal nocturnal haemoglobinuria, which had 8\xa0states, based on breakthrough haemolysis in addition to a spontaneous remission and death state. It understood that the company considered that the ravulizumab model was not appropriate for capturing the benefits associated with pegcetacoplan, such as preventing extravascular haemolysis or improving fatigue. The committee discussed the company's summary of product characteristics for pegcetacoplan, which indicated that for the first 4\xa0weeks of treatment, pegcetacoplan should be given in addition to a person's current dose of C5\xa0inhibitor treatment. This is to reduce the risk of haemolysis from abruptly stopping treatment with either eculizumab or ravulizumab. It noted that the company's model assumed that there was no overlap of treatments and people started taking pegcetacoplan on its own without a concurrent C5 inhibitor. This was because the company's model had included data from the randomised controlled period, in which patients had either pegcetacoplan or eculizumab, and not the run-in period in which both treatments were given (see section\xa03.3). The company explained that, since the trial, it had consulted with clinical experts who considered that such an overlap of treatments would not likely happen in clinical practice. This is because people who switch from eculizumab or ravulizumab to pegcetacoplan will still experience an ongoing effect of C5 inhibition after stopping treatment and so having treatments concurrently is not needed. The committee considered that the company's assumption was reasonable and reflected how pegcetacoplan would likely be used in NHS clinical practice. It noted that the ERG considered that the company's model was well built, and the model structure reflects the PNH treatment pathway with 2\xa0minor exceptions. The ERG considered that the proportion of people having a C5 inhibitor who were having chelation therapies at baseline in the model should be based on the PEGASUS clinical study report rather than the trial run-in period, as used in the company's base case. It also considered that the application of half-cycle corrections should start from cycle\xa01 rather than cycle\xa00 as in the company's model, but that implementing this change would have a negligible effect on the cost-effectiveness results. The committee considered the ERG's critique and that the company's model structure was validated by the company's advisory board. It concluded that the company's model was suitable for decision making.\n\n## Pegcetacoplan is recommended as a cost-effective use of NHS resources\n\nThe committee considered the ERG's preferred modelling assumptions that included 2\xa0minor revisions to the company's base case:\n\nusing chelation therapy proportions from the PEGASUS clinical study report (see section\xa03.7)\n\nincluding adverse event costs.Using the confidential discounts for pegcetacoplan and ravulizumab, pegcetacoplan was more effective and less costly compared with both eculizumab and ravulizumab in the company and ERG base cases and in all scenario analyses presented by the company and ERG. Exact results are confidential and cannot be reported here. The committee noted that the total modelled costs were the least expensive for pegcetacoplan, partly because it is self-administered and reduces the need for blood transfusions. The committee concluded that pegcetacoplan, when compared with eculizumab and ravulizumab, was a cost-effective use of NHS resources. It therefore recommended pegcetacoplan as an option for treating PNH in adults.\n\n# Other factors\n\n## There are no equality issues relevant to the recommendations\n\nThe committee discussed the potential equality issues raised during scoping. It noted stakeholder comments that pegcetacoplan is given by a subcutaneous infusion and can be self-administered at home. This may have implications for people with physical or learning disabilities, particularly if they have manual dexterity issues. The company explained that if pegcetacoplan was recommended by the committee, it would provide a patient support programme that would identify and support people who may need additional help to take their subcutaneous infusions at home. The committee considered that this would help to reduce inequalities in access to pegcetacoplan treatment because of its method of administration. It noted stakeholder comments that age and pregnancy are protected characteristics and inequalities may arise if different recommendations are made for children and pregnant women. The committee discussed that children and pregnant women were excluded from the PEGASUS trial. It noted a comment from a clinical expert submission that pegcetacoplan should not be used in pregnancy. The committee considered the pegcetacoplan indication is currently limited to adults and it can only recommend a treatment within its marketing authorisation. The committee concluded that there were no equality issues relevant to the recommendations.\n\n## The benefits of pegcetacoplan are captured in the cost-effectiveness analysis\n\nThe company considers pegcetacoplan to be innovative because it prevents both intravascular and extravascular haemolysis by targeting the complement cascade earlier than C5 inhibitors. The committee agreed that these are important benefits and recognised that pegcetacoplan will be the first C3 inhibitor licensed for PNH. It recalled patient expert statements highlighting that treatment with eculizumab and ravulizumab can be inconvenient for some people because of frequent cannulation and because a healthcare professional is needed to administer the intravenous infusion at a person's home. The committee recognised that pegcetacoplan is available as a subcutaneous infusion that can be self-administered and that this may offer benefits for some people compared with current treatments. However, it recalled patient expert statements that because pegcetacoplan is administered more frequently than existing treatments, it may be less convenient for other people. The committee considered that these potential advantages and disadvantages associated with pegcetacoplan's administration may have already been captured in the company's model. This is because the company modelled a disutility for eculizumab to reflect that it has more regular dosing than ravulizumab, and that it is an intravenous infusion whereas pegcetacoplan is a subcutaneous infusion. It assumed no disutility for ravulizumab and pegcetacoplan because they were both assumed to reduce the burden of administration compared with eculizumab. The committee concluded that the benefits of pegcetacoplan are captured in the cost-effectiveness analysis."}
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https://www.nice.org.uk/guidance/ta778
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Evidence-based recommendations on pegcetacoplan (Aspaveli) for treating paroxysmal nocturnal haemoglobinuria in adults who have anaemia after at least 3 months of treatment with a C5 inhibitor.
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37178a231cc9aec4e1888eae190575409c97d0e2
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nice
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Prontosan for treating acute and chronic wounds
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Prontosan for treating acute and chronic wounds
Evidence-based recommendations on Prontosan for treating acute and chronic wounds.
# Recommendations
More research is recommended on Prontosan for treating chronic wounds. There is some evidence that it is clinically effective but not enough to recommend it for routine use. Prontosan is not recommended for treating acute wounds because the evidence is very limited.
Research should be a randomised controlled trial on the effectiveness of Prontosan compared with saline or water in chronic wounds of different types. Wounds should be followed up until completely healed, and time to healing should be measured. Find out more details in further research.
Why the committee made these recommendations
Care of acute or chronic wounds aims to improve their condition, help with healing and minimise risk of complications. Usually, wounds are cleansed with saline or water.
Prontosan is available in 3 different formats: a solution, a gel, and extra thick gel. The solution is used for rinsing and soaking wounds. It can be used alone or with one of the gels. After soaking, the gel can be applied to the wound and left in place until the next dressing change. It aims to prevent build-up of microbes such as bacteria in the wound to help with healing.
Most of the evidence about Prontosan's effectiveness is not of good quality. It may speed up wound healing and reduce infections compared with saline in chronic wounds, but more evidence is needed to confirm this. There is very little evidence about using Prontosan for treating acute wounds.
Cost analyses suggest that Prontosan is cost saving compared with saline in chronic wounds. But there is not enough good quality evidence about its clinical effectiveness, which limits how reliable the cost analysis is. So, more research is recommended to address the uncertainties.# The technology
# Technology
Prontosan (B Braun) is a range of topical solutions and gels used for cleansing, rinsing and moistening acute and chronic wounds. Prontosan includes:
Prontosan Wound Irrigation Solution, which is used for rinsing wounds or applied to gauze as a soak. It is available as a 350 ml bottle, as 40 ml single-use pods and as a 1,000 ml bottle for instillation.
Prontosan Wound Gel, which is applied to the wound bed after cleansing, during dressing changes and before further dressings are applied. It is available as a 30 ml bottle. It can be used in deep and tunnelling wounds, wound cavities or wounds that are difficult to access.
Prontosan Wound Gel X (extra thick gel), which is applied in the same way as the Wound Gel. It is available as a 50 g or 250 g tube. It can be used in flat wounds or wounds with a large surface area, such as leg ulcers.
Prontosan received a CE mark in February 2009 as a class 3 medical device. The CE mark covers the Prontosan solution and gels.
# Innovative aspects
The solution and gels contain an antimicrobial polyhexanide (0.1% polyhexamethylene biguanide) and a betaine surfactant (0.1% undecylenamidopropyl betaine). Prontosan is the only wound cleansing solution or gel that contains these 2 active ingredients. The company claims they work together to prevent biofilm forming in the wound bed and break it down if it has formed. The company claims that it cleanses and removes slough, devitalised tissue and other wound debris.
# Intended use
Prontosan is intended for cleansing, rinsing or moistening acute and chronic wounds. It can be used by healthcare professionals in community and acute care settings, such as outpatient clinics, hospital inpatient care, GP surgeries, postoperative care and at the patient's home. The company states that brief training may be needed, but this is likely to be unnecessary for staff who are already trained in cleansing wounds with saline or water.
# Costs
Prontosan is available in several forms, quantities and costs:
Prontosan Wound Irrigation Solution: £5.03 for a 350 ml bottle (cost per dressing change £0.57); £0.62 per 40 ml ampoule
Prontosan Wound Gel: £6.71 for 30 ml
Prontosan Wound Gel X: £12.29 for 50 g (cost per dressing change £2.51); £32.89 for 250 g (cost per dressing change £1.34). For more details, see the website for Prontosan.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The main clinical evidence comprises 18 studies
The evidence assessed by the EAC included 18 studies. Seventeen were full-text peer-reviewed publications and 1 was an unpublished study. Of the included studies, 9 were comparative studies (7 randomised controlled trials and 2 observational studies) and 9 were non-comparative observational studies. The comparative evidence included a total of 792 people, of which 415 had Prontosan, 281 had saline, 53 had saline or Ringer's solution, 23 had silver sulfadiazine, and 20 had sterile water. For full details of the clinical evidence, see section 4 of the assessment report in the supporting documentation for this guidance.
## There are weaknesses in the evidence with only 1 study at low risk of bias
The EAC considered the strength of the evidence to be limited, with only 1 randomised controlled trial at low risk of bias. Five randomised controlled trials had some methodological concerns. The remaining studies were considered to be at high risk of bias. Further limitations of the evidence base included the following points:
Most of the included studies had small sample sizes and some of the larger randomised controlled trials were underpowered (meaning they do not have enough people in them to draw meaningful conclusions). However, the EAC noted that larger sample sizes might not be achievable.
Prontosan use varied across the studies. For example, in 3 studies Prontosan solution was used only once, to irrigate the wound. In 4 studies only the gel was used. It was not always used in a way that reflects NHS practice, or in line with the company's instructions for use.
Outcomes were not always clearly reported and similar outcomes were reported differently across different studies. This made it difficult to make comparisons and draw conclusions across the evidence base.
## The evidence for different types of chronic wounds was varied with 3 comparative and 7 non-comparative studies
Ten studies included different subgroups of chronic wounds, for example, venous leg ulcers, vascular ulcers, pressure ulcers, arterial leg ulcers, diabetic foot ulcers, burns, trauma wounds and surgical wounds). These included 2 randomised controlled trials (Bellingeri 2016; Valenzuela 2008), 1 comparative cohort study (Assadian 2018) and 7 non-comparative studies (Atkin 2020; Ricci 2018; Moore 2016; Durante 2014; Moller 2008; Horrocks 2006; Oropallo, 2021). Bellingeri 2016 was at low risk of bias, but the study was underpowered based on its own statistical analysis plan. It was also potentially at risk of selective reporting. Clinical experts advised that Prontosan gel may not be used at every dressing change and depends on the clinical assessment of the wound (For full details of the cost evidence, see section 4.2 of the assessment report in the supporting documentation for this guidance). Valenzuela 2008 used the gel only. Assadian 2018 had a small sample size and had limited applicability to the NHS because only a single application of Prontosan was used. Reported outcomes included wound healing, wound bed condition, wound infection, pain, dressing changes and quality of life.
## There are 4 comparative studies for venous leg ulcers
Four studies were included for venous leg ulcers: 3 randomised controlled trials (Borges 2018; Harding 2012, unpublished; Romanelli 2010) and 1 comparative retrospective analysis (Andriessen 2008). All 3 randomised controlled trials had a small sample size and may have been underpowered. The control group in Andriessen 2008 had either saline or Ringer's solution. The clinical experts advised the EAC that Ringer's solution is not routinely used in the NHS to cleanse venous leg ulcers. Reported outcomes included rate of wound healing, time to wound healing, wound size, wound infection and factors associated with wound infection (bacterial burden and number of microorganisms) and pain.
## There is limited evidence for burn wounds with no NHS comparators
Only 3 studies were included for burns: 1 randomised controlled trial (Wattanaploy 2017) and 2 non-comparative studies (Ciprandi 2018; Kiefer 2018). The sample size in the randomised controlled trial was small, saline was used in both arms, and the comparator was silver sulfadiazine. This was not considered to be standard care in the NHS so was not included in the scope for this guidance as a comparator for Prontosan. However, silver sulfadiazine is indicated for prevention and treatment of infection in burns. Reported outcomes included wound healing, wound infection, pain and treatment satisfaction. No significant differences were found for healing burn wounds and improving wound infection with Prontosan compared with silver sulfadiazine (Wattanaploy 2017).
## There is limited evidence for surgical site wounds
Only 1 study, a randomised controlled trial, was included for surgical site wounds (Saleh 2016). This study had a small sample size, and the comparator was sterile water. The EAC included this study because surgical site wounds were considered relevant to the decision problem. The EAC noted that although the study compared Prontosan with dressings soaked with sterile water, only one dressing was applied after surgery. This treatment approach may have limited applicability to the NHS. The study outcomes included wound infection but not wound healing. The study reported a statistically significant higher rate of infection in the Prontosan group compared with the sterile water group.
## It is not certain if Prontosan has better outcomes than saline
In total, 6 randomised controlled trials and 1 comparative retrospective analysis compared Prontosan with saline. Wound healing was reported in 2 studies (Harding 2012, unpublished; Andriessen 2008), wound size in 3 studies (Romanelli 2010; Valenzuela 2008; Harding 2012, unpublished) and wound condition improvement in 2 studies (Bellingeri 2016; Valenzuela 2008). Of these 4 studies, 2 showed statistical significance in wound improvement (Bellingeri 2016; Valenzuela 2008). Infection rate was reported in 2 studies (Harding 2012, unpublished; Andriessen 2008), bacterial burden in 2 studies (Assadian 2018; Romanelli 2010), bacterial load in 1 study (Borges 2018), inflammation score in 1 study (Bellingeri 2016), and microbiological cultures and redness around the skin (a clinical sign of infection) in 1 study (Valenzuela 2008). Of these 6 studies reporting on wound infection and associated factors, only 3 showed a statistically significant reduction in:
bacterial burden (Romanelli 2010)
inflammation score (change in inflammatory signs; Bellingeri 2016)
microbiological cultures and redness around the skin (Valenzuela 2008).Pain was reported in 4 studies (Bellingeri 2016; Harding 2012, unpublished; Romanelli 2010; Valenzuela 2008). Only 1 study found a significant reduction in pain when using Prontosan (Romanelli 2010). The EAC concluded that Prontosan appeared to be effective for some clinical parameters in chronic wounds, but there is not enough good quality comparative evidence with saline.
## Prontosan is safe and easy to use
Prontosan is safe, provided clinical staff are aware of the contraindications outlined in the instructions for use. Adverse events are rare and easily managed. The products are easy to use and the clinical experts said that minimal training is needed. Training resources are available from the company.
# Cost evidence
## The company's cost modelling finds Prontosan to be cost saving
The company submitted 2 de novo cost analyses with different model structures. One used a Markov model (wound closure model) that compared costs for Prontosan with saline to treat venous leg ulcers until full wound closure. The time horizon was 1 year. The clinical experts advised the EAC that when using Prontosan, wounds healed within a year. The company provided 2 alternative data sets for rate of wound healing for this model (Andriessen 2008 and Harding 2012, unpublished). The other model was a simple cost model (wound bed preparation model) that compared costs for Prontosan with saline to treat chronic wounds (for example, leg ulcers and pressure ulcers) until the wound bed is fully granulated. This means that there are visible signs that the wound is healing. The time horizon used was the time to reach a Bates-Jensen wound assessment tool (BWAT) score of 14. The BWAT score is a clinical tool used for scoring wound healing. The time taken to reach a score of 14 was 4.1 weeks for Prontosan and 11.3 weeks for saline (Bellingeri 2016). The company reported base-case cost savings per person with Prontosan of £1,118.26 and £1,188.47 for the wound closure model (with data from Andriessen 2008 and Harding 2012, unpublished, respectively) and £1,134.40 for the wound bed preparation model. The key drivers for cost savings in both models included reduced:
time to healing or time to wound bed improvement
costs of healthcare visits
time in infected state. For full details of the cost evidence, see section 9 of the assessment report in the supporting documentation for this guidance.
## The EAC agrees with the company's cost models but the key limitation is that the clinical evidence is uncertain
The EAC agreed with the structure of both of the company's models and its assumptions and made minor alterations to the costs and resource use. This had little impact on the cost savings (for full details see section 9 of the assessment report in the supporting documentation for this guidance). The EAC noted that the inputs for wound healing and infection rates in the wound closure model were uncertain, as were the inputs for wound bed improvement in the wound bed preparation model. The EAC acknowledged uncertainty in the cost modelling but noted that the approach was conservative. It made the following comments:
Andriessen (2008) is a retrospective comparative case series of 112 patients with venous leg ulcers with a follow-up time of 6 months. The EAC considered that Andriessen 2008 was a suitable data source because of the larger number of patients and longer follow up. However, the study was at high risk of bias because of potential selection and reporting bias.
Harding (2012) is a small, unpublished, UK pilot randomised controlled trial with 34 patients. The shorter follow-up period of 12 weeks meant that there was greater reliance on extrapolation for the calculation of transition probabilities for wound healing. There were some concerns about the randomisation process.
Bellingeri (2016) is a randomised controlled trial of 289 patients with pressure ulcers or vascular leg ulcers at low risk of bias. The follow up was 28 days, and wounds were assessed using the BWAT score. The company used an Excel trendline to extend the graphs to reach a mean BWAT score for both arms. However, there were concerns about the data. The study seemed to use only 8 out of the 13 dimensions of the BWAT. This meant the overall score was not on a scale of 13 to 65, but on a scale of 8 to 40. As a result, the EAC could not be confident that a reported BWAT score of 13 or 14 in Bellingeri (2018) accurately corresponded to a wound approaching healing or one that has healed. However, no improved data source has been identified.
## The EAC base case uses the wound closure model with inputs from Andriessen 2008 and estimates a cost saving of £951 per person
The EAC considered that the wound closure model with clinical inputs from Andriessen 2008 was the most appropriate base case. It concluded that Andriessen 2008 was the most suitable data source and provided the most robust estimates for wound improvement, deterioration and recurrence that reflected the clinical reality of treating chronic wounds. This model estimated a cost saving from the use of Prontosan compared with saline of £951 per patient over a time horizon of 1 year.# Committee discussion
# Clinical effectiveness overview
## Prontosan shows promise but there is not enough evidence of its clinical benefit
The committee noted that much of the evidence comparing Prontosan and saline in treating chronic wounds had some concerns or was at high risk of bias. The committee noted that there was very limited evidence for acute wounds. The committee agreed that the technology showed promise based on clinical expert advice, but that this was not supported by the evidence. The committee concluded that there was not enough good quality evidence to make a clear judgement about the benefits of Prontosan compared with saline or water.
## The evidence is heterogeneous in terms of wound type
The committee noted that the patient populations in the evidence were heterogeneous, including different wound types such as venous leg ulcers, chronic wounds of mixed aetiology, burns and surgical site wounds. The clinical experts agreed that Prontosan could be used for a broad patient population. Some experts suggested that chronic wound management approaches are likely to be similar in the basic principles of dressing management, despite differences in the underlying causes and treatment. Nevertheless, the committee understood that there is a diversity of wound types in the chronic wound population and that it is difficult to generalise the evidence from the trials to the total population with chronic wounds. Ideally, further evidence is needed to detect clinically meaningful results in specific wound types (for example, pressure ulcers or venous leg ulcers).
## How Prontosan products are used in the studies varies but this is likely to reflect NHS practice
The committee noted that how Prontosan products were used ranged across the studies. Prontosan solution was used alone, with the gel or gel X, or the gel or gel X were used alone. The clinical experts agreed that the choice of Prontosan product used depends on the wound and the person's situation. The clinical experts said that the Prontosan solution is used as a soak for chronic wounds. Soak times can vary between 5 and 15 minutes depending on the wound condition and size. Guidelines recommend using cleansing solutions such as Prontosan during dressing changes. For example, during consultation, the committee was made aware of the National Association of Tissue Viability Nurse Specialists (Scotland) wound cleansing pathway which recommends: 'if the wound is chronic, infected, have debris or residual dressing in place OR if the patient is at high risk of wound infection, consider using a biofilm disrupting cleansing solution'. The committee also noted that the National Wound Care Strategy Programme's lower limb recommendations recommend cleansing the wound bed at each dressing change. The clinical experts noted that the gel is used less often, and almost always in combination with the solution to support and maintain the soak process. The clinical experts said the gel is most often used for more complex and chronic wounds and for people with a history of recurrent infections. The clinical experts agreed that both the solution and gel have the same ingredients and should be considered the same product. The committee recognised the heterogeneity in the way the Prontosan products were used but concluded there may also be differing approaches used in the NHS.
## Prontosan has plausible benefits
The clinical experts noted that, in their experience, using Prontosan on static (non-healing) chronic wounds with a dull brown colour causes the wound bed to change to vibrant red granulated tissue (tissue in the process of healing). No adverse events or allergic or instant reactions to Prontosan were observed by the clinical experts. The clinical experts said that Prontosan is easy to use, soothing and does not sting. The committee recognised that patient reported outcomes such as pain and odour are important considerations when treating chronic and acute wounds and concluded that Prontosan has plausible benefits.
# Outcome measures
## Complete wound healing is the preferred outcome
The clinical experts said that they would use Prontosan when clinically indicated, typically until the wound bed was completely clean and looking healthy and epithelised (when a layer of new tissue forms over the wound). The clinical experts clarified that wounds can epithelialise and close, but this does not mean the wound is healed. For people with a history of recurrent infection, the wound can break down again if treatment is stopped before the wound is healed. Some types of chronic wounds, specifically leg ulcers, often deteriorate and recur. To measure Prontosan's effectiveness compared with saline, the committee concluded that evidence is needed that follows wounds until they are completely healed. This evidence should also measure the time it takes for complete healing to happen.
## Improved wound bed condition is an important outcome
Chronic wounds can be complex and may become static or have high levels of recurrence. The clinical experts noted that some people have wounds for several years and some may never heal. The experts agreed that improved wound bed condition is an important outcome. Wounds move through different stages of healing. Unless the wound bed is prepared through debridement, removing slough and clearing biofilm, the wound becomes stagnant and cannot heal. Improving wound bed condition has the potential to improve quality of life because it may reduce odour, exudate, pain or result in fewer dressing changes. The clinical experts noted that it is difficult to robustly measure wound improvement. However, validated quality of life tools should capture aspects of wound improvement. The committee considered that improved wound bed condition has an important place in wound care, particularly for some people who have long-term chronic wounds that do not heal within 12 months.
## Uncertainties in the reporting of the BWAT score from Bellingeri 2016
The most robust evidence (a randomised controlled trial by Bellingeri 2016) was at low risk of bias but underpowered based on the statistical analysis plan. It showed a significant reduction in Bates-Jensen wound assessment tool (BWAT) score for Prontosan compared with saline. The external assessment centre noted that it is unclear from the study whether all 13 dimensions of the tool were used. It was not confident that a reported BWAT score of 13 or 14 in this paper can be interpreted as wounds that have healed, or that are approaching healing.
# Relevance to the NHS
## The evidence from Bellingeri 2016 may be generalisable to NHS practice
The clinical experts said that they had not used the BWAT score in NHS practice. However, they agreed that it is a comprehensive wound assessment tool. They said most of the factors in the BWAT, including state of wound bed, wound size, sign of infection, pain, exudate and type of dressing, are part of wound assessment tools used in the NHS. However, clinical experts also noted that there are no universally agreed wound assessment tools. The committee concluded that the BWAT is likely to reflect clinical assessments of wounds and may be generalisable to other wound assessment tools used in the NHS.
# NHS considerations overview
## Prontosan does not add to the appointment time if the soak is applied at the start of the appointment
The clinical experts told the committee that Prontosan solution is often applied as a soak (for 10 to 15 minutes) for chronic wounds. The experts noted that this can lead to an increase in appointment times in some cases (primarily wound clinics) but that if the tasks are switched around and the soak is applied at the start of the appointment this should not extend the appointment time. The committee concluded that some education and training may be needed to ensure healthcare professionals know to soak with Prontosan solution at the start of an appointment.
## Prontosan is part of a wound care package, so the treatment effect is hard to establish
The committee noted that Prontosan is part of a wound care package and almost uniformly not used on its own. This means it is difficult to isolate the treatment effect of Prontosan on chronic wounds. The clinical experts stressed the importance of using a locally agreed wound care pathway and explained that treatments are selected using a holistic approach and clinician experience. People with chronic wounds do not necessarily see the same clinician, and use of products and dressings can vary between visits based on what is available. One clinical expert said it would be easier to use one solution consistently rather than decide between multiple solutions (water, saline or Prontosan). Examples of local wound care pathways where Prontosan had been implemented were provided during consultation. The committee concluded that it is hard to isolate the direct effect of Prontosan and recognised the need for an appropriate wound care pathway for chronic wounds.
# Cost modelling overview
## The cost models are acceptable but any cost modelling using the available evidence is likely to be flawed
The committee agreed that the clinical and cost case were dependent on each other. Prontosan would result in cost savings even if there was only a small benefit in healing rate or reduction in infection rate. The clinical inputs in the model had some concerns or were at high risk of bias. They were also subject to the same uncertainty as discussed in the clinical evidence section. The committee concluded that more research was needed to establish the clinical and cost benefits of using Prontosan in the NHS. Until then, any cost modelling is likely to be flawed.
# Further research
## Randomised controlled trials comparing Prontosan with saline or water in the NHS are needed
The committee concluded that further research is needed to address the uncertainties about the clinical effectiveness of Prontosan compared with saline or water. It recommended that randomised controlled trials should be done in the NHS. These should compare Prontosan with saline or water in different types of chronic wounds. The randomised controlled trial needs to be well designed to detect clinically meaningful results in subgroups (for example, pressure ulcers or venous leg ulcers). The committee agreed that a key outcome should be time to complete wound healing. The number of dressing changes should also be recorded for each wound included in the study. Other important outcomes should include pain and wound odour, measured using patient-reported outcome measures (PROMs).
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{'Recommendations': "More research is recommended on Prontosan for treating chronic wounds. There is some evidence that it is clinically effective but not enough to recommend it for routine use. Prontosan is not recommended for treating acute wounds because the evidence is very limited.\n\nResearch should be a randomised controlled trial on the effectiveness of Prontosan compared with saline or water in chronic wounds of different types. Wounds should be followed up until completely healed, and time to healing should be measured. Find out more details in further research.\n\nWhy the committee made these recommendations\n\nCare of acute or chronic wounds aims to improve their condition, help with healing and minimise risk of complications. Usually, wounds are cleansed with saline or water.\n\nProntosan is available in 3 different formats: a solution, a gel, and extra thick gel. The solution is used for rinsing and soaking wounds. It can be used alone or with one of the gels. After soaking, the gel can be applied to the wound and left in place until the next dressing change. It aims to prevent build-up of microbes such as bacteria in the wound to help with healing.\n\nMost of the evidence about Prontosan's effectiveness is not of good quality. It may speed up wound healing and reduce infections compared with saline in chronic wounds, but more evidence is needed to confirm this. There is very little evidence about using Prontosan for treating acute wounds.\n\nCost analyses suggest that Prontosan is cost saving compared with saline in chronic wounds. But there is not enough good quality evidence about its clinical effectiveness, which limits how reliable the cost analysis is. So, more research is recommended to address the uncertainties.", 'The technology': "# Technology\n\nProntosan (B\xa0Braun) is a range of topical solutions and gels used for cleansing, rinsing and moistening acute and chronic wounds. Prontosan includes:\n\nProntosan Wound Irrigation Solution, which is used for rinsing wounds or applied to gauze as a soak. It is available as a 350\xa0ml bottle, as 40\xa0ml single-use pods and as a 1,000\xa0ml bottle for instillation.\n\nProntosan Wound Gel, which is applied to the wound bed after cleansing, during dressing changes and before further dressings are applied. It is available as a 30\xa0ml bottle. It can be used in deep and tunnelling wounds, wound cavities or wounds that are difficult to access.\n\nProntosan Wound Gel\xa0X (extra thick gel), which is applied in the same way as the Wound Gel. It is available as a 50\xa0g or 250\xa0g tube. It can be used in flat wounds or wounds with a large surface area, such as leg ulcers.\n\nProntosan received a CE mark in February 2009 as a class\xa03 medical device. The CE mark covers the Prontosan solution and gels.\n\n# Innovative aspects\n\nThe solution and gels contain an antimicrobial polyhexanide (0.1%\xa0polyhexamethylene biguanide) and a betaine surfactant (0.1%\xa0undecylenamidopropyl betaine). Prontosan is the only wound cleansing solution or gel that contains these 2\xa0active ingredients. The company claims they work together to prevent biofilm forming in the wound bed and break it down if it has formed. The company claims that it cleanses and removes slough, devitalised tissue and other wound debris.\n\n# Intended use\n\nProntosan is intended for cleansing, rinsing or moistening acute and chronic wounds. It can be used by healthcare professionals in community and acute care settings, such as outpatient clinics, hospital inpatient care, GP surgeries, postoperative care and at the patient's home. The company states that brief training may be needed, but this is likely to be unnecessary for staff who are already trained in cleansing wounds with saline or water.\n\n# Costs\n\nProntosan is available in several forms, quantities and costs:\n\nProntosan Wound Irrigation Solution: £5.03 for a 350\xa0ml bottle (cost per dressing change £0.57); £0.62 per 40\xa0ml ampoule\n\nProntosan Wound Gel: £6.71 for 30\xa0ml\n\nProntosan Wound Gel X: £12.29 for 50\xa0g (cost per dressing change £2.51); £32.89 for 250\xa0g (cost per dressing change £1.34). For more details, see the website for Prontosan.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 18 studies\n\nThe evidence assessed by the EAC included 18\xa0studies. Seventeen were full-text peer-reviewed publications and 1 was an unpublished study. Of the included studies, 9 were comparative studies (7\xa0randomised controlled trials and 2\xa0observational studies) and 9 were non-comparative observational studies. The comparative evidence included a total of 792\xa0people, of which 415 had Prontosan, 281 had saline, 53 had saline or Ringer's solution, 23 had silver sulfadiazine, and 20 had sterile water. For full details of the clinical evidence, see section 4 of the assessment report in the supporting documentation for this guidance.\n\n## There are weaknesses in the evidence with only 1 study at low risk of bias\n\nThe EAC considered the strength of the evidence to be limited, with only 1\xa0randomised controlled trial at low risk of bias. Five randomised controlled trials had some methodological concerns. The remaining studies were considered to be at high risk of bias. Further limitations of the evidence base included the following points:\n\nMost of the included studies had small sample sizes and some of the larger randomised controlled trials were underpowered (meaning they do not have enough people in them to draw meaningful conclusions). However, the EAC noted that larger sample sizes might not be achievable.\n\nProntosan use varied across the studies. For example, in 3\xa0studies Prontosan solution was used only once, to irrigate the wound. In 4\xa0studies only the gel was used. It was not always used in a way that reflects NHS practice, or in line with the company's instructions for use.\n\nOutcomes were not always clearly reported and similar outcomes were reported differently across different studies. This made it difficult to make comparisons and draw conclusions across the evidence base.\n\n## The evidence for different types of chronic wounds was varied with 3 comparative and 7 non-comparative studies\n\nTen studies included different subgroups of chronic wounds, for example, venous leg ulcers, vascular ulcers, pressure ulcers, arterial leg ulcers, diabetic foot ulcers, burns, trauma wounds and surgical wounds). These included 2\xa0randomised controlled trials (Bellingeri 2016; Valenzuela 2008), 1\xa0comparative cohort study (Assadian 2018) and 7\xa0non-comparative studies (Atkin 2020; Ricci 2018; Moore 2016; Durante 2014; Moller 2008; Horrocks 2006; Oropallo, 2021). Bellingeri 2016 was at low risk of bias, but the study was underpowered based on its own statistical analysis plan. It was also potentially at risk of selective reporting. Clinical experts advised that Prontosan gel may not be used at every dressing change and depends on the clinical assessment of the wound (For full details of the cost evidence, see section 4.2 of the assessment report in the supporting documentation for this guidance). Valenzuela 2008 used the gel only. Assadian 2018 had a small sample size and had limited applicability to the NHS because only a single application of Prontosan was used. Reported outcomes included wound healing, wound bed condition, wound infection, pain, dressing changes and quality of life.\n\n## There are 4 comparative studies for venous leg ulcers\n\nFour studies were included for venous leg ulcers: 3\xa0randomised controlled trials (Borges 2018; Harding 2012, unpublished; Romanelli 2010) and 1\xa0comparative retrospective analysis (Andriessen 2008). All 3\xa0randomised controlled trials had a small sample size and may have been underpowered. The control group in Andriessen 2008 had either saline or Ringer's solution. The clinical experts advised the EAC that Ringer's solution is not routinely used in the NHS to cleanse venous leg ulcers. Reported outcomes included rate of wound healing, time to wound healing, wound size, wound infection and factors associated with wound infection (bacterial burden and number of microorganisms) and pain.\n\n## There is limited evidence for burn wounds with no NHS comparators\n\nOnly 3\xa0studies were included for burns: 1\xa0randomised controlled trial (Wattanaploy 2017) and 2\xa0non-comparative studies (Ciprandi 2018; Kiefer 2018). The sample size in the randomised controlled trial was small, saline was used in both arms, and the comparator was silver sulfadiazine. This was not considered to be standard care in the NHS so was not included in the scope for this guidance as a comparator for Prontosan. However, silver sulfadiazine is indicated for prevention and treatment of infection in burns. Reported outcomes included wound healing, wound infection, pain and treatment satisfaction. No significant differences were found for healing burn wounds and improving wound infection with Prontosan compared with silver sulfadiazine (Wattanaploy 2017).\n\n## There is limited evidence for surgical site wounds\n\nOnly 1\xa0study, a randomised controlled trial, was included for surgical site wounds (Saleh 2016). This study had a small sample size, and the comparator was sterile water. The EAC included this study because surgical site wounds were considered relevant to the decision problem. The EAC noted that although the study compared Prontosan with dressings soaked with sterile water, only one dressing was applied after surgery. This treatment approach may have limited applicability to the NHS. The study outcomes included wound infection but not wound healing. The study reported a statistically significant higher rate of infection in the Prontosan group compared with the sterile water group.\n\n## It is not certain if Prontosan has better outcomes than saline\n\nIn total, 6\xa0randomised controlled trials and 1\xa0comparative retrospective analysis compared Prontosan with saline. Wound healing was reported in 2\xa0studies (Harding 2012, unpublished; Andriessen 2008), wound size in 3\xa0studies (Romanelli 2010; Valenzuela 2008; Harding 2012, unpublished) and wound condition improvement in 2\xa0studies (Bellingeri 2016; Valenzuela 2008). Of these 4\xa0studies, 2 showed statistical significance in wound improvement (Bellingeri 2016; Valenzuela 2008). Infection rate was reported in 2\xa0studies (Harding 2012, unpublished; Andriessen 2008), bacterial burden in 2\xa0studies (Assadian 2018; Romanelli 2010), bacterial load in 1\xa0study (Borges 2018), inflammation score in 1\xa0study (Bellingeri 2016), and microbiological cultures and redness around the skin (a clinical sign of infection) in 1\xa0study (Valenzuela 2008). Of these 6\xa0studies reporting on wound infection and associated factors, only 3 showed a statistically significant reduction in:\n\nbacterial burden (Romanelli 2010)\n\ninflammation score (change in inflammatory signs; Bellingeri 2016)\n\nmicrobiological cultures and redness around the skin (Valenzuela 2008).Pain was reported in 4\xa0studies (Bellingeri 2016; Harding 2012, unpublished; Romanelli 2010; Valenzuela 2008). Only 1\xa0study found a significant reduction in pain when using Prontosan (Romanelli 2010). The EAC concluded that Prontosan appeared to be effective for some clinical parameters in chronic wounds, but there is not enough good quality comparative evidence with saline.\n\n## Prontosan is safe and easy to use\n\nProntosan is safe, provided clinical staff are aware of the contraindications outlined in the instructions for use. Adverse events are rare and easily managed. The products are easy to use and the clinical experts said that minimal training is needed. Training resources are available from the company.\n\n# Cost evidence\n\n## The company's cost modelling finds Prontosan to be cost saving\n\nThe company submitted 2 de novo cost analyses with different model structures. One used a Markov model (wound closure model) that compared costs for Prontosan with saline to treat venous leg ulcers until full wound closure. The time horizon was 1\xa0year. The clinical experts advised the EAC that when using Prontosan, wounds healed within a year. The company provided 2\xa0alternative data sets for rate of wound healing for this model (Andriessen 2008 and Harding 2012, unpublished). The other model was a simple cost model (wound bed preparation model) that compared costs for Prontosan with saline to treat chronic wounds (for example, leg ulcers and pressure ulcers) until the wound bed is fully granulated. This means that there are visible signs that the wound is healing. The time horizon used was the time to reach a Bates-Jensen wound assessment tool (BWAT) score of 14. The BWAT score is a clinical tool used for scoring wound healing. The time taken to reach a score of 14 was 4.1\xa0weeks for Prontosan and 11.3\xa0weeks for saline (Bellingeri 2016). The company reported base-case cost savings per person with Prontosan of £1,118.26 and £1,188.47 for the wound closure model (with data from Andriessen 2008 and Harding 2012, unpublished, respectively) and £1,134.40 for the wound bed preparation model. The key drivers for cost savings in both models included reduced:\n\ntime to healing or time to wound bed improvement\n\ncosts of healthcare visits\n\ntime in infected state. For full details of the cost evidence, see section 9 of the assessment report in the supporting documentation for this guidance.\n\n## The EAC agrees with the company's cost models but the key limitation is that the clinical evidence is uncertain\n\nThe EAC agreed with the structure of both of the company's models and its assumptions and made minor alterations to the costs and resource use. This had little impact on the cost savings (for full details see section 9 of the assessment report in the supporting documentation for this guidance). The EAC noted that the inputs for wound healing and infection rates in the wound closure model were uncertain, as were the inputs for wound bed improvement in the wound bed preparation model. The EAC acknowledged uncertainty in the cost modelling but noted that the approach was conservative. It made the following comments:\n\nAndriessen (2008) is a retrospective comparative case series of 112\xa0patients with venous leg ulcers with a follow-up time of 6\xa0months. The EAC considered that Andriessen 2008 was a suitable data source because of the larger number of patients and longer follow up. However, the study was at high risk of bias because of potential selection and reporting bias.\n\nHarding (2012) is a small, unpublished, UK pilot randomised controlled trial with 34\xa0patients. The shorter follow-up period of 12\xa0weeks meant that there was greater reliance on extrapolation for the calculation of transition probabilities for wound healing. There were some concerns about the randomisation process.\n\nBellingeri (2016) is a randomised controlled trial of 289\xa0patients with pressure ulcers or vascular leg ulcers at low risk of bias. The follow up was 28\xa0days, and wounds were assessed using the BWAT score. The company used an Excel trendline to extend the graphs to reach a mean BWAT score for both arms. However, there were concerns about the data. The study seemed to use only 8 out of the 13\xa0dimensions of the BWAT. This meant the overall score was not on a scale of 13 to 65, but on a scale of 8 to 40. As a result, the EAC could not be confident that a reported BWAT score of 13 or 14 in Bellingeri (2018) accurately corresponded to a wound approaching healing or one that has healed. However, no improved data source has been identified.\n\n## The EAC base case uses the wound closure model with inputs from Andriessen 2008 and estimates a cost saving of £951 per person\n\nThe EAC considered that the wound closure model with clinical inputs from Andriessen 2008 was the most appropriate base case. It concluded that Andriessen 2008 was the most suitable data source and provided the most robust estimates for wound improvement, deterioration and recurrence that reflected the clinical reality of treating chronic wounds. This model estimated a cost saving from the use of Prontosan compared with saline of £951 per patient over a time horizon of 1\xa0year.", 'Committee discussion': "# Clinical effectiveness overview\n\n## Prontosan shows promise but there is not enough evidence of its clinical benefit\n\nThe committee noted that much of the evidence comparing Prontosan and saline in treating chronic wounds had some concerns or was at high risk of bias. The committee noted that there was very limited evidence for acute wounds. The committee agreed that the technology showed promise based on clinical expert advice, but that this was not supported by the evidence. The committee concluded that there was not enough good quality evidence to make a clear judgement about the benefits of Prontosan compared with saline or water.\n\n## The evidence is heterogeneous in terms of wound type\n\nThe committee noted that the patient populations in the evidence were heterogeneous, including different wound types such as venous leg ulcers, chronic wounds of mixed aetiology, burns and surgical site wounds. The clinical experts agreed that Prontosan could be used for a broad patient population. Some experts suggested that chronic wound management approaches are likely to be similar in the basic principles of dressing management, despite differences in the underlying causes and treatment. Nevertheless, the committee understood that there is a diversity of wound types in the chronic wound population and that it is difficult to generalise the evidence from the trials to the total population with chronic wounds. Ideally, further evidence is needed to detect clinically meaningful results in specific wound types (for example, pressure ulcers or venous leg ulcers).\n\n## How Prontosan products are used in the studies varies but this is likely to reflect NHS practice\n\nThe committee noted that how Prontosan products were used ranged across the studies. Prontosan solution was used alone, with the gel or gel\xa0X, or the gel or gel\xa0X were used alone. The clinical experts agreed that the choice of Prontosan product used depends on the wound and the person's situation. The clinical experts said that the Prontosan solution is used as a soak for chronic wounds. Soak times can vary between 5 and 15\xa0minutes depending on the wound condition and size. Guidelines recommend using cleansing solutions such as Prontosan during dressing changes. For example, during consultation, the committee was made aware of the National Association of Tissue Viability Nurse Specialists (Scotland) wound cleansing pathway which recommends: 'if the wound is chronic, infected, have debris or residual dressing in place OR if the patient is at high risk of wound infection, consider using a biofilm disrupting cleansing solution'. The committee also noted that the National Wound Care Strategy Programme's lower limb recommendations recommend cleansing the wound bed at each dressing change. The clinical experts noted that the gel is used less often, and almost always in combination with the solution to support and maintain the soak process. The clinical experts said the gel is most often used for more complex and chronic wounds and for people with a history of recurrent infections. The clinical experts agreed that both the solution and gel have the same ingredients and should be considered the same product. The committee recognised the heterogeneity in the way the Prontosan products were used but concluded there may also be differing approaches used in the NHS.\n\n## Prontosan has plausible benefits\n\nThe clinical experts noted that, in their experience, using Prontosan on static (non-healing) chronic wounds with a dull brown colour causes the wound bed to change to vibrant red granulated tissue (tissue in the process of healing). No adverse events or allergic or instant reactions to Prontosan were observed by the clinical experts. The clinical experts said that Prontosan is easy to use, soothing and does not sting. The committee recognised that patient reported outcomes such as pain and odour are important considerations when treating chronic and acute wounds and concluded that Prontosan has plausible benefits.\n\n# Outcome measures\n\n## Complete wound healing is the preferred outcome\n\nThe clinical experts said that they would use Prontosan when clinically indicated, typically until the wound bed was completely clean and looking healthy and epithelised (when a layer of new tissue forms over the wound). The clinical experts clarified that wounds can epithelialise and close, but this does not mean the wound is healed. For people with a history of recurrent infection, the wound can break down again if treatment is stopped before the wound is healed. Some types of chronic wounds, specifically leg ulcers, often deteriorate and recur. To measure Prontosan's effectiveness compared with saline, the committee concluded that evidence is needed that follows wounds until they are completely healed. This evidence should also measure the time it takes for complete healing to happen.\n\n## Improved wound bed condition is an important outcome\n\nChronic wounds can be complex and may become static or have high levels of recurrence. The clinical experts noted that some people have wounds for several years and some may never heal. The experts agreed that improved wound bed condition is an important outcome. Wounds move through different stages of healing. Unless the wound bed is prepared through debridement, removing slough and clearing biofilm, the wound becomes stagnant and cannot heal. Improving wound bed condition has the potential to improve quality of life because it may reduce odour, exudate, pain or result in fewer dressing changes. The clinical experts noted that it is difficult to robustly measure wound improvement. However, validated quality of life tools should capture aspects of wound improvement. The committee considered that improved wound bed condition has an important place in wound care, particularly for some people who have long-term chronic wounds that do not heal within 12\xa0months.\n\n## Uncertainties in the reporting of the BWAT score from Bellingeri 2016\n\nThe most robust evidence (a randomised controlled trial by Bellingeri 2016) was at low risk of bias but underpowered based on the statistical analysis plan. It showed a significant reduction in Bates-Jensen wound assessment tool (BWAT) score for Prontosan compared with saline. The external assessment centre noted that it is unclear from the study whether all 13\xa0dimensions of the tool were used. It was not confident that a reported BWAT score of 13 or 14 in this paper can be interpreted as wounds that have healed, or that are approaching healing.\n\n# Relevance to the NHS\n\n## The evidence from Bellingeri 2016 may be generalisable to NHS practice\n\nThe clinical experts said that they had not used the BWAT score in NHS practice. However, they agreed that it is a comprehensive wound assessment tool. They said most of the factors in the BWAT, including state of wound bed, wound size, sign of infection, pain, exudate and type of dressing, are part of wound assessment tools used in the NHS. However, clinical experts also noted that there are no universally agreed wound assessment tools. The committee concluded that the BWAT is likely to reflect clinical assessments of wounds and may be generalisable to other wound assessment tools used in the NHS.\n\n# NHS considerations overview\n\n## Prontosan does not add to the appointment time if the soak is applied at the start of the appointment\n\nThe clinical experts told the committee that Prontosan solution is often applied as a soak (for 10 to 15\xa0minutes) for chronic wounds. The experts noted that this can lead to an increase in appointment times in some cases (primarily wound clinics) but that if the tasks are switched around and the soak is applied at the start of the appointment this should not extend the appointment time. The committee concluded that some education and training may be needed to ensure healthcare professionals know to soak with Prontosan solution at the start of an appointment.\n\n## Prontosan is part of a wound care package, so the treatment effect is hard to establish\n\nThe committee noted that Prontosan is part of a wound care package and almost uniformly not used on its own. This means it is difficult to isolate the treatment effect of Prontosan on chronic wounds. The clinical experts stressed the importance of using a locally agreed wound care pathway and explained that treatments are selected using a holistic approach and clinician experience. People with chronic wounds do not necessarily see the same clinician, and use of products and dressings can vary between visits based on what is available. One clinical expert said it would be easier to use one solution consistently rather than decide between multiple solutions (water, saline or Prontosan). Examples of local wound care pathways where Prontosan had been implemented were provided during consultation. The committee concluded that it is hard to isolate the direct effect of Prontosan and recognised the need for an appropriate wound care pathway for chronic wounds.\n\n# Cost modelling overview\n\n## The cost models are acceptable but any cost modelling using the available evidence is likely to be flawed\n\nThe committee agreed that the clinical and cost case were dependent on each other. Prontosan would result in cost savings even if there was only a small benefit in healing rate or reduction in infection rate. The clinical inputs in the model had some concerns or were at high risk of bias. They were also subject to the same uncertainty as discussed in the clinical evidence section. The committee concluded that more research was needed to establish the clinical and cost benefits of using Prontosan in the NHS. Until then, any cost modelling is likely to be flawed.\n\n# Further research\n\n## Randomised controlled trials comparing Prontosan with saline or water in the NHS are needed\n\nThe committee concluded that further research is needed to address the uncertainties about the clinical effectiveness of Prontosan compared with saline or water. It recommended that randomised controlled trials should be done in the NHS. These should compare Prontosan with saline or water in different types of chronic wounds. The randomised controlled trial needs to be well designed to detect clinically meaningful results in subgroups (for example, pressure ulcers or venous leg ulcers). The committee agreed that a key outcome should be time to complete wound healing. The number of dressing changes should also be recorded for each wound included in the study. Other important outcomes should include pain and wound odour, measured using patient-reported outcome measures (PROMs)."}
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https://www.nice.org.uk/guidance/mtg67
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Evidence-based recommendations on Prontosan for treating acute and chronic wounds.
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a79d9dcd770adf93331742a5dd02f7d9612bd704
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nice
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3C Patch for treating diabetic foot ulcers
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3C Patch for treating diabetic foot ulcers
Evidence-based recommendations on 3C Patch for treating diabetic foot ulcers.
# Recommendations
3C Patch is not recommended as a cost-saving option for diabetic foot ulcers.
Why the committee made these recommendations
Diabetic foot ulcers are treated by reducing pressure on the ulcer, removing damaged tissue, controlling poor blood flow and using dressings, including UrgoStart or other advanced dressings. The 3C Patch system uses a person's own blood to create a biological patch that promotes wound healing. It is intended to be used for diabetic foot ulcers that have not healed after 4 weeks of treatment.
The clinical evidence on ulcers that are not healing shows that using 3C Patch led to more ulcers healing at 20 weeks and faster ulcer healing. However, there were uncertainties around whether the evidence would generalise to current NHS practice because of how and when the treatment would be used. Cost analysis also showed that the clinical benefits seen in the trial are unlikely to lead to cost savings in practice. Therefore, 3C Patch cannot be recommended.# The technology
# Technology
3C Patch is a single-use medical device that is used as part of wound care for foot ulcers in people with diabetes. 3C Patch is used in combination with the 3CP centrifuge. Together the device and the centrifuge are referred to as the 3C Patch system.
The system is used to make an individual, biological patch from a person's own blood. The patch is a disc-shaped layered matrix of fibrin, leukocytes and platelets and acts as a concentrated source of cells, growth factors and signalling molecules, which are thought to promote wound healing.
To make the patch, blood is drawn directly into the 3C Patch device, and then spun for about 20 minutes in the 3CP centrifuge. The centrifuge has optical sensors and uses an automatic prespecified programme that performs all the steps needed to create the patch. The patch is applied directly to the ulcer and kept in place with a non-adhesive primary dressing. A separate secondary dressing can also be used to manage exudate.
# Care pathway
This evaluation focuses on the use of 3C Patch for the treatment of diabetic foot ulcers (DFUs) that are not healing despite standard care. Current care for DFUs (as outlined in NICE's guideline on diabetic foot problems: prevention and management) includes offloading, debridement, control of ischaemia, and use of dressings. It recommends that clinical assessment and patient preference are taken into account when choosing dressings, but healthcare professionals should choose the lowest cost dressing that is likely to achieve the desired results. This could include use of advanced dressings such as UrgoStart (see NICE's medical technologies guidance on UrgoStart for treating diabetic foot ulcers and leg ulcers). NICE's diabetic foot guideline recommends that other treatments like dermal or skin substitutes should only be considered as an adjunct to standard care when healing has not progressed. The guideline also recommends that other treatments, including autologous platelet-rich plasma gel, should only be used as part of a clinical trial.
3C Patch is intended to be applied and replaced every 7 days. The company recommends that 3C Patch should be considered when 4 weeks of treatment with standard care has not reduced the ulcer area by at least 50%. The company suggests 3C Patch treatment should be used for 4 to 6 weeks initially, and up to 20 weeks in total, depending on response to treatment as measured by reduction in ulcer area.
# Innovative aspects
3C Patch is innovative because it uses the person's own blood sample, which is then centrifuged to create a solid patch, with no additional reagents needed from outside the person's body. Immune cells, platelets and growth factors captured in the patch are associated with the processes of tissue repair and the inflammatory response.
# Intended use
3C Patch is indicated for the management of recalcitrant wounds. The scope of this evaluation is limited to its use for the treatment of DFUs that are not healing despite standard wound care. For this population, the intervention is usually delivered in a multidisciplinary diabetic foot clinic. Healthcare professionals involved in delivering the intervention need to be trained on preparing and applying the patch.
# Costs
The 3C Patch kit costs £150 (excluding VAT) and can be used to make 1 patch. Each kit includes the 3C Patch device, needle holder, winged blood sampling set with protector, primary cover dressing (Tricotex), alcohol swab, post-blood-sample adhesive bandage and a ruler with adhesive. The 3CP centrifuge is provided on loan by the company free of charge. Servicing and maintenance of the 3CP centrifuge is also free of charge and the expected lifespan of the centrifuge is at least 7 years. A non-sterile 3CP counterbalance is also needed for balancing the centrifuge.For more details, see the website for 3C Patch.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The main clinical evidence comprises 4 studies, 1 of which is a randomised controlled trial
The EAC assessed 4 studies including 332 people with diabetic foot ulcers (DFUs). One study was a randomised controlled trial (RCT; n=266) and 3 were case series, 1 of which was published as an abstract (the case series included 44, 5 and 17 people). Two further studies identified by the company were not included by the EAC because these were not relevant to the decision problem. For full details of the clinical evidence, see section 3 of the assessment report.
## The RCT was well conducted but some aspects of the design do not reflect NHS practice
The Game et al. (2018) RCT was considered to provide the best available data on the use of 3C Patch in relation to the decision problem. This was because it is a UK-based RCT that included people whose ulcers had a less than 50% reduction in area after 4 weeks of standard care (described as 'hard-to-heal' ulcers by the study authors). The trial also measured clinically relevant outcomes and the EAC judged it to have a low risk of bias. However, the EAC noted some issues with the generalisability of the results to current clinical practice. Expert advice indicated that, following the publication of NICE's medical technologies guidance on UrgoStart for treating diabetic foot ulcers and leg ulcers, UrgoStart has become the standard of care. As the Game et al. study took place between 2013 and 2017, only 1 person had UrgoStart in the run-in period. Other protease modulating dressings (classified by the BNF) were used by 2% of people during the run-in. Additionally, clinical experts had different opinions on whether 3C Patch would be continued if there was an infection and advised that the treatment will be at least temporarily halted to evaluate the infection severity. The EAC noted that 3C Patch treatment was continued while ulcers were infected in the Game et al. trial in most cases, in line with the trial protocol. The EAC concluded that although the trial was well conducted, some aspects of the study design may not reflect NHS practice.
## The company's proposed stopping rule was not used in the RCT
The EAC noted the way the intervention was delivered in the trial did not align to the company's proposed treatment pathway. The company stated that 3C Patch use should be reviewed after 4 to 6 weeks and stopped if adequate progress in healing has not been seen, such as a reduction of 50% or more in ulcer area. This stopping rule was not followed in the clinical trial because everyone in the treatment group had 3C Patch until healing or up to 20 weeks. Clinical experts stated that a 50% ulcer area reduction rule to mark adequate healing progress is not routinely used in practice to judge response to treatment. The EAC considered this an important limitation of the evidence base.
## C Patch increases the proportion of people with complete epithelialisation or healing at 20 weeks in the trial population
RCT evidence (Game et al. 2018) found that 34% of ulcers (45 out of 132) in the intervention group had complete epithelialisation or healing at 20 weeks compared with 22% (29 out of 137) in the standard care group (odds ratio 1.58; 95% confidence interval 1.04 to 2.40; p=0.0235). In the case series, healing rates at 20 weeks were 52% (23 people out of 44) and 61.9% (13 ulcers out of 21; Löndahl et al. 2015 and Katzman et al. 2014, respectively).
## C Patch reduced time to healing and ulcer area at 20 weeks in the trial population
RCT evidence (Game et al. 2018) found that 3C Patch reduced time to healing compared with standard care over 20 weeks (hazard ratio 1.709; 95% CI 1.071 to 2.728; p=0.0246). In the subgroup that had healed at 20 weeks, the median time to healing was 72 days (interquartile range 56 to 103) in the 3C Patch group compared with 84 days (IQR 64 to 98) in the standard care group (difference 12 days; p=0.0343). This study also found a statistically significant decrease in ulcer area over a 20‑week period in the 3C Patch group (p=0.0168).
## Evidence does not support 3C Patch reducing the risk of amputation or ulcer infection and direct clinical evidence for the other company-claimed benefits is limited
Game et al. (2018) found no significant difference in those with a new infection within 20 weeks, visits reporting infection (as a proportion of total visits) or total days of antibiotic therapy. The study also found no significant difference in new minor or major amputations affecting the index or contralateral limb. However, the study was not powered to detect differences in these parameters. The EAC further noted that although there was a reduced time to healing seen, no data on the demand for care across NHS settings (outpatient, community, primary and inpatient) were presented. Any improvement in quality of life was uncertain as these measures were only reported in an abstract for a small subgroup of people (10 people in the 3C Patch group and 8 people in the standard care group, all with ulcers extending into tendons; Löndahl et al. 2019).
# Cost evidence
## The company's cost model uses a Markov model comparing 3C Patch with standard care in those with hard-to-heal DFUs
A Markov model was used to estimate costs and quality-adjusted life years associated with the use of 3C Patch plus standard care compared with standard care alone. It took into account the impact of each treatment option on the likelihood of healing, re-ulceration, major amputation, minor amputation and death over a 2‑year time horizon. The population included in the model were those with hard-to-heal DFUs, which aligned with the population included in Game et al. (2018). For full details of the cost evidence, see section 4 of the assessment report.
## The company's cost model uses a stopping rule for 3C Patch treatment and makes use of data from an unplanned post-hoc analysis of the trial
The company's model included a number of assumptions that reflect the company's proposed use of 3C Patch within the DFU treatment pathway. It incorporated an assumption that 3C Patch use would be stopped if an ulcer has not reduced in area by 50% or more within 5 weeks of treatment. This stopping rule was not used in the Game et al. (2018) trial, so the company did an unplanned post-hoc analysis of the trial data to generate the following clinical inputs:
the proportion of people who would stop 3C Patch treatment at 5 weeks (57.9%)
healing rates with 3C Patch at weeks 0 to 5, weeks 6 to 20 and week 21 onwards
healing rates for people who would stop using 3C Patch after week 5 if a stopping rule had been applied.
## The company's model structure is appropriate, but the EAC created a second model to consider a 'moderate or severe' infection state
The EAC judged the overall model structure and time horizon to be appropriate. However, it disagreed with some of the key clinical and cost parameters used in the company's model (see sections 3.10 to 3.13). Additionally, in light of the varying clinical expert views on whether 3C Patch use should continue when an ulcer is infected (see section 3.2), the EAC created a second model (model B) that added a 'moderate or severe' infection state. In this state, people with a moderate or severe infection stop using 3C Patch until their ulcer is no longer infected. The company's model did not have a separate infection state as it followed the protocol used in the Game et al. (2018) RCT whereby 3C Patch was not stopped while an ulcer was infected. Instead, the company's model included infections as recorded in the RCT, with their associated impact on costs and healing rates.
## The EAC made changes to the costs used in the company's model
The EAC made amendments to the costs in the base-case model by using resource use data, when possible, from an unpublished economic analysis of the Game et al. (2018) RCT (Farr et al., unpublished). These changes included adjusting the number and length of outpatient visits and adjusting the proportion of people having inpatient procedures. Dressing costs were also changed from BNF to supply chain. Additionally, the EAC made 3 further changes to the cost inputs:
changed relative costs to absolute costs for additional care for dressing changes, done by district nurses, between outpatient consultations (in both arms of the model)
removed the cost of a district nurse to avoid double counting in the EAC model (as the EAC changed the way in which district nurse costs were included in their model when compared with the company's model) for outpatient and community care costs (in both arms of the model)
applied cost of training up front (as opposed to weekly).These changes resulted in almost all costs in the EAC model being updated.
## The EAC revised 3C Patch discontinuation rates in the model
As stated in section 3.7, the company model included a stopping rule applied in the 3C Patch arm, which was implemented at week 5. The EAC noted that in Game et al. (2018), everyone in the treatment arm continued to use 3C Patch until healing or for up to 20 weeks. It also noted that clinical experts stated that the stopping rule used in the company model was unlikely to be implemented in clinical practice. This is because 3C Patch treatment would likely continue if any significant improvement in ulcer size is seen when compared with previous treatments. Therefore, the EAC changed the discontinuation rate to 0% (meaning everyone in the treatment arm would continue 3C Patch until healing or for 20 weeks).
## The EAC revised the healing rates in the model in line with published RCT data and its preferred discontinuation rates
As noted in section 3.7, the healing rates in the company's model were based on an unplanned post-hoc analysis of the Game et al. (2018) trial data. The EAC revised these parameters in their model to reflect the healing and discontinuation rates seen in the intention-to-treat population published in the RCT (Game et al.). This was because the post-hoc analysis excluded a substantial amount of the data, particularly for healing at 6 to 20 weeks in the 3C Patch arm. This increased uncertainty in the probabilities of healing used in the model. This was important because the probability of healing with 3C Patch in weeks 6 to 20 was a key driver in the company model and an absolute reduction in healing rate of around 0.6% changed the direction of the company's cost case.
## The EAC's base case suggests that 3C Patch is cost incurring compared with current care
The company's base-case results showed cost savings of £191 per person over 2 years when 3C Patch is used instead of standard care. But, the EAC's base-case results found that 3C Patch is cost incurring compared with standard care. The incurred costs were £1,590 per person over 2 years when modelled without an infection state (model A) and £1,993 when modelled with an infection state (model B).
## The EAC's sensitivity analysis found the cost of index ulcers and discontinuation rate to be the biggest cost drivers
The EAC's sensitivity analysis found that the biggest cost drivers in the economic model were the probability of discontinuing 3C Patch and the cost of ulcer treatment when using 3C Patch, standard care or when 3C Patch is discontinued and replaced with standard care. The EAC did a 2‑way sensitivity analysis to explore the impact of varying the probability of discontinuing 3C Patch and the probability of healing with 3C Patch in weeks 6 to 20 simultaneously. The EAC recognised that there is likely to be interaction between these variables. The results suggested that if there is no discontinuation of treatment at 5 weeks (0% discontinuation rate), and weekly healing rates after week 5 are over 4.5%, then 3C Patch would be cost saving. However, this healing rate is significantly higher than the rate used in the EAC base case (2.7%), which was aligned with the Game et al. (2018) RCT.# Committee discussion
# Clinical-effectiveness overview
## The committee recognised that there is an unmet need for new treatments for hard-to-heal diabetic foot ulcers and that 3C Patch is biologically plausible
The committee acknowledged that there is biological plausibility in the device's mechanism of action. This is because the device separates and concentrates autologous blood components associated with tissue healing, including platelets, growth factors and immune cells involved in the inflammatory response. It is feasible that the components forming the biological patch could promote ulcer healing. The committee also acknowledged that hard-to-heal diabetic foot ulcers (DFUs) can reduce quality of life. It stated that there is an unmet need for new treatments for these ulcers and recognised that not all treatments will work for all ulcers. The committee was concerned that the treatment program, with weekly appointments and blood draws, would be difficult to follow for some people. Clinical and patient experts stated that the 3C Patch treatment program would likely be adhered to if progress is seen. This is because those who are likely to be considered for 3C Patch already have ulcers that are not healing despite standard care and have become chronic. However, it was still appreciated that weekly visits to secondary care could be challenging for some people because of difficulties with transportation or regularly taking time off work. The committee acknowledged that for some people, 3C Patch might fulfil an unmet need in DFU care.
## Randomised controlled trial evidence shows improvements in ulcer healing for a proportion of people
The main evidence presented was from a well-conducted randomised controlled trial (RCT) done mostly in the UK. The committee acknowledged the strengths and limitations noted by the external assessment centre (EAC; see sections 3.1 to 3.3). Clinical experts confirmed that the trial population was broadly in keeping with the population of interest. However, they were unsure if the results of the current study would have been different if UrgoStart (see NICE's medical technologies guidance on UrgoStart for treating diabetic foot ulcers and leg ulcers) had been used by everyone in the run-in period. The committee considered the lack of data in an UrgoStart-experienced population to be an important evidence gap. The committee also noted that a sizeable group of people healed with standard care (22% in the RCT at 20 weeks), and clinical experts were not able to identify a subgroup of people who would be unable to heal with standard care but likely to heal with 3C Patch. Overall, the committee accepted that 3C Patch had some beneficial impact relative to other dressings for a proportion of people in the trial population. However, it is not possible to further identify those people most likely to benefit and it remains unclear whether the same impact would be observed if the treatment is used after UrgoStart.
# Other patient benefits or issues
## The use of 3C Patch should be re-evaluated while wounds have an infection
The committee recognised that there was a clinical rationale for discontinuing 3C Patch when infection was present. The company acknowledged that it may be clinically appropriate to stop 3C Patch treatment if there was a moderate or severe infection, but that treatment could continue if the infection was mild. Clinical experts agreed that clinical judgement around 3C Patch treatment continuation is needed when an ulcer becomes infected. The committee concluded that 3C Patch should not be used in those with moderate or severe infections. It also noted that this did not happen in most cases in the RCT, which added uncertainty to the clinical evidence and company cost case.
## Blood sampling and blood disorders could affect appropriateness of 3C Patch treatment
Clinical experts stated that some people with diabetes may struggle to have weekly blood draws, making 3C Patch challenging and potentially distressing. The committee also questioned the suitability of the patch for people with certain blood conditions. The Game et al. (2018) RCT excluded people with platelet counts below 100×109/litre and other clinically significant blood disorders. The committee was concerned that there was no evidence on the impact these conditions could have on patch coagulation, efficacy and the ability to have weekly blood sampling. It also noted that for people on anticoagulation therapy, patch formation may take longer, leading to longer appointment times. Clinical experts stated that weekly blood draws did not seem to lead to anaemia and that patch coagulation could vary independently of blood disorders. The committee concluded that blood sampling and blood disorders should be considered when selecting treatment options, but this should not prevent 3C Patch usage.
# NHS considerations overview
## C Patch could have an impact on service organisation, depending on how they are currently structured
There is variation in the organisation of diabetic footcare services across the NHS. Some clinical experts stated that 3C Patch use could make up a relatively small proportion of their foot clinic referrals. The use of 3C Patch would also have a limited impact on appointment times because the appointments have been structured to accommodate blood taking and centrifugation time. Some centres also have podiatrists and nurses trained in blood taking or have phlebotomists available to help with 3C Patch preparation. Although 3C Patch needs weekly appointments, some clinical experts noted that there are weekly appointments for other care options, especially for those with hard-to-heal ulcers. The committee heard from another expert that when 3C Patch is not currently being used, there may not be the resources available to introduce the service. The committee concluded that in some settings, 3C Patch use may need some reorganisation of services and potentially an increase in use of NHS resources including time, space for equipment and staffing requirements.
# Cost modelling overview
## The stopping rule applied in the 3C Patch arm of the company model is not appropriate
The committee agreed with the EAC that the model structure was generally appropriate, and modelling discontinuation for infection by the inclusion of a moderate or severe infection state was justified based on clinical opinion. It also agreed with the concerns raised by the EAC around the stopping rule used in the 3C Patch arm. The committee recognised that the key concerns were that:
The stopping rule was not used in the Game et al. (2018) RCT and there was no evidence on how this rule would work in practice.
A lack of access to digital wound-measuring tools may make wound area changes more difficult to track.
Clinical experts felt that any notable improvement in healing would justify continuation of the patch and that the 50% rule was difficult to follow in practice.
The use of a strict stopping rule, when progress is being seen but the 50% threshold is not met, could have a negative effect on the physical and mental wellbeing of the patient.Clinical experts stated that they would review ulcer healing at 4 to 6 weeks of treatment and regularly thereafter. They would measure any improvement relative to the rate of healing before 3C Patch use and stop treatment if there was no or limited progress. The company clarified that the 5‑week stopping rule was used as a proxy for discontinuation of 3C Patch at any point within the 20‑week period. It also stated that healing at 5 weeks was a good predictor of healing at 20 weeks, based on analysis of patient-level data. The company suggested that further research could be done, using a Delphi Panel or a Sheffield Elicitation Framework (SHELF) methodology, to inform what stopping rule to use in clinical practice and how long 3C Patch treatment would continue. The EAC confirmed that further clinical evidence collection would be needed alongside this to reduce uncertainty in the economic model after the implementation of the proposed stopping rule. Overall, the committee acknowledged that a stopping rule would be needed in the economic model, but that there was currently no clarity on what the most appropriate rule would be.
## Economic modelling is limited by the available clinical evidence and its relevance to the proposed NHS clinical pathway
The committee recognised the uncertainty in the healing rates used in the company model as outlined by the EAC. This includes the use of unplanned post-hoc analyses when data used was based on 42% of people in the 3C Patch arm (for weeks 6 to 20). It also acknowledged that there was no clinical evidence on the healing rates for those who would stop 3C Patch treatment if a stopping rule had been used in the trial. The committee recognised that the EAC's modelling, based on healing rates in the intention-to-treat population, resulted in very different cost estimates. This highlighted the impact of the uncertainty in the healing rate parameters. It also noted that because the EAC analysis included no discontinuation of treatment at all, it was unlikely to provide a true estimate of the cost impacts of 3C Patch. The committee concluded that the lack of direct clinical trial evidence for the company's proposed treatment pathway is a major limitation of the economic analysis.
## The EAC and company used different data sources in the cost modelling, which changed the direction of the cost case for 3C Patch
The committee heard that EAC changes to the data sources used in the cost modelling meant that the overall cost of 3C Patch was increased by around £800 in the EAC's model A (a model without a separate infection state). The EAC confirmed that although the Farr et al. report was unpublished, it was based on direct trial evidence rather than a more general published study on the cost of DFUs to the NHS in England (Kerr et al. 2019). It was acknowledged that both sources of data had limitations but the EAC's approach using costs from Kerr et al. (2019) with resource use data from Farr et al. (unpublished) was preferred given that it uses direct trial evidence that is most relevant to the population. The committee was concerned that changing the source of the costs for the economic model was sufficient to make 3C Patch cost incurring. It concluded that the EAC changes to the costs further highlighted the uncertainty in the company base case for 3C Patch.
## The company's base case is unstable and 3C Patch is unlikely to be cost saving
The committee acknowledged that the only way to offset the higher upfront costs of 3C Patch treatment was to reduce the resources needed later in the pathway for managing unhealed ulcers and their complications. It acknowledged that the company had presented results that indicated that such savings were possible. But the committee noted that these results were based on a model populated with uncertain clinical and cost inputs that had been questioned by the EAC. The committee also noted that varying the model inputs for treatment discontinuation, healing rates and inpatient and outpatient care costs, within ranges that reflected the uncertainty in the underlying data, led to a change in direction of the cost case for 3C Patch. Further to this, the committee noted that if 3C Patch is discontinued because of an ulcer having a moderate or severe infection, the EAC's model B (which included an additional state to capture moderate or severe infections) may be the most appropriate model structure. It acknowledged that this model led to 3C Patch being more cost incurring. The committee considered that the EAC's 2‑way sensitivity analysis was helpful in demonstrating that there are few combinations of discontinuation and healing rates that can lead to 3C Patch becoming cost saving, with the combinations that were associated with cost savings being less clinically plausible. It also noted that the company model was sensitive to changes in the cost parameters and that using the EAC's costs alone (without adjusting the company's healing and discontinuation rates) also led to 3C Patch becoming cost incurring. The committee concluded that the case for adoption was not supported because the estimated cost-saving case presented by the company was not robust. Large savings in care costs would be needed to offset the cost of 3C Patch and there was insufficient evidence presented to show that care needs would be significantly reduced after 3C Patch treatment.
# Potential research
## Additional research could help address uncertainties in the evidence, although the case for cost savings remains unlikely
Although the committee acknowledged that the Game et al. (2018) RCT was well conducted, it felt that additional research could help resolve some uncertainties around the cost and clinical case for 3C Patch. Specifically, research identifying the most appropriate stopping rule, and the associated clinical outcomes of implementing the rule, would help address key uncertainties within the cost case. Additional collection of resource use data on unhealed hard-to-heal ulcers could also reduce uncertainty in the cost case. Further to this, evidence could be collected on an UrgoStart-experienced population, as this would be reflective of current NHS care. Clinical experts thought a trial on this population would be feasible. The committee concluded that although further research could be done, on balance it was unlikely to result in a cost-saving case for 3C Patch based on the decision problem evaluated in this guidance.
|
{'Recommendations': "3C Patch is not recommended as a cost-saving option for diabetic foot ulcers.\n\nWhy the committee made these recommendations\n\nDiabetic foot ulcers are treated by reducing pressure on the ulcer, removing damaged tissue, controlling poor blood flow and using dressings, including UrgoStart or other advanced dressings. The 3C\xa0Patch system uses a person's own blood to create a biological patch that promotes wound healing. It is intended to be used for diabetic foot ulcers that have not healed after 4\xa0weeks of treatment.\n\nThe clinical evidence on ulcers that are not healing shows that using 3C\xa0Patch led to more ulcers healing at 20\xa0weeks and faster ulcer healing. However, there were uncertainties around whether the evidence would generalise to current NHS practice because of how and when the treatment would be used. Cost analysis also showed that the clinical benefits seen in the trial are unlikely to lead to cost savings in practice. Therefore, 3C\xa0Patch cannot be recommended.", 'The technology': "# Technology\n\n3C\xa0Patch is a single-use medical device that is used as part of wound care for foot ulcers in people with diabetes. 3C\xa0Patch is used in combination with the 3CP centrifuge. Together the device and the centrifuge are referred to as the 3C\xa0Patch system.\n\nThe system is used to make an individual, biological patch from a person's own blood. The patch is a disc-shaped layered matrix of fibrin, leukocytes and platelets and acts as a concentrated source of cells, growth factors and signalling molecules, which are thought to promote wound healing.\n\nTo make the patch, blood is drawn directly into the 3C\xa0Patch device, and then spun for about 20\xa0minutes in the 3CP centrifuge. The centrifuge has optical sensors and uses an automatic prespecified programme that performs all the steps needed to create the patch. The patch is applied directly to the ulcer and kept in place with a non-adhesive primary dressing. A separate secondary dressing can also be used to manage exudate.\n\n# Care pathway\n\nThis evaluation focuses on the use of 3C\xa0Patch for the treatment of diabetic foot ulcers (DFUs) that are not healing despite standard care. Current care for DFUs (as outlined in NICE's guideline on diabetic foot problems: prevention and management) includes offloading, debridement, control of ischaemia, and use of dressings. It recommends that clinical assessment and patient preference are taken into account when choosing dressings, but healthcare professionals should choose the lowest cost dressing that is likely to achieve the desired results. This could include use of advanced dressings such as UrgoStart (see NICE's medical technologies guidance on UrgoStart for treating diabetic foot ulcers and leg ulcers). NICE's diabetic foot guideline recommends that other treatments like dermal or skin substitutes should only be considered as an adjunct to standard care when healing has not progressed. The guideline also recommends that other treatments, including autologous platelet-rich plasma gel, should only be used as part of a clinical trial.\n\n3C\xa0Patch is intended to be applied and replaced every 7\xa0days. The company recommends that 3C\xa0Patch should be considered when 4\xa0weeks of treatment with standard care has not reduced the ulcer area by at least 50%. The company suggests 3C\xa0Patch treatment should be used for 4\xa0to 6\xa0weeks initially, and up to 20\xa0weeks in total, depending on response to treatment as measured by reduction in ulcer area.\n\n# Innovative aspects\n\n3C\xa0Patch is innovative because it uses the person's own blood sample, which is then centrifuged to create a solid patch, with no additional reagents needed from outside the person's body. Immune cells, platelets and growth factors captured in the patch are associated with the processes of tissue repair and the inflammatory response.\n\n# Intended use\n\n3C\xa0Patch is indicated for the management of recalcitrant wounds. The scope of this evaluation is limited to its use for the treatment of DFUs that are not healing despite standard wound care. For this population, the intervention is usually delivered in a multidisciplinary diabetic foot clinic. Healthcare professionals involved in delivering the intervention need to be trained on preparing and applying the patch.\n\n# Costs\n\nThe 3C\xa0Patch kit costs £150 (excluding VAT) and can be used to make 1\xa0patch. Each kit includes the 3C\xa0Patch device, needle holder, winged blood sampling set with protector, primary cover dressing (Tricotex), alcohol swab, post-blood-sample adhesive bandage and a ruler with adhesive. The 3CP centrifuge is provided on loan by the company free of charge. Servicing and maintenance of the 3CP centrifuge is also free of charge and the expected lifespan of the centrifuge is at least 7\xa0years. A non-sterile 3CP counterbalance is also needed for balancing the centrifuge.For more details, see the website for 3C\xa0Patch.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 4\xa0studies, 1 of which is a randomised controlled trial\n\nThe EAC assessed 4\xa0studies including 332\xa0people with diabetic foot ulcers (DFUs). One study was a randomised controlled trial (RCT; n=266) and 3\xa0were case series, 1 of which was published as an abstract (the case series included 44, 5 and 17\xa0people). Two further studies identified by the company were not included by the EAC because these were not relevant to the decision problem. For full details of the clinical evidence, see section\xa03 of the assessment report.\n\n## The RCT was well conducted but some aspects of the design do not reflect NHS practice\n\nThe Game et\xa0al. (2018) RCT was considered to provide the best available data on the use of 3C\xa0Patch in relation to the decision problem. This was because it is a UK-based RCT that included people whose ulcers had a less than 50% reduction in area after 4\xa0weeks of standard care (described as 'hard-to-heal' ulcers by the study authors). The trial also measured clinically relevant outcomes and the EAC judged it to have a low risk of bias. However, the EAC noted some issues with the generalisability of the results to current clinical practice. Expert advice indicated that, following the publication of NICE's medical technologies guidance on UrgoStart for treating diabetic foot ulcers and leg ulcers, UrgoStart has become the standard of care. As the Game et al. study took place between 2013 and 2017, only 1\xa0person had UrgoStart in the run-in period. Other protease modulating dressings (classified by the BNF) were used by 2% of people during the run-in. Additionally, clinical experts had different opinions on whether 3C\xa0Patch would be continued if there was an infection and advised that the treatment will be at least temporarily halted to evaluate the infection severity. The EAC noted that 3C\xa0Patch treatment was continued while ulcers were infected in the Game et al. trial in most cases, in line with the trial protocol. The EAC concluded that although the trial was well conducted, some aspects of the study design may not reflect NHS practice.\n\n## The company's proposed stopping rule was not used in the RCT\n\nThe EAC noted the way the intervention was delivered in the trial did not align to the company's proposed treatment pathway. The company stated that 3C\xa0Patch use should be reviewed after 4\xa0to 6\xa0weeks and stopped if adequate progress in healing has not been seen, such as a reduction of 50% or more in ulcer area. This stopping rule was not followed in the clinical trial because everyone in the treatment group had 3C\xa0Patch until healing or up to 20\xa0weeks. Clinical experts stated that a 50% ulcer area reduction rule to mark adequate healing progress is not routinely used in practice to judge response to treatment. The EAC considered this an important limitation of the evidence base.\n\n## C\xa0Patch increases the proportion of people with complete epithelialisation or healing at 20\xa0weeks in the trial population\n\nRCT evidence (Game et\xa0al. 2018) found that 34% of ulcers (45 out of 132) in the intervention group had complete epithelialisation or healing at 20\xa0weeks compared with 22% (29 out of 137) in the standard care group (odds ratio 1.58; 95% confidence interval [CI] 1.04 to 2.40; p=0.0235). In the case series, healing rates at 20\xa0weeks were 52% (23\xa0people out of 44) and 61.9% (13\xa0ulcers out of 21; Löndahl et al. 2015 and Katzman et al. 2014, respectively).\n\n## C\xa0Patch reduced time to healing and ulcer area at 20\xa0weeks in the trial population\n\nRCT evidence (Game et\xa0al. 2018) found that 3C\xa0Patch reduced time to healing compared with standard care over 20\xa0weeks (hazard ratio 1.709; 95% CI 1.071 to 2.728; p=0.0246). In the subgroup that had healed at 20\xa0weeks, the median time to healing was 72\xa0days (interquartile range [IQR] 56 to 103) in the 3C\xa0Patch group compared with 84\xa0days (IQR 64 to 98) in the standard care group (difference 12\xa0days; p=0.0343). This study also found a statistically significant decrease in ulcer area over a 20‑week period in the 3C\xa0Patch group (p=0.0168).\n\n## Evidence does not support 3C\xa0Patch reducing the risk of amputation or ulcer infection and direct clinical evidence for the other company-claimed benefits is limited\n\nGame et\xa0al. (2018) found no significant difference in those with a new infection within 20\xa0weeks, visits reporting infection (as a proportion of total visits) or total days of antibiotic therapy. The study also found no significant difference in new minor or major amputations affecting the index or contralateral limb. However, the study was not powered to detect differences in these parameters. The EAC further noted that although there was a reduced time to healing seen, no data on the demand for care across NHS settings (outpatient, community, primary and inpatient) were presented. Any improvement in quality of life was uncertain as these measures were only reported in an abstract for a small subgroup of people (10\xa0people in the 3C\xa0Patch group and 8\xa0people in the standard care group, all with ulcers extending into tendons; Löndahl et al. 2019).\n\n# Cost evidence\n\n## The company's cost model uses a Markov model comparing 3C\xa0Patch with standard care in those with hard-to-heal DFUs\n\nA Markov model was used to estimate costs and quality-adjusted life years associated with the use of 3C\xa0Patch plus standard care compared with standard care alone. It took into account the impact of each treatment option on the likelihood of healing, re-ulceration, major amputation, minor amputation and death over a 2‑year time horizon. The population included in the model were those with hard-to-heal DFUs, which aligned with the population included in Game et\xa0al. (2018). For full details of the cost evidence, see section\xa04 of the assessment report.\n\n## The company's cost model uses a stopping rule for 3C\xa0Patch treatment and makes use of data from an unplanned post-hoc analysis of the trial\n\nThe company's model included a number of assumptions that reflect the company's proposed use of 3C\xa0Patch within the DFU treatment pathway. It incorporated an assumption that 3C\xa0Patch use would be stopped if an ulcer has not reduced in area by 50% or more within 5\xa0weeks of treatment. This stopping rule was not used in the Game et\xa0al. (2018) trial, so the company did an unplanned post-hoc analysis of the trial data to generate the following clinical inputs:\n\nthe proportion of people who would stop 3C\xa0Patch treatment at 5\xa0weeks (57.9%)\n\nhealing rates with 3C\xa0Patch at weeks\xa00 to 5, weeks\xa06 to 20 and week\xa021 onwards\n\nhealing rates for people who would stop using 3C\xa0Patch after week\xa05 if a stopping rule had been applied.\n\n## The company's model structure is appropriate, but the EAC created a second model to consider a 'moderate or severe' infection state\n\nThe EAC judged the overall model structure and time horizon to be appropriate. However, it disagreed with some of the key clinical and cost parameters used in the company's model (see sections\xa03.10 to 3.13). Additionally, in light of the varying clinical expert views on whether 3C\xa0Patch use should continue when an ulcer is infected (see section 3.2), the EAC created a second model (model\xa0B) that added a 'moderate or severe' infection state. In this state, people with a moderate or severe infection stop using 3C\xa0Patch until their ulcer is no longer infected. The company's model did not have a separate infection state as it followed the protocol used in the Game et al. (2018) RCT whereby 3C\xa0Patch was not stopped while an ulcer was infected. Instead, the company's model included infections as recorded in the RCT, with their associated impact on costs and healing rates.\n\n## The EAC made changes to the costs used in the company's model\n\nThe EAC made amendments to the costs in the base-case model by using resource use data, when possible, from an unpublished economic analysis of the Game et\xa0al. (2018) RCT (Farr et\xa0al., unpublished). These changes included adjusting the number and length of outpatient visits and adjusting the proportion of people having inpatient procedures. Dressing costs were also changed from BNF to supply chain. Additionally, the EAC made 3\xa0further changes to the cost inputs:\n\nchanged relative costs to absolute costs for additional care for dressing changes, done by district nurses, between outpatient consultations (in both arms of the model)\n\nremoved the cost of a district nurse to avoid double counting in the EAC model (as the EAC changed the way in which district nurse costs were included in their model when compared with the company's model) for outpatient and community care costs (in both arms of the model)\n\napplied cost of training up front (as opposed to weekly).These changes resulted in almost all costs in the EAC model being updated.\n\n## The EAC revised 3C\xa0Patch discontinuation rates in the model\n\nAs stated in section\xa03.7, the company model included a stopping rule applied in the 3C\xa0Patch arm, which was implemented at week\xa05. The EAC noted that in Game et\xa0al. (2018), everyone in the treatment arm continued to use 3C\xa0Patch until healing or for up to 20\xa0weeks. It also noted that clinical experts stated that the stopping rule used in the company model was unlikely to be implemented in clinical practice. This is because 3C\xa0Patch treatment would likely continue if any significant improvement in ulcer size is seen when compared with previous treatments. Therefore, the EAC changed the discontinuation rate to 0% (meaning everyone in the treatment arm would continue 3C\xa0Patch until healing or for 20\xa0weeks).\n\n## The EAC revised the healing rates in the model in line with published RCT data and its preferred discontinuation rates\n\nAs noted in section 3.7, the healing rates in the company's model were based on an unplanned post-hoc analysis of the Game et\xa0al. (2018) trial data. The EAC revised these parameters in their model to reflect the healing and discontinuation rates seen in the intention-to-treat population published in the RCT (Game et\xa0al.). This was because the post-hoc analysis excluded a substantial amount of the data, particularly for healing at 6 to 20\xa0weeks in the 3C\xa0Patch arm. This increased uncertainty in the probabilities of healing used in the model. This was important because the probability of healing with 3C\xa0Patch in weeks\xa06 to 20 was a key driver in the company model and an absolute reduction in healing rate of around 0.6% changed the direction of the company's cost case.\n\n## The EAC's base case suggests that 3C\xa0Patch is cost incurring compared with current care\n\nThe company's base-case results showed cost savings of £191 per person over 2\xa0years when 3C\xa0Patch is used instead of standard care. But, the EAC's base-case results found that 3C\xa0Patch is cost incurring compared with standard care. The incurred costs were £1,590 per person over 2\xa0years when modelled without an infection state (model\xa0A) and £1,993 when modelled with an infection state (model\xa0B).\n\n## The EAC's sensitivity analysis found the cost of index ulcers and discontinuation rate to be the biggest cost drivers\n\nThe EAC's sensitivity analysis found that the biggest cost drivers in the economic model were the probability of discontinuing 3C\xa0Patch and the cost of ulcer treatment when using 3C\xa0Patch, standard care or when 3C\xa0Patch is discontinued and replaced with standard care. The EAC did a 2‑way sensitivity analysis to explore the impact of varying the probability of discontinuing 3C\xa0Patch and the probability of healing with 3C\xa0Patch in weeks\xa06 to 20 simultaneously. The EAC recognised that there is likely to be interaction between these variables. The results suggested that if there is no discontinuation of treatment at 5\xa0weeks (0% discontinuation rate), and weekly healing rates after week\xa05 are over 4.5%, then 3C\xa0Patch would be cost saving. However, this healing rate is significantly higher than the rate used in the EAC base case (2.7%), which was aligned with the Game et al. (2018) RCT.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## The committee recognised that there is an unmet need for new treatments for hard-to-heal diabetic foot ulcers and that 3C\xa0Patch is biologically plausible\n\nThe committee acknowledged that there is biological plausibility in the device's mechanism of action. This is because the device separates and concentrates autologous blood components associated with tissue healing, including platelets, growth factors and immune cells involved in the inflammatory response. It is feasible that the components forming the biological patch could promote ulcer healing. The committee also acknowledged that hard-to-heal diabetic foot ulcers (DFUs) can reduce quality of life. It stated that there is an unmet need for new treatments for these ulcers and recognised that not all treatments will work for all ulcers. The committee was concerned that the treatment program, with weekly appointments and blood draws, would be difficult to follow for some people. Clinical and patient experts stated that the 3C\xa0Patch treatment program would likely be adhered to if progress is seen. This is because those who are likely to be considered for 3C\xa0Patch already have ulcers that are not healing despite standard care and have become chronic. However, it was still appreciated that weekly visits to secondary care could be challenging for some people because of difficulties with transportation or regularly taking time off work. The committee acknowledged that for some people, 3C\xa0Patch might fulfil an unmet need in DFU care.\n\n## Randomised controlled trial evidence shows improvements in ulcer healing for a proportion of people\n\nThe main evidence presented was from a well-conducted randomised controlled trial (RCT) done mostly in the UK. The committee acknowledged the strengths and limitations noted by the external assessment centre (EAC; see sections 3.1 to 3.3). Clinical experts confirmed that the trial population was broadly in keeping with the population of interest. However, they were unsure if the results of the current study would have been different if UrgoStart (see NICE's medical technologies guidance on UrgoStart for treating diabetic foot ulcers and leg ulcers) had been used by everyone in the run-in period. The committee considered the lack of data in an UrgoStart-experienced population to be an important evidence gap. The committee also noted that a sizeable group of people healed with standard care (22% in the RCT at 20\xa0weeks), and clinical experts were not able to identify a subgroup of people who would be unable to heal with standard care but likely to heal with 3C\xa0Patch. Overall, the committee accepted that 3C\xa0Patch had some beneficial impact relative to other dressings for a proportion of people in the trial population. However, it is not possible to further identify those people most likely to benefit and it remains unclear whether the same impact would be observed if the treatment is used after UrgoStart.\n\n# Other patient benefits or issues\n\n## The use of 3C\xa0Patch should be re-evaluated while wounds have an infection\n\nThe committee recognised that there was a clinical rationale for discontinuing 3C\xa0Patch when infection was present. The company acknowledged that it may be clinically appropriate to stop 3C\xa0Patch treatment if there was a moderate or severe infection, but that treatment could continue if the infection was mild. Clinical experts agreed that clinical judgement around 3C\xa0Patch treatment continuation is needed when an ulcer becomes infected. The committee concluded that 3C\xa0Patch should not be used in those with moderate or severe infections. It also noted that this did not happen in most cases in the RCT, which added uncertainty to the clinical evidence and company cost case.\n\n## Blood sampling and blood disorders could affect appropriateness of 3C\xa0Patch treatment\n\nClinical experts stated that some people with diabetes may struggle to have weekly blood draws, making 3C\xa0Patch challenging and potentially distressing. The committee also questioned the suitability of the patch for people with certain blood conditions. The Game et\xa0al. (2018) RCT excluded people with platelet counts below 100×109/litre and other clinically significant blood disorders. The committee was concerned that there was no evidence on the impact these conditions could have on patch coagulation, efficacy and the ability to have weekly blood sampling. It also noted that for people on anticoagulation therapy, patch formation may take longer, leading to longer appointment times. Clinical experts stated that weekly blood draws did not seem to lead to anaemia and that patch coagulation could vary independently of blood disorders. The committee concluded that blood sampling and blood disorders should be considered when selecting treatment options, but this should not prevent 3C\xa0Patch usage.\n\n# NHS considerations overview\n\n## C\xa0Patch could have an impact on service organisation, depending on how they are currently structured\n\nThere is variation in the organisation of diabetic footcare services across the NHS. Some clinical experts stated that 3C\xa0Patch use could make up a relatively small proportion of their foot clinic referrals. The use of 3C\xa0Patch would also have a limited impact on appointment times because the appointments have been structured to accommodate blood taking and centrifugation time. Some centres also have podiatrists and nurses trained in blood taking or have phlebotomists available to help with 3C\xa0Patch preparation. Although 3C\xa0Patch needs weekly appointments, some clinical experts noted that there are weekly appointments for other care options, especially for those with hard-to-heal ulcers. The committee heard from another expert that when 3C\xa0Patch is not currently being used, there may not be the resources available to introduce the service. The committee concluded that in some settings, 3C\xa0Patch use may need some reorganisation of services and potentially an increase in use of NHS resources including time, space for equipment and staffing requirements.\n\n# Cost modelling overview\n\n## The stopping rule applied in the 3C\xa0Patch arm of the company model is not appropriate\n\nThe committee agreed with the EAC that the model structure was generally appropriate, and modelling discontinuation for infection by the inclusion of a moderate or severe infection state was justified based on clinical opinion. It also agreed with the concerns raised by the EAC around the stopping rule used in the 3C\xa0Patch arm. The committee recognised that the key concerns were that:\n\nThe stopping rule was not used in the Game et\xa0al. (2018) RCT and there was no evidence on how this rule would work in practice.\n\nA lack of access to digital wound-measuring tools may make wound area changes more difficult to track.\n\nClinical experts felt that any notable improvement in healing would justify continuation of the patch and that the 50% rule was difficult to follow in practice.\n\nThe use of a strict stopping rule, when progress is being seen but the 50% threshold is not met, could have a negative effect on the physical and mental wellbeing of the patient.Clinical experts stated that they would review ulcer healing at 4\xa0to 6\xa0weeks of treatment and regularly thereafter. They would measure any improvement relative to the rate of healing before 3C\xa0Patch use and stop treatment if there was no or limited progress. The company clarified that the 5‑week stopping rule was used as a proxy for discontinuation of 3C\xa0Patch at any point within the 20‑week period. It also stated that healing at 5\xa0weeks was a good predictor of healing at 20\xa0weeks, based on analysis of patient-level data. The company suggested that further research could be done, using a Delphi Panel or a Sheffield Elicitation Framework (SHELF) methodology, to inform what stopping rule to use in clinical practice and how long 3C\xa0Patch treatment would continue. The EAC confirmed that further clinical evidence collection would be needed alongside this to reduce uncertainty in the economic model after the implementation of the proposed stopping rule. Overall, the committee acknowledged that a stopping rule would be needed in the economic model, but that there was currently no clarity on what the most appropriate rule would be.\n\n## Economic modelling is limited by the available clinical evidence and its relevance to the proposed NHS clinical pathway\n\nThe committee recognised the uncertainty in the healing rates used in the company model as outlined by the EAC. This includes the use of unplanned post-hoc analyses when data used was based on 42% of people in the 3C\xa0Patch arm (for weeks\xa06 to 20). It also acknowledged that there was no clinical evidence on the healing rates for those who would stop 3C\xa0Patch treatment if a stopping rule had been used in the trial. The committee recognised that the EAC's modelling, based on healing rates in the intention-to-treat population, resulted in very different cost estimates. This highlighted the impact of the uncertainty in the healing rate parameters. It also noted that because the EAC analysis included no discontinuation of treatment at all, it was unlikely to provide a true estimate of the cost impacts of 3C\xa0Patch. The committee concluded that the lack of direct clinical trial evidence for the company's proposed treatment pathway is a major limitation of the economic analysis.\n\n## The EAC and company used different data sources in the cost modelling, which changed the direction of the cost case for 3C\xa0Patch\n\nThe committee heard that EAC changes to the data sources used in the cost modelling meant that the overall cost of 3C\xa0Patch was increased by around £800 in the EAC's model\xa0A (a model without a separate infection state). The EAC confirmed that although the Farr et\xa0al. report was unpublished, it was based on direct trial evidence rather than a more general published study on the cost of DFUs to the NHS in England (Kerr et\xa0al. 2019). It was acknowledged that both sources of data had limitations but the EAC's approach using costs from Kerr et al. (2019) with resource use data from Farr et al. (unpublished) was preferred given that it uses direct trial evidence that is most relevant to the population. The committee was concerned that changing the source of the costs for the economic model was sufficient to make 3C\xa0Patch cost incurring. It concluded that the EAC changes to the costs further highlighted the uncertainty in the company base case for 3C\xa0Patch.\n\n## The company's base case is unstable and 3C\xa0Patch is unlikely to be cost saving\n\nThe committee acknowledged that the only way to offset the higher upfront costs of 3C\xa0Patch treatment was to reduce the resources needed later in the pathway for managing unhealed ulcers and their complications. It acknowledged that the company had presented results that indicated that such savings were possible. But the committee noted that these results were based on a model populated with uncertain clinical and cost inputs that had been questioned by the EAC. The committee also noted that varying the model inputs for treatment discontinuation, healing rates and inpatient and outpatient care costs, within ranges that reflected the uncertainty in the underlying data, led to a change in direction of the cost case for 3C\xa0Patch. Further to this, the committee noted that if 3C\xa0Patch is discontinued because of an ulcer having a moderate or severe infection, the EAC's model\xa0B (which included an additional state to capture moderate or severe infections) may be the most appropriate model structure. It acknowledged that this model led to 3C\xa0Patch being more cost incurring. The committee considered that the EAC's 2‑way sensitivity analysis was helpful in demonstrating that there are few combinations of discontinuation and healing rates that can lead to 3C\xa0Patch becoming cost saving, with the combinations that were associated with cost savings being less clinically plausible. It also noted that the company model was sensitive to changes in the cost parameters and that using the EAC's costs alone (without adjusting the company's healing and discontinuation rates) also led to 3C\xa0Patch becoming cost incurring. The committee concluded that the case for adoption was not supported because the estimated cost-saving case presented by the company was not robust. Large savings in care costs would be needed to offset the cost of 3C\xa0Patch and there was insufficient evidence presented to show that care needs would be significantly reduced after 3C\xa0Patch treatment.\n\n# Potential research\n\n## Additional research could help address uncertainties in the evidence, although the case for cost savings remains unlikely\n\nAlthough the committee acknowledged that the Game et al. (2018) RCT was well conducted, it felt that additional research could help resolve some uncertainties around the cost and clinical case for 3C\xa0Patch. Specifically, research identifying the most appropriate stopping rule, and the associated clinical outcomes of implementing the rule, would help address key uncertainties within the cost case. Additional collection of resource use data on unhealed hard-to-heal ulcers could also reduce uncertainty in the cost case. Further to this, evidence could be collected on an UrgoStart-experienced population, as this would be reflective of current NHS care. Clinical experts thought a trial on this population would be feasible. The committee concluded that although further research could be done, on balance it was unlikely to result in a cost-saving case for 3C\xa0Patch based on the decision problem evaluated in this guidance."}
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https://www.nice.org.uk/guidance/mtg66
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Evidence-based recommendations on 3C Patch for treating diabetic foot ulcers.
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39fcacf191ce0a146abdbf748957b73da7bf3779
|
nice
|
Endoscopic full thickness removal of gastrointestinal stromal tumours of the stomach
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Endoscopic full thickness removal of gastrointestinal stromal tumours of the stomach
Evidence-based recommendations on endoscopic full thickness removal of gastrointestinal stromal tumours of the stomach. This involves removing a tumour using an endoscope and forceps. The aim is to remove the tumour without the need for open surgery.
# Recommendations
Evidence on the safety and efficacy of endoscopic full thickness removal of gastrointestinal stromal tumours of the stomach is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should ideally be randomised controlled trials or registry studies. It should report patient selection, tumour type, size and anatomical position, and long-term outcomes (such as tumour recurrence).
Patient selection should be done by a multidisciplinary team.
This procedure should only be done in specialist centres by interventional upper gastrointestinal endoscopists with specific training in this procedure.# The condition, current treatments and procedure
# The condition
Gastrointestinal stromal tumours are a type of soft tissue sarcoma formed from abnormal cells in the tissues of the gastrointestinal tract. Gastrointestinal stromal tumours are most common in the stomach and small intestine but they can develop anywhere along the length of the gastrointestinal tract.
The grade of gastrointestinal stromal tumour is based on the mitotic rate. There are 2 grades: G1 (low grade – the cancer cells have a low mitotic rate, they are growing slowly and less likely to spread) and G2 (high grade – the cancer cells have a high mitotic rate, they are growing faster and more likely to spread).
# Current treatments
The choice of treatment for gastrointestinal stromal tumours depends on several factors, including the location, size and mitotic rate of the tumour, whether the tumour is metastatic, recurrent or refractory, and the person's overall health. The standard treatments include surgery (open, laparoscopic, robotic or endoscopic surgery), targeted therapy using drugs or other substances, watchful waiting and supportive care.
# The procedure
This procedure uses a full thickness resection device, which allows endoscopic resection with a single step, clip and cut technique. For example, 1 device comprises a modified snare to remove the tumour and deeper layers of the stomach wall, and a clasp device that closes the full thickness of the stomach wall.
The device is attached to the end of an endoscope and advanced through the mouth and the oesophagus to the stomach. Gradual dilation may be needed to help the device pass through the upper and lower oesophageal sphincters. The tumour is grasped at its centre and slowly pulled into the cap of the device completely. A clip is released, closing the site of a potential defect in the stomach wall. A snare simultaneously encloses the tumour and cuts it away, then it is retrieved for histological analysis.
After the tumour is removed, the endoscope is reinserted and the surgical site is examined for signs of haemorrhage and to check that the clip has closed the stomach wall. The procedure is usually done with the patient under sedation, but sometimes general anaesthesia is needed.
|
{'Recommendations': 'Evidence on the safety and efficacy of endoscopic full thickness removal of gastrointestinal stromal tumours of the stomach is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should ideally be randomised controlled trials or registry studies. It should report patient selection, tumour type, size and anatomical position, and long-term outcomes (such as tumour recurrence).\n\nPatient selection should be done by a multidisciplinary team.\n\nThis procedure should only be done in specialist centres by interventional upper gastrointestinal endoscopists with specific training in this procedure.', 'The condition, current treatments and procedure': "# The condition\n\nGastrointestinal stromal tumours are a type of soft tissue sarcoma formed from abnormal cells in the tissues of the gastrointestinal tract. Gastrointestinal stromal tumours are most common in the stomach and small intestine but they can develop anywhere along the length of the gastrointestinal tract.\n\nThe grade of gastrointestinal stromal tumour is based on the mitotic rate. There are 2\xa0grades: G1 (low grade – the cancer cells have a low mitotic rate, they are growing slowly and less likely to spread) and G2 (high grade – the cancer cells have a high mitotic rate, they are growing faster and more likely to spread).\n\n# Current treatments\n\nThe choice of treatment for gastrointestinal stromal tumours depends on several factors, including the location, size and mitotic rate of the tumour, whether the tumour is metastatic, recurrent or refractory, and the person's overall health. The standard treatments include surgery (open, laparoscopic, robotic or endoscopic surgery), targeted therapy using drugs or other substances, watchful waiting and supportive care.\n\n# The procedure\n\nThis procedure uses a full thickness resection device, which allows endoscopic resection with a single step, clip and cut technique. For example, 1\xa0device comprises a modified snare to remove the tumour and deeper layers of the stomach wall, and a clasp device that closes the full thickness of the stomach wall.\n\nThe device is attached to the end of an endoscope and advanced through the mouth and the oesophagus to the stomach. Gradual dilation may be needed to help the device pass through the upper and lower oesophageal sphincters. The tumour is grasped at its centre and slowly pulled into the cap of the device completely. A clip is released, closing the site of a potential defect in the stomach wall. A snare simultaneously encloses the tumour and cuts it away, then it is retrieved for histological analysis.\n\nAfter the tumour is removed, the endoscope is reinserted and the surgical site is examined for signs of haemorrhage and to check that the clip has closed the stomach wall. The procedure is usually done with the patient under sedation, but sometimes general anaesthesia is needed."}
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https://www.nice.org.uk/guidance/ipg717
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Evidence-based recommendations on endoscopic full thickness removal of gastrointestinal stromal tumours of the stomach. This involves removing a tumour using an endoscope and forceps. The aim is to remove the tumour without the need for open surgery.
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377b7eb1837c124837067d796cbc3c614e464ff1
|
nice
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Intramedullary distraction for lower limb lengthening
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Intramedullary distraction for lower limb lengthening
Evidence-based recommendations on intramedullary distraction for lower limb lengthening in children, young people and adults. This involves surgically inserting a metal lengthening device in the shorter leg.
# Recommendations
Evidence on the safety and efficacy of intramedullary distraction for lower limb lengthening is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. This guidance is not intended to cover this procedure for bilateral lower limb lengthening for people with short stature.
Clinicians wanting to do intramedullary distraction for lower limb lengthening should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by a multidisciplinary team that ideally includes physiotherapy and psychological support.
This technically challenging procedure should only be done in specialist centres by surgeons with training and specific experience in limb lengthening techniques.
Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.
Further research should report details of patient selection, device selection, procedural outcomes, long-term outcomes including quality of life, the need for repeat interventions or surgery, and complication rates. This research could be registry data.# The condition, current treatments and procedure
# The condition
People may have different limb lengths because of trauma or infection (acquired) or, because of hypoplasia or dysplasia of the femur or tibial (congenital). Unequal leg length can cause a limp, limit functional ability and have effect on other joints.
# Current treatments
Lengthening of an abnormally short lower limb can be done after an osteotomy using an external fixation device. This exerts force along the long axis of the bone to induce new bone formation (distraction osteogenesis). The main problems with external fixation include infection of the pin tracts, and external frames that are impractical and aesthetically unacceptable. Once the external fixation is removed, in some people with underlying bone pathology, new bone is augmented by either an internal plate fixation or an intramedullary nail.
# The procedure
Once inserted and fixed, intramedullary distraction systems can be lengthened over time using different techniques. The aim is to lengthen the bone in a controlled manner.
With this procedure, under general anaesthesia, an osteotomy is done while avoiding damage to the periosteum and its blood supply. The adjustable intramedullary nail-like device is then implanted into the intramedullary space. Its proximal and distal sections are fixed to the relevant section of the bone with sterile locking screws. It then exerts a force along the long axis of the bone, which stimulates new bone formation (distraction osteogenesis) in the gap, causing bone lengthening. Over days, weeks or months, sequential distractions are used to produce the target limb length.
Different devices achieve distraction in different ways.
Soon after the procedure, with help from the physiotherapy team, people are able to partially weight bear. After clinical assessment, and when there is radiological evidence of adequate bone consolidation across the gap, full weight bearing is possible. The intramedullary device is usually removed after about 2 years using standard surgical techniques.
|
{'Recommendations': "Evidence on the safety and efficacy of intramedullary distraction for lower limb lengthening is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page. This guidance is not intended to cover this procedure for bilateral lower limb lengthening for people with short stature.\n\nClinicians wanting to do intramedullary distraction for lower limb lengthening should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team that ideally includes physiotherapy and psychological support.\n\nThis technically challenging procedure should only be done in specialist centres by surgeons with training and specific experience in limb lengthening techniques.\n\nReport any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nFurther research should report details of patient selection, device selection, procedural outcomes, long-term outcomes including quality of life, the need for repeat interventions or surgery, and complication rates. This research could be registry data.", 'The condition, current treatments and procedure': '# The condition\n\nPeople may have different limb lengths because of trauma or infection (acquired) or, because of hypoplasia or dysplasia of the femur or tibial (congenital). Unequal leg length can cause a limp, limit functional ability and have effect on other joints.\n\n# Current treatments\n\nLengthening of an abnormally short lower limb can be done after an osteotomy using an external fixation device. This exerts force along the long axis of the bone to induce new bone formation (distraction osteogenesis). The main problems with external fixation include infection of the pin tracts, and external frames that are impractical and aesthetically unacceptable. Once the external fixation is removed, in some people with underlying bone pathology, new bone is augmented by either an internal plate fixation or an intramedullary nail.\n\n# The procedure\n\nOnce inserted and fixed, intramedullary distraction systems can be lengthened over time using different techniques. The aim is to lengthen the bone in a controlled manner.\n\nWith this procedure, under general anaesthesia, an osteotomy is done while avoiding damage to the periosteum and its blood supply. The adjustable intramedullary nail-like device is then implanted into the intramedullary space. Its proximal and distal sections are fixed to the relevant section of the bone with sterile locking screws. It then exerts a force along the long axis of the bone, which stimulates new bone formation (distraction osteogenesis) in the gap, causing bone lengthening. Over days, weeks or months, sequential distractions are used to produce the target limb length.\n\nDifferent devices achieve distraction in different ways.\n\nSoon after the procedure, with help from the physiotherapy team, people are able to partially weight bear. After clinical assessment, and when there is radiological evidence of adequate bone consolidation across the gap, full weight bearing is possible. The intramedullary device is usually removed after about 2\xa0years using standard surgical techniques.'}
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https://www.nice.org.uk/guidance/ipg718
|
Evidence-based recommendations on intramedullary distraction for lower limb lengthening in children, young people and adults. This involves surgically inserting a metal lengthening device in the shorter leg.
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360b56c23e3c5d83840a3a0bce8af2053582dce6
|
nice
|
Endoscopic balloon dilation for subglottic or tracheal stenosis
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Endoscopic balloon dilation for subglottic or tracheal stenosis
Evidence-based recommendations on endoscopic balloon dilation for subglottic or tracheal stenosis. This involves introducing a balloon device with the aim of widening the stenotic airway to improve symptoms.
# Recommendations
Evidence on the safety of endoscopic balloon dilation for subglottic or tracheal stenosis is adequate. The most serious complication related to the procedure, independent of age, is tracheal laceration but this is well recognised.
For babies, children, and young people, evidence on the efficacy of the procedure is adequate to support using it, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
For adults, evidence on the efficacy of the procedure is limited. So, it should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wanting to do endoscopic balloon dilation for subglottic or tracheal stenosis in adults should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
This procedure should only be done in specialist centres by clinicians trained in the technique, and with anaesthesia and intensive care support.
Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.# The condition, current treatments and procedure
# The condition
Subglottic or tracheal stenosis is a narrowing of the airway. It can be congenital, traumatic or, most commonly, iatrogenic after prolonged endotracheal intubation. Symptoms include hoarseness, stridor, exercise intolerance and respiratory distress. In severe cases complete obstruction may happen, needing continued intubation or tracheostomy.
# Current treatments
Treatment options include inhaled or oral steroids to treat inflammation and reduce the severity of stenosis. A cricoid-split operation can decompress the subglottis and prevent development of stenosis in babies. For people with severe and established stenosis, endoscopic techniques such as stent insertion or laser ablation are used. Alternatively, open surgical repair is done to increase the diameter of the stenosed segment with a graft or stent (expansion surgery) or to remove the stenotic area (resection surgery).
# The procedure
The aim of endoscopic balloon dilation is to dilate airway strictures with minimal mucosal trauma by applying pressure to an area of stenosis. The procedure is most commonly done on iatrogenic stenoses, which are typically soft. It is less commonly done on harder, established stenoses.
The procedure is usually done under general anaesthesia, using direct laryngoscopic or bronchoscopic visualisation. A balloon device is introduced into the airway and the balloon is gently inflated, applying radial pressure circumferentially to the stricture. After dilation, the balloon is deflated and the device is withdrawn. The procedure may be used in combination with other treatments. It can be repeated if needed. The aim is to widen the stenotic airway and improve symptoms.
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{'Recommendations': "Evidence on the safety of endoscopic balloon dilation for subglottic or tracheal stenosis is adequate. The most serious complication related to the procedure, independent of age, is tracheal laceration but this is well recognised.\n\nFor babies, children, and young people, evidence on the efficacy of the procedure is adequate to support using it, provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nFor adults, evidence on the efficacy of the procedure is limited. So, it should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do endoscopic balloon dilation for subglottic or tracheal stenosis in adults should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThis procedure should only be done in specialist centres by clinicians trained in the technique, and with anaesthesia and intensive care support.\n\nReport any problems with a medical device using the\xa0Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.", 'The condition, current treatments and procedure': '# The condition\n\nSubglottic or tracheal stenosis is a narrowing of the airway. It can be congenital, traumatic or, most commonly, iatrogenic after prolonged endotracheal intubation. Symptoms include hoarseness, stridor, exercise intolerance and respiratory distress. In severe cases complete obstruction may happen, needing continued intubation or tracheostomy.\n\n# Current treatments\n\nTreatment options include inhaled or oral steroids to treat inflammation and reduce the severity of stenosis. A cricoid-split operation can decompress the subglottis and prevent development of stenosis in babies. For people with severe and established stenosis, endoscopic techniques such as stent insertion or laser ablation are used. Alternatively, open surgical repair is done to increase the diameter of the stenosed segment with a graft or stent (expansion surgery) or to remove the stenotic area (resection surgery).\n\n# The procedure\n\nThe aim of endoscopic balloon dilation is to dilate airway strictures with minimal mucosal trauma by applying pressure to an area of stenosis. The procedure is most commonly done on iatrogenic stenoses, which are typically soft. It is less commonly done on harder, established stenoses.\n\nThe procedure is usually done under general anaesthesia, using direct laryngoscopic or bronchoscopic visualisation. A balloon device is introduced into the airway and the balloon is gently inflated, applying radial pressure circumferentially to the stricture. After dilation, the balloon is deflated and the device is withdrawn. The procedure may be used in combination with other treatments. It can be repeated if needed. The aim is to widen the stenotic airway and improve symptoms.'}
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https://www.nice.org.uk/guidance/ipg719
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Evidence-based recommendations on endoscopic balloon dilation for subglottic or tracheal stenosis. This involves introducing a balloon device with the aim of widening the stenotic airway to improve symptoms.
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3631da2099cbb8580345cf1521d0cabd93235a02
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nice
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Mental wellbeing at work
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Mental wellbeing at work
This guideline covers how to create the right conditions for mental wellbeing at work. It aims to promote a supportive and inclusive work environment, including training and support for managers and helping people who have or are at risk of poor mental health.
# Recommendations
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The recommendations in this guideline apply to micro, small, medium-sized and large organisations equally, although some recommendations may need to be tailored to specific organisations and circumstances.
# Strategic approaches to improving mental wellbeing in the workplace
Adopt a tiered approach to mental wellbeing in the workplace by using organisational-level approaches as the foundation for good mental wellbeing (the first tier), followed by individual approaches (the second tier) and targeted approaches (the third tier).
Adopt a preventive and proactive strategic approach to mental wellbeing at work in your organisation. Take into account:
workplace culture
workload
job quality and role autonomy
concerns that employers and employees may have about mental health, including stigma.See also the section on organisation-wide approaches.
Proactively promote mental wellbeing by ensuring that it is embedded in the overall business strategy of all organisational policies and practices. Take into account the recommendations in the section on supportive work environment.
Ensure that a stress risk assessment is carried out for each role as required by the Health and Safety at Work etc Act 1974, for example using the Health and Safety Executive's risk assessment template:
If any risks are identified, take proactive steps to reduce the risks and their negative impacts.
If a high-risk role is indicated, see the section on organisational-level approaches for high-risk occupations.
Discuss with employees as necessary and feed back the results of the assessment to them.
Ensure that systems are in place to provide support for employees for whom external factors are influencing their mental wellbeing. See the section on training and support for managers.
Monitor and evaluate the support you provide at least on an annual basis using a relevant evaluation tool. Public Health England's evaluation in health and wellbeing provides a list of resources and summarises what they are used for.
When measuring mental wellbeing, use a validated measure of mental wellbeing, for example the government's voluntary reporting on disability, mental health and wellbeing: a framework to support employers (for large employers), What Works Wellbeing's workplace wellbeing questionnaire or Warwick Medical School's Warwick-Edinburgh Mental Wellbeing Scales (WEMWBS).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on strategic approaches to improving mental wellbeing in the workplace .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review B: manager interventions
evidence review C: targeted organisational-level approaches
evidence review D: universal individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work
evidence review G: expert testimony.
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# Supportive work environment
Foster a positive, compassionate and inclusive workplace environment and culture to support psychological safety and mental wellbeing by:
ensuring active leadership and management support and engagement
increasing mental health literacy
encouraging and facilitating peer support (for example, using mental health champions and peer mentoring or 'buddying')
supporting people who manage and support employees
encouraging employees to recognise and take action to prevent discrimination in the workplace, for example by establishing and supporting staff networks
being aware that mental wellbeing in the workplace also depends on factors beyond the workplace itself (such as physical health, domestic relationships, home environment and financial circumstances) and also on societal discrimination (such as racism, homophobia and sexism)
promoting good communication and engagement with employees
including mental health awareness in manager training (see the section on training and support for managers).
Develop policies, processes and ways of working with staff that are equitable and inclusive, and that encourage a fair and supportive workplace environment and culture, in order to maximise employee wellbeing. Take into account:
legal obligations (such as the Equality Act 2010 and Health and Safety at Work etc Act 1974)
statutory requirements (such as the ACAS codes of practice)
employer-led strategies or interventions (such as anti-bullying, work-life balance, confidentiality and flexible working).
Offer employees a private space and protected time to engage with interventions, taking into account the need for confidentiality.
Ensure that all employees have the opportunity and the means to access interventions (such as private access to the internet and IT equipment for remotely delivered interventions).See also the sections on organisational commitment, senior leadership and leadership style of line managers in the NICE guideline on workplace health: management practices, and the section on workplace culture and policies in NICE's guideline on workplace health: long-term sickness absence and capability to work.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supportive work environment .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review B: manager interventions
evidence review C: targeted organisational-level approaches
evidence review D: universal individual-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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# External sources of support
Use external expertise in the local authority (see the section on local and regional strategies and plans), Department for Work and Pensions and other agencies (for example, from the voluntary, charity and social enterprise sector or chambers of commerce) to access support for employees, including action plans and toolkits (for example, from What Works Wellbeing, Business in the Community, Mind and the Health and Safety Executive).
Make employees aware that if they have mental health problems, they can use the Department for Work and Pensions' access to work mental health support service. NHS and social care staff can use the staff mental health and wellbeing hubs (and other national health and wellbeing support offers).
Use local and national resources, and advice from a variety of evidence-informed sources, such as the local Improving Access to Psychological Therapies services offer, the employee's GP, professional bodies, unions and trade organisations (for example, Federation of Small Businesses, ACAS and the Chartered Institute of Personnel and Development ).See also the section on early intervention in NICE's guideline on workplace health: long-term sickness absence and capability to work.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on external sources of support .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work
evidence review G: expert testimony.
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# Organisation-wide approaches
Involve employees and workplace representatives in identifying and minimising sources of stress at work. (See also the section on job design in NICE's guideline on workplace health: management practices.)
Consider using workplace accreditations or charters, such as guidance to improve the organisation-wide workplace environment and culture (for example, the Workplace Wellbeing Charter, Mindful Employer and Mind's Workplace Wellbeing Index).
Tailor interventions to meet the needs of the organisation and its employees (for example, according to the industry sector or the size of the organisation).
Refer to existing guidance and best practice on job quality, work design and organisation to identify and reduce work stressors, such as Health and Safety Executive's Management Standards for work-related stress, Mindful Employer or COVID‑19-specific advice (for example, from the CIPD).
Consider using staff surveys or other engagement approaches, for example working with employee representative organisations (such as trade unions or staff networks), to determine whether tailored solutions are needed to improve mental wellbeing in the workplace (for example, What Works Wellbeing's employee wellbeing snapshot survey).
Consider giving all employees free access to an employee assistance programme and occupational health services, and raise awareness of them if they are offered (for small and medium-sized enterprises). (See also the section on making this guideline relevant for small and medium-sized enterprises ).
Have a plan for responding to unexpected traumatic events affecting employees, such as the death of a colleague, a pandemic or a terrorist attack. This should include supporting people socially and with their mental wellbeing. For example, see the UK Health Security Agency's course on COVID-19: psychological first aid or NHS England and NHS Improvement's guidance on responding to the needs of people affected by incidents and emergencies.See also the section on monitoring and evaluation in NICE's guideline on workplace health: management practices.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisation-wide approaches .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work
evidence review G: expert testimony.
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# Training and support for managers
Offer systematic support for managers. Include training, and regular refresher training, in:
line management
communication skills (the ability to listen, communicate clearly, understand and empathise).
Equip managers with the knowledge, tools, skills and resources to:
improve awareness of mental wellbeing at work
promote mental wellbeing and prevent poor mental wellbeing
improve employees' understanding of and engagement in organisational decisions
improve communication between managers and employees.This should include managing people remotely.
When offering mental health training for managers, consider including:
how to have a conversation on mental wellbeing with an employee, including at times of crisis
information about mental wellbeing
how to identify early warning signs of poor mental wellbeing
resources on mental wellbeing, including knowing where to go for further help or support in complex situations
awareness of the stigma associated with poor mental wellbeing
-ngoing management and monitoring of mental wellbeing in the workplace
topics suggested by managers.
Ensure that all managers have time to attend relevant training sessions.
Empower managers to make necessary adjustments to workload or work intensity for their employees, for example flexible or hybrid working.
Encourage managers to address their own mental health needs as well as those of their employees, for example by peer-to-peer support for managers on mental wellbeing.
Consider a group approach to deliver mental health training. Training could be delivered either face to face or using online formats.
Evaluate how mental health training for managers affects employee outcomes (for example, by surveying employees and managers or focus groups) and feed the results back into future training and strategy.See also the section on training in NICE's guideline on workplace health: management practices.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on training and support for managers .
Full details of the evidence and the committee's discussion are in:
evidence review B: manager interventions
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work
evidence review G: expert testimony.
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# Individual-level approaches
Do not use individual-level approaches to replace organisational strategies for reducing work stressors, or for the main purpose of increasing productivity.
Encourage managers to create opportunities for fostering good relationships with (and between) employees, for example by socialising with them at work (in person or virtually). Create opportunities to talk with them about their general health and wellbeing.
Encourage managers to discuss mental wellbeing with employees, and employees to discuss any mental wellbeing concerns they may have with their manager or another relevant person (for example, another manager, a mental wellbeing champion or a union representative):
Use these conversations to identify and understand any sources of stress.
Agree whether any additional support is needed and what this might be (see the section on external sources of support).
Agree steps to minimise work-related stressors (see the section on approaches for employees who have or are at risk of poor mental health).
Offer all employees (or help them to access) mindfulness, yoga or meditation on an ongoing basis. This can be delivered in a group or online, or using a combination of both.See also the section on supporting employers in NICE's guideline on physical activity in the workplace.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on individual-level approaches .
Full details of the evidence and the committee's discussion are in:
evidence review C: targeted organisational-level approaches
evidence review D: universal individual-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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# Approaches for employees who have or are at risk of poor mental health
Ensure that confidentiality is discussed when talking with someone about their mental health (see recommendation 1.2.2), and be clear about when confidentiality will and will not be respected (that is, when the employee is considered at risk to themselves or others because of their mental health).
Offer organisational support to employees identified as having or being at risk of poor mental health. This may include flexible working hours; changes to the job, workplace or culture to minimise any risks to mental wellbeing; or maintaining supportive line management relationships. (See recommendation 1.5.5 and recommendation 1.6.3.) Remind them that they can visit their GP for further assessment and support.
Consider working with them to create a wellness action plan (see Mind's guides to wellness action plans).
Assess whether this has highlighted if changes need to be made at an organisational level.
Discuss with the employee if they would like to:
have further support and, if so, whether they prefer a particular type of support
have ongoing regular, confidential discussions about their mental health support needs.
For employees who want further support, offer (or provide access to):
cognitive behavioural therapy sessions or
mindfulness training or
stress management training.If employees choose not to have an intervention now, tell them that the offer will still be available in the future if they reconsider.
Reassure colleagues that it is their choice whether to continue with an intervention or restart it at any time.See also the sections on sustainable return to work and reducing recurrence of absence in NICE's guideline on workplace health: long-term sickness absence and capability to work.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on approaches for employees who have or are at risk of poor mental health .
Full details of the evidence and the committee's discussion are in:
evidence review C: targeted organisational-level approaches
evidence review D: universal individual-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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# Organisational-level approaches for high-risk occupations
The following recommendations are aimed at organisations, workplaces or workforces where employees are likely to experience traumatic events in the normal course of their work (such as the emergency services). See also recommendation 1.1.4.
Regularly review organisational-level policies and protocols on how to support employees in high-risk occupations after an occupational traumatic event. Use data such as reasons for absence and staff turnover to ensure that support is targeted in the right way.
Ensure that practice is consistent with established best practice (for example, Mind's Blue Light Programme).
Offer task-focused skills training (for example, through imagery, simulation and skills training) before deployment for employees in high-risk occupations (such as emergency services) to ensure that they have the skills needed to deal with predictable and stressful occupational events.See also NICE's guideline on post-traumatic stress disorder.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisational-level approaches for high-risk occupations .
Full details of the evidence and the committee's discussion are in:
evidence review D: universal individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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# Engaging with employees and their representatives
Work with employees and their representative organisations (for example, trade unions and staff networks; see recommendation 1.2.1) to consult about how, when and where mental wellbeing interventions are offered and delivered, for example through staff surveys.
Take account of the following potential barriers and facilitators when consulting with employees about interventions:
workplace culture (including the concern that raising issues can impact negatively on staff roles or job security)
workload
concerns that employers and employees may have about mental health, including stigma, and how this may affect their ability to discuss any difficulties or engage with certain forms of support
timing of the intervention and the option of delivering it in and outside the workplace and work hours
specific needs and preferences of employees
specific reasonable needs of the employing organisation.
Ensure that factors associated with an employee such as contract type, income level, protected characteristics and job role are not barriers to accessing interventions. Do this by:
monitoring intervention uptake and identifying groups where uptake is relatively low
having a mechanism to identify, understand and overcome barriers to participating in the intervention.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on engaging with employees and their representatives .
Full details of the evidence and the committee's discussion are in evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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# Local and regional strategies and plans
These recommendations are for local and regional authorities.
Take a leadership role in championing mental wellbeing and preventing poor mental wellbeing at work as part of the local authority role in public health and wellbeing.
Engage with local and regional employers, employee representatives, chambers of commerce, local enterprise partnerships and voluntary, charity and social enterprises to develop and promote health and wellbeing strategies to include mental wellbeing at work.
Integrate mental wellbeing at work into local and regional public health activities and strategies.
Raise awareness among the general public and employers of the importance of mental wellbeing at work, for example through social media.
Identify and address local barriers and facilitators to employer engagement with local mental wellbeing at work initiatives. This could include, for example, working with employers to ensure they know about resources or services that can help them improve the mental wellbeing of their employees and minimise the resource impact that this will have, especially for micro, small and medium-sized enterprises.
Offer support to help local employers improve the mental wellbeing and prevent poor mental wellbeing of their employees. This support could include advice on enablers of mental health and on developing action plans towards accreditation (see recommendation 1.4.2) or setting up a Local Workplace Health Accreditation Scheme.
Curate or work with local business support organisations to list local and national sources of support for employers and employees, such as Mind, Mental Health at Work, the Department for Work and Pensions' access to work mental health support service and, for NHS and social care staff, staff mental health and wellbeing hubs (and other national health and wellbeing support offers).
Explore and evaluate the value of incentives or pilot incentive programmes to promote uptake of support and encourage employers to participate in accreditation schemes (see recommendation 1.4.2).
Use contracting and ethical procurement arrangements to strongly encourage supply chain organisations to promote mental wellbeing among their employees (for example, public sector organisations must use the Public Services Act 2012).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on local and regional strategies and plans .
Full details of the evidence and the committee's discussion are in:
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work
evidence review G: expert testimony.
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# Making this guideline relevant for small and medium-sized enterprises (including micro-enterprises)
Business owners and owner-managers should address their own mental health needs as well as those of their employees.
Take a preventive approach to mental wellbeing at work, for example using mental health and communication skills training to foster positive mental wellbeing, as well as tackling poor mental wellbeing. Refer to the Mental Health at Work website for curated resources and toolkits on how to improve the mental wellbeing of your employees.
Seek advice and support from local authorities; local enterprise partnerships; voluntary, charity and social enterprises; trade unions and other bodies; and, for NHS and social care staff, staff mental health and wellbeing hubs (and other national health and wellbeing support offers), on how to prevent poor mental wellbeing in your employees, and how to support employees through mental ill health.
Think about signing up to the Mental Health at Work Commitment to help achieve better mental health outcomes for employees.
Think about accessing employee assistance programmes and occupational health services. See the Department for Work and Pensions' access to work mental health support service as an example of a low-cost service (see recommendation 1.11.2).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on additional approaches for small and medium-sized enterprises .
Full details of the evidence and the committee's discussion are in:
evidence review D: universal individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work
evidence review G: expert testimony.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local Act Personal's Care and Support Jargon Buster.
## Employee
Everyone aged 16 or over in full- or part-time employment, including people on permanent, training, temporary or zero-hours contracts, those who are self-employed and volunteers.
## Mental health literacy
A person's knowledge and beliefs about mental health problems and how to look after their own mental health. It includes knowing how mental health problems are managed and treated, how to seek information about them and how to recognise them.
## Organisation
For the purposes of this guideline, organisation refers to any size of workplace, including micro, small and medium-sized enterprises.
## Psychological safety
A person's desire and need to feel comfortable and safe in the workplace to express themselves and communicate openly.
## Role autonomy
A person's ability to influence what happens in their work environment, in particular to influence matters that are relevant to their personal goals and the way in which they carry out their work.
## Staff networks
Groups of employees who come together in a safe environment for discussion and support, and from which they can be a voice for change in the workplace. This includes raising awareness of issues in the wider organisation. They are commonly groups of people who identify as an under-represented group or who have a protected characteristic in the Equality Act 2010.
## Stress
The Health and Safety Executive (HSE) guide on working together to reduce stress at work defines stress as the adverse reaction people have to excessive pressures or other types of demand placed on them.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Individual-level interventions
What is the long-term effectiveness and cost effectiveness of universal individual-level interventions on mental wellbeing in different types of organisations?
For a short explanation of why the committee made the recommendation for research, see the rationale section on individual-level approaches .
Full details of the evidence and the committee's discussion are in:
evidence review D: universal individual-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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## Organisational-level approaches for all organisations
What is the long-term impact and cost effectiveness of employee assistance programme provision on mental wellbeing?
For a short explanation of why the committee made the recommendation for research, see the rationale section on organisation-wide approaches .
Full details of the evidence and the committee's discussion are in evidence review A: organisational universal-level approaches.
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## Training for managers
What is the long-term effectiveness (more than 6 months) of manager training on employee mental wellbeing?
For a short explanation of why the committee made the recommendation for research, see the rationale section on training and support for managers .
Full details of the evidence and the committee's discussion are in:
evidence review B: manager interventions
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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## Approaches for micro, small and medium-sized enterprises
What are the specific needs of different kinds of micro, small and medium-sized enterprises (SMEs) in promoting mental wellbeing in the workplace, including organisational, targeted and individual level approaches?
For a short explanation of why the committee made the recommendation for research, see the rationale section on additional approaches for small and medium-sized enterprises .
Full details of the evidence and the committee's discussion are in:
evidence review D: universal individual-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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## Core outcomes for study reporting
Which mental wellbeing and productivity outcomes should be used in a core outcome set for research into workplace mental wellbeing?
For a short explanation of why the committee made the recommendation for research, see the rationale section on strategic approaches to improving mental wellbeing in the workplace .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review B: manager interventions
evidence review C: targeted organisational-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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# Other recommendations for research
## Supportive work environment
What are the views of organisations about the benefits of investing in mental wellbeing?
For a short explanation of why the committee made the recommendation for research, see the rationale section on supportive work environment .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review B: manager interventions
evidence review C: targeted organisational-level approaches
evidence review D: universal individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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## Identifying employees at risk of poor mental wellbeing
What tools (for example, wellbeing surveys) can be used to identify employees at risk of poor mental wellbeing rather than mental ill health?
For a short explanation of why the committee made the recommendation for research, see the rationale section on approaches for employees who have or are at risk of poor mental health .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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## Needs of different employee groups
What specific needs of employees from different groups (such as income levels, ethnic groups, male or female groups, and age groups) need addressing to facilitate access to individual-level interventions?
How effective are individual-level interventions across different groups (such as income levels, ethnic groups, male or female groups, and age groups)?
For a short explanation of why the committee made the recommendations for research, see the rationale section on individual-level approaches .
Full details of the evidence and the committee's discussion are in:
evidence review C: targeted organisational-level approaches
evidence review D: universal individual-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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## Approaches for micro, small and medium-sized enterprises
What is the long-term effectiveness of universal individual-level interventions in different kinds of SMEs?
For a short explanation of why the committee made the recommendation for research, see the rationale section on making this guideline relevant for small and medium-sized enterprises (including micro-enterprises) .
Full details of the evidence and the committee's discussion are in:
evidence review D: universal individual-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
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## Addressing study reporting
What are the key characteristics of an organisation and its employees that need to be included in reporting research into workplace mental wellbeing?
For a short explanation of why the committee made the recommendation for research, see the rationale section on strategic approaches to improving mental wellbeing in the workplace .
Full details of the evidence and the committee's discussion are in:
evidence review A: organisational universal-level approaches
evidence review B: manager interventions
evidence review C: targeted organisational-level approaches
evidence review E: targeted individual-level approaches
evidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Strategic approaches to improving mental wellbeing in the workplace
Recommendations 1.1.1 to 1.1.7
## Why the committee made the recommendations
The committee noted that the range and nature of workplaces and organisations (especially in terms of the number of employees) made it challenging to make generic recommendations for all organisations. They agreed that some organisations might need to tailor the recommendations to make them relevant.
The committee agreed on the need for organisations to embed strategic approaches to mental wellbeing into their organisational policies and practices, based on their understanding that this approach was fundamental to mental wellbeing at work and based on the evidence and expert testimony.
The committee recognised that the ability of organisations to promote and support mental wellbeing is negatively affected by health inequalities and by work stressors such as bullying, poor communication, job insecurity (including zero-hours contracts), workload, monotony, isolation and poor prospects. In contrast, it is enhanced by good job quality (including a fair wage), role autonomy, organisational fairness, respect, recognition, peer support and clear communication. The committee were clear that some of these factors were outside of the remit of this guideline.
A wide range of evidence from the UK showed that organisation-wide interventions may help to improve mental wellbeing and stress outcomes for employees, and may also benefit employers. The committee agreed that, in their experience, 1 of the key foundations of mental wellbeing in the workplace was an organisational commitment to it, together with a recognition that mental wellbeing is a spectrum and poor mental wellbeing is not a weakness. Organisations that took a strategic and whole-hearted approach to improving mental wellbeing from the top down tended to have the most success. The committee agreed that this was best demonstrated by organisations with a preventive and proactive approach to mental wellbeing – that is, they proactively took steps to promote mental wellbeing rather than simply tackling poor mental wellbeing. They agreed that because these organisational-level responses were so important, the first recommendations in the guideline should establish that organisation-wide strategic approaches were the foundation of good mental wellbeing at work, and that individual and targeted approaches could enhance these but were not a substitute for them. In the committee's experience, it is unlikely that individual or targeted interventions would be successful without an organisation-wide approach, but it noted the temptation for organisations to start with individual approaches because it seems easier.
The committee also agreed with expert testimony on the impacts of the pandemic on mental wellbeing in the workplace that highlighted the need to view mental wellbeing as equally important to physical wellbeing in the workplace and to take it into account when drafting polices or introducing new practices.
Expert testimony about the long-term impacts of the COVID‑19 pandemic on mental wellbeing in the workplace highlighted that employers of all sizes are legally required to carry out a stress risk assessment for each role (and record it if they have more than 5 employees) under the Health and Safety at Work etc Act 1974. The committee saw this as a good opportunity for organisations to identify risks to employees' mental wellbeing, and subsequently take steps to reduce stressors.
The committee also highlighted that employees may have poor mental wellbeing as a result of external factors that are beyond the control of the employer, such as caring responsibilities, health concerns and discrimination (such as homophobia or racism). But they agreed that it is important for organisations to ensure that they provide additional support to groups affected by these issues.
The committee also agreed, based on their experience, that it is important for any interventions to be evaluated and monitored as part of an ongoing strategy of employee engagement, and that validated measures of wellbeing need to be part of this process.
The committee noted that further research is needed to understand how data and outcomes could best be used to improve mental wellbeing in the workplace. In particular, research could investigate which outcomes would be useful in a core outcome set for research into workplace mental wellbeing, and to understand how more detailed reporting of the nature of organisation and employee characteristics can be included in research into workplace mental wellbeing (see the recommendations for research on core outcomes for study reporting and addressing study reporting).
## How the recommendations might affect practice
The use of tiered approaches to support mental wellbeing at work reflects best practice and therefore would not have a large resource impact in organisations that have already adopted best practice. This may have more of an impact for other organisations. Smaller organisations may not always have the resources to offer all aspects of the tiered approach. They can best use resources by concentrating on ensuring that they have an organisation-wide approach in place. Improving employee wellbeing might lead to less absenteeism and presenteeism and may improve staff retention and productivity.
Return to recommendations
# Supportive work environment
Recommendations 1.2.1 to 1.2.4
## Why the committee made the recommendations
The committee agreed that overall, a supportive, inclusive work environment and climate is crucial for good mental wellbeing in the workforce. Social interactions, including those between managers and employees, play an important role in this.
Having the right policies can help to create a supportive workplace environment and culture. It can help to ensure that leadership is supportive and engaged, that there are effective peer support networks and there is good organisational-wide mental health literacy. A supportive work environment can be achieved by adhering to existing legal obligations (such as health and safety) and statutory requirements (such as the ACAS codes of practice), and engaging with employees to draft and refine policies such as anti-bullying.
Organisations can also promote mental wellbeing interventions by reducing any potential barriers to using them and supporting employees to access them. This would embed the importance of mental wellbeing into the organisational culture (see the section on engaging with employees and their representatives).
Despite the lack of strong evidence for leadership interventions, the committee were confident that management buy‑in is important for promoting the wellbeing of employees. They cited the government review Thriving at work, which provides an evidence-based whole-settings approach to improving mental wellbeing, including the importance of leadership, culture and effective people management.
The committee noted that there was little evidence on the views of organisations about mental wellbeing. (See the recommendation for research on supportive work environment.)
## How the recommendations might affect practice
The recommendations reflect current good practice around communication across the organisation, active leadership involvement and engagement with employees. The committee noted that many organisations would already have structures in place like those they recommended, and that to align them with the recommendations would not have a large resource impact. The committee agreed that for organisations that were resource poor and that had not previously invested in a supportive work environment, the use of freely available external resources could help minimise costs.
Return to recommendations
# External sources of support
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
The committee agreed that supporting mental wellbeing in the workplace might be particularly challenging for organisations with limited resources, especially micro, small and medium-sized ones. They agreed that it was important to help employers find external, low-cost or free resources to support them in promoting mental wellbeing.
Based on expert testimony from a mental health and productivity pilot and their experience, the committee agreed that it was the responsibility of employers and local and regional authorities to be aware of sources of support available in their area. These sources could be national, local or within the organisation, for example an occupational health service or an employee assistance programme (if the organisation has these). By being able to direct employees to these, employers will be helping and supporting employees by providing them with tools and resources.
The Department for Work and Pensions' access to work mental health support service has guidance to help employers understand mental ill health and how to support employees with mental health concerns. It can also support employees by offering eligible employees an assessment to find out their needs and help them develop a support plan.
## How the recommendations might affect practice
The recommendations encourage employers to use expertise and resources that are external to their organisation when appropriate. These sources of support are freely available and will provide employers with information and resources to support their employees. They will also help organisations who are committed to improving the mental wellbeing of their employees to manage the resource impact.
Return to recommendations
# Organisation-wide approaches
Recommendations 1.4.1 to 1.4.7
## Why the committee made the recommendations
Evidence from the UK showed that organisation-wide interventions may help to improve mental wellbeing and stress outcomes for employees and may also benefit employers. Although the evidence had some limitations in terms of its quality, the committee concluded that the work environment can be improved in 2 ways: employers can work with their employees to identify work stressors and put in place solutions to deal with these stressors, or employers can use evidence-based methods that are specifically tailored to their organisation. The committee clarified their use of the word 'stress' to be the adverse reaction people have to excessive pressures or other types of demand placed on them.
Based on the evidence and their experience, the committee strongly advised that organisational-level approaches are the best starting point when considering strategies to improve mental wellbeing at work. These approaches demonstrate a commitment to mental wellbeing at work, which is essential for encouraging employees to take up interventions. The committee emphasised that individual-level approaches are not a suitable alternative to organisational-level approaches because these are less likely to be effective on their own. They noted that because of the variation in the size and structure of workplaces, many interventions might need to be tailored to match the specific workplace in which they were going to be delivered. This could be done through staff surveys, for example.
The committee heard expert testimonies about insights from the Thriving at Work Leadership Council, the mental health and productivity pilot, participatory organisational interventions, and prevention and management of work-related stress and mental ill health. They agreed with the experts that striving to attain workplace charters or accreditation was a useful way for organisations to work with external bodies to improve mental wellbeing and make their organisation a more attractive place to work. These would also allow employers to access external support and advice about improving and maintaining mental wellbeing at work. The committee also agreed that existing guidance, such as the Health and Safety Executive's Management Standards for work-related stress, would be useful.
The committee agreed that employee assistance programmes and occupational health services are good options for supporting employees' mental wellbeing, although they noted that there was a lack of evidence about how effective they are. They agreed with expert testimony about major challenges to small and medium-sized enterprises in improving the mental wellbeing of staff, what they can do to improve staff mental wellbeing and that low-cost schemes such as Mindful Employer may be useful for smaller organisations with limited resources. The committee also discussed that some employees in occupations that are not generally considered high-risk may be exposed to traumatic events at work – for example, because of a pandemic or terror attack – and that employers need to have plans in place to support employees in case such events do occur.
The lack of published evidence about the effectiveness of employee assistance programmes led the committee to make a recommendation for research on organisational-level approaches for all organisations because evidence on this could help NICE to make more specific recommendations on this topic in future.
## How the recommendations might affect practice
The recommendations reflect good practice in communication across the organisation, in active leadership involvement and in engaging with employees. There should not be an extensive resource impact because the recommendations involve adhering to existing best practice.
Return to recommendations
# Training and support for managers
Recommendations 1.5.1 to 1.5.8
## Why the committee made the recommendations
The committee agreed it was important that all line managers received training and support. They considered that this was good practice in all industries and all sizes of organisation, and that managers benefit in terms of their mental wellbeing from feeling skilled to perform their line management duties.
There was a range of evidence showing that manager training interventions were effective (especially in terms of outcomes for the manager who had been trained) or had no effect, although the committee noted that much of this evidence was uncertain. There was no evidence of unintended consequences associated with these interventions. There was some higher quality evidence that manager training can help to increase managers' knowledge of how to reduce stigma, and also help to increase their confidence in identifying and supporting employees who may be at risk of poor mental health. This agreed with the experience of the committee, who found that training managers in mental health awareness can increase their knowledge and willingness to discuss mental health.
Reducing stigma and equipping managers with skills to have conversations with employees about mental health is likely to facilitate conversations between managers and employees about any concerns about their mental wellbeing. This makes it more likely that managers can support employees with mental health issues. Providing managers with skills to discuss mental wellbeing improves the relationship between manager and employee so that they can identify and reduce work stressors. The evidence also showed that increasing managers' knowledge leads to more employees using the support services on offer. Although the evidence was not strong in this area, the committee agreed some points that would be a useful core for the content of mental health training for managers. They also agreed it was important for people to be able to suggest topics they thought were important.
The committee agreed with the qualitative evidence that manager training interventions delivered in groups had added benefit because they allow managers to learn from each other and to reinforce best practice. Therefore, the committee agreed, based on their experience and the evidence, that it can be helpful to offer group training as part of mental health awareness training. But they acknowledged that this might not be possible, for example in smaller organisations. Expert testimony about major challenges to small and medium-sized enterprises in improving the mental wellbeing of staff and what they can do to improve staff mental wellbeing, managing mental health in the workplace during and after COVID‑19, and committee experience, highlighted that managers have additional pressures related to their role, and that delivering any training in a group format would provide peer support. The committee also discussed that because of the increased pressures faced by managers, it is important that they are supported by human resources, occupational safety, and health and wellbeing professionals.
The committee discussed expert testimony about managing mental health in the workplace during the COVID‑19 pandemic and about the likely long-term impacts of COVID‑19 on mental wellbeing in the workplace. It helped them to make recommendations about the content of management training to support mental wellbeing. They agreed that managers should be empowered to make reasonable adjustments to the workload or intensity to reduce stressors for employees. This would give employees relief from work stress sooner because requests would not need to be escalated before support could be given. This expert testimony also highlighted the value of peer-to-peer support for managers, which the committee agreed matched their own expert experience.
The committee further discussed that although there was some data on the effectiveness of the interventions reviewed in terms of employee outcomes, overall, there was insufficient data and they had to extrapolate from their expertise and experience along with the small amount of evidence they had. They suggested that this may be because interventions had a short follow up of 3 months. This might be sufficiently long to show a difference in manager outcomes, but it may not be long enough to show a change in employee outcomes, including mental wellbeing. Therefore, the committee agreed that further research is needed on employee outcomes with longer follow ups (see the recommendation for research on training for managers).
## How the recommendations might affect practice
The committee agreed that most organisations with a management structure would have some form of manager training programme, and that these recommendations reflect good practice in training managers. If the recommendations are built into those existing training structures, the committee agreed the resource impact of these recommendations would be small. For other organisations, the committee agreed that buying in external training could be expensive, but that training costs could be minimised by using free training resources.
Return to recommendations
# Individual-level approaches
Recommendations 1.6.1 to 1.6.4
## Why the committee made the recommendations
The committee agreed that within the 3‑tiered approach covered in the section on strategic approaches to improving mental wellbeing in the workplace, it was important for organisations to prioritise an organisational approach to improving mental wellbeing in the workplace. The committee emphasised that individual-level approaches are not a suitable alternative to organisational-level approaches because these are less likely to be effective on their own. So, individual approaches need to be additional to organisational approaches and not a substitute for them.
The committee recognised the importance of good relationships between managers and employees, and of employees being able to approach managers to discuss any concerns. Making opportunities – for example, for small talk – to develop good relationships could help with this. This would help employees to discuss issues they may have outside work and it may help to identify support that could be put into place. The committee also highlighted that in some cases, a manager could have a negative impact on an employee's mental wellbeing. Therefore, mechanisms are needed for employees to discuss any concerns with an appropriate person.
The committee saw evidence on a range of individual-level interventions that aimed to improve mental wellbeing in an unselected population. They were clear that these were not a substitute for organisational-level approaches. The evidence they were presented with had some limitations, but the committee agreed that mindfulness, meditation and yoga were most effective overall in reducing job stress and mental health symptoms and having a positive effect on employee mental wellbeing. The evidence showed that these interventions were effective when delivered either in a group or online. The committee decided that employees should be able to choose how the interventions are delivered (see the section on engaging with employees and their representatives).
The committee noted a lack of evidence about the long-term effectiveness of universal individual-level interventions in all organisations (see the recommendation for research on individual-level interventions) and a lack of evidence about the specific needs of different groups, for example different age groups or employees from different cultural backgrounds that prevented them from making specific recommendations about this. (See the recommendations for research on the needs of different employee groups.)
## How the recommendations might affect practice
The committee recognised that many small businesses would not have the resources to provide mindfulness, yoga or meditation interventions, but noted that there are free or low-cost options for all of these, which would only need signposting by employers.
Return to recommendations
# Approaches for employees who have or are at risk of poor mental health
Recommendations 1.7.1 to 1.7.5
## Why the committee made the recommendations
The committee raised concerns that managers may face difficulties around confidentiality if they think that an employee is at risk of harming themselves or others. To reduce the burden placed on individuals, the committee decided that organisations should have clear policies on confidentiality.
The committee discussed that a preventive approach is important for reducing poor mental wellbeing. But they acknowledged that some employees will already have poor mental health and others will be at increased risk of poor mental health. Therefore, these employees should be offered support. The committee suggested that, although there was no specific evidence for them, wellness action plans were likely to be a useful way to open a dialogue between managers and employees about mental health concerns and what support could be put in place to help employees. They could also help to highlight needs for organisational change.
The evidence agreed with the committee's collective experience and showed that cognitive behavioural therapy, mindfulness and stress management were effective in improving mental wellbeing outcomes in employees with poor mental health. However, there was more limited evidence for cognitive behavioural therapy than for the other 2 options. They noted that if treatment is commissioned by the employer, they are required to check that the provider has the necessary qualifications and is accredited and regulated by relevant professional organisations to offer the interventions.
The committee noted that there was a potential resource impact for offering these and that for smaller organisations, free or low-cost options existed (for example, online resources such as the local Improving Access to Psychological Therapies scheme). The committee thought it was important that employees were made aware of the option to not have an intervention and to take up an offer of it at a later date, or to stop an intervention at any time and restart it later. This avoids employees feeling pressured to start or continue an intervention. They also agreed it was important that employers recognise that an employee may prefer a particular type of intervention, possibly because of their previous experiences with interventions.
The committee noted the lack of evidence about which strategies can be used to identify employees at risk of poor mental wellbeing. (See the recommendation for research on identifying employees at risk of poor mental wellbeing.)
## How the recommendations might affect practice
The recommendations reflect good practice around managing and supporting employees. The committee noted a potential resource impact to implement interventions, both in terms of work hours and financial resources. But this could be limited by using free resources.
They noted that there may be a resource impact to offering flexible working hours, job changes or other organisational support to people at risk of poor mental health but assessed that this would often be very low.
Return to recommendations
# Organisational-level approaches for high-risk occupations
Recommendations 1.8.1 to 1.8.3
## Why the committee made the recommendations
If the psychosocial risk assessment (see the section on strategic approaches to improving mental wellbeing in the workplace) for a role indicates that it is high risk, it is important that organisations have additional processes in place to support employees. The committee agreed that it was important to make sure these processes conformed to best practice in the field, and from their experience, they were able to identify Mind's Blue Light Programme as an example of best practice.
There was good evidence showing that when police and healthcare professionals were given the skills to deal with stressful occupational events through task-focused skills training (including imagery and simulation), mental health symptoms were reduced, and mental wellbeing and quality of life improved. Based on this evidence, the committee decided that organisations should provide task-focused skills training for employees in high-risk occupations. They also recommended, in line with the evidence, that employees in high-risk occupations are offered support after a traumatic event.
The committee noted that there were exceptional circumstances, for example, the COVID‑19 pandemic, which could cause stressful occupational events more widely (for example, some people might find homeworking or social distancing in the workplace stressful).
## How the recommendations might affect practice
All high-risk occupations should already have policies and procedures in place on how to deal with predictable and stressful occupational events. These recommendations will not affect the resources needed for this.
Return to recommendations
# Engaging with employees and their representatives
Recommendations 1.9.1 to 1.9.3
## Why the committee made the recommendations
The committee suggested that consulting employees about the type and format of organisational approaches and individual interventions offered would help employers understand what good mental wellbeing would look like in their organisation. It would also help them to tailor their approach to the needs of their employees and the organisation. They believed that this would give employers the opportunity to raise awareness about why the interventions are being implemented, which could improve employee support for them.
The committee discussed that by providing interventions during the working day, employers would give employees a beneficial break from work and send a clear message about the importance of mental wellbeing. However, organisations should be flexible because employees may also prefer to access interventions outside work hours. The committee also noted that people will have different preferences about how they learn. For example, some employees would benefit from a group setting, whereas others would prefer one-to-one or online interventions. This highlights the importance of engaging with employees to ensure that their needs are considered, and that if online interventions are offered, digital exclusion does not prevent any employee from accessing the intervention.
The committee also discussed, based on their experience, that the effectiveness of certain interventions may be different for different groups. Factors may include socioeconomic factors such as low income and whether people have disabilities, work in urban or rural locations or have good digital access. The committee agreed that staff surveys and consultation could be used to regularly monitor intervention accessibility.
## How the recommendations might affect practice
The committee discussed the resource implications of these recommendations but overall did not think they would be significant in most cases. They noted that some organisations may not be able to provide interventions during work hours for financial reasons. In these cases, it may be better to provide interventions outside work hours rather than not making them available at all. They also noted that some organisations may not have the space to provide certain interventions on site, and this may affect the type or format of intervention offered.
Return to recommendations
# Local and regional strategies and plans
Recommendations 1.10.1 to 1.10.9
## Why the committee made the recommendations
The committee discussed that local and regional authorities should be role models in ensuring that their own workplaces actively promote mental wellbeing, given their role in public health. The committee highlighted that many local and regional authorities already have strategies in place to improve physical wellbeing in their population, and that these could be expanded to include mental wellbeing as part of a more holistic approach to wellbeing. This includes working with employers to ensure they know about resources or services that can help them improve the mental wellbeing of their employees and minimise the resource impact that this will have, especially for small and medium-sized enterprises and micro-enterprises. This could be done together with local enterprise partnerships and chambers of commerce. This can also be tailored to the needs of each organisation.
The committee heard expert testimony about a mental health and productivity pilot that included the possibility of local authorities using financial incentives to encourage employers to think about job quality and wellbeing in their workplaces. The committee discussed this and also discussed that in times of financial hardship, there may be non-financial incentives that are more achievable for local authorities. Because there was limited evidence about this, the committee agreed that it would not be appropriate to recommend incentive schemes, but that any authorities interested in them could introduce them as a pilot or as an evaluation.
Local and regional authorities will have ethical procurement frameworks in place, and a duty under the Social Value Act to consider wider social, economic and environmental factors during procurement. Therefore, the committee suggested that local and regional authorities could consider how organisations in their supply chains value job quality and mental wellbeing in the workplace.
## How the recommendations might affect practice
Local and regional authorities already have schemes in place to help employers improve mental wellbeing in their workplaces, including the Department for Work and Pensions' access to work mental health support service. Many sources of support have already been curated by organisations such as Mind and Business in the Community, and local and regional authorities would only need to signpost employers to these.
The committee were aware that some local authorities may be having funding difficulties and did not want to place too much of a burden on them. Expert testimony about a mental health and productivity pilot discussed the possibility of local authorities using financial incentives to encourage employers to think about job quality and wellbeing in their workplaces. However, the committee noted that local and regional authorities may be able to provide other forms of incentives that do not need extra funds, for example dedicated advice and guidance.
Return to recommendations
# Making this guideline relevant for small and medium-sized enterprises (including micro-enterprises)
Recommendations 1.11.1 to 1.11.5
## Why the committee made the recommendations
The committee heard from expert testimony from the Thriving at Work Leadership Council that many business owners are at risk of poor mental health and exhaustion as a result of the pandemic. They noted that leaders need to ensure that they also consider their own mental wellbeing.
The committee noted that a lot of the evidence was from larger organisations, and that small and medium-sized enterprises (SMEs) are likely to have fewer resources to help them address mental wellbeing in the workplace, such as occupational health and human resource professionals. The committee discussed that taking a preventive approach to ensuring good mental wellbeing could avoid problems later on (for employees and for the organisation). They agreed that employers could find a lot of guidance and resources on how to do this through the Mental Health at Work website, and Health and Safety Executive resources.
Public bodies such as local authorities and local enterprise partnerships should also be able to signpost employees of SMEs to information on how to prevent poor mental wellbeing at work and promote positive mental wellbeing, as well as signposting them to resources and services to support employees with poor mental health, such as the Department for Work and Pensions' access to work mental health support service. The committee suggested that SMEs may also want to sign up to the Mental Health at Work Commitment, which is a framework to help organisations improve the mental wellbeing of their employees.
The committee agreed that further research into SMEs was needed – particularly on the specific needs of SMEs for implementing individual-level interventions and the long-term effectiveness of universal individual-level interventions in both larger organisations and SMEs. So they made a recommendation for research on specific needs of different kinds of micro, small and medium-sized enterprises (SMEs) in promoting mental wellbeing in the workplace, including organisational, targeted and individual-level approaches and a recommendation for research on long-term effectiveness of universal individual-level interventions in different kinds of SMEs. These would enable NICE to make more specific recommendations for SMEs in future.
## How the recommendations might affect practice
The committee were aware that, compared with larger organisations, SMEs may face additional constraints in terms of time and resources. The recommendations reflect ways that smaller organisations can look after the mental wellbeing of their workforce, without needing too much time or specialist knowledge about mental wellbeing.
The committee also discussed that employee assistance programmes and occupational health services may be a useful way of helping employees, and that smaller organisations may benefit from free or low-cost services such as the Department for Work and Pensions' access to work mental health support service or Mindful Employer.
Return to recommendations# Context
This guideline is for all people aged 16 or over in full-time or part-time employment, including those on permanent, training, temporary or zero-hours contracts, and those who are self-employed and volunteers.
This guideline has been updated because NICE identified new evidence that could affect the recommendations.
Despite evidence that better mental wellbeing and job satisfaction are associated with increased workplace performance and productivity, the government review Thriving at work estimates that 15% of UK workers have an existing mental health condition. Poor mental wellbeing costs employers in the UK an estimated £42 billion to £45 billion annually through presenteeism, sickness absence and staff turnover (Deloitte Mental health and employers: refreshing the case for investment).
The total annual cost of poor mental wellbeing to the government, including NHS costs, benefit provision and tax revenue losses, is between £24 billion and £27 billion. Lost output costs the economy between £74 billion and £99 billion (Thriving at work). Changes to workplaces and working patterns as a result of the COVID‑19 pandemic have had a large impact on working practices and organisational cultures; however, it is unclear what the longer-term effects of this will be.
Workplace policies and activities to promote and protect employee mental wellbeing vary widely. Mental wellbeing has been described as 'feeling good and functioning well', reinforcing that mental wellbeing is on a spectrum and positive mental wellbeing is not just the absence of symptoms of poor mental health. Consequently, the aim of interventions should not just be to prevent poor mental health, but instead should promote positive mental wellbeing.
The Department for Work and Pensions reports that most employers have basic health and wellbeing policies, including at least 1 covering flexible working, sick pay or injury training (Department for Work and Pensions Health and wellbeing at work: a survey of employees). Larger and public sector organisations are more likely to offer at least 1 of the following: health screening, occupational health services, independent counselling or stress management.
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{'Recommendations': "Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe recommendations in this guideline apply to micro, small, medium-sized and large organisations equally, although some recommendations may need to be tailored to specific organisations and circumstances.\n\n# Strategic approaches to improving mental wellbeing in the workplace\n\nAdopt a tiered approach to mental wellbeing in the workplace by using organisational-level approaches as the foundation for good mental wellbeing (the first [bottom] tier), followed by individual approaches (the second [middle] tier) and targeted approaches (the third [top] tier).\n\nAdopt a preventive and proactive strategic approach to mental wellbeing at work in your organisation. Take into account:\n\nworkplace culture\n\nworkload\n\njob quality and role autonomy\n\nconcerns that employers and employees may have about mental health, including stigma.See also the section on organisation-wide approaches.\n\nProactively promote mental wellbeing by ensuring that it is embedded in the overall business strategy of all organisational policies and practices. Take into account the recommendations in the section on supportive work environment.\n\nEnsure that a stress risk assessment is carried out for each role as required by the Health and Safety at Work etc Act 1974, for example using the Health and Safety Executive's risk assessment template:\n\nIf any risks are identified, take proactive steps to reduce the risks and their negative impacts.\n\nIf a high-risk role is indicated, see the section on organisational-level approaches for high-risk occupations.\n\nDiscuss with employees as necessary and feed back the results of the assessment to them.\n\nEnsure that systems are in place to provide support for employees for whom external factors are influencing their mental wellbeing. See the section on training and support for managers.\n\nMonitor and evaluate the support you provide at least on an annual basis using a relevant evaluation tool. Public Health England's evaluation in health and wellbeing provides a list of resources and summarises what they are used for.\n\nWhen measuring mental wellbeing, use a validated measure of mental wellbeing, for example the government's voluntary reporting on disability, mental health and wellbeing: a framework to support employers (for large employers), What Works Wellbeing's workplace wellbeing questionnaire or Warwick Medical School's Warwick-Edinburgh Mental Wellbeing Scales (WEMWBS).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on strategic approaches to improving mental wellbeing in the workplace\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: organisational universal-level approaches\n\nevidence review\xa0B: manager interventions\n\nevidence review\xa0C: targeted organisational-level approaches\n\nevidence review\xa0D: universal individual-level approaches\n\nevidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work\n\nevidence review\xa0G: expert testimony.\n\nLoading. Please wait.\n\n# Supportive work environment\n\nFoster a positive, compassionate and inclusive workplace environment and culture to support psychological safety and mental wellbeing by:\n\nensuring active leadership and management support and engagement\n\nincreasing mental health literacy\n\nencouraging and facilitating peer support (for example, using mental health champions and peer mentoring or 'buddying')\n\nsupporting people who manage and support employees\n\nencouraging employees to recognise and take action to prevent discrimination in the workplace, for example by establishing and supporting staff networks\n\nbeing aware that mental wellbeing in the workplace also depends on factors beyond the workplace itself (such as physical health, domestic relationships, home environment and financial circumstances) and also on societal discrimination (such as racism, homophobia and sexism)\n\npromoting good communication and engagement with employees\n\nincluding mental health awareness in manager training (see the section on training and support for managers).\n\nDevelop policies, processes and ways of working with staff that are equitable and inclusive, and that encourage a fair and supportive workplace environment and culture, in order to maximise employee wellbeing. Take into account:\n\nlegal obligations (such as the Equality Act 2010 and Health and Safety at Work etc Act\xa01974)\n\nstatutory requirements (such as the ACAS codes of practice)\n\nemployer-led strategies or interventions (such as anti-bullying, work-life balance, confidentiality and flexible working).\n\nOffer employees a private space and protected time to engage with interventions, taking into account the need for confidentiality.\n\nEnsure that all employees have the opportunity and the means to access interventions (such as private access to the internet and IT equipment for remotely delivered interventions).See also the sections on organisational commitment, senior leadership and leadership style of line managers in the NICE guideline on workplace health: management practices, and the section on workplace culture and policies in NICE's guideline on workplace health: long-term sickness absence and capability to work.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supportive work environment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: organisational universal-level approaches\n\nevidence review\xa0B: manager interventions\n\nevidence review\xa0C: targeted organisational-level approaches\n\nevidence review\xa0D: universal individual-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n# External sources of support\n\nUse external expertise in the local authority (see the section on local and regional strategies and plans), Department for Work and Pensions and other agencies (for example, from the voluntary, charity and social enterprise sector or chambers of commerce) to access support for employees, including action plans and toolkits (for example, from What Works Wellbeing, Business in the Community, Mind and the Health and Safety Executive).\n\nMake employees aware that if they have mental health problems, they can use the Department for Work and Pensions' access to work mental health support service. NHS and social care staff can use the staff mental health and wellbeing hubs (and other national health and wellbeing support offers).\n\nUse local and national resources, and advice from a variety of evidence-informed sources, such as the local Improving Access to Psychological Therapies services offer, the employee's GP, professional bodies, unions and trade organisations (for example, Federation of Small Businesses, ACAS and the Chartered Institute of Personnel and Development [CIPD]).See also the section on early intervention in NICE's guideline on workplace health: long-term sickness absence and capability to work.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on external sources of support\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: organisational universal-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work\n\nevidence review G: expert testimony.\n\nLoading. Please wait.\n\n# Organisation-wide approaches\n\nInvolve employees and workplace representatives in identifying and minimising sources of stress at work. (See also the section on job design in NICE's guideline on workplace health: management practices.)\n\nConsider using workplace accreditations or charters, such as guidance to improve the organisation-wide workplace environment and culture (for example, the Workplace Wellbeing Charter, Mindful Employer and Mind's Workplace Wellbeing Index).\n\nTailor interventions to meet the needs of the organisation and its employees (for example, according to the industry sector or the size of the organisation).\n\nRefer to existing guidance and best practice on job quality, work design and organisation to identify and reduce work stressors, such as Health and Safety Executive's Management Standards for work-related stress, Mindful Employer or COVID‑19-specific advice (for example, from the CIPD).\n\nConsider using staff surveys or other engagement approaches, for example working with employee representative organisations (such as trade unions or staff networks), to determine whether tailored solutions are needed to improve mental wellbeing in the workplace (for example, What Works Wellbeing's employee wellbeing snapshot survey).\n\nConsider giving all employees free access to an employee assistance programme and occupational health services, and raise awareness of them if they are offered (for small and medium-sized enterprises). (See also the section on making this guideline relevant for small and medium-sized enterprises [including micro-enterprises]).\n\nHave a plan for responding to unexpected traumatic events affecting employees, such as the death of a colleague, a pandemic or a terrorist attack. This should include supporting people socially and with their mental wellbeing. For example, see the UK Health Security Agency's course on COVID-19: psychological first aid or NHS England and NHS Improvement's guidance on responding to the needs of people affected by incidents and emergencies.See also the section on monitoring and evaluation in NICE's guideline on workplace health: management practices.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisation-wide approaches\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: organisational universal-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work\n\nevidence review G: expert testimony.\n\nLoading. Please wait.\n\n# Training and support for managers\n\nOffer systematic support for managers. Include training, and regular refresher training, in:\n\nline management\n\ncommunication skills (the ability to listen, communicate clearly, understand and empathise).\n\nEquip managers with the knowledge, tools, skills and resources to:\n\nimprove awareness of mental wellbeing at work\n\npromote mental wellbeing and prevent poor mental wellbeing\n\nimprove employees' understanding of and engagement in organisational decisions\n\nimprove communication between managers and employees.This should include managing people remotely.\n\nWhen offering mental health training for managers, consider including:\n\nhow to have a conversation on mental wellbeing with an employee, including at times of crisis\n\ninformation about mental wellbeing\n\nhow to identify early warning signs of poor mental wellbeing\n\nresources on mental wellbeing, including knowing where to go for further help or support in complex situations\n\nawareness of the stigma associated with poor mental wellbeing\n\nongoing management and monitoring of mental wellbeing in the workplace\n\ntopics suggested by managers.\n\nEnsure that all managers have time to attend relevant training sessions.\n\nEmpower managers to make necessary adjustments to workload or work intensity for their employees, for example flexible or hybrid working.\n\nEncourage managers to address their own mental health needs as well as those of their employees, for example by peer-to-peer support for managers on mental wellbeing.\n\nConsider a group approach to deliver mental health training. Training could be delivered either face to face or using online formats.\n\nEvaluate how mental health training for managers affects employee outcomes (for example, by surveying employees and managers or focus groups) and feed the results back into future training and strategy.See also the section on training in NICE's guideline on workplace health: management practices.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on training and support for managers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B: manager interventions\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work\n\nevidence review G: expert testimony.\n\nLoading. Please wait.\n\n# Individual-level approaches\n\nDo not use individual-level approaches to replace organisational strategies for reducing work stressors, or for the main purpose of increasing productivity.\n\nEncourage managers to create opportunities for fostering good relationships with (and between) employees, for example by socialising with them at work (in person or virtually). Create opportunities to talk with them about their general health and wellbeing.\n\nEncourage managers to discuss mental wellbeing with employees, and employees to discuss any mental wellbeing concerns they may have with their manager or another relevant person (for example, another manager, a mental wellbeing champion or a union representative):\n\nUse these conversations to identify and understand any sources of stress.\n\nAgree whether any additional support is needed and what this might be (see the section on external sources of support).\n\nAgree steps to minimise work-related stressors (see the section on approaches for employees who have or are at risk of poor mental health).\n\nOffer all employees (or help them to access) mindfulness, yoga or meditation on an ongoing basis. This can be delivered in a group or online, or using a combination of both.See also the section on supporting employers in NICE's guideline on physical activity in the workplace.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on individual-level approaches\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: targeted organisational-level approaches\n\nevidence review D: universal individual-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n# Approaches for employees who have or are at risk of poor mental health\n\nEnsure that confidentiality is discussed when talking with someone about their mental health (see recommendation\xa01.2.2), and be clear about when confidentiality will and will not be respected (that is, when the employee is considered at risk to themselves or others because of their mental health).\n\nOffer organisational support to employees identified as having or being at risk of poor mental health. This may include flexible working hours; changes to the job, workplace or culture to minimise any risks to mental wellbeing; or maintaining supportive line management relationships. (See recommendation\xa01.5.5 and recommendation\xa01.6.3.) Remind them that they can visit their GP for further assessment and support.\n\nConsider working with them to create a wellness action plan (see Mind's guides to wellness action plans).\n\nAssess whether this has highlighted if changes need to be made at an organisational level.\n\nDiscuss with the employee if they would like to:\n\nhave further support and, if so, whether they prefer a particular type of support\n\nhave ongoing regular, confidential discussions about their mental health support needs.\n\nFor employees who want further support, offer (or provide access to):\n\ncognitive behavioural therapy sessions or\n\nmindfulness training or\n\nstress management training.If employees choose not to have an intervention now, tell them that the offer will still be available in the future if they reconsider.\n\nReassure colleagues that it is their choice whether to continue with an intervention or restart it at any time.See also the sections on sustainable return to work and reducing recurrence of absence in NICE's guideline on workplace health: long-term sickness absence and capability to work.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on approaches for employees who have or are at risk of poor mental health\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C: targeted organisational-level approaches\n\nevidence review D: universal individual-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n# Organisational-level approaches for high-risk occupations\n\nThe following recommendations are aimed at organisations, workplaces or workforces where employees are likely to experience traumatic events in the normal course of their work (such as the emergency services). See also recommendation\xa01.1.4.\n\nRegularly review organisational-level policies and protocols on how to support employees in high-risk occupations after an occupational traumatic event. Use data such as reasons for absence and staff turnover to ensure that support is targeted in the right way.\n\nEnsure that practice is consistent with established best practice (for example, Mind's Blue Light Programme).\n\nOffer task-focused skills training (for example, through imagery, simulation and skills training) before deployment for employees in high-risk occupations (such as emergency services) to ensure that they have the skills needed to deal with predictable and stressful occupational events.See also NICE's guideline on post-traumatic stress disorder.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisational-level approaches for high-risk occupations\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: universal individual-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n# Engaging with employees and their representatives\n\nWork with employees and their representative organisations (for example, trade unions and staff networks; see recommendation\xa01.2.1) to consult about how, when and where mental wellbeing interventions are offered and delivered, for example through staff surveys.\n\nTake account of the following potential barriers and facilitators when consulting with employees about interventions:\n\nworkplace culture (including the concern that raising issues can impact negatively on staff roles or job security)\n\nworkload\n\nconcerns that employers and employees may have about mental health, including stigma, and how this may affect their ability to discuss any difficulties or engage with certain forms of support\n\ntiming of the intervention and the option of delivering it in and outside the workplace and work hours\n\nspecific needs and preferences of employees\n\nspecific reasonable needs of the employing organisation.\n\nEnsure that factors associated with an employee such as contract type, income level, protected characteristics and job role are not barriers to accessing interventions. Do this by:\n\nmonitoring intervention uptake and identifying groups where uptake is relatively low\n\nhaving a mechanism to identify, understand and overcome barriers to participating in the intervention.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on engaging with employees and their representatives\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n# Local and regional strategies and plans\n\nThese recommendations are for local and regional authorities.\n\nTake a leadership role in championing mental wellbeing and preventing poor mental wellbeing at work as part of the local authority role in public health and wellbeing.\n\nEngage with local and regional employers, employee representatives, chambers of commerce, local enterprise partnerships and voluntary, charity and social enterprises to develop and promote health and wellbeing strategies to include mental wellbeing at work.\n\nIntegrate mental wellbeing at work into local and regional public health activities and strategies.\n\nRaise awareness among the general public and employers of the importance of mental wellbeing at work, for example through social media.\n\nIdentify and address local barriers and facilitators to employer engagement with local mental wellbeing at work initiatives. This could include, for example, working with employers to ensure they know about resources or services that can help them improve the mental wellbeing of their employees and minimise the resource impact that this will have, especially for micro, small and medium-sized enterprises.\n\nOffer support to help local employers improve the mental wellbeing and prevent poor mental wellbeing of their employees. This support could include advice on enablers of mental health and on developing action plans towards accreditation (see recommendation\xa01.4.2) or setting up a Local Workplace Health Accreditation Scheme.\n\nCurate or work with local business support organisations to list local and national sources of support for employers and employees, such as Mind, Mental Health at Work, the Department for Work and Pensions' access to work mental health support service and, for NHS and social care staff, staff mental health and wellbeing hubs (and other national health and wellbeing support offers).\n\nExplore and evaluate the value of incentives or pilot incentive programmes to promote uptake of support and encourage employers to participate in accreditation schemes (see recommendation\xa01.4.2).\n\nUse contracting and ethical procurement arrangements to strongly encourage supply chain organisations to promote mental wellbeing among their employees (for example, public sector organisations must use the Public Services [Social Value] Act 2012).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on local and regional strategies and plans\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work\n\nevidence review G: expert testimony.\n\nLoading. Please wait.\n\n# Making this guideline relevant for small and medium-sized enterprises (including micro-enterprises)\n\nBusiness owners and owner-managers should address their own mental health needs as well as those of their employees.\n\nTake a preventive approach to mental wellbeing at work, for example using mental health and communication skills training to foster positive mental wellbeing, as well as tackling poor mental wellbeing. Refer to the Mental Health at Work website for curated resources and toolkits on how to improve the mental wellbeing of your employees.\n\nSeek advice and support from local authorities; local enterprise partnerships; voluntary, charity and social enterprises; trade unions and other bodies; and, for NHS and social care staff, staff mental health and wellbeing hubs (and other national health and wellbeing support offers), on how to prevent poor mental wellbeing in your employees, and how to support employees through mental ill health.\n\nThink about signing up to the Mental Health at Work Commitment to help achieve better mental health outcomes for employees.\n\nThink about accessing employee assistance programmes and occupational health services. See the Department for Work and Pensions' access to work mental health support service as an example of a low-cost service (see recommendation 1.11.2).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on additional approaches for small and medium-sized enterprises\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: universal individual-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work\n\nevidence review G: expert testimony.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions, see the NICE glossary and the Think Local Act Personal's Care and Support Jargon Buster.\n\n## Employee\n\nEveryone aged 16\xa0or over in full- or part-time employment, including people on permanent, training, temporary or zero-hours contracts, those who are self-employed and volunteers.\n\n## Mental health literacy\n\nA person's knowledge and beliefs about mental health problems and how to look after their own mental health. It includes knowing how mental health problems are managed and treated, how to seek information about them and how to recognise them.\n\n## Organisation\n\nFor the purposes of this guideline, organisation refers to any size of workplace, including micro, small and medium-sized enterprises.\n\n## Psychological safety\n\nA person's desire and need to feel comfortable and safe in the workplace to express themselves and communicate openly.\n\n## Role autonomy\n\nA person's ability to influence what happens in their work environment, in particular to influence matters that are relevant to their personal goals and the way in which they carry out their work.\n\n## Staff networks\n\nGroups of employees who come together in a safe environment for discussion and support, and from which they can be a voice for change in the workplace. This includes raising awareness of issues in the wider organisation. They are commonly groups of people who identify as an under-represented group or who have a protected characteristic in the Equality Act\xa02010.\n\n## Stress\n\nThe Health and Safety Executive (HSE) guide on working together to reduce stress at work defines stress as the adverse reaction people have to excessive pressures or other types of demand placed on them.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Individual-level interventions\n\nWhat is the long-term effectiveness and cost effectiveness of universal individual-level interventions on mental wellbeing in different types of organisations?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on individual-level approaches\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: universal individual-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n## Organisational-level approaches for all organisations\n\nWhat is the long-term impact and cost effectiveness of employee assistance programme provision on mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on organisation-wide approaches\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: organisational universal-level approaches.\n\nLoading. Please wait.\n\n## Training for managers\n\nWhat is the long-term effectiveness (more than 6\xa0months) of manager training on employee mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on training and support for managers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B: manager interventions\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n## Approaches for micro, small and medium-sized enterprises\n\nWhat are the specific needs of different kinds of micro, small and medium-sized enterprises (SMEs) in promoting mental wellbeing in the workplace, including organisational, targeted and individual level approaches?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on additional approaches for small and medium-sized enterprises\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: universal individual-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n## Core outcomes for study reporting\n\nWhich mental wellbeing and productivity outcomes should be used in a core outcome set for research into workplace mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on strategic approaches to improving mental wellbeing in the workplace\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: organisational universal-level approaches\n\nevidence review\xa0B: manager interventions\n\nevidence review\xa0C: targeted organisational-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Supportive work environment\n\nWhat are the views of organisations about the benefits of investing in mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on supportive work environment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: organisational universal-level approaches\n\nevidence review\xa0B: manager interventions\n\nevidence review\xa0C: targeted organisational-level approaches\n\nevidence review\xa0D: universal individual-level approaches\n\nevidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n## Identifying employees at risk of poor mental wellbeing\n\nWhat tools (for example, wellbeing surveys) can be used to identify employees at risk of poor mental wellbeing rather than mental ill health?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on approaches for employees who have or are at risk of poor mental health\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A: organisational universal-level approaches\n\nevidence review F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n## Needs of different employee groups\n\nWhat specific needs of employees from different groups (such as income levels, ethnic groups, male or female groups, and age groups) need addressing to facilitate access to individual-level interventions?\n\nHow effective are individual-level interventions across different groups (such as income levels, ethnic groups, male or female groups, and age groups)?\n\nFor a short explanation of why the committee made the recommendations for research, see the rationale section on individual-level approaches\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: targeted organisational-level approaches\n\nevidence review\xa0D: universal individual-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n## Approaches for micro, small and medium-sized enterprises\n\nWhat is the long-term effectiveness of universal individual-level interventions in different kinds of SMEs?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on making this guideline relevant for small and medium-sized enterprises (including micro-enterprises)\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0D: universal individual-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.\n\n## Addressing study reporting\n\nWhat are the key characteristics of an organisation and its employees that need to be included in reporting research into workplace mental wellbeing?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on strategic approaches to improving mental wellbeing in the workplace\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: organisational universal-level approaches\n\nevidence review\xa0B: manager interventions\n\nevidence review\xa0C: targeted organisational-level approaches\n\nevidence review\xa0E: targeted individual-level approaches\n\nevidence review\xa0F: barriers and facilitators to the implementation and delivery of interventions to improve and protect mental wellbeing at work.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Strategic approaches to improving mental wellbeing in the workplace\n\nRecommendations 1.1.1 to 1.1.7\n\n## Why the committee made the recommendations\n\nThe committee noted that the range and nature of workplaces and organisations (especially in terms of the number of employees) made it challenging to make generic recommendations for all organisations. They agreed that some organisations might need to tailor the recommendations to make them relevant.\n\nThe committee agreed on the need for organisations to embed strategic approaches to mental wellbeing into their organisational policies and practices, based on their understanding that this approach was fundamental to mental wellbeing at work and based on the evidence and expert testimony.\n\nThe committee recognised that the ability of organisations to promote and support mental wellbeing is negatively affected by health inequalities and by work stressors such as bullying, poor communication, job insecurity (including zero-hours contracts), workload, monotony, isolation and poor prospects. In contrast, it is enhanced by good job quality (including a fair wage), role autonomy, organisational fairness, respect, recognition, peer support and clear communication. The committee were clear that some of these factors were outside of the remit of this guideline.\n\nA wide range of evidence from the UK showed that organisation-wide interventions may help to improve mental wellbeing and stress outcomes for employees, and may also benefit employers. The committee agreed that, in their experience, 1\xa0of the key foundations of mental wellbeing in the workplace was an organisational commitment to it, together with a recognition that mental wellbeing is a spectrum and poor mental wellbeing is not a weakness. Organisations that took a strategic and whole-hearted approach to improving mental wellbeing from the top down tended to have the most success. The committee agreed that this was best demonstrated by organisations with a preventive and proactive approach to mental wellbeing – that is, they proactively took steps to promote mental wellbeing rather than simply tackling poor mental wellbeing. They agreed that because these organisational-level responses were so important, the first recommendations in the guideline should establish that organisation-wide strategic approaches were the foundation of good mental wellbeing at work, and that individual and targeted approaches could enhance these but were not a substitute for them. In the committee's experience, it is unlikely that individual or targeted interventions would be successful without an organisation-wide approach, but it noted the temptation for organisations to start with individual approaches because it seems easier.\n\nThe committee also agreed with expert testimony on the impacts of the pandemic on mental wellbeing in the workplace that highlighted the need to view mental wellbeing as equally important to physical wellbeing in the workplace and to take it into account when drafting polices or introducing new practices.\n\nExpert testimony about the long-term impacts of the COVID‑19 pandemic on mental wellbeing in the workplace highlighted that employers of all sizes are legally required to carry out a stress risk assessment for each role (and record it if they have more than 5\xa0employees) under the Health and Safety at Work etc Act 1974. The committee saw this as a good opportunity for organisations to identify risks to employees' mental wellbeing, and subsequently take steps to reduce stressors.\n\nThe committee also highlighted that employees may have poor mental wellbeing as a result of external factors that are beyond the control of the employer, such as caring responsibilities, health concerns and discrimination (such as homophobia or racism). But they agreed that it is important for organisations to ensure that they provide additional support to groups affected by these issues.\n\nThe committee also agreed, based on their experience, that it is important for any interventions to be evaluated and monitored as part of an ongoing strategy of employee engagement, and that validated measures of wellbeing need to be part of this process.\n\nThe committee noted that further research is needed to understand how data and outcomes could best be used to improve mental wellbeing in the workplace. In particular, research could investigate which outcomes would be useful in a core outcome set for research into workplace mental wellbeing, and to understand how more detailed reporting of the nature of organisation and employee characteristics can be included in research into workplace mental wellbeing (see the recommendations for research on core outcomes for study reporting and addressing study reporting).\n\n## How the recommendations might affect practice\n\nThe use of tiered approaches to support mental wellbeing at work reflects best practice and therefore would not have a large resource impact in organisations that have already adopted best practice. This may have more of an impact for other organisations. Smaller organisations may not always have the resources to offer all aspects of the tiered approach. They can best use resources by concentrating on ensuring that they have an organisation-wide approach in place. Improving employee wellbeing might lead to less absenteeism and presenteeism and may improve staff retention and productivity.\n\nReturn to recommendations\n\n# Supportive work environment\n\nRecommendations 1.2.1 to 1.2.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that overall, a supportive, inclusive work environment and climate is crucial for good mental wellbeing in the workforce. Social interactions, including those between managers and employees, play an important role in this.\n\nHaving the right policies can help to create a supportive workplace environment and culture. It can help to ensure that leadership is supportive and engaged, that there are effective peer support networks and there is good organisational-wide mental health literacy. A supportive work environment can be achieved by adhering to existing legal obligations (such as health and safety) and statutory requirements (such as the ACAS codes of practice), and engaging with employees to draft and refine policies such as anti-bullying.\n\nOrganisations can also promote mental wellbeing interventions by reducing any potential barriers to using them and supporting employees to access them. This would embed the importance of mental wellbeing into the organisational culture (see the section on engaging with employees and their representatives).\n\nDespite the lack of strong evidence for leadership interventions, the committee were confident that management buy‑in is important for promoting the wellbeing of employees. They cited the government review Thriving at work, which provides an evidence-based whole-settings approach to improving mental wellbeing, including the importance of leadership, culture and effective people management.\n\nThe committee noted that there was little evidence on the views of organisations about mental wellbeing. (See the recommendation for research on supportive work environment.)\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current good practice around communication across the organisation, active leadership involvement and engagement with employees. The committee noted that many organisations would already have structures in place like those they recommended, and that to align them with the recommendations would not have a large resource impact. The committee agreed that for organisations that were resource poor and that had not previously invested in a supportive work environment, the use of freely available external resources could help minimise costs.\n\nReturn to recommendations\n\n# External sources of support\n\nRecommendations 1.3.1 to 1.3.3\n\n## Why the committee made the recommendations\n\nThe committee agreed that supporting mental wellbeing in the workplace might be particularly challenging for organisations with limited resources, especially micro, small and medium-sized ones. They agreed that it was important to help employers find external, low-cost or free resources to support them in promoting mental wellbeing.\n\nBased on expert testimony from a mental health and productivity pilot and their experience, the committee agreed that it was the responsibility of employers and local and regional authorities to be aware of sources of support available in their area. These sources could be national, local or within the organisation, for example an occupational health service or an employee assistance programme (if the organisation has these). By being able to direct employees to these, employers will be helping and supporting employees by providing them with tools and resources.\n\nThe Department for Work and Pensions' access to work mental health support service has guidance to help employers understand mental ill health and how to support employees with mental health concerns. It can also support employees by offering eligible employees an assessment to find out their needs and help them develop a support plan.\n\n## How the recommendations might affect practice\n\nThe recommendations encourage employers to use expertise and resources that are external to their organisation when appropriate. These sources of support are freely available and will provide employers with information and resources to support their employees. They will also help organisations who are committed to improving the mental wellbeing of their employees to manage the resource impact.\n\nReturn to recommendations\n\n# Organisation-wide approaches\n\nRecommendations 1.4.1 to 1.4.7\n\n## Why the committee made the recommendations\n\nEvidence from the UK showed that organisation-wide interventions may help to improve mental wellbeing and stress outcomes for employees and may also benefit employers. Although the evidence had some limitations in terms of its quality, the committee concluded that the work environment can be improved in 2\xa0ways: employers can work with their employees to identify work stressors and put in place solutions to deal with these stressors, or employers can use evidence-based methods that are specifically tailored to their organisation. The committee clarified their use of the word 'stress' to be the adverse reaction people have to excessive pressures or other types of demand placed on them.\n\nBased on the evidence and their experience, the committee strongly advised that organisational-level approaches are the best starting point when considering strategies to improve mental wellbeing at work. These approaches demonstrate a commitment to mental wellbeing at work, which is essential for encouraging employees to take up interventions. The committee emphasised that individual-level approaches are not a suitable alternative to organisational-level approaches because these are less likely to be effective on their own. They noted that because of the variation in the size and structure of workplaces, many interventions might need to be tailored to match the specific workplace in which they were going to be delivered. This could be done through staff surveys, for example.\n\nThe committee heard expert testimonies about insights from the Thriving at Work Leadership Council, the mental health and productivity pilot, participatory organisational interventions, and prevention and management of work-related stress and mental ill health. They agreed with the experts that striving to attain workplace charters or accreditation was a useful way for organisations to work with external bodies to improve mental wellbeing and make their organisation a more attractive place to work. These would also allow employers to access external support and advice about improving and maintaining mental wellbeing at work. The committee also agreed that existing guidance, such as the Health and Safety Executive's Management Standards for work-related stress, would be useful.\n\nThe committee agreed that employee assistance programmes and occupational health services are good options for supporting employees' mental wellbeing, although they noted that there was a lack of evidence about how effective they are. They agreed with expert testimony about major challenges to small and medium-sized enterprises in improving the mental wellbeing of staff, what they can do to improve staff mental wellbeing and that low-cost schemes such as Mindful Employer may be useful for smaller organisations with limited resources. The committee also discussed that some employees in occupations that are not generally considered high-risk may be exposed to traumatic events at work – for example, because of a pandemic or terror attack – and that employers need to have plans in place to support employees in case such events do occur.\n\nThe lack of published evidence about the effectiveness of employee assistance programmes led the committee to make a recommendation for research on organisational-level approaches for all organisations because evidence on this could help NICE to make more specific recommendations on this topic in future.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good practice in communication across the organisation, in active leadership involvement and in engaging with employees. There should not be an extensive resource impact because the recommendations involve adhering to existing best practice.\n\nReturn to recommendations\n\n# Training and support for managers\n\nRecommendations 1.5.1 to 1.5.8\n\n## Why the committee made the recommendations\n\nThe committee agreed it was important that all line managers received training and support. They considered that this was good practice in all industries and all sizes of organisation, and that managers benefit in terms of their mental wellbeing from feeling skilled to perform their line management duties.\n\nThere was a range of evidence showing that manager training interventions were effective (especially in terms of outcomes for the manager who had been trained) or had no effect, although the committee noted that much of this evidence was uncertain. There was no evidence of unintended consequences associated with these interventions. There was some higher quality evidence that manager training can help to increase managers' knowledge of how to reduce stigma, and also help to increase their confidence in identifying and supporting employees who may be at risk of poor mental health. This agreed with the experience of the committee, who found that training managers in mental health awareness can increase their knowledge and willingness to discuss mental health.\n\nReducing stigma and equipping managers with skills to have conversations with employees about mental health is likely to facilitate conversations between managers and employees about any concerns about their mental wellbeing. This makes it more likely that managers can support employees with mental health issues. Providing managers with skills to discuss mental wellbeing improves the relationship between manager and employee so that they can identify and reduce work stressors. The evidence also showed that increasing managers' knowledge leads to more employees using the support services on offer. Although the evidence was not strong in this area, the committee agreed some points that would be a useful core for the content of mental health training for managers. They also agreed it was important for people to be able to suggest topics they thought were important.\n\nThe committee agreed with the qualitative evidence that manager training interventions delivered in groups had added benefit because they allow managers to learn from each other and to reinforce best practice. Therefore, the committee agreed, based on their experience and the evidence, that it can be helpful to offer group training as part of mental health awareness training. But they acknowledged that this might not be possible, for example in smaller organisations. Expert testimony about major challenges to small and medium-sized enterprises in improving the mental wellbeing of staff and what they can do to improve staff mental wellbeing, managing mental health in the workplace during and after COVID‑19, and committee experience, highlighted that managers have additional pressures related to their role, and that delivering any training in a group format would provide peer support. The committee also discussed that because of the increased pressures faced by managers, it is important that they are supported by human resources, occupational safety, and health and wellbeing professionals.\n\nThe committee discussed expert testimony about managing mental health in the workplace during the COVID‑19 pandemic and about the likely long-term impacts of COVID‑19 on mental wellbeing in the workplace. It helped them to make recommendations about the content of management training to support mental wellbeing. They agreed that managers should be empowered to make reasonable adjustments to the workload or intensity to reduce stressors for employees. This would give employees relief from work stress sooner because requests would not need to be escalated before support could be given. This expert testimony also highlighted the value of peer-to-peer support for managers, which the committee agreed matched their own expert experience.\n\nThe committee further discussed that although there was some data on the effectiveness of the interventions reviewed in terms of employee outcomes, overall, there was insufficient data and they had to extrapolate from their expertise and experience along with the small amount of evidence they had. They suggested that this may be because interventions had a short follow\xa0up of 3\xa0months. This might be sufficiently long to show a difference in manager outcomes, but it may not be long enough to show a change in employee outcomes, including mental wellbeing. Therefore, the committee agreed that further research is needed on employee outcomes with longer follow\xa0ups (see the recommendation for research on training for managers).\n\n## How the recommendations might affect practice\n\nThe committee agreed that most organisations with a management structure would have some form of manager training programme, and that these recommendations reflect good practice in training managers. If the recommendations are built into those existing training structures, the committee agreed the resource impact of these recommendations would be small. For other organisations, the committee agreed that buying in external training could be expensive, but that training costs could be minimised by using free training resources.\n\nReturn to recommendations\n\n# Individual-level approaches\n\nRecommendations 1.6.1 to 1.6.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that within the 3‑tiered approach covered in the section on strategic approaches to improving mental wellbeing in the workplace, it was important for organisations to prioritise an organisational approach to improving mental wellbeing in the workplace. The committee emphasised that individual-level approaches are not a suitable alternative to organisational-level approaches because these are less likely to be effective on their own. So, individual approaches need to be additional to organisational approaches and not a substitute for them.\n\nThe committee recognised the importance of good relationships between managers and employees, and of employees being able to approach managers to discuss any concerns. Making opportunities – for example, for small talk – to develop good relationships could help with this. This would help employees to discuss issues they may have outside work and it may help to identify support that could be put into place. The committee also highlighted that in some cases, a manager could have a negative impact on an employee's mental wellbeing. Therefore, mechanisms are needed for employees to discuss any concerns with an appropriate person.\n\nThe committee saw evidence on a range of individual-level interventions that aimed to improve mental wellbeing in an unselected population. They were clear that these were not a substitute for organisational-level approaches. The evidence they were presented with had some limitations, but the committee agreed that mindfulness, meditation and yoga were most effective overall in reducing job stress and mental health symptoms and having a positive effect on employee mental wellbeing. The evidence showed that these interventions were effective when delivered either in a group or online. The committee decided that employees should be able to choose how the interventions are delivered (see the section on engaging with employees and their representatives).\n\nThe committee noted a lack of evidence about the long-term effectiveness of universal individual-level interventions in all organisations (see the recommendation for research on individual-level interventions) and a lack of evidence about the specific needs of different groups, for example different age groups or employees from different cultural backgrounds that prevented them from making specific recommendations about this. (See the recommendations for research on the needs of different employee groups.)\n\n## How the recommendations might affect practice\n\nThe committee recognised that many small businesses would not have the resources to provide mindfulness, yoga or meditation interventions, but noted that there are free or low-cost options for all of these, which would only need signposting by employers.\n\nReturn to recommendations\n\n# Approaches for employees who have or are at risk of poor mental health\n\nRecommendations 1.7.1 to 1.7.5\n\n## Why the committee made the recommendations\n\nThe committee raised concerns that managers may face difficulties around confidentiality if they think that an employee is at risk of harming themselves or others. To reduce the burden placed on individuals, the committee decided that organisations should have clear policies on confidentiality.\n\nThe committee discussed that a preventive approach is important for reducing poor mental wellbeing. But they acknowledged that some employees will already have poor mental health and others will be at increased risk of poor mental health. Therefore, these employees should be offered support. The committee suggested that, although there was no specific evidence for them, wellness action plans were likely to be a useful way to open a dialogue between managers and employees about mental health concerns and what support could be put in place to help employees. They could also help to highlight needs for organisational change.\n\nThe evidence agreed with the committee's collective experience and showed that cognitive behavioural therapy, mindfulness and stress management were effective in improving mental wellbeing outcomes in employees with poor mental health. However, there was more limited evidence for cognitive behavioural therapy than for the other 2\xa0options. They noted that if treatment is commissioned by the employer, they are required to check that the provider has the necessary qualifications and is accredited and regulated by relevant professional organisations to offer the interventions.\n\nThe committee noted that there was a potential resource impact for offering these and that for smaller organisations, free or low-cost options existed (for example, online resources such as the local Improving Access to Psychological Therapies scheme). The committee thought it was important that employees were made aware of the option to not have an intervention and to take up an offer of it at a later date, or to stop an intervention at any time and restart it later. This avoids employees feeling pressured to start or continue an intervention. They also agreed it was important that employers recognise that an employee may prefer a particular type of intervention, possibly because of their previous experiences with interventions.\n\nThe committee noted the lack of evidence about which strategies can be used to identify employees at risk of poor mental wellbeing. (See the recommendation for research on identifying employees at risk of poor mental wellbeing.)\n\n## How the recommendations might affect practice\n\nThe recommendations reflect good practice around managing and supporting employees. The committee noted a potential resource impact to implement interventions, both in terms of work hours and financial resources. But this could be limited by using free resources.\n\nThey noted that there may be a resource impact to offering flexible working hours, job changes or other organisational support to people at risk of poor mental health but assessed that this would often be very low.\n\nReturn to recommendations\n\n# Organisational-level approaches for high-risk occupations\n\nRecommendations 1.8.1 to 1.8.3\n\n## Why the committee made the recommendations\n\nIf the psychosocial risk assessment (see the section on strategic approaches to improving mental wellbeing in the workplace) for a role indicates that it is high risk, it is important that organisations have additional processes in place to support employees. The committee agreed that it was important to make sure these processes conformed to best practice in the field, and from their experience, they were able to identify Mind's Blue Light Programme as an example of best practice.\n\nThere was good evidence showing that when police and healthcare professionals were given the skills to deal with stressful occupational events through task-focused skills training (including imagery and simulation), mental health symptoms were reduced, and mental wellbeing and quality of life improved. Based on this evidence, the committee decided that organisations should provide task-focused skills training for employees in high-risk occupations. They also recommended, in line with the evidence, that employees in high-risk occupations are offered support after a traumatic event.\n\nThe committee noted that there were exceptional circumstances, for example, the COVID‑19 pandemic, which could cause stressful occupational events more widely (for example, some people might find homeworking or social distancing in the workplace stressful).\n\n## How the recommendations might affect practice\n\nAll high-risk occupations should already have policies and procedures in place on how to deal with predictable and stressful occupational events. These recommendations will not affect the resources needed for this.\n\nReturn to recommendations\n\n# Engaging with employees and their representatives\n\nRecommendations 1.9.1 to 1.9.3\n\n## Why the committee made the recommendations\n\nThe committee suggested that consulting employees about the type and format of organisational approaches and individual interventions offered would help employers understand what good mental wellbeing would look like in their organisation. It would also help them to tailor their approach to the needs of their employees and the organisation. They believed that this would give employers the opportunity to raise awareness about why the interventions are being implemented, which could improve employee support for them.\n\nThe committee discussed that by providing interventions during the working day, employers would give employees a beneficial break from work and send a clear message about the importance of mental wellbeing. However, organisations should be flexible because employees may also prefer to access interventions outside work hours. The committee also noted that people will have different preferences about how they learn. For example, some employees would benefit from a group setting, whereas others would prefer one-to-one or online interventions. This highlights the importance of engaging with employees to ensure that their needs are considered, and that if online interventions are offered, digital exclusion does not prevent any employee from accessing the intervention.\n\nThe committee also discussed, based on their experience, that the effectiveness of certain interventions may be different for different groups. Factors may include socioeconomic factors such as low income and whether people have disabilities, work in urban or rural locations or have good digital access. The committee agreed that staff surveys and consultation could be used to regularly monitor intervention accessibility.\n\n## How the recommendations might affect practice\n\nThe committee discussed the resource implications of these recommendations but overall did not think they would be significant in most cases. They noted that some organisations may not be able to provide interventions during work hours for financial reasons. In these cases, it may be better to provide interventions outside work hours rather than not making them available at all. They also noted that some organisations may not have the space to provide certain interventions on site, and this may affect the type or format of intervention offered.\n\nReturn to recommendations\n\n# Local and regional strategies and plans\n\nRecommendations 1.10.1 to 1.10.9\n\n## Why the committee made the recommendations\n\nThe committee discussed that local and regional authorities should be role models in ensuring that their own workplaces actively promote mental wellbeing, given their role in public health. The committee highlighted that many local and regional authorities already have strategies in place to improve physical wellbeing in their population, and that these could be expanded to include mental wellbeing as part of a more holistic approach to wellbeing. This includes working with employers to ensure they know about resources or services that can help them improve the mental wellbeing of their employees and minimise the resource impact that this will have, especially for small and medium-sized enterprises and micro-enterprises. This could be done together with local enterprise partnerships and chambers of commerce. This can also be tailored to the needs of each organisation.\n\nThe committee heard expert testimony about a mental health and productivity pilot that included the possibility of local authorities using financial incentives to encourage employers to think about job quality and wellbeing in their workplaces. The committee discussed this and also discussed that in times of financial hardship, there may be non-financial incentives that are more achievable for local authorities. Because there was limited evidence about this, the committee agreed that it would not be appropriate to recommend incentive schemes, but that any authorities interested in them could introduce them as a pilot or as an evaluation.\n\nLocal and regional authorities will have ethical procurement frameworks in place, and a duty under the Social Value Act to consider wider social, economic and environmental factors during procurement. Therefore, the committee suggested that local and regional authorities could consider how organisations in their supply chains value job quality and mental wellbeing in the workplace.\n\n## How the recommendations might affect practice\n\nLocal and regional authorities already have schemes in place to help employers improve mental wellbeing in their workplaces, including the Department for Work and Pensions' access to work mental health support service. Many sources of support have already been curated by organisations such as Mind and Business in the Community, and local and regional authorities would only need to signpost employers to these.\n\nThe committee were aware that some local authorities may be having funding difficulties and did not want to place too much of a burden on them. Expert testimony about a mental health and productivity pilot discussed the possibility of local authorities using financial incentives to encourage employers to think about job quality and wellbeing in their workplaces. However, the committee noted that local and regional authorities may be able to provide other forms of incentives that do not need extra funds, for example dedicated advice and guidance.\n\nReturn to recommendations\n\n# Making this guideline relevant for small and medium-sized enterprises (including micro-enterprises)\n\nRecommendations 1.11.1 to 1.11.5\n\n## Why the committee made the recommendations\n\nThe committee heard from expert testimony from the Thriving at Work Leadership Council that many business owners are at risk of poor mental health and exhaustion as a result of the pandemic. They noted that leaders need to ensure that they also consider their own mental wellbeing.\n\nThe committee noted that a lot of the evidence was from larger organisations, and that small and medium-sized enterprises (SMEs) are likely to have fewer resources to help them address mental wellbeing in the workplace, such as occupational health and human resource professionals. The committee discussed that taking a preventive approach to ensuring good mental wellbeing could avoid problems later on (for employees and for the organisation). They agreed that employers could find a lot of guidance and resources on how to do this through the Mental Health at Work website, and Health and Safety Executive resources.\n\nPublic bodies such as local authorities and local enterprise partnerships should also be able to signpost employees of SMEs to information on how to prevent poor mental wellbeing at work and promote positive mental wellbeing, as well as signposting them to resources and services to support employees with poor mental health, such as the Department for Work and Pensions' access to work mental health support service. The committee suggested that SMEs may also want to sign up to the Mental Health at Work Commitment, which is a framework to help organisations improve the mental wellbeing of their employees.\n\nThe committee agreed that further research into SMEs was needed – particularly on the specific needs of SMEs for implementing individual-level interventions and the long-term effectiveness of universal individual-level interventions in both larger organisations and SMEs. So they made a recommendation for research on specific needs of different kinds of micro, small and medium-sized enterprises (SMEs) in promoting mental wellbeing in the workplace, including organisational, targeted and individual-level approaches and a recommendation for research on long-term effectiveness of universal individual-level interventions in different kinds of SMEs. These would enable NICE to make more specific recommendations for SMEs in future.\n\n## How the recommendations might affect practice\n\nThe committee were aware that, compared with larger organisations, SMEs may face additional constraints in terms of time and resources. The recommendations reflect ways that smaller organisations can look after the mental wellbeing of their workforce, without needing too much time or specialist knowledge about mental wellbeing.\n\nThe committee also discussed that employee assistance programmes and occupational health services may be a useful way of helping employees, and that smaller organisations may benefit from free or low-cost services such as the Department for Work and Pensions' access to work mental health support service or Mindful Employer.\n\nReturn to recommendations", 'Context': "This guideline is for all people aged 16\xa0or over in full-time or part-time employment, including those on permanent, training, temporary or zero-hours contracts, and those who are self-employed and volunteers.\n\nThis guideline has been updated because NICE identified new evidence that could affect the recommendations.\n\nDespite evidence that better mental wellbeing and job satisfaction are associated with increased workplace performance and productivity, the government review Thriving at work estimates that 15% of UK workers have an existing mental health condition. Poor mental wellbeing costs employers in the UK an estimated £42\xa0billion to £45\xa0billion annually through presenteeism, sickness absence and staff turnover (Deloitte Mental health and employers: refreshing the case for investment).\n\nThe total annual cost of poor mental wellbeing to the government, including NHS costs, benefit provision and tax revenue losses, is between £24\xa0billion and £27\xa0billion. Lost output costs the economy between £74\xa0billion and £99\xa0billion (Thriving at work). Changes to workplaces and working patterns as a result of the COVID‑19 pandemic have had a large impact on working practices and organisational cultures; however, it is unclear what the longer-term effects of this will be.\n\nWorkplace policies and activities to promote and protect employee mental wellbeing vary widely. Mental wellbeing has been described as 'feeling good and functioning well', reinforcing that mental wellbeing is on a spectrum and positive mental wellbeing is not just the absence of symptoms of poor mental health. Consequently, the aim of interventions should not just be to prevent poor mental health, but instead should promote positive mental wellbeing.\n\nThe Department for Work and Pensions reports that most employers have basic health and wellbeing policies, including at least 1\xa0covering flexible working, sick pay or injury training (Department for Work and Pensions Health and wellbeing at work: a survey of employees). Larger and public sector organisations are more likely to offer at least 1\xa0of the following: health screening, occupational health services, independent counselling or stress management."}
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https://www.nice.org.uk/guidance/ng212
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This guideline covers how to create the right conditions for mental wellbeing at work. It aims to promote a supportive and inclusive work environment, including training and support for managers and helping people who have or are at risk of poor mental health.
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f4a8dd074487e0a850da6643d48fbbe52f20c4ef
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nice
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PredictSURE IBD and IBDX to guide treatment of Crohn's disease
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PredictSURE IBD and IBDX to guide treatment of Crohn's disease
Evidence-based recommendations on PredictSURE IBD and IBDX for guiding treatment of Crohn’s disease.
# Recommendations
There is not enough evidence to recommend the use of the PredictSURE IBD and IBDX tests. They should only be used in the context of research to help identify people at high risk of a severe course of Crohn's disease and guide treatment.
Further research is recommended (see section 5) to:
assess how accurate the tests are for identifying a low or high risk of a severe course of Crohn's disease
understand how the tests affect decisions about treatment
assess the clinical outcomes and costs associated with different treatment strategies
assess how the tests affect clinical outcomes.
Why the committee made these recommendations
PredictSURE IBD and IBDX are tests that may be able to identify people at high risk of severe Crohn's disease. If people can be identified in this way, clinicians could offer the most appropriate treatment to control symptoms while minimising side effects. 'Top-down' treatment has been suggested to be more effective for people with severe Crohn's disease. This reverses the standard order of treatment, starting with biological therapies such as tumour necrosis factor (TNF)-alpha inhibitors.
The clinical evidence for the tests comes from only a small number of people, which does not give confidence in the results reported. There's also not much evidence on how effective top-down treatment is in people who would be classified as high risk using the test, particularly in the NHS where it is not standard practice.
Because of this and other assumptions made in the economic model, the cost-effectiveness estimates are very uncertain and lack face validity (that is, the results are unexpected). More research is needed to resolve the clinical uncertainties. Therefore, these tests are not recommended for routine use in the NHS.# The diagnostic tests
# Clinical need and practice
Crohn's disease is a chronic condition that causes inflammation of the gastrointestinal tract, particularly the large intestine and the last section of the small intestine. This condition is characterised by recurring periods of active symptoms (flares). At other times health is generally good (remission). According to Crohn's & Colitis UK, 1 in every 650 people in the UK is affected by Crohn's disease. Complications of Crohn's disease include intestinal strictures (narrowing of the affected area of the intestine), fistulas (ulceration of the lining of the gastrointestinal tract) and perforation. Children may also have growth problems because of poor absorption of nutrients.
The disease course varies a lot from person to person. Some people are at a higher risk of more frequent flares and relapses that do not respond to standard drug treatment. In the long term, they may be at a higher risk of developing complications and may need surgery.
Crohn's disease has no cure. The goal of treatment is to induce remission by controlling symptoms and maintain remission to prevent relapse. Current standard care is a 'step-up' strategy, which starts with corticosteroids, then immunosuppressants, then biological therapies if the disease does not respond, or loses response, to treatment. NICE's guideline on Crohn's disease covers the management of Crohn's disease in children, young people and adults and recommends the step-up strategy. Step-up treatment involves multiple courses of steroids before changing to a stronger treatment. 'Accelerated step-up' treatment involves rapidly changing to stronger treatments if the expected response is not seen in the time frame. Adequate response can be defined as no clinical symptoms, no signs of ongoing inflammation, or both.
An alternative approach not currently recommended as standard care is the top-down strategy, which reverses the order of treatment in the step-up strategy, starting with biologics such as tumour necrosis factor (TNF)-alpha inhibitors. It has been suggested that for some people with Crohn's disease, the top-down strategy could achieve a faster and higher rate of mucosal healing. This could potentially modify the natural disease course and allow people with a severe disease course to control it better. Biologics are more clinically effective but are also associated with more side effects.
Neither the step-up nor the top-down approach are suitable for all people with Crohn's disease. Clinicians in specialist centres may offer the top-down strategy to people if at diagnosis they consider them to have a poor prognosis (for example, if they have significant fistulising disease, complex perianal disease or multiple risk factors). Being able to predict the course of the disease could allow the clinician to identify people who may benefit from the top-down strategy, that is, early treatment with biologics. There is currently no standard means of categorising people based on their risk of having a severe disease course.
PredictSURE IBD and IBDX tests could identify people at a higher risk of a severe course of Crohn's disease, potentially guiding more personalised disease management.
# The interventions
## PredictSURE IBD
PredictSURE IBD (PredictImmune) is a whole blood-based biomarker prognostic laboratory-based test combined with a proprietary algorithm to categorise people into a high or low risk of a severe course of Crohn's disease. The test is based on detecting CD8+ T‑cell exhaustion. People with a non-exhausted CD8+ T‑cell signature were linked to a higher risk of frequently relapsing disease. The test involves isolating mRNA from the whole blood sample using the PAXgene Blood RNA kit (QIAGEN), followed by quantitative polymerase chain reaction with reverse transcription (RT‑qPCR) to assess expression of 15 target genes and 2 controls. RT‑qPCR is a 2‑step process: cDNA synthesis in the reverse transcription reaction, and then a qPCR on a 384‑well plate. A maximum of 4 samples may be analysed per plate because cDNA derived from each RNA sample is run in triplicate.
## IBDX
IBDX (Glycominds) is a panel of 6 indirect solid-phase enzyme-linked immunosorbent assay (ELISA) kits, each of which detects serum levels of specific antiglycan antibodies. Antiglycan antibodies are serological biomarkers thought to be highly specific for Crohn's disease and associated with a severe disease course. The IBDX ELISA kits available to detect specific antibodies include:
IBDX anti-chitobioside (ACCA) immunoglobulin A (IgA)
IBDX anti-laminaribioside (ALCA) IgG
IBDX anti-mannobioside (AMCA) IgG
IBDX anti-Saccharomyces cerevisiae (gASCA) IgG
IBDX anti-laminarin (anti‑L) IgA
IBDX anti-chitin antibody (anti‑C) IgA.
# The comparator
The comparator is standard clinical care in which no test or algorithm is used to predict the disease course. Instead, prognosis is based on clinical judgement of presenting signs and symptoms and known clinical risk factors for a severe disease course.# Evidence
The diagnostics advisory committee considered evidence on PredictSURE IBD and IBDX to guide treatment of Crohn's disease from several sources. Full details of all the evidence are in the diagnostics assessment report.
# Clinical effectiveness
The external assessment group (EAG) systematically reviewed evidence to evaluate the prognostic ability and clinical effectiveness of the PredictSURE IBD and IBDX tests to predict severe disease course and guide treatment in people with Crohn's disease who:
have newly or recently diagnosed disease
have moderate to severe active disease
are currently not having any concomitant steroids, immunomodulators or biological treatments
would not have top-down treatment with current standard care in the NHS.
The EAG identified 8 primary studies (reported in 12 publications) that met the selection criteria for the literature review (see page 18 of the diagnostics assessment report for details of the selection criteria). The studies were all observational. Of the included studies, 7 reported on the diagnostic performance of IBDX. In these studies, a higher number of positive biomarkers was associated with poorer prognosis. Two of the IBDX studies (Wolfel et al. 2017 and Reider et al. 2010c) prospectively assessed the prognostic ability of IBDX for predicting complications (fistulas and stenoses) and Crohn's disease-related surgery. A third prospective study reported a correlation of IBDX with either a history of complication or surgery at baseline, or their occurrence during follow up (Rieder et al. 2010b). The other 4 studies were cross sectional, reporting a correlation between the number of positive IBDX biomarkers and outcomes associated with a severe disease course (a presence or history of complications or surgery) at the time of testing. Only 1 study (Biasci et al. 2019) reported on the predictive ability of PredictSURE IBD to classify people into either a high or low risk of a severe course of Crohn's disease, as defined by the study investigators.
Of the studies identified for IBDX, 3 were done in Germany and 1 study each in Canada, France and the US. One study, published as an abstract, had an unclear location. The study on PredictSURE IBD was done across 4 centres in the UK.
## Study quality
The EAG assessed the risk of bias in the included studies using the quality in prognosis studies (QUIPS) tool. All the studies for IBDX were considered to be at a moderate or unclear risk of bias in the measurement of confounding factors domain. Three studies were considered to be at a moderate risk of bias in the participation domain. The study identified for PredictSURE IBD was assessed to be at a low or unclear risk of bias.
## Prognostic accuracy
None of the studies for IBDX were done in only people with newly diagnosed Crohn's disease. The studies had people with an established diagnosis and with a recent diagnosis of Crohn's disease. Median duration of disease at the time of testing ranged from 10.6 months (interquartile range 1.7 to 52.3) to 9.4 years (IQR 1 to 44). One prognostic study by Rieder et al. (2010c) assessed the ability of IBDX to predict developing a complication or needing surgery in people with no prior complication or surgery at baseline (n=76). People who tested positive for 2 or more out of 6 IBDX markers had a significantly higher risk of complications (hazard ratio 2.5; 95% confidence interval 1.03 to 6.1; p=0.043), or surgery (HR 3.6; 95% CI 1.2 to 11.0; p=0.023) during the median follow up of 53.7 months, than people who tested positive for 0 or 1 markers. A prognostic study by Wolfel et al. (2017), reported as a conference abstract, showed that the number of positive IBDX markers did not predict a shorter time to repeat intestinal surgery (n=118; median follow up of 100 months).
Reider et al. (2010b) reported that people who had surgery (before or during follow up) had a higher number of positive IBDX markers (median 2.0 ) than those who did not (median 1.0 ; odds ratio 1.5 ; p<0.001). Similarly, people with a complication had a higher number of positive IBDX markers (median 2.0 ) than those who did not (median 0.0 ; OR 1.5 ; p<0.001). The remaining 4 IBDX studies reported the correlation between IBDX markers and disease phenotype at the time of testing. None of the studies for IBDX estimated sensitivity or specificity.
Biasci et al. (2019) reported on the prognostic ability of PredictSURE IBD in adults with newly diagnosed Crohn's disease who were not having concomitant treatment. The study included 2 training cohorts (66 people in the biomarker discovery cohort and 39 people in the whole blood classifier cohort) and 1 validation cohort (n=66). The validation cohort and the whole blood classifier cohort were considered relevant to this assessment. In the validation cohort, people categorised as high risk (n=27; 40.9%) had a statistically significantly higher risk of at least 1 treatment escalation than those categorised as low risk (n=39; 59.1%), with a HR of 2.65 (95% CI 1.32 to 5.34; p=0.006). Median duration of follow up was 1.6 years (IQR 1.0 to 3.7) in the high-risk group and 2.4 years (IQR 1.8 to 3.8) in the low-risk group. Sensitivity and specificity for predicting the need for 2 or more escalations in the first 12 months were 77.8% and 70.6% respectively, and within 18 months 72.7% and 73.2% respectively. Negative predictive value for predicting multiple escalations in the first 18 months was 90.9%. Positive predictive value calculated by the EAG was 42.1%.
## Comparative evidence
A sub-study by Lyons (2020) based on the same cohort as Biasci et al. (2019) and published as an abstract, compared the ability of PredictSURE IBD and IBDX to predict the need for multiple treatment escalations in 74 people with Crohn's disease at Addenbrooke's Hospital, Cambridge. Everyone had active disease at enrolment, and all had accelerated step-up treatment. The author concluded that there was no significant difference between the group who tested positive for at least 1 IBDX marker and those who tested positive for 2 or more IBDX markers, in terms of time to, or frequency of, treatment escalation. In comparison, when the cohort was stratified by PredictSURE IBD, people classed as high risk had a significantly shorter time to treatment escalation than people classed as low risk (p=0.001).
## Clinical utility
No evidence was identified on how the tests affect the decision in clinical practice to offer top-down strategy to people at high risk of a severe disease course. There was also no evidence on how the tests affect the clinical outcomes of people with severe Crohn's disease.
# Cost effectiveness
## Systematic review of cost-effectiveness evidence
The EAG searched for studies on the cost effectiveness of PredictSURE IBD and IBDX in Crohn's disease and economic evaluations of treatments for people with newly diagnosed and moderate to severe Crohn's disease. It did not identify any economic studies for PredictSURE IBD and IBDX, but it did find 11 evaluations relevant to treatment options in Crohn's disease.
One study by Marchetti et al. (2013) specifically compared the cost effectiveness of top-down (step 1: infliximab plus azathioprine, step 2: additional infliximab plus azathioprine, step 3: methylprednisolone plus azathioprine) and step-up (step 1: methylprednisolone, step 2: methylprednisolone plus azathioprine, step 3: infliximab plus azathioprine) approaches in Italy. The authors concluded that the top-down strategy was better and less costly than the step-up strategy. The treatment strategies modelled in the study by Marchetti are not representative of UK NHS practice. The health economics report for NICE's guideline on Crohn's disease explored the cost effectiveness of 9 induction treatment sequences (composed of 4 treatment lines) for Crohn's disease from the NHS perspective. The remaining 9 studies compared individual treatment steps.
The company submitted an abstract of a study evaluating the cost effectiveness of PredictSURE IBD to guide early use of biologics in Crohn's disease and ulcerative colitis in the UK. The model structure comprised a decision tree then a Markov transition model. Study results were presented at the European Crohn's and Colitis Organisation Conference in February 2020. The results show that, over a 15‑year time horizon, top-down treatment guided by PredictSURE IBD produced an incremental cost-effectiveness ratio (ICER) of £7,179 per quality-adjusted life year (QALY) gained when compared with standard care.
## Economic analysis
The EAG developed a de novo model to assess the cost effectiveness of PredictSURE IBD and IBDX to guide treatment in Crohn's disease. There was no detailed data for IBDX so the EAG assessed its cost effectiveness in an exploratory scenario analysis only.
The economic analysis was done from the UK NHS and personal social services perspective. The model had a lifetime time horizon (65 years) with a cycle length of 2 weeks. Costs and benefits were discounted at 3.5% per year.
## Model structure
The model was a hybrid model, with a decision tree for the induction treatment and a Markov transition model for the maintenance treatment. In the induction model, people whose disease does not respond (defined as deterioration; no change; or an improvement of 70 or less in Crohn's Disease Activity Index score) have second-line treatment, according to their treatment allocation (top down or step up). People whose disease responds to the induction treatment (defined as an improvement in CDAI score above 70) move to the maintenance model. They can enter the maintenance model in either remission, mild, or moderate to severe health states. People can then move between these states during maintenance treatment, reflecting the different levels of response to maintenance treatment. People in the mild and moderate to severe states are at risk of relapse and escalating to the next treatment step.
Escalations from corticosteroids to immunomodulators (step up) and from corticosteroids to tumour necrosis factor (TNF)-alpha inhibitors (top down) were not modelled because in both strategies all people have initial induction treatment with corticosteroids, so they cancel each other out.
Surgical events are modelled as a standalone outcome in the model, that is, people did not leave their respective health states to enter a surgery health state. Complications and long-term consequences of surgery were not modelled. Time to surgery in the high-risk, top-down cohort was estimated by applying a hazard function generated from the study by Hoekman et al. (2018).
## Model inputs
The population modelled was based on the UK study by Biasci et al. (2019), which the company provided anonymised individual patient data for. There were 105 people in the cohort with Crohn's disease; 88 had newly diagnosed disease. However, the EAG based its analysis on 40 people in the study whose treatment matched the standard definition of step-up treatment in the UK, that is, people who had first-line treatment with corticosteroids and second-line treatment with immunomodulators (after failure of corticosteroids). This informed the estimates of time to treatment escalation and time to surgery in the base case. To extrapolate time to treatment escalation data to the time horizon of the model, the EAG used individual patient data to generate time to event data for time to first escalation.
D'Haens et al. (2008) and its 10‑year follow-up study by Hoekman et al. (2018) informed estimates for effectiveness of top-down compared with step-up treatment. The study by D'Haens was a 2‑year multicentre randomised trial that assessed the clinical efficacy of early combined immunosuppression compared with conventional treatment in people with newly diagnosed Crohn's disease. People randomised to early combined immunosuppression had induction treatment with infliximab and azathioprine. People had no infliximab maintenance but were allowed infliximab as needed and, if necessary, corticosteroids, to control disease activity. People randomised to conventional treatment had corticosteroids, followed, in sequence, by azathioprine and infliximab. The study by Hoekman retrospectively reviewed the medical records of people included in the D'Haens trial, which collected data on hospitalisation, flares, surgery, clinical activity and other outcomes, for a median follow up of 10 years.
## Effectiveness of induction and maintenance therapies
Probabilities of response and remission with induction and maintenance therapies were based on data from a pragmatic search and from NICE's technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn's disease after prior therapy. Based on this guidance, the EAG estimated that 21.2% of responders remained in the moderate to severe disease state. The probability of response is the same for top down and step up, except for immunomodulators in the step-up strategy (table 1).
Treatment strategy
Induction: response
Induction: remission
Maintenance: response
Maintenance: remission
Top down: biologics
Top down: anti-tumour necrosis factor (TNF)
Step up: biologics
Step up: anti-TNF
Step up: immunomodulator
The costs considered in the model are the costs of the diagnostic tests, treatment and care of Crohn's disease. The total cost of testing charged by the laboratory was £1,250 for PredictSURE IBD and £347 (estimated) for IBDX. Table 2 shows the dose prices and induction dosages for induction treatment in top-down and step-up strategies, taken from BNF and NHS reference costs, and maintenance treatment dosages based on clinical opinion.
Treatment
Dose per unit (mg)
List price per unit
Induction dosages
Maintenance dosages
Ustekinumab
Induction dose at week 0 depends on body weight:
mg for 56 kg
mg for 56 kg to 85 kg
mg for 86 kg or over
mg every 8 weeks
Vedolizumab
mg at week 0, 2 and 6
mg every 8 weeks
Infliximab
mg/kg at week 0, 2 and 6
mg/kg every 8 weeks
Adalimumab
mg at week 0; 80 mg at week 2
mg every 2 weeks
Azathioprine
mg/kg/week for 8 weeks
mg/kg/week
Mercaptopurine
mg/kg/week
mg/kg/week
Methotrexate
£16.64 or £14.92
mg/week for 8 weeks
mg/week
Prednisolone
mg; tapered by 5 mg per week – 8 weeks total
No maintenance with prednisolone
Intravenous administration (outpatient)
First: £199
Follow up: £212
Not applicable
Not applicable
The total cost of managing maintenance health states for 2 weeks was £17 for remission, £27 for a mild state and £122 for a moderate to severe state. This included outpatient, radiology, endoscopy and hospitalisation costs.
The EAG used the utility values from NICE's technology appraisal guidance on vedolizumab (based on EQ‑5D data from GEMINI studies) in the base-case analysis and a mapping algorithm based on NICE's technology appraisal guidance on ustekinumab for moderately to severely active Crohn's disease after previous treatment in a scenario analysis. All utilities were adjusted to account for the age and sex of the modelled population, according to Ara and Brazier (2010). Surgery-related disutility was estimated from the Marchetti study. Table 3 shows the utility values used in the modelling.
Health state
NICE guidance on vedolizumab
NICE guidance on ustekinumab
Remission
Mild disease
Moderate to severe
## Key assumptions
The EAG assumed that:
PredictSURE IBD (and IBDX in the scenario analysis) are 100% accurate in categorising people into high and low risk of a severe disease course.
People categorised as high risk by the test have top-down treatment.
People have the same baseline probability of escalating to the next step in the step-up strategy (estimated from time to first escalation in Biasci et al. 2019) regardless of the number of previous escalations.
% of people having anti-TNF and 20% of people having non-anti-TNF biologics have combination treatment with immunomodulators.
Response to anti-TNF does not depend on the prior lines of treatment.
People in the top-down strategy have a longer time to treatment escalation and a longer time to surgery than people in the step-up strategy, based on extrapolation of results from D'Haens et al. (2008) and Hoekman et al. (2018).
To use the D'Haens study the EAG assumed that:
The relative treatment effect of top-down and step-up strategies in a mixed-risk population is the same as the relative treatment effect in a high-risk population.
Time to relapse is a proxy measure for time to the next treatment escalation.
The effectiveness of treatment strategies in this study is a proxy for the treatment effectiveness of the first step in the top-down (anti-TNF) and step-up (immunomodulators) strategies modelled.
To estimate the relative treatment effect of top-down and step-up treatment on time to treatment escalation, the EAG digitised the time to relapse Kaplan–Meier data from D'Haens et al. (2008) to estimate a hazard function. This was applied to the first treatment step in the high-risk, top-down arm of the model.
The base case was revised to reflect the assumption that time to treatment escalation restarts on each new treatment rather than reducing over time and as treatment sequences progress. Cost-effectiveness results presented are from the revised base case.
## Base-case results
Results of the revised base case (detailed in the addendum to the diagnostics assessment report) superseded results of the primary analysis. In the revised analysis, the time to treatment escalation restarts on each new treatment.
The base case compared the top-down strategy (using PredictSURE IBD to predict who was high risk) with standard care, in which a high-risk person has step-up treatment. In both the deterministic and probabilistic analyses PredictSURE IBD was dominated by standard care, meaning it costs more and has fewer QALYs:
Deterministic result: incremental cost was £9,084 and incremental QALY was -0.08.
Probabilistic result: incremental cost was £12,132 and incremental QALY was -0.03. The testing strategy had a less than 10% probability of being cost effective against standard care at the maximum acceptable ICERs of £20,000 and £30,000 per QALY gained.
The EAG revised its base case again, adding a corticosteroid step to the start of the step-up treatment strategy before immunomodulators. The PredictSURE IBD arm was still dominated by the standard care arm.
## Cost-effectiveness results: scenario analyses
The dominance of the step-up strategy may be because of the benefit some people get from having immunomodulators first, before biologics. The clinical experts told the EAG that people on the top-down strategy do not have immunomodulators after 3 lines of biologics. However, the EAG explored a scenario that had immunomodulators as the last treatment option in the top-down arm. Deterministic base-case results for this scenario showed that PredictSURE IBD (top-down strategy) generated 0.07 more QALYs than the step-up strategy, at an additional cost of £7,502, producing an ICER of £105,148 per QALY gained. This is higher than £20,000 to £30,000 per QALY gained, the range NICE normally considers an acceptable use of NHS resources.
The EAG ran a series of individual scenario analyses, most of which showed that PredictSURE IBD was dominated by standard care. The EAG also ran a combination of individual scenarios, because these were thought to have more impact than individual scenarios.
If the analysis assumed that the condition did not respond to treatment with immunomodulators for any high-risk person in the step-up arm, so they had no benefit from them, PredictSURE IBD had an ICER of £170,180 per QALY gained. The proportion of people who responded to immunomodulators was then varied. This showed that the 2 strategies became clinically equivalent when it was assumed that 97% of high-risk people in the step-up arm do not benefit from immunomodulators.
The EAG explored a scenario that assumed PredictSURE IBD had a lower test accuracy, and the effect of misdiagnosis. In this scenario, PredictSURE IBD was more costly and generated a QALY gain of 0.15, producing an ICER of £64,876 per QALY gained. This gain in QALY, despite the lower accuracy of the test, can be attributed to the assumption that some lower-risk people misdiagnosed as high risk go on to have top-down treatment, without the need for further escalation.
Assumptions about treatment stopping were based on Marchetti 2013, which reported that 76% of people had mucosal healing after 2 years in remission with biologic treatments using a top-down strategy and 40% using a step-up strategy. In a scenario analysis that assumed 76% of people in the top-down arm and 40% of people in the step-up arm stopped biologics, PredictSURE IBD was less costly and less effective than standard care, producing an ICER of £46,263 per QALY gained. Scenarios combining the effect of misdiagnosis with the same proportion of people stopping biologics in both arms, that is, 40% in step up and top down or 76% in step up and top down, produced ICERs of £48,034 and £32,875 per QALY gained respectively.
Individual scenarios were combined to explore the impact of increasing the effectiveness of the top-down strategy while reducing the treatment cost of biologics. The results of these combined scenarios varied. One scenario combined 3 assumptions, that:
base-case risk of relapse for second and later treatment steps is the same
discontinuation of biologic treatment is 76% for top down and step up
% of people in the step-up arm do not respond to immunomodulators.This produced an ICER of £29,225 per QALY gained in favour of top down.
A tornado plot of the one-way sensitivity analyses showed that response to biologics in the top-down arm of the model was a key driver of the deterministic ICER.
The EAG reduced the time horizon to 5 years in the model with the corticosteroid step at the start of the step-up treatment strategy. This resulted in a QALY gain of 0.004 associated with the PredictSURE IBD arm of the model and a cost of £13,728, giving an ICER of £3,814,576 per QALY gained.# Committee discussion
# Clinical effectiveness
## Knowing the likely course of the disease may help people with Crohn's disease and the NHS
The patient expert explained that having Crohn's disease can substantially affect the quality of life of the person and their family. Crohn's disease is a complex disease associated with symptoms that can be highly debilitating. Symptoms include abdominal pain, profound fatigue, weight loss and a constant urge to have a bowel movement, and extraintestinal manifestations, which can affect the joints, skin, bones, eyes, kidneys and liver. Recent research from the Secured Anonymised Information Linkage (SAIL) databank in Wales estimates that the prevalence of Crohn's disease is 1 in 271. The starting age of Crohn's disease is between 10 and 40 years so most people face a lifetime of medication and repeated major surgery. Most are not eligible for help with the cost of prescriptions. Currently the extent of inflammation is monitored using endoscopic imaging and faecal calprotectin blood tests, but they do not predict disease progression or the likelihood of needing surgery in the future. People may not want invasive monitoring using colonoscopy because it is stressful to prepare for, has unpleasant side effects and may aggravate symptoms. The patient expert suggested that a test that predicts long-term disease course could help give people a better understanding and acceptance of their condition, and make planning review appointments more efficient. It could also help increase quality of life outcomes, reduce potential side effects from first-line treatments, allow more effective earlier drug treatment, and reduce demands on NHS services.
## Studies on the prognostic ability of the tests are heterogenous and have small sample sizes
The reviewed studies on prognostic ability had mixed populations, including people with ulcerative colitis. The number of people with Crohn's disease in each study was small, given the prevalence of the condition in the wider population. The committee noted that the small sample sizes could mean that the reviewed studies were underpowered to produce robust estimates of the prognostic ability of the tests. The committee also noted that there are other predictive studies for Crohn's disease with larger populations, showing that larger sample sizes are possible. The committee concluded that the heterogeneity in the population and the population size added substantial uncertainty to the interpretation of study results.
## There is no standard definition of a high or low risk of a severe disease course
The reviewed studies used different measures to define a person as being at high or low risk of following a severe course of Crohn's disease. IBDX studies used poor outcomes, such as surgery and complications, as a proxy for a severe disease course (see sections 3.5 and 3.6), whereas the PredictSURE IBD study used the need for multiple treatment escalations (see section 3.7). This inconsistency is a source of additional uncertainty.
## The accuracy of PredictSURE IBD and IBDX in predicting a severe disease course is uncertain
Little data was identified on the prognostic accuracy of the tests. Sensitivity, specificity and negative predictive value were only reported for the PredictSURE IBD test, and in only 1 study (Biasci 2019). The clinical expert said that, at the moment, severe disease course may be predicted by known risk factors such as age and smoking status. But there is no consensus on, or algorithm for, how these risk factors should be combined, and their predictive value is limited. The clinical expert also said that, based on the findings of the Biasci study, the PredictSURE IBD test appears to perform better than risk prediction based on clinical features or endoscopic findings, and therefore has the potential to be a useful test. The committee noted that it would help to understand if the tests can give a more accurate prognosis when used alongside clinical features rather than as a substitute. The committee concluded that overall, the evidence on the prognostic accuracy of PredictSURE IBD and IBDX is weak, and encouraged further research on their accuracy when used alongside clinical features (see section 5).
## There is little evidence on how the tests affect treatment decisions
The proposed value of the tests is to categorise people with Crohn's disease according to their risk of following a severe disease course. People predicted to have a severe disease course could have top-down treatment, which may help control the disease early, leading to better outcomes like fewer flare-ups, and prevent bowel damage and limit the need for surgery. The committee noted that currently there was no evidence on how the tests can help with decisions about personalised treatment plans. It concluded that it would help to have research on how the tests affect treatment decisions (see section 5). PROFILE, a randomised, multicentre, biomarker-stratified, open-label study is ongoing in the UK with results expected in 2022. This trial uses PredictSURE IBD to assign people to top-down or step-up treatment, and may help address this evidence gap.
## There is no evidence on how the tests affect clinical outcomes
The committee considered that there was no evidence to show that using the prognostic tests to identify people at high risk of a severe disease course and help guide treatment improves clinical outcomes. The committee encouraged studies assessing how the tests affect clinical outcomes (see section 5).
# Cost effectiveness
## Corticosteroids are often used as a first-line treatment for adults with moderately active or severely active Crohn's disease
The committee noted that the treatment sequences modelled by the external assessment group (EAG) in the original base case may not reflect treatment in the NHS. Corticosteroid treatment was not included in the original model because all high-risk patients (in the top-down and step-up arms) were assumed to have initial induction treatment with corticosteroids before moving to the next treatment steps. Therefore, the impact of corticosteroid use would be the same in both arms. Because of this, the EAG excluded people in the Biasci study who did not escalate from steroids to immunomodulators or anti-tumour necrosis factor (TNF) treatment (see section 3.18). The committee heard that the recent consensus guidelines from the British Society of Gastroenterology (Lamb et al. 2020) recommended minimising steroid use because of toxicity and lack of efficacy, except in moderate to severely uncomplicated luminal Crohn's disease, which systemic corticosteroids may have some benefit for. However, the clinical experts said that corticosteroids are still used as a first-line treatment in adults with moderately active or severely active Crohn's disease, unless there is a contraindication. In a top-down treatment strategy, a shorter period of corticosteroids, or sometimes no corticosteroids, may be used before starting treatment on biologics. The committee considered a revised base-case model, which had treatment with a corticosteroid first in the step-up strategy. The committee concluded that adding the corticosteroid step better reflected current NHS practice.
## Managing Crohn's disease is complex, and rapidly evolving because of new treatments and tests
Clinical experts explained that treatment of Crohn's disease varies across the NHS. Many treatments are already available and new drugs are entering the market. Treatments are often combined, for example, in the EAG model 30% of people who had a TNF-alpha inhibitor, and 20% of people who had a biological treatment that was not an anti-TNF, also had an immunomodulator. This is because there is evidence to show that combination treatment reduces the chances of losing response to biologics (immunogenicity). However, the clinical experts said there is no consensus on using monotherapy or combination therapy, and that it varies in clinical practice. Tests that monitor levels of biologics and presence of antibodies to biologics are also being more widely used. These tests can guide a personalised treatment strategy to help maintain a treatment response for longer. The committee noted that an important study used to provide model inputs for the top-down and step-up treatment strategies (D'Haens et al. 2008) was over 10 years old. It used treatment strategies that do not reflect current practice in the NHS or the top-down treatment strategy that was included in the EAG model (see section 4.10). The committee concluded that variation in clinical practice, and the absence of more recent data comparing top-down and step-up strategies, make modelling of the treatment strategies difficult. This creates great uncertainty around the model structure.
## It is uncertain what a top-down treatment strategy in the NHS would look like
Top-down treatment is not widely used in the NHS and so it is uncertain what the treatment pathway would look like. The clinical experts noted that de-escalation of biologics in Crohn's disease is often unsuccessful and therefore not often used because of a high risk of relapse. The company model included an immunomodulator step after biologics but the EAG base case did not (see section 4.14). The EAG explored this as a scenario analysis (see section 3.30). In addition, the biologics modelled as second and third line can also be used as first line. The committee noted that lack of clinical consensus about the top-down treatment strategy adds extra uncertainty into the model.
## It is not certain if top-down treatment has clinical benefits over step-up treatment
Clinical experts explained that early rather than late treatment with biologics could improve outcomes for people likely to have a more severe disease course. The EAG noted that the evidence on the effectiveness of top-down (early treatment with biologics) compared with step-up (late treatment with biologics) in the model was from the D'Haens study. This showed that people who had early combined immunosuppression had a longer time to relapse than people who had conventional treatment. The hazard function (based on the assumption that time to relapse is a proxy for time to next treatment escalation) derived from D'Haens was applied only to the first step of the model (the anti-TNF compared with immunomodulator step). In the model, people in the top-down arm of the model remained on initial treatment for longer than those in the step-up arm of the model (anti-TNF compared with immunomodulator). This resulted in people in the first step of the top-down arm having a higher probability of having and maintaining remission, which is associated with lower costs and higher quality-adjusted life years (QALYs). Later treatment steps in both the top-down and step-up strategies were assumed to have the same time to treatment escalation as anti-TNF in the top-down arm. This assumption was made because there was no evidence either way. The early combined immunosuppression used in D'Haens differed from the top-down treatment sequence described by the clinical experts because people did not carry on having maintenance treatment with infliximab but were allowed infliximab as needed (see section 3.19). This might have underestimated the benefits of top-down treatment in the model. The EAG said that in the long term, top down may not have an advantage over step up because the 10‑year follow-up study of D'Haens (Hoekman 2018) showed no difference in hospitalisation, surgery and endoscopic remission between both strategies. The clinical experts considered that early treatment with biologics does make a difference, and that there is a trend towards using biologics earlier, but said that there is not much good-quality evidence generalisable to the NHS to support this. The EAG noted that the evidence available was heterogeneous. It noted that a Canadian Agency for Drugs and Technologies in Health review published in 2019 also found that it is not clear if early biologic therapy is more effective than conventional therapy for Crohn's disease in adults because there are few studies and the ones that exist are heterogenous. Registry data could have been useful. The committee concluded that more evidence is needed on the effectiveness of top-down compared with step-up strategies. This is because if there is no evidence of benefit, there is no clinical rationale for identifying people at high risk of a severe disease course and treating them using a top-down strategy.
## Because of the lack of data and the need for many assumptions, the model results are not certain
The committee noted that interpreting the modelling was difficult because of the very weak data feeding into it. There was limited data on the prognostic accuracy of the tests (see section 4.4), on the effectiveness of a top-down strategy compared with a step-up strategy (see section 4.8), and no information from studies on how these 2 steps would combine to affect clinical outcomes. The EAG explained that it had to make many assumptions to be able to link the evidence in the model. There was great variation in the results of the model. Because of the limited data and assumptions that needed to be made, the cost effectiveness of the tests is highly uncertain.
## The economic model lacks face validity because top-down treatment is associated with a QALY loss
In the EAG's base-case model, a standard care strategy of no testing and step-up treatment dominated the strategy of testing with PredictSURE IBD followed by top-down or step-up treatment depending on the test result. In the revised base case when a corticosteroid step was included in the step-up treatment strategy, the PredictSURE IBD arm was still dominated by the standard care arm. The clinical experts had previously explained that early treatment with biologics could improve outcomes for people with severe Crohn's disease (see section 4.10). The committee therefore considered that the base-case results from the economic model, which show that top-down treatment is associated with a QALY loss compared with step-up treatment, lacks face validity. The EAG said that the QALY loss is because there are more treatment options in the step-up strategy because it has an immunomodulator step as the first-line treatment. The most recent revision of the model had both a corticosteroid step and an immunomodulator step at the start of the step-up strategy. In the model the treatment steps are incorporated independently of each other because of a lack of evidence on response to the full treatment strategy or on how response to each treatment is correlated. The consequence of this is that people on the step-up treatment arm have the opportunity to respond, even if just temporarily, to corticosteroids and immunomodulators, and therefore take longer to exhaust all their treatment options. This results in people on step-up treatment spending more time in the health states of response or remission, and therefore gaining more QALYs compared with people in the top-down treatment arm. The committee concluded that the QALY difference in favour of step-up treatment is unexpected and might not be seen in a real-world setting.
## Changing some of the key assumptions in the model leads to a QALY gain in the PredictSURE IBD arm, but ICERs are high
The EAG explained that some scenario and sensitivity analyses did result in a QALY gain for the PredictSURE IBD arm of the model. For example, in the one-way sensitivity analyses, using higher response and remission rates for biologics in the top-down treatment strategy, and using lower response and remission rates for biologics in the step-up treatment strategy, all resulted in a QALY gain for PredictSURE IBD. Other scenarios that resulted in QALY gain for the PredictSURE IBD arm of the model were:
after 2 years in remission with biologics, a proportion of people have mucosal healing and do not need more treatment escalations
when some low-risk people were assumed to be misdiagnosed as high risk (see section 3.34) because they did not need any more treatment escalation
when an additional immunomodulator step was included at the end of the top-down treatment strategy
when it was assumed that all high-risk patients who receive step-up treatment do not respond to an immunomodulator and therefore escalate to anti-TNF.The ICERs from these sensitivity and scenario analyses were well above the range normally considered to be cost effective.
## The EAG's model results are different from the company's model and the most relevant published economic model
The base-case probabilistic and deterministic results of the EAG's model produced QALYs in favour of standard care. This suggests that a no testing strategy with step-up treatment is better for people at high risk of a severe course of Crohn's disease than top-down treatment using the prognostic tool. This result was not consistent with the company's model and the model reported by Marchetti (2013), both of which reported that a top-down strategy is associated with more QALYs. The EAG noted that the difference between its model and the company's was that the treatment sequence modelled by the company had an immunomodulator as a last treatment step in the top-down arm. This was not modelled in the EAG's base case but as a scenario analysis. This scenario produced an ICER in favour of top-down treatment that was much higher than what NICE normally considers a cost-effective use of NHS resources (see section 3.30). The company's model also assumed a constant relative treatment effect, capped at 10 years, whereas the EAG's model assumed a diminishing relative treatment effect (see further details in the addendum to the diagnostic assessment report). Marchetti modelled a different treatment sequence (see section 3.11) to the EAG's, and a different time horizon – 5 years compared with the EAG's 65 years. The EAG explored changing the time horizon in their model to 5 years, which showed a small QALY gain for the PredictSURE IBD arm (see section 3.37). The difference in the results was likely because of the uncertainties in the top-down treatment pathway and the effectiveness of top-down compared with step-up strategies.
## Assuming that IBDX and PredictSURE IBD have the same prognostic ability is not appropriate
Only data on the prognostic ability of PredictSURE IBD was included in the base case. The EAG included IBDX in an exploratory analysis that assumed that the ability of IBDX to identify people at high or low risk was the same as PredictSURE IBD. The committee heard that the tools identify different markers and need different test samples. The committee also noted that there was 1 abstract (Lyons 2020), which compared both tools and showed that PredictSURE IBD predicted a shorter time to treatment escalation in people classed as high risk. IBDX did not predict a difference in time to treatment escalation between people positive for 2 or more markers and those positive for only 1 marker (see section 3.8). The committee concluded it was not appropriate to assume the tests had the same prognostic accuracy, and that more evidence is needed (see section 5).
## Evidence from a different starting cohort that includes children and teenagers would be useful
The committee heard that the average age in the EAG's model was 35. It considered that the model might not reflect other age groups that are first diagnosed with Crohn's, for example, one peak is in teenagers and another is at around 60. A clinical expert noted that the treatment pathway for children or teenagers would be different from adults because children often follow a more severe disease course and may need enteral nutrition. The committee heard that modelling this population may need an entirely new model rather than an adaptation of the model built by the EAG for the adult population.
## Modelling adverse events or varying the cost of surgery may not have a huge impact on the results
The EAG did not model adverse events, to keep the model simple. It predicted that, if it had modelled adverse events, top-down treatment would have been more dominated. The committee thought the cost of surgery might have been underestimated and that its impact on the model results was not clear. The EAG noted that, although it did not vary the costs of surgery, the number of surgical events modelled was very small, so it did not anticipate a significant difference in results.
## Multiple uncertainties make it difficult to determine cost effectiveness so the tests cannot be recommended for routine use in the NHS
Lack of evidence on the prognostic ability, and the effect on treatment decisions and clinical outcomes (see sections 4.4 to 4.6) of the PredictSURE IBD and IBDX tests makes it difficult to assess the cost effectiveness of the tests for assigning people to top-down or step-up treatment. The base-case model was based on data for PredictSURE IBD. IBDX was only included in an exploratory scenario analysis (see section 3.13). Uncertainties in the modelling (see sections 4.7 to 4.10) relate to:
the effectiveness of the top-down strategy
the assumed equivalence in prognostic accuracy of both tools
the sequence of treatments modelled in the step-up and top-down treatment strategies.These, and the many assumptions needed to link the data because of limited evidence, make the cost effectiveness of the tests to the NHS uncertain. Because of this, the committee considered the model to be illustrative of the likely key drivers of cost effectiveness to show where it may be best to focus research. In the absence of the evidence that the committee would have liked to see (see section 5), changes to the model at this time would not change the overall conclusion. Outcomes from new studies that address the evidence gaps identified will be considered as part of the review process and could need the model structure to change in future updates.# Recommendations for further research
The committee recommends more research on:
the accuracy of PredictSURE IBD and IBDX tests in identifying people at high or low risk of following a severe course of Crohn's disease
how PredictSURE IBD and IBDX tests, when used alongside clinical features, affect clinical decisions about whether step-up or top-down treatment is offered
the clinical outcomes and costs resulting from a top-down treatment strategy compared with a step-up treatment strategy
how PredictSURE IBD and IBDX tests affect clinical outcomes once someone has been assigned to top-down or step-up treatment, considering the different pathways that children and adults may follow.
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{'Recommendations': "There is not enough evidence to recommend the use of the PredictSURE IBD and IBDX tests. They should only be used in the context of research to help identify people at high risk of a severe course of Crohn's disease and guide treatment.\n\nFurther research is recommended (see section\xa05) to:\n\nassess how accurate the tests are for identifying a low or high risk of a severe course of Crohn's disease\n\nunderstand how the tests affect decisions about treatment\n\nassess the clinical outcomes and costs associated with different treatment strategies\n\nassess how the tests affect clinical outcomes.\n\nWhy the committee made these recommendations\n\nPredictSURE IBD and IBDX are tests that may be able to identify people at high risk of severe Crohn's disease. If people can be identified in this way, clinicians could offer the most appropriate treatment to control symptoms while minimising side effects. 'Top-down' treatment has been suggested to be more effective for people with severe Crohn's disease. This reverses the standard order of treatment, starting with biological therapies such as tumour necrosis factor (TNF)-alpha inhibitors.\n\nThe clinical evidence for the tests comes from only a small number of people, which does not give confidence in the results reported. There's also not much evidence on how effective top-down treatment is in people who would be classified as high risk using the test, particularly in the NHS where it is not standard practice.\n\nBecause of this and other assumptions made in the economic model, the cost-effectiveness estimates are very uncertain and lack face validity (that is, the results are unexpected). More research is needed to resolve the clinical uncertainties. Therefore, these tests are not recommended for routine use in the NHS.", 'The diagnostic tests': "# Clinical need and practice\n\nCrohn's disease is a chronic condition that causes inflammation of the gastrointestinal tract, particularly the large intestine and the last section of the small intestine. This condition is characterised by recurring periods of active symptoms (flares). At other times health is generally good (remission). According to Crohn's & Colitis UK, 1\xa0in every 650\xa0people in the UK is affected by Crohn's disease. Complications of Crohn's disease include intestinal strictures (narrowing of the affected area of the intestine), fistulas (ulceration of the lining of the gastrointestinal tract) and perforation. Children may also have growth problems because of poor absorption of nutrients.\n\nThe disease course varies a lot from person to person. Some people are at a higher risk of more frequent flares and relapses that do not respond to standard drug treatment. In the long term, they may be at a higher risk of developing complications and may need surgery.\n\nCrohn's disease has no cure. The goal of treatment is to induce remission by controlling symptoms and maintain remission to prevent relapse. Current standard care is a 'step-up' strategy, which starts with corticosteroids, then immunosuppressants, then biological therapies if the disease does not respond, or loses response, to treatment. NICE's guideline on Crohn's disease covers the management of Crohn's disease in children, young people and adults and recommends the step-up strategy. Step-up treatment involves multiple courses of steroids before changing to a stronger treatment. 'Accelerated step-up' treatment involves rapidly changing to stronger treatments if the expected response is not seen in the time frame. Adequate response can be defined as no clinical symptoms, no signs of ongoing inflammation, or both.\n\nAn alternative approach not currently recommended as standard care is the top-down strategy, which reverses the order of treatment in the step-up strategy, starting with biologics such as tumour necrosis factor (TNF)-alpha inhibitors. It has been suggested that for some people with Crohn's disease, the top-down strategy could achieve a faster and higher rate of mucosal healing. This could potentially modify the natural disease course and allow people with a severe disease course to control it better. Biologics are more clinically effective but are also associated with more side effects.\n\nNeither the step-up nor the top-down approach are suitable for all people with Crohn's disease. Clinicians in specialist centres may offer the top-down strategy to people if at diagnosis they consider them to have a poor prognosis (for example, if they have significant fistulising disease, complex perianal disease or multiple risk factors). Being able to predict the course of the disease could allow the clinician to identify people who may benefit from the top-down strategy, that is, early treatment with biologics. There is currently no standard means of categorising people based on their risk of having a severe disease course.\n\nPredictSURE IBD and IBDX tests could identify people at a higher risk of a severe course of Crohn's disease, potentially guiding more personalised disease management.\n\n# The interventions\n\n## PredictSURE IBD\n\nPredictSURE IBD (PredictImmune) is a whole blood-based biomarker prognostic laboratory-based test combined with a proprietary algorithm to categorise people into a high or low risk of a severe course of Crohn's disease. The test is based on detecting CD8+ T‑cell exhaustion. People with a non-exhausted CD8+ T‑cell signature were linked to a higher risk of frequently relapsing disease. The test involves isolating mRNA from the whole blood sample using the PAXgene Blood RNA kit (QIAGEN), followed by quantitative polymerase chain reaction with reverse transcription (RT‑qPCR) to assess expression of 15\xa0target genes and 2\xa0controls. RT‑qPCR is a 2‑step process: cDNA synthesis in the reverse transcription reaction, and then a qPCR on a 384‑well plate. A maximum of 4\xa0samples may be analysed per plate because cDNA derived from each RNA sample is run in triplicate.\n\n## IBDX\n\nIBDX (Glycominds) is a panel of 6\xa0indirect solid-phase enzyme-linked immunosorbent assay (ELISA) kits, each of which detects serum levels of specific antiglycan antibodies. Antiglycan antibodies are serological biomarkers thought to be highly specific for Crohn's disease and associated with a severe disease course. The IBDX ELISA kits available to detect specific antibodies include:\n\nIBDX anti-chitobioside (ACCA) immunoglobulin\xa0A (IgA)\n\nIBDX anti-laminaribioside (ALCA) IgG\n\nIBDX anti-mannobioside (AMCA) IgG\n\nIBDX anti-Saccharomyces cerevisiae (gASCA) IgG\n\nIBDX anti-laminarin (anti‑L) IgA\n\nIBDX anti-chitin antibody (anti‑C) IgA.\n\n# The comparator\n\nThe comparator is standard clinical care in which no test or algorithm is used to predict the disease course. Instead, prognosis is based on clinical judgement of presenting signs and symptoms and known clinical risk factors for a severe disease course.", 'Evidence': "The diagnostics advisory committee considered evidence on PredictSURE IBD and IBDX to guide treatment of Crohn's disease from several sources. Full details of all the evidence are in the diagnostics assessment report.\n\n# Clinical effectiveness\n\nThe external assessment group (EAG) systematically reviewed evidence to evaluate the prognostic ability and clinical effectiveness of the PredictSURE IBD and IBDX tests to predict severe disease course and guide treatment in people with Crohn's disease who:\n\nhave newly or recently diagnosed disease\n\nhave moderate to severe active disease\n\nare currently not having any concomitant steroids, immunomodulators or biological treatments\n\nwould not have top-down treatment with current standard care in the NHS.\n\nThe EAG identified 8\xa0primary studies (reported in 12\xa0publications) that met the selection criteria for the literature review (see page\xa018 of the diagnostics assessment report for details of the selection criteria). The studies were all observational. Of the included studies, 7\xa0reported on the diagnostic performance of IBDX. In these studies, a higher number of positive biomarkers was associated with poorer prognosis. Two of the IBDX studies (Wolfel et al. 2017 and Reider et al. 2010c) prospectively assessed the prognostic ability of IBDX for predicting complications (fistulas and stenoses) and Crohn's disease-related surgery. A third prospective study reported a correlation of IBDX with either a history of complication or surgery at baseline, or their occurrence during follow up (Rieder et al. 2010b). The other 4\xa0studies were cross sectional, reporting a correlation between the number of positive IBDX biomarkers and outcomes associated with a severe disease course (a presence or history of complications or surgery) at the time of testing. Only 1\xa0study (Biasci et al. 2019) reported on the predictive ability of PredictSURE IBD to classify people into either a high or low risk of a severe course of Crohn's disease, as defined by the study investigators.\n\nOf the studies identified for IBDX, 3\xa0were done in Germany and 1\xa0study each in Canada, France and the US. One study, published as an abstract, had an unclear location. The study on PredictSURE IBD was done across 4\xa0centres in the UK.\n\n## Study quality\n\nThe EAG assessed the risk of bias in the included studies using the quality in prognosis studies (QUIPS) tool. All the studies for IBDX were considered to be at a moderate or unclear risk of bias in the measurement of confounding factors domain. Three studies were considered to be at a moderate risk of bias in the participation domain. The study identified for PredictSURE IBD was assessed to be at a low or unclear risk of bias.\n\n## Prognostic accuracy\n\nNone of the studies for IBDX were done in only people with newly diagnosed Crohn's disease. The studies had people with an established diagnosis and with a recent diagnosis of Crohn's disease. Median duration of disease at the time of testing ranged from 10.6\xa0months (interquartile range [IQR] 1.7 to 52.3) to 9.4\xa0years (IQR 1 to 44). One prognostic study by Rieder et al. (2010c) assessed the ability of IBDX to predict developing a complication or needing surgery in people with no prior complication or surgery at baseline (n=76). People who tested positive for 2\xa0or more out of 6\xa0IBDX markers had a significantly higher risk of complications (hazard ratio [HR] 2.5; 95% confidence interval [CI] 1.03 to 6.1; p=0.043), or surgery (HR 3.6; 95% CI 1.2 to 11.0; p=0.023) during the median follow up of 53.7\xa0months, than people who tested positive for 0\xa0or 1\xa0markers. A prognostic study by Wolfel et al. (2017), reported as a conference abstract, showed that the number of positive IBDX markers did not predict a shorter time to repeat intestinal surgery (n=118; median follow up of 100\xa0months).\n\nReider et al. (2010b) reported that people who had surgery (before or during follow up) had a higher number of positive IBDX markers (median 2.0 [range 1.0 to 3.0]) than those who did not (median 1.0 [range 0.0 to 2.0]; odds ratio [OR] 1.5 [95% CI 1.3 to 1.8]; p<0.001). Similarly, people with a complication had a higher number of positive IBDX markers (median 2.0 [range 1.0 to 3.0]) than those who did not (median 0.0 [range 0.0 to 2.0]; OR 1.5 [95% CI 1.3 to 1.9]; p<0.001). The remaining 4\xa0IBDX studies reported the correlation between IBDX markers and disease phenotype at the time of testing. None of the studies for IBDX estimated sensitivity or specificity.\n\nBiasci et al. (2019) reported on the prognostic ability of PredictSURE IBD in adults with newly diagnosed Crohn's disease who were not having concomitant treatment. The study included 2\xa0training cohorts (66\xa0people in the biomarker discovery cohort and 39\xa0people in the whole blood classifier cohort) and 1\xa0validation cohort (n=66). The validation cohort and the whole blood classifier cohort were considered relevant to this assessment. In the validation cohort, people categorised as high risk (n=27; 40.9%) had a statistically significantly higher risk of at least 1\xa0treatment escalation than those categorised as low risk (n=39; 59.1%), with a HR of 2.65 (95% CI 1.32 to 5.34; p=0.006). Median duration of follow up was 1.6\xa0years (IQR 1.0 to 3.7) in the high-risk group and 2.4\xa0years (IQR 1.8 to 3.8) in the low-risk group. Sensitivity and specificity for predicting the need for 2\xa0or more escalations in the first 12\xa0months were 77.8% and 70.6% respectively, and within 18\xa0months 72.7% and 73.2% respectively. Negative predictive value for predicting multiple escalations in the first 18\xa0months was 90.9%. Positive predictive value calculated by the EAG was\xa042.1%.\n\n## Comparative evidence\n\nA sub-study by Lyons (2020) based on the same cohort as Biasci et al. (2019) and published as an abstract, compared the ability of PredictSURE IBD and IBDX to predict the need for multiple treatment escalations in 74\xa0people with Crohn's disease at Addenbrooke's Hospital, Cambridge. Everyone had active disease at enrolment, and all had accelerated step-up treatment. The author concluded that there was no significant difference between the group who tested positive for at least 1\xa0IBDX marker and those who tested positive for 2\xa0or more IBDX markers, in terms of time to, or frequency of, treatment escalation. In comparison, when the cohort was stratified by PredictSURE IBD, people classed as high risk had a significantly shorter time to treatment escalation than people classed as low risk (p=0.001).\n\n## Clinical utility\n\nNo evidence was identified on how the tests affect the decision in clinical practice to offer top-down strategy to people at high risk of a severe disease course. There was also no evidence on how the tests affect the clinical outcomes of people with severe Crohn's disease.\n\n# Cost effectiveness\n\n## Systematic review of cost-effectiveness evidence\n\nThe EAG searched for studies on the cost effectiveness of PredictSURE IBD and IBDX in Crohn's disease and economic evaluations of treatments for people with newly diagnosed and moderate to severe Crohn's disease. It did not identify any economic studies for PredictSURE IBD and IBDX, but it did find 11\xa0evaluations relevant to treatment options in Crohn's disease.\n\nOne study by Marchetti et al. (2013) specifically compared the cost effectiveness of top-down (step\xa01: infliximab plus azathioprine, step\xa02: additional infliximab plus azathioprine, step\xa03: methylprednisolone plus azathioprine) and step-up (step\xa01: methylprednisolone, step\xa02: methylprednisolone plus azathioprine, step\xa03: infliximab plus azathioprine) approaches in Italy. The authors concluded that the top-down strategy was better and less costly than the step-up strategy. The treatment strategies modelled in the study by Marchetti are not representative of UK NHS practice. The health economics report for NICE's guideline on Crohn's disease explored the cost effectiveness of 9\xa0induction treatment sequences (composed of 4\xa0treatment lines) for Crohn's disease from the NHS perspective. The remaining 9\xa0studies compared individual treatment steps.\n\nThe company submitted an abstract of a study evaluating the cost effectiveness of PredictSURE IBD to guide early use of biologics in Crohn's disease and ulcerative colitis in the UK. The model structure comprised a decision tree then a Markov transition model. Study results were presented at the European Crohn's and Colitis Organisation Conference in February 2020. The results show that, over a 15‑year time horizon, top-down treatment guided by PredictSURE IBD produced an incremental cost-effectiveness ratio (ICER) of £7,179 per quality-adjusted life year (QALY) gained when compared with standard care.\n\n## Economic analysis\n\nThe EAG developed a de novo model to assess the cost effectiveness of PredictSURE IBD and IBDX to guide treatment in Crohn's disease. There was no detailed data for IBDX so the EAG assessed its cost effectiveness in an exploratory scenario analysis only.\n\nThe economic analysis was done from the UK NHS and personal social services perspective. The model had a lifetime time horizon (65\xa0years) with a cycle length of 2\xa0weeks. Costs and benefits were discounted at 3.5% per year.\n\n## Model structure\n\nThe model was a hybrid model, with a decision tree for the induction treatment and a Markov transition model for the maintenance treatment. In the induction model, people whose disease does not respond (defined as deterioration; no change; or an improvement of 70\xa0or less in Crohn's Disease Activity Index [CDAI] score) have second-line treatment, according to their treatment allocation (top down or step up). People whose disease responds to the induction treatment (defined as an improvement in CDAI score above\xa070) move to the maintenance model. They can enter the maintenance model in either remission, mild, or moderate to severe health states. People can then move between these states during maintenance treatment, reflecting the different levels of response to maintenance treatment. People in the mild and moderate to severe states are at risk of relapse and escalating to the next treatment step.\n\nEscalations from corticosteroids to immunomodulators (step up) and from corticosteroids to tumour necrosis factor (TNF)-alpha inhibitors (top down) were not modelled because in both strategies all people have initial induction treatment with corticosteroids, so they cancel each other out.\n\nSurgical events are modelled as a standalone outcome in the model, that is, people did not leave their respective health states to enter a surgery health state. Complications and long-term consequences of surgery were not modelled. Time to surgery in the high-risk, top-down cohort was estimated by applying a hazard function generated from the study by Hoekman et al.\xa0(2018).\n\n## Model inputs\n\nThe population modelled was based on the UK study by Biasci et al. (2019), which the company provided anonymised individual patient data for. There were 105\xa0people in the cohort with Crohn's disease; 88\xa0had newly diagnosed disease. However, the EAG based its analysis on 40\xa0people in the study whose treatment matched the standard definition of step-up treatment in the UK, that is, people who had first-line treatment with corticosteroids and second-line treatment with immunomodulators (after failure of corticosteroids). This informed the estimates of time to treatment escalation and time to surgery in the base case. To extrapolate time to treatment escalation data to the time horizon of the model, the EAG used individual patient data to generate time to event data for time to first escalation.\n\nD'Haens et al. (2008) and its 10‑year follow-up study by Hoekman et al. (2018) informed estimates for effectiveness of top-down compared with step-up treatment. The study by D'Haens was a 2‑year multicentre randomised trial that assessed the clinical efficacy of early combined immunosuppression compared with conventional treatment in people with newly diagnosed Crohn's disease. People randomised to early combined immunosuppression had induction treatment with infliximab and azathioprine. People had no infliximab maintenance but were allowed infliximab as needed and, if necessary, corticosteroids, to control disease activity. People randomised to conventional treatment had corticosteroids, followed, in sequence, by azathioprine and infliximab. The study by Hoekman retrospectively reviewed the medical records of people included in the D'Haens trial, which collected data on hospitalisation, flares, surgery, clinical activity and other outcomes, for a median follow up of 10\xa0years.\n\n## Effectiveness of induction and maintenance therapies\n\nProbabilities of response and remission with induction and maintenance therapies were based on data from a pragmatic search and from NICE's technology appraisal guidance on vedolizumab for treating moderately to severely active Crohn's disease after prior therapy. Based on this guidance, the EAG estimated that 21.2% of responders remained in the moderate to severe disease state. The probability of response is the same for top down and step up, except for immunomodulators in the step-up strategy (table\xa01).\n\nTreatment strategy\n\nInduction: response\n\nInduction: remission\n\nMaintenance: response\n\nMaintenance: remission\n\nTop down: biologics\n\n%\n\n%\n\n%\n\n%\n\nTop down: anti-tumour necrosis factor (TNF)\n\n%\n\n%\n\n%\n\n%\n\nStep up: biologics\n\n%\n\n%\n\n%\n\n%\n\nStep up: anti-TNF\n\n%\n\n%\n\n%\n\n%\n\nStep up: immunomodulator\n\n%\n\n%\n\n%\n\n%\n\nThe costs considered in the model are the costs of the diagnostic tests, treatment and care of Crohn's disease. The total cost of testing charged by the laboratory was £1,250 for PredictSURE IBD and £347 (estimated) for IBDX. Table\xa02 shows the dose prices and induction dosages for induction treatment in top-down and step-up strategies, taken from BNF and NHS reference costs, and maintenance treatment dosages based on clinical opinion.\n\nTreatment\n\nDose per unit (mg)\n\nList price per unit\n\nInduction dosages\n\nMaintenance dosages\n\nUstekinumab\n\n\n\n£2,147.00\n\nInduction dose at week\xa00 depends on body weight:\n\nmg for 56\xa0kg\n\nmg for 56\xa0kg to 85\xa0kg\n\nmg for 86\xa0kg or over\n\nmg every 8\xa0weeks\n\nVedolizumab\n\n\n\n£2,050.00\n\nmg at week\xa00, 2 and 6\n\nmg every 8\xa0weeks\n\nInfliximab\n\n\n\n£377.66\n\nmg/kg at week\xa00, 2\u202fand 6\n\nmg/kg every 8\xa0weeks\n\nAdalimumab\n\n\n\n£308.13\n\nmg at week\xa00; 80\xa0mg at week\xa02\n\nmg every 2\xa0weeks\n\nAzathioprine\n\n\n\n£0.04\n\nmg/kg/week for 8\xa0weeks\n\nmg/kg/week\n\nMercaptopurine\n\n\n\n£1.97\n\nmg/kg/week\n\nmg/kg/week\n\nMethotrexate\n\n/15\n\n£16.64 or £14.92\n\nmg/week for 8\xa0weeks\n\nmg/week\n\nPrednisolone\n\n\n\n£0.04\n\nmg; tapered by 5\xa0mg per week – 8\xa0weeks total\n\nNo maintenance with prednisolone\n\nIntravenous administration (outpatient)\n\n\n\nFirst: £199\n\nFollow up: £212\n\nNot applicable\n\nNot applicable\n\nThe total cost of managing maintenance health states for 2\xa0weeks was £17 for remission, £27 for a mild state and £122 for a moderate to severe state. This included outpatient, radiology, endoscopy and hospitalisation costs.\n\nThe EAG used the utility values from NICE's technology appraisal guidance on vedolizumab (based on EQ‑5D data from GEMINI studies) in the base-case analysis and a mapping algorithm based on NICE's technology appraisal guidance on ustekinumab for moderately to severely active Crohn's disease after previous treatment in a scenario analysis. All utilities were adjusted to account for the age and sex of the modelled population, according to Ara and Brazier (2010). Surgery-related disutility was estimated from the Marchetti study. Table\xa03 shows the utility values used in the modelling.\n\nHealth state\n\nNICE guidance on vedolizumab\n\nNICE guidance on ustekinumab\n\nRemission\n\n\n\n\n\nMild disease\n\n\n\n\n\nModerate to severe\n\n\n\n\n\n## Key assumptions\n\nThe EAG assumed that:\n\nPredictSURE IBD (and IBDX in the scenario analysis) are 100% accurate in categorising people into high and low risk of a severe disease course.\n\nPeople categorised as high risk by the test have top-down treatment.\n\nPeople have the same baseline probability of escalating to the next step in the step-up strategy (estimated from time to first escalation in Biasci et al. 2019) regardless of the number of previous escalations.\n\n% of people having anti-TNF and 20% of people having non-anti-TNF biologics have combination treatment with immunomodulators.\n\nResponse to anti-TNF does not depend on the prior lines of treatment.\n\nPeople in the top-down strategy have a longer time to treatment escalation and a longer time to surgery than people in the step-up strategy, based on extrapolation of results from D'Haens et al. (2008) and Hoekman et al. (2018).\n\nTo use the D'Haens study the EAG assumed that:\n\nThe relative treatment effect of top-down and step-up strategies in a mixed-risk population is the same as the relative treatment effect in a high-risk population.\n\nTime to relapse is a proxy measure for time to the next treatment escalation.\n\nThe effectiveness of treatment strategies in this study is a proxy for the treatment effectiveness of the first step in the top-down (anti-TNF) and step-up (immunomodulators) strategies modelled.\n\nTo estimate the relative treatment effect of top-down and step-up treatment on time to treatment escalation, the EAG digitised the time to relapse Kaplan–Meier data from D'Haens et al. (2008) to estimate a hazard function. This was applied to the first treatment step in the high-risk, top-down arm of the model.\n\nThe base case was revised to reflect the assumption that time to treatment escalation restarts on each new treatment rather than reducing over time and as treatment sequences progress. Cost-effectiveness results presented are from the revised base case.\n\n## Base-case results\n\nResults of the revised base case (detailed in the addendum to the diagnostics assessment report) superseded results of the primary analysis. In the revised analysis, the time to treatment escalation restarts on each new treatment.\n\nThe base case compared the top-down strategy (using PredictSURE IBD to predict who was high risk) with standard care, in which a high-risk person has step-up treatment. In both the deterministic and probabilistic analyses PredictSURE IBD was dominated by standard care, meaning it costs more and has fewer QALYs:\n\nDeterministic result: incremental cost was £9,084 and incremental QALY was -0.08.\n\nProbabilistic result: incremental cost was £12,132 and incremental QALY was -0.03. The testing strategy had a less than 10% probability of being cost effective against standard care at the maximum acceptable ICERs of £20,000 and £30,000 per QALY gained.\n\nThe EAG revised its base case again, adding a corticosteroid step to the start of the step-up treatment strategy before immunomodulators. The PredictSURE IBD arm was still dominated by the standard care arm.\n\n## Cost-effectiveness results: scenario analyses\n\nThe dominance of the step-up strategy may be because of the benefit some people get from having immunomodulators first, before biologics. The clinical experts told the EAG that people on the top-down strategy do not have immunomodulators after 3\xa0lines of biologics. However, the EAG explored a scenario that had immunomodulators as the last treatment option in the top-down arm. Deterministic base-case results for this scenario showed that PredictSURE IBD (top-down strategy) generated 0.07 more QALYs than the step-up strategy, at an additional cost of £7,502, producing an ICER of £105,148 per QALY gained. This is higher than £20,000 to £30,000 per QALY gained, the range NICE normally considers an acceptable use of NHS resources.\n\nThe EAG ran a series of individual scenario analyses, most of which showed that PredictSURE IBD was dominated by standard care. The EAG also ran a combination of individual scenarios, because these were thought to have more impact than individual scenarios.\n\nIf the analysis assumed that the condition did not respond to treatment with immunomodulators for any high-risk person in the step-up arm, so they had no benefit from them, PredictSURE IBD had an ICER of £170,180 per QALY gained. The proportion of people who responded to immunomodulators was then varied. This showed that the 2\xa0strategies became clinically equivalent when it was assumed that 97% of high-risk people in the step-up arm do not benefit from immunomodulators.\n\nThe EAG explored a scenario that assumed PredictSURE IBD had a lower test accuracy, and the effect of misdiagnosis. In this scenario, PredictSURE IBD was more costly and generated a QALY gain of 0.15, producing an ICER of £64,876 per QALY gained. This gain in QALY, despite the lower accuracy of the test, can be attributed to the assumption that some lower-risk people misdiagnosed as high risk go on to have top-down treatment, without the need for further escalation.\n\nAssumptions about treatment stopping were based on Marchetti 2013, which reported that 76% of people had mucosal healing after 2\xa0years in remission with biologic treatments using a top-down strategy and 40% using a step-up strategy. In a scenario analysis that assumed 76% of people in the top-down arm and 40% of people in the step-up arm stopped biologics, PredictSURE IBD was less costly and less effective than standard care, producing an ICER of £46,263 per QALY gained. Scenarios combining the effect of misdiagnosis with the same proportion of people stopping biologics in both arms, that is, 40% in step up and top down or 76% in step up and top down, produced ICERs of £48,034 and £32,875 per QALY gained respectively.\n\nIndividual scenarios were combined to explore the impact of increasing the effectiveness of the top-down strategy while reducing the treatment cost of biologics. The results of these combined scenarios varied. One scenario combined 3\xa0assumptions, that:\n\nbase-case risk of relapse for second and later treatment steps is the same\n\ndiscontinuation of biologic treatment is 76% for top down and step up\n\n% of people in the step-up arm do not respond to immunomodulators.This produced an ICER of £29,225 per QALY gained in favour of top down.\n\nA tornado plot of the one-way sensitivity analyses showed that response to biologics in the top-down arm of the model was a key driver of the deterministic ICER.\n\nThe EAG reduced the time horizon to 5\xa0years in the model with the corticosteroid step at the start of the step-up treatment strategy. This resulted in a QALY gain of 0.004 associated with the PredictSURE IBD arm of the model and a cost of £13,728, giving an ICER of £3,814,576 per QALY gained.", 'Committee discussion': "# Clinical effectiveness\n\n## Knowing the likely course of the disease may help people with Crohn's disease and the NHS\n\nThe patient expert explained that having Crohn's disease can substantially affect the quality of life of the person and their family. Crohn's disease is a complex disease associated with symptoms that can be highly debilitating. Symptoms include abdominal pain, profound fatigue, weight loss and a constant urge to have a bowel movement, and extraintestinal manifestations, which can affect the joints, skin, bones, eyes, kidneys and liver. Recent research from the Secured Anonymised Information Linkage (SAIL) databank in Wales estimates that the prevalence of Crohn's disease is 1\xa0in\xa0271. The starting age of Crohn's disease is between 10\xa0and 40\xa0years so most people face a lifetime of medication and repeated major surgery. Most are not eligible for help with the cost of prescriptions. Currently the extent of inflammation is monitored using endoscopic imaging and faecal calprotectin blood tests, but they do not predict disease progression or the likelihood of needing surgery in the future. People may not want invasive monitoring using colonoscopy because it is stressful to prepare for, has unpleasant side effects and may aggravate symptoms. The patient expert suggested that a test that predicts long-term disease course could help give people a better understanding and acceptance of their condition, and make planning review appointments more efficient. It could also help increase quality of life outcomes, reduce potential side effects from first-line treatments, allow more effective earlier drug treatment, and reduce demands on NHS services.\n\n## Studies on the prognostic ability of the tests are heterogenous and have small sample sizes\n\nThe reviewed studies on prognostic ability had mixed populations, including people with ulcerative colitis. The number of people with Crohn's disease in each study was small, given the prevalence of the condition in the wider population. The committee noted that the small sample sizes could mean that the reviewed studies were underpowered to produce robust estimates of the prognostic ability of the tests. The committee also noted that there are other predictive studies for Crohn's disease with larger populations, showing that larger sample sizes are possible. The committee concluded that the heterogeneity in the population and the population size added substantial uncertainty to the interpretation of study results.\n\n## There is no standard definition of a high or low risk of a severe disease course\n\nThe reviewed studies used different measures to define a person as being at high or low risk of following a severe course of Crohn's disease. IBDX studies used poor outcomes, such as surgery and complications, as a proxy for a severe disease course (see sections\xa03.5 and\xa03.6), whereas the PredictSURE IBD study used the need for multiple treatment escalations (see section\xa03.7). This inconsistency is a source of additional uncertainty.\n\n## The accuracy of PredictSURE IBD and IBDX in predicting a severe disease course is uncertain\n\nLittle data was identified on the prognostic accuracy of the tests. Sensitivity, specificity and negative predictive value were only reported for the PredictSURE IBD test, and in only 1\xa0study (Biasci 2019). The clinical expert said that, at the moment, severe disease course may be predicted by known risk factors such as age and smoking status. But there is no consensus on, or algorithm for, how these risk factors should be combined, and their predictive value is limited. The clinical expert also said that, based on the findings of the Biasci study, the PredictSURE IBD test appears to perform better than risk prediction based on clinical features or endoscopic findings, and therefore has the potential to be a useful test. The committee noted that it would help to understand if the tests can give a more accurate prognosis when used alongside clinical features rather than as a substitute. The committee concluded that overall, the evidence on the prognostic accuracy of PredictSURE IBD and IBDX is weak, and encouraged further research on their accuracy when used alongside clinical features (see section\xa05).\n\n## There is little evidence on how the tests affect treatment decisions\n\nThe proposed value of the tests is to categorise people with Crohn's disease according to their risk of following a severe disease course. People predicted to have a severe disease course could have top-down treatment, which may help control the disease early, leading to better outcomes like fewer flare-ups, and prevent bowel damage and limit the need for surgery. The committee noted that currently there was no evidence on how the tests can help with decisions about personalised treatment plans. It concluded that it would help to have research on how the tests affect treatment decisions (see section\xa05). PROFILE, a randomised, multicentre, biomarker-stratified, open-label study is ongoing in the UK with results expected in 2022. This trial uses PredictSURE IBD to assign people to top-down or step-up treatment, and may help address this evidence gap.\n\n## There is no evidence on how the tests affect clinical outcomes\n\nThe committee considered that there was no evidence to show that using the prognostic tests to identify people at high risk of a severe disease course and help guide treatment improves clinical outcomes. The committee encouraged studies assessing how the tests affect clinical outcomes (see section\xa05).\n\n# Cost effectiveness\n\n## Corticosteroids are often used as a first-line treatment for adults with moderately active or severely active Crohn's disease\n\nThe committee noted that the treatment sequences modelled by the external assessment group (EAG) in the original base case may not reflect treatment in the NHS. Corticosteroid treatment was not included in the original model because all high-risk patients (in the top-down and step-up arms) were assumed to have initial induction treatment with corticosteroids before moving to the next treatment steps. Therefore, the impact of corticosteroid use would be the same in both arms. Because of this, the EAG excluded people in the Biasci study who did not escalate from steroids to immunomodulators or anti-tumour necrosis factor (TNF) treatment (see section\xa03.18). The committee heard that the recent consensus guidelines from the British Society of Gastroenterology (Lamb et al. 2020) recommended minimising steroid use because of toxicity and lack of efficacy, except in moderate to severely uncomplicated luminal Crohn's disease, which systemic corticosteroids may have some benefit for. However, the clinical experts said that corticosteroids are still used as a first-line treatment in adults with moderately active or severely active Crohn's disease, unless there is a contraindication. In a top-down treatment strategy, a shorter period of corticosteroids, or sometimes no corticosteroids, may be used before starting treatment on biologics. The committee considered a revised base-case model, which had treatment with a corticosteroid first in the step-up strategy. The committee concluded that adding the corticosteroid step better reflected current NHS practice.\n\n## Managing Crohn's disease is complex, and rapidly evolving because of new treatments and tests\n\nClinical experts explained that treatment of Crohn's disease varies across the NHS. Many treatments are already available and new drugs are entering the market. Treatments are often combined, for example, in the EAG model 30% of people who had a TNF-alpha inhibitor, and 20% of people who had a biological treatment that was not an anti-TNF, also had an immunomodulator. This is because there is evidence to show that combination treatment reduces the chances of losing response to biologics (immunogenicity). However, the clinical experts said there is no consensus on using monotherapy or combination therapy, and that it varies in clinical practice. Tests that monitor levels of biologics and presence of antibodies to biologics are also being more widely used. These tests can guide a personalised treatment strategy to help maintain a treatment response for longer. The committee noted that an important study used to provide model inputs for the top-down and step-up treatment strategies (D'Haens et al. 2008) was over 10\xa0years old. It used treatment strategies that do not reflect current practice in the NHS or the top-down treatment strategy that was included in the EAG model (see section\xa04.10). The committee concluded that variation in clinical practice, and the absence of more recent data comparing top-down and step-up strategies, make modelling of the treatment strategies difficult. This creates great uncertainty around the model structure.\n\n## It is uncertain what a top-down treatment strategy in the NHS would look like\n\nTop-down treatment is not widely used in the NHS and so it is uncertain what the treatment pathway would look like. The clinical experts noted that de-escalation of biologics in Crohn's disease is often unsuccessful and therefore not often used because of a high risk of relapse. The company model included an immunomodulator step after biologics but the EAG base case did not (see section\xa04.14). The EAG explored this as a scenario analysis (see section\xa03.30). In addition, the biologics modelled as second and third line can also be used as first line. The committee noted that lack of clinical consensus about the top-down treatment strategy adds extra uncertainty into the model.\n\n## It is not certain if top-down treatment has clinical benefits over step-up treatment\n\nClinical experts explained that early rather than late treatment with biologics could improve outcomes for people likely to have a more severe disease course. The EAG noted that the evidence on the effectiveness of top-down (early treatment with biologics) compared with step-up (late treatment with biologics) in the model was from the D'Haens study. This showed that people who had early combined immunosuppression had a longer time to relapse than people who had conventional treatment. The hazard function (based on the assumption that time to relapse is a proxy for time to next treatment escalation) derived from D'Haens was applied only to the first step of the model (the anti-TNF compared with immunomodulator step). In the model, people in the top-down arm of the model remained on initial treatment for longer than those in the step-up arm of the model (anti-TNF compared with immunomodulator). This resulted in people in the first step of the top-down arm having a higher probability of having and maintaining remission, which is associated with lower costs and higher quality-adjusted life years (QALYs). Later treatment steps in both the top-down and step-up strategies were assumed to have the same time to treatment escalation as anti-TNF in the top-down arm. This assumption was made because there was no evidence either way. The early combined immunosuppression used in D'Haens differed from the top-down treatment sequence described by the clinical experts because people did not carry on having maintenance treatment with infliximab but were allowed infliximab as needed (see section\xa03.19). This might have underestimated the benefits of top-down treatment in the model. The EAG said that in the long term, top down may not have an advantage over step up because the 10‑year follow-up study of D'Haens (Hoekman 2018) showed no difference in hospitalisation, surgery and endoscopic remission between both strategies. The clinical experts considered that early treatment with biologics does make a difference, and that there is a trend towards using biologics earlier, but said that there is not much good-quality evidence generalisable to the NHS to support this. The EAG noted that the evidence available was heterogeneous. It noted that a Canadian Agency for Drugs and Technologies in Health review published in 2019 also found that it is not clear if early biologic therapy is more effective than conventional therapy for Crohn's disease in adults because there are few studies and the ones that exist are heterogenous. Registry data could have been useful. The committee concluded that more evidence is needed on the effectiveness of top-down compared with step-up strategies. This is because if there is no evidence of benefit, there is no clinical rationale for identifying people at high risk of a severe disease course and treating them using a top-down strategy.\n\n## Because of the lack of data and the need for many assumptions, the model results are not certain\n\nThe committee noted that interpreting the modelling was difficult because of the very weak data feeding into it. There was limited data on the prognostic accuracy of the tests (see section\xa04.4), on the effectiveness of a top-down strategy compared with a step-up strategy (see section\xa04.8), and no information from studies on how these 2\xa0steps would combine to affect clinical outcomes. The EAG explained that it had to make many assumptions to be able to link the evidence in the model. There was great variation in the results of the model. Because of the limited data and assumptions that needed to be made, the cost effectiveness of the tests is highly uncertain.\n\n## The economic model lacks face validity because top-down treatment is associated with a QALY loss\n\nIn the EAG's base-case model, a standard care strategy of no testing and step-up treatment dominated the strategy of testing with PredictSURE IBD followed by top-down or step-up treatment depending on the test result. In the revised base case when a corticosteroid step was included in the step-up treatment strategy, the PredictSURE IBD arm was still dominated by the standard care arm. The clinical experts had previously explained that early treatment with biologics could improve outcomes for people with severe Crohn's disease (see section\xa04.10). The committee therefore considered that the base-case results from the economic model, which show that top-down treatment is associated with a QALY loss compared with step-up treatment, lacks face validity. The EAG said that the QALY loss is because there are more treatment options in the step-up strategy because it has an immunomodulator step as the first-line treatment. The most recent revision of the model had both a corticosteroid step and an immunomodulator step at the start of the step-up strategy. In the model the treatment steps are incorporated independently of each other because of a lack of evidence on response to the full treatment strategy or on how response to each treatment is correlated. The consequence of this is that people on the step-up treatment arm have the opportunity to respond, even if just temporarily, to corticosteroids and immunomodulators, and therefore take longer to exhaust all their treatment options. This results in people on step-up treatment spending more time in the health states of response or remission, and therefore gaining more QALYs compared with people in the top-down treatment arm. The committee concluded that the QALY difference in favour of step-up treatment is unexpected and might not be seen in a real-world setting.\n\n## Changing some of the key assumptions in the model leads to a QALY gain in the PredictSURE IBD arm, but ICERs are high\n\nThe EAG explained that some scenario and sensitivity analyses did result in a QALY gain for the PredictSURE IBD arm of the model. For example, in the one-way sensitivity analyses, using higher response and remission rates for biologics in the top-down treatment strategy, and using lower response and remission rates for biologics in the step-up treatment strategy, all resulted in a QALY gain for PredictSURE IBD. Other scenarios that resulted in QALY gain for the PredictSURE IBD arm of the model were:\n\nafter 2\xa0years in remission with biologics, a proportion of people have mucosal healing and do not need more treatment escalations\n\nwhen some low-risk people were assumed to be misdiagnosed as high risk (see section\xa03.34) because they did not need any more treatment escalation\n\nwhen an additional immunomodulator step was included at the end of the top-down treatment strategy\n\nwhen it was assumed that all high-risk patients who receive step-up treatment do not respond to an immunomodulator and therefore escalate to anti-TNF.The ICERs from these sensitivity and scenario analyses were well above the range normally considered to be cost effective.\n\n## The EAG's model results are different from the company's model and the most relevant published economic model\n\nThe base-case probabilistic and deterministic results of the EAG's model produced QALYs in favour of standard care. This suggests that a no testing strategy with step-up treatment is better for people at high risk of a severe course of Crohn's disease than top-down treatment using the prognostic tool. This result was not consistent with the company's model and the model reported by Marchetti (2013), both of which reported that a top-down strategy is associated with more QALYs. The EAG noted that the difference between its model and the company's was that the treatment sequence modelled by the company had an immunomodulator as a last treatment step in the top-down arm. This was not modelled in the EAG's base case but as a scenario analysis. This scenario produced an ICER in favour of top-down treatment that was much higher than what NICE normally considers a cost-effective use of NHS resources (see section\xa03.30). The company's model also assumed a constant relative treatment effect, capped at 10\xa0years, whereas the EAG's model assumed a diminishing relative treatment effect (see further details in the addendum to the diagnostic assessment report). Marchetti modelled a different treatment sequence (see section\xa03.11) to the EAG's, and a different time horizon – 5\xa0years compared with the EAG's 65\xa0years. The EAG explored changing the time horizon in their model to 5\xa0years, which showed a small QALY gain for the PredictSURE IBD arm (see section\xa03.37). The difference in the results was likely because of the uncertainties in the top-down treatment pathway and the effectiveness of top-down compared with step-up strategies.\n\n## Assuming that IBDX and PredictSURE IBD have the same prognostic ability is not appropriate\n\nOnly data on the prognostic ability of PredictSURE IBD was included in the base case. The EAG included IBDX in an exploratory analysis that assumed that the ability of IBDX to identify people at high or low risk was the same as PredictSURE IBD. The committee heard that the tools identify different markers and need different test samples. The committee also noted that there was 1\xa0abstract (Lyons 2020), which compared both tools and showed that PredictSURE IBD predicted a shorter time to treatment escalation in people classed as high risk. IBDX did not predict a difference in time to treatment escalation between people positive for 2\xa0or more markers and those positive for only 1\xa0marker (see section\xa03.8). The committee concluded it was not appropriate to assume the tests had the same prognostic accuracy, and that more evidence is needed (see section\xa05).\n\n## Evidence from a different starting cohort that includes children and teenagers would be useful\n\nThe committee heard that the average age in the EAG's model was\xa035. It considered that the model might not reflect other age groups that are first diagnosed with Crohn's, for example, one peak is in teenagers and another is at around\xa060. A clinical expert noted that the treatment pathway for children or teenagers would be different from adults because children often follow a more severe disease course and may need enteral nutrition. The committee heard that modelling this population may need an entirely new model rather than an adaptation of the model built by the EAG for the adult population.\n\n## Modelling adverse events or varying the cost of surgery may not have a huge impact on the results\n\nThe EAG did not model adverse events, to keep the model simple. It predicted that, if it had modelled adverse events, top-down treatment would have been more dominated. The committee thought the cost of surgery might have been underestimated and that its impact on the model results was not clear. The EAG noted that, although it did not vary the costs of surgery, the number of surgical events modelled was very small, so it did not anticipate a significant difference in results.\n\n## Multiple uncertainties make it difficult to determine cost effectiveness so the tests cannot be recommended for routine use in the NHS\n\nLack of evidence on the prognostic ability, and the effect on treatment decisions and clinical outcomes (see sections\xa04.4 to\xa04.6) of the PredictSURE IBD and IBDX tests makes it difficult to assess the cost effectiveness of the tests for assigning people to top-down or step-up treatment. The base-case model was based on data for PredictSURE IBD. IBDX was only included in an exploratory scenario analysis (see section\xa03.13). Uncertainties in the modelling (see sections\xa04.7 to\xa04.10) relate to:\n\nthe effectiveness of the top-down strategy\n\nthe assumed equivalence in prognostic accuracy of both tools\n\nthe sequence of treatments modelled in the step-up and top-down treatment strategies.These, and the many assumptions needed to link the data because of limited evidence, make the cost effectiveness of the tests to the NHS uncertain. Because of this, the committee considered the model to be illustrative of the likely key drivers of cost effectiveness to show where it may be best to focus research. In the absence of the evidence that the committee would have liked to see (see section\xa05), changes to the model at this time would not change the overall conclusion. Outcomes from new studies that address the evidence gaps identified will be considered as part of the review process and could need the model structure to change in future updates.", 'Recommendations for further research': "The committee recommends more research on:\n\nthe accuracy of PredictSURE IBD and IBDX tests in identifying people at high or low risk of following a severe course of Crohn's disease\n\nhow PredictSURE IBD and IBDX tests, when used alongside clinical features, affect clinical decisions about whether step-up or top-down treatment is offered\n\nthe clinical outcomes and costs resulting from a top-down treatment strategy compared with a step-up treatment strategy\n\nhow PredictSURE IBD and IBDX tests affect clinical outcomes once someone has been assigned to top-down or step-up treatment, considering the different pathways that children and adults may follow."}
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https://www.nice.org.uk/guidance/dg45
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Evidence-based recommendations on PredictSURE IBD and IBDX for guiding treatment of Crohn’s disease.
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8d042ab4b95b10500af24cc0698a0428cda59ad8
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EarlyCDT Lung for assessing risk of lung cancer in solid lung nodules
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EarlyCDT Lung for assessing risk of lung cancer in solid lung nodules
Evidence-based recommendations on EarlyCDT Lung for assessing the risk of lung cancer in solid lung nodules.
# Recommendations
There is not enough evidence to recommend routine use of EarlyCDT Lung for assessing the risk of lung cancer in solid lung nodules.
Further research is recommended (see section 4) on:
the diagnostic accuracy of EarlyCDT Lung, its performance when used with existing risk models and its effect on clinical management decisions
patient and nodule characteristics that may relate to the prevalence of malignant disease and disease progression
current practice for managing intermediate-risk lung nodules
the clinical consequences of CT surveillance
the likelihood and impact of overtreatment of benign and indolent nodules.
Why the committee made these recommendations
EarlyCDT Lung is used to assess the risk of lung cancer in solid lung nodules. Accurate risk assessment can prevent delayed treatment of malignant nodules or unnecessary biopsies of benign nodules. But, the evidence of how well EarlyCDT Lung works is limited and uncertain.
The company intends for EarlyCDT Lung results to be used to update a person's existing lung cancer risk assessment. But, most studies used EarlyCDT Lung results to classify nodules as benign or malignant. Therefore, most of the existing data does not represent the intended use of the test in updating estimates of lung cancer risk and further validation is needed.
It is also unclear how EarlyCDT Lung will affect lung nodule management in the NHS. This is because there were no studies to show how EarlyCDT Lung affects clinical decision making for people with lung nodules and there is significant variation in management of intermediate-risk nodules in the NHS.
It is also difficult to assess the impact of EarlyCDT Lung on long-term patient outcomes. This is because there is limited data on the factors that might affect disease progression, how lung nodules change during CT surveillance and the likelihood and impact of unnecessary biopsy or surgical removal.
Because of the limited clinical evidence, the cost effectiveness of EarlyCDT Lung was not assessed and so it has not been recommended. Further research is needed on both the EarlyCDT Lung test and on the impact of current lung nodule management. Without more data on current management, it will be difficult to quantify the impact of EarlyCDT Lung and other new tests for assessing lung nodules.# The diagnostic tests
# Clinical need and practice
In the NHS, lung nodules are managed in line with the British Thoracic Society's guidelines for the investigation and management of pulmonary nodules (2015). The guidelines recommend the same diagnostic approach for nodules detected incidentally, due to symptomatic presentation, or through routine screening. People with nodules below 5 mm in diameter or 80 mm3 in volume are discharged without follow up. CT surveillance is offered for nodules between 5 mm and 8 mm in diameter or 80 mm3 and 300 m3 in volume. For nodules over 8 mm in diameter or 300 m3 in volume, the Brock model is used to calculate risk of malignancy. CT surveillance is offered to people with nodules that are below a 10% risk score using the Brock model.
The Herder model is used to calculate malignancy risk of nodules after a Brock risk assessment of 10% or above and a subsequent positron emission tomography CT (PET-CT) scan. For nodules with a Herder risk score below 10%, CT surveillance is offered. People with risk over 70% are considered for excision or non-surgical treatment. Within the intermediate group (between 10% and 70% risk of malignancy) the guidelines for subsequent care are more varied, with possible management options including image-guided biopsy, CT surveillance and excisional biopsy. Decisions are based on risk of malignancy, patient fitness and preferences and nodule characteristics.
Accurately differentiating between malignant and benign nodules as soon as possible is important. People have more treatment options and potentially better outcomes when lung cancer is diagnosed in its early stages. However, misdiagnosis of a benign nodule as malignant, could result in further imaging tests (with higher radiation exposure) or invasive procedures, such as biopsy or resection, which carry risks of adverse events.
EarlyCDT Lung could help identify malignant lung nodules that need immediate treatment or a biopsy. This could result in treatment being offered earlier, potentially giving improved patient outcomes. It could also reduce the number of people on CT surveillance, patient waiting times and radiologist time and enable more efficient use of NHS resources.
# The intervention
## EarlyCDT Lung
EarlyCDT Lung (Oncimmune) is a blood test to assess the malignancy risk of solid lung nodules found by chest CT or X-ray. It is an enzyme-linked immunosorbent assay and is available as a CE-IVD kit. EarlyCDT Lung measures the presence of autoantibodies to a panel of 7 lung cancer associated antigens (p53, NY-ESO-1, CAGE, GBU4-5, HuD, MAGE A4 and SOX2). After blood collection, the test is carried out in a laboratory in a secondary healthcare setting. Positive results are reported as 'positive-moderate' if at least 1 of the 7 autoantibodies is elevated above a predetermined 'low' threshold, but all are below the 'high' threshold. If at least 1 of the 7 autoantibodies is elevated above the 'high' predetermined threshold, the test is reported as 'positive-high'.
EarlyCDT Lung is proposed as a 'rule-in' test to be used in addition to standard care for the detection of lung cancer. A positive EarlyCDT Lung result would be used to update a pre-test malignancy risk from either the Brock or Herder risk models. The pre-test risk would be unchanged if the EarlyCDT Lung result is negative. The estimated post-test risk is intended to help clinicians make decisions about further testing or intervention.
# The comparators
## Brock and Herder risk models
The Brock model is used to calculate a nodule's risk of malignancy, which is based on patient characteristics (such as age, gender and smoking history) and on nodule characteristics. The Herder model is used to calculate malignancy risk after a Brock risk assessment of 10% or above and a PET-CT scan. The Herder model is based on patient characteristics, nodule characteristics, and the degree of F-fluorodeoxyglucose uptake on PET-CT.# Committee discussion
The diagnostics advisory committee considered evidence on EarlyCDT Lung for lung cancer classification of solid lung nodules from several sources, including a diagnostics assessment report and an overview of that report. Full details of the evidence are in the project documents on the NICE website.
# A test that accurately predicts lung nodule malignancy risk could reduce anxiety in people with nodules
The patient expert emphasised the importance of people understanding their options based on malignancy risk assessments. A test that correctly identifies malignant nodules in people who would otherwise be placed on surveillance, could reduce the number of people on CT surveillance and the anxiety associated with waiting. Malignant nodules could be biopsied and treated earlier, potentially leading to better health outcomes. However, patient experts were aware of the trade-off between the benefits of earlier diagnosis and treatment, and the risks of overdiagnosis leading to harms from unnecessary biopsies and treatment. The committee acknowledged the potential benefit of EarlyCDT Lung in reducing anxiety and the impact it could have in helping people, along with their clinician, to decide which further testing or treatment steps are best.
# Clinical effectiveness
## The evidence on the diagnostic accuracy of EarlyCDT Lung in people with lung nodules is limited and accuracy estimates are very uncertain
The external assessment group's (EAG) systematic review found only 5 study populations in which EarlyCDT Lung data on people with nodules was reported. Of the 5 studies, 3 were conference abstracts and only 2 were reported in full. The 2 complete publications had a high risk of bias in terms of patient selection, and the German study (Gonzalez et al. 2021) was also at high risk of bias in the flow and timing domain of the quality assessment. There were also serious concerns about the applicability of the results of these studies to NHS practice because of the position in the pathway where the test was used and how the test was used and interpreted. The EAG's meta-analysis estimated that EarlyCDT Lung has a sensitivity of 20.2% (95% confidence interval 10.5 to 35.5) and specificity of 92.2% (95% CI 86.2 to 95.8). The committee discussed that the EAG's estimate was uncertain with wide confidence intervals for the sensitivity. It noted that these results are different to the company's estimates, which were based on a single study that had 41.3% sensitivity (95% CI 35.0 to 47.6) and 90.6% specificity (95% CI 87.1 to 94.1; Healey et al. 2017). The EAG suggest that the inclusion of case-control data in Healey et al. (2017), where cases were people diagnosed with lung cancer and controls were healthy volunteers, could account for the difference in accuracy estimates. It suggested that poorer diagnostic accuracy among smaller nodules, which are less likely to be present in the confirmed cancer cases, could bias the results. The committee discussed if accuracy data from screening studies was generalisable to this decision question. The EAG commented that the malignancy risk is likely to differ between a screening population – that is people who may or may not have nodules – and a population of people who have nodules. Therefore, the screening data cannot be extrapolated reliably. The committee concluded that given the uncertainties around the accuracy estimates and the populations studied, further evidence of the accuracy of EarlyCDT Lung in people with nodules is needed (see section 4.1).
## The risk model used to calculate post-test malignancy risk from the EarlyCDT Lung result and the pre-test risk needs further validation
The committee understood that positive EarlyCDT Lung results are intended to be combined with a pre-test risk (using existing malignancy risk assessment models) to give a post-test risk. The EAG's report highlighted that the risk model (Healey et al. 2017) provided by the company to recalculate risk scores, may overestimate diagnostic accuracy as it was based on evidence from case-control studies (see section 3.2). The committee agreed that combining the tests was an appropriate way to estimate malignancy risk, but also noted that the accuracy data on these test combinations is very limited. The committee recommended that further validation of the model that combines the EarlyCDT Lung result with existing risk models is needed (see section 4.1).
## It is unclear whether ongoing studies will provide relevant accuracy data
The EAG report identified 2 potentially relevant ongoing studies of EarlyCDT Lung: 1 case-control study in China aiming to recruit 1,000 people and the other an observational screening study in the US. The committee heard that the study in China is assessing a different version of EarlyCDT Lung that was specifically developed for the market in China and would therefore not be generalisable to the UK. They also heard that the US study is due to be published in 2022. The committee also discussed the IDx Lung study that started in May 2021. It is unclear from published literature where in the pathway EarlyCDT Lung is positioned in these trials, and whether it will be used to update risk scores as indicated. The committee concluded that further research is needed on the accuracy of EarlyCDT Lung itself (see section 3.2) and on the accuracy of combining the test results with other risk models (see section 3.3). The committee also noted that the gold standard reference test in a diagnostic accuracy study should be histological confirmation of cancer or minimum 2 years follow up with CT surveillance (see section 4.1).
## Evidence on the impact of EarlyCDT Lung on clinical management decisions is limited
The EAG's report found no evidence on how EarlyCDT Lung testing affects changes in clinical decision making for people with lung nodules. The EAG's simulation study indicated that EarlyCDT Lung is unlikely to significantly impact clinical management in low-risk nodules (below 10%). EarlyCDT Lung may improve clinical management in intermediate-risk nodules, particularly for those with a higher pre-test risk (above 48%). The data feeding into the simulations however was at high risk of bias, and the simulation had to use assumptions because of weak evidence. The committee discussed that data is needed to demonstrate if a positive EarlyCDT Lung test result changes decision making such as moving from CT surveillance to biopsy or from biopsy to immediate excision without biopsy (see section 4.1).
## The likelihood and impact of unnecessary biopsy or resection of indolent and benign nodules is unknown
The EAG and committee discussed the risk and harms of false-positive test results (benign nodules incorrectly identified as malignant). The committee discussed that the safety of biopsy and surgical excision has improved in recent years, but it noted that there may still be adverse effects and anxiety for patients. It also discussed the harms of diagnoses in people with limited life expectancy or with multiple comorbidities, for whom treatment is not possible but the test could cause unnecessary anxiety. The committee discussed that data on the harms of biopsy and excision should be available through existing databases and recommended that it could be obtained as part of a large audit (see section 4.2).
## There is limited understanding of how knowledge of nodule malignancy risk and CT surveillance impact health-related quality of life
In the EAG report no studies of EarlyCDT Lung in the target population reported health-related quality of life outcomes. One screening study (Early Detection of Cancer of the Lung Scotland trial) did report that there were no statistically significant differences in lung cancer worry, health anxiety, illness perceptions, lung cancer risk perception or intrusive thoughts, between people with and without lung nodules at 3 months and 6 months. The committee heard that the ongoing Artificial intelligence and Big Data for Early Lung Cancer Diagnosis (IDEAL) study is exploring the quality of life of people with lung nodules on CT surveillance. The committee concluded that EarlyCDT Lung test results could have an impact on anxiety, but that no evidence is available to support this.
## A linked-evidence modelling approach would be appropriate to estimate the impact of EarlyCDT Lung on long-term patient outcomes
No direct trial evidence was found on how EarlyCDT Lung impacts on long-term patient outcomes, such as lung cancer related mortality and morbidity, morbidity associated with other diagnostic tests or procedures, and overall and disease-free survival. The committee noted that this was an important factor to understand, but heard that a randomised control trial for assessing the impact of EarlyCDT Lung on patient outcomes would not be feasible because of the number of patients needed to power the study. The committee agreed that a linked-evidence modelling approach could be used to estimate the impact of EarlyCDT Lung on long-term patient outcomes. This method would link new diagnostic accuracy and decision impact data to existing clinical outcome data on lung nodules and lung cancer (see section 4.1).
# Cost effectiveness
## Current management practice for intermediate-risk nodules is undefined
The EAG's report highlighted variation in management practices and a lack of evidence around decisions in managing intermediate nodules. Under the British Thoracic Society's (BTS) guidelines for the investigation and management of pulmonary nodules (2015) people with nodules in the intermediate 10% to 70% risk group may be offered CT surveillance, biopsy or surgical excision. A clinical expert explained that in the BTS guidelines, the defined malignancy risk categories for initiating Brock and Herder risk assessment, and for guiding further testing and treatment, were mostly based on evidence graded at a level 3 (non-analytical studies; for example, case reports, case series). The committee recommended that an audit of existing data should be carried out to determine how these nodules are currently managed in NHS practice. It considered that the impact of EarlyCDT Lung and other tests would be difficult to ascertain without first understanding what happens in current clinical practice (see section 4.2).
## The clinical consequences of CT surveillance of lung nodules, such as stage progression, are uncertain
The committee noted that the potential benefit of EarlyCDT Lung is that it could identify malignant lung nodules earlier than standard tests such as CT surveillance. This could lead to earlier treatment and improved patient outcomes. It also noted that there was no evidence that stage progression of malignant nodules happens in the timeframe of CT surveillance. The EAG commented that modelling studies of lung cancer screening strategies often evaluate the likelihood of pre-clinical stage progression over time, but cautioned that the generalisability of this evidence is unclear. The committee noted that it is important to understand if and how lung nodules progress during CT surveillance. This information could then be used in a linked-evidence modelling approach to understand if EarlyCDT Lung could result in meaningful earlier diagnosis of malignant lung nodules. The committee discussed that this data should be available through existing databases and recommended that it could be obtained as part of a large audit (see section 4.2).
## Data on patient and nodule characteristics and how different factors impact disease progression would be helpful for future modelling
The EAG report highlighted that better characterisation of the target population and nodule characteristics is needed for future assessments. It noted that the group of people with lung nodules is heterogeneous and different factors may impact on the speed of progression of malignant lung nodules. The committee agreed that this is important data to collect because it could be used in future modelling of the clinical and cost effectiveness of EarlyCDT Lung or other new tests in this area (see section 4.2).
## EarlyCDT Lung is not recommended for routine use in the NHS
The committee acknowledged that the evidence to support the use of the EarlyCDT Lung to assess the malignancy risk of solid lung nodules is weak. So, the full benefits and potential harms of widespread use of EarlyCDT Lung testing cannot be reliably quantified. There is no robust data to show the clinical utility of EarlyCDT Lung testing, specifically:
how well it distinguishes between benign and malignant nodules
how it influences clinical decision making
the impact it has on longer-term clinical outcomes.The committee concluded that it was unable to recommend the widespread use of EarlyCDT Lung testing. It recommended that further research is needed to address the limitations in the evidence (see section 4.2).
## A better understanding of the target population and the current diagnostic pathway is needed
The committee noted that a better understanding of the population with lung nodules and of the current diagnostic pathway is critical for supporting a linked-evidence model for EarlyCDT Lung and for other new technologies that would be used in the same pathway (see section 2.3). These issues include:
How patient and nodule characteristics impact disease progression (see section 3.11).
How intermediate-risk nodules are currently managed (see section 3.9).
The clinical consequences of CT surveillance of lung nodules (see section 3.10).
The prevalence, likelihood and impact of false-positive test results and overdiagnosis (see section 3.6).# Recommendations for further research
Further research is recommended on:
The accuracy of EarlyCDT Lung, and the validity of the risk models used to combine EarlyCDT Lung results with the Brock and the Herder risk models.
The impact of EarlyCDT Lung on clinical management decisions.
A large retrospective audit is recommended to:
Understand how patient and nodule characteristics impact on malignancy prevalence and disease progression.
Understand current practice regarding clinical management of people with intermediate-risk lung nodules.
Determine the clinical consequences of CT surveillance, including the likelihood of disease progression during CT surveillance.
Determine the likelihood and impact of unnecessary biopsy or resection of indolent and benign nodules If existing data on these points is limited or not routinely collected, a prospective data collection should be undertaken to obtain it.
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{'Recommendations': "There is not enough evidence to recommend routine use of EarlyCDT Lung for assessing the risk of lung cancer in solid lung nodules.\n\nFurther research is recommended (see section 4) on:\n\nthe diagnostic accuracy of EarlyCDT Lung, its performance when used with existing risk models and its effect on clinical management decisions\n\npatient and nodule characteristics that may relate to the prevalence of malignant disease and disease progression\n\ncurrent practice for managing intermediate-risk lung nodules\n\nthe clinical consequences of CT surveillance\n\nthe likelihood and impact of overtreatment of benign and indolent nodules.\n\nWhy the committee made these recommendations\n\nEarlyCDT Lung is used to assess the risk of lung cancer in solid lung nodules. Accurate risk assessment can prevent delayed treatment of malignant nodules or unnecessary biopsies of benign nodules. But, the evidence of how well EarlyCDT Lung works is limited and uncertain.\n\nThe company intends for EarlyCDT Lung results to be used to update a person's existing lung cancer risk assessment. But, most studies used EarlyCDT Lung results to classify nodules as benign or malignant. Therefore, most of the existing data does not represent the intended use of the test in updating estimates of lung cancer risk and further validation is needed.\n\nIt is also unclear how EarlyCDT Lung will affect lung nodule management in the NHS. This is because there were no studies to show how EarlyCDT Lung affects clinical decision making for people with lung nodules and there is significant variation in management of intermediate-risk nodules in the NHS.\n\nIt is also difficult to assess the impact of EarlyCDT Lung on long-term patient outcomes. This is because there is limited data on the factors that might affect disease progression, how lung nodules change during CT surveillance and the likelihood and impact of unnecessary biopsy or surgical removal.\n\nBecause of the limited clinical evidence, the cost\xa0effectiveness of EarlyCDT Lung was not assessed and so it has not been recommended. Further research is needed on both the EarlyCDT Lung test and on the impact of current lung nodule management. Without more data on current management, it will be difficult to quantify the impact of EarlyCDT Lung and other new tests for assessing lung nodules.", 'The diagnostic tests': "# Clinical need and practice\n\nIn the NHS, lung nodules are managed in line with the British Thoracic Society's guidelines for the investigation and management of pulmonary nodules (2015). The guidelines recommend the same diagnostic approach for nodules detected incidentally, due to symptomatic presentation, or through routine screening. People with nodules below 5\xa0mm in diameter or 80\xa0mm3 in volume are discharged without follow\xa0up. CT surveillance is offered for nodules between 5\xa0mm and 8\xa0mm in diameter or 80\xa0mm3 and 300\xa0m3 in volume. For nodules over 8\xa0mm in diameter or 300\xa0m3 in volume, the Brock model is used to calculate risk of malignancy. CT surveillance is offered to people with nodules that are below a 10% risk score using the Brock model.\n\nThe Herder model is used to calculate malignancy risk of nodules after a Brock risk assessment of 10% or above and a subsequent positron emission tomography CT (PET-CT) scan. For nodules with a Herder risk score below 10%, CT surveillance is offered. People with risk over 70% are considered for excision or non-surgical treatment. Within the intermediate group (between 10% and 70% risk of malignancy) the guidelines for subsequent care are more varied, with possible management options including image-guided biopsy, CT surveillance and excisional biopsy. Decisions are based on risk of malignancy, patient fitness and preferences and nodule characteristics.\n\nAccurately differentiating between malignant and benign nodules as soon as possible is important. People have more treatment options and potentially better outcomes when lung cancer is diagnosed in its early stages. However, misdiagnosis of a benign nodule as malignant, could result in further imaging tests (with higher radiation exposure) or invasive procedures, such as biopsy or resection, which carry risks of adverse events.\n\nEarlyCDT Lung could help identify malignant lung nodules that need immediate treatment or a biopsy. This could result in treatment being offered earlier, potentially giving improved patient outcomes. It could also reduce the number of people on CT surveillance, patient waiting times and radiologist time and enable more efficient use of NHS resources.\n\n# The intervention\n\n## EarlyCDT Lung\n\nEarlyCDT Lung (Oncimmune) is a blood test to assess the malignancy risk of solid lung nodules found by chest CT or X-ray. It is an enzyme-linked immunosorbent assay and is available as a CE-IVD kit. EarlyCDT Lung measures the presence of autoantibodies to a panel of 7\xa0lung cancer associated antigens (p53, NY-ESO-1, CAGE, GBU4-5, HuD, MAGE A4 and SOX2). After blood collection, the test is carried out in a laboratory in a secondary healthcare setting. Positive results are reported as 'positive-moderate' if at least 1 of the 7\xa0autoantibodies is elevated above a predetermined 'low' threshold, but all are below the 'high' threshold. If at least 1 of the 7\xa0autoantibodies is elevated above the 'high' predetermined threshold, the test is reported as 'positive-high'.\n\nEarlyCDT Lung is proposed as a 'rule-in' test to be used in addition to standard care for the detection of lung cancer. A positive EarlyCDT Lung result would be used to update a pre-test malignancy risk from either the Brock or Herder risk models. The pre-test risk would be unchanged if the EarlyCDT Lung result is negative. The estimated post-test risk is intended to help clinicians make decisions about further testing or intervention.\n\n# The comparators\n\n## Brock and Herder risk models\n\nThe Brock model is used to calculate a nodule's risk of malignancy, which is based on patient characteristics (such as age, gender and smoking history) and on nodule characteristics. The Herder model is used to calculate malignancy risk after a Brock risk assessment of 10% or above and a PET-CT scan. The Herder model is based on patient characteristics, nodule characteristics, and the degree of F-fluorodeoxyglucose uptake on PET-CT.", 'Committee discussion': "The diagnostics advisory committee considered evidence on EarlyCDT Lung for lung cancer classification of solid lung nodules from several sources, including a diagnostics assessment report and an overview of that report. Full details of the evidence are in the project documents on the NICE website.\n\n# A test that accurately predicts lung nodule malignancy risk could reduce anxiety in people with nodules\n\nThe patient expert emphasised the importance of people understanding their options based on malignancy risk assessments. A test that correctly identifies malignant nodules in people who would otherwise be placed on surveillance, could reduce the number of people on CT surveillance and the anxiety associated with waiting. Malignant nodules could be biopsied and treated earlier, potentially leading to better health outcomes. However, patient experts were aware of the trade-off between the benefits of earlier diagnosis and treatment, and the risks of overdiagnosis leading to harms from unnecessary biopsies and treatment. The committee acknowledged the potential benefit of EarlyCDT Lung in reducing anxiety and the impact it could have in helping people, along with their clinician, to decide which further testing or treatment steps are best.\n\n# Clinical effectiveness\n\n## The evidence on the diagnostic accuracy of EarlyCDT Lung in people with lung nodules is limited and accuracy estimates are very uncertain\n\nThe external assessment group's (EAG) systematic review found only 5\xa0study populations in which EarlyCDT Lung data on people with nodules was reported. Of the 5\xa0studies, 3 were conference abstracts and only 2 were reported in full. The 2 complete publications had a high risk of bias in terms of patient selection, and the German study (Gonzalez et al. 2021) was also at high risk of bias in the flow and timing domain of the quality assessment. There were also serious concerns about the applicability of the results of these studies to NHS practice because of the position in the pathway where the test was used and how the test was used and interpreted. The EAG's meta-analysis estimated that EarlyCDT Lung has a sensitivity of 20.2% (95% confidence interval [CI] 10.5 to 35.5) and specificity of 92.2% (95% CI 86.2 to 95.8). The committee discussed that the EAG's estimate was uncertain with wide confidence intervals for the sensitivity. It noted that these results are different to the company's estimates, which were based on a single study that had 41.3% sensitivity (95% CI 35.0 to 47.6) and 90.6% specificity (95% CI 87.1 to 94.1; Healey et al. 2017). The EAG suggest that the inclusion of case-control data in Healey et al. (2017), where cases were people diagnosed with lung cancer and controls were healthy volunteers, could account for the difference in accuracy estimates. It suggested that poorer diagnostic accuracy among smaller nodules, which are less likely to be present in the confirmed cancer cases, could bias the results. The committee discussed if accuracy data from screening studies was generalisable to this decision question. The EAG commented that the malignancy risk is likely to differ between a screening population – that is people who may or may not have nodules – and a population of people who have nodules. Therefore, the screening data cannot be extrapolated reliably. The committee concluded that given the uncertainties around the accuracy estimates and the populations studied, further evidence of the accuracy of EarlyCDT Lung in people with nodules is needed (see section 4.1).\n\n## The risk model used to calculate post-test malignancy risk from the EarlyCDT Lung result and the pre-test risk needs further validation\n\nThe committee understood that positive EarlyCDT Lung results are intended to be combined with a pre-test risk (using existing malignancy risk assessment models) to give a post-test risk. The EAG's report highlighted that the risk model (Healey et al. 2017) provided by the company to recalculate risk scores, may overestimate diagnostic accuracy as it was based on evidence from case-control studies (see section 3.2). The committee agreed that combining the tests was an appropriate way to estimate malignancy risk, but also noted that the accuracy data on these test combinations is very limited. The committee recommended that further validation of the model that combines the EarlyCDT Lung result with existing risk models is needed (see section 4.1).\n\n## It is unclear whether ongoing studies will provide relevant accuracy data\n\nThe EAG report identified 2 potentially relevant ongoing studies of EarlyCDT Lung: 1\xa0case-control study in China aiming to recruit 1,000 people and the other an observational screening study in the US. The committee heard that the study in China is assessing a different version of EarlyCDT Lung that was specifically developed for the market in China and would therefore not be generalisable to the UK. They also heard that the US study is due to be published in 2022. The committee also discussed the IDx Lung study that started in May\xa02021. It is unclear from published literature where in the pathway EarlyCDT Lung is positioned in these trials, and whether it will be used to update risk scores as indicated. The committee concluded that further research is needed on the accuracy of EarlyCDT Lung itself (see section 3.2) and on the accuracy of combining the test results with other risk models (see section 3.3). The committee also noted that the gold standard reference test in a diagnostic accuracy study should be histological confirmation of cancer or minimum 2\xa0years follow\xa0up with CT surveillance (see section 4.1).\n\n## Evidence on the impact of EarlyCDT Lung on clinical management decisions is limited\n\nThe EAG's report found no evidence on how EarlyCDT Lung testing affects changes in clinical decision making for people with lung nodules. The EAG's simulation study indicated that EarlyCDT Lung is unlikely to significantly impact clinical management in low-risk nodules (below 10%). EarlyCDT Lung may improve clinical management in intermediate-risk nodules, particularly for those with a higher pre-test risk (above 48%). The data feeding into the simulations however was at high risk of bias, and the simulation had to use assumptions because of weak evidence. The committee discussed that data is needed to demonstrate if a positive EarlyCDT Lung test result changes decision making such as moving from CT surveillance to biopsy or from biopsy to immediate excision without biopsy (see section 4.1).\n\n## The likelihood and impact of unnecessary biopsy or resection of indolent and benign nodules is unknown\n\nThe EAG and committee discussed the risk and harms of false-positive test results (benign nodules incorrectly identified as malignant). The committee discussed that the safety of biopsy and surgical excision has improved in recent years, but it noted that there may still be adverse effects and anxiety for patients. It also discussed the harms of diagnoses in people with limited life expectancy or with multiple comorbidities, for whom treatment is not possible but the test could cause unnecessary anxiety. The committee discussed that data on the harms of biopsy and excision should be available through existing databases and recommended that it could be obtained as part of a large audit (see section 4.2).\n\n## There is limited understanding of how knowledge of nodule malignancy risk and CT surveillance impact health-related quality of life\n\nIn the EAG report no studies of EarlyCDT Lung in the target population reported health-related quality of life outcomes. One screening study (Early Detection of Cancer of the Lung Scotland trial) did report that there were no statistically significant differences in lung cancer worry, health anxiety, illness perceptions, lung cancer risk perception or intrusive thoughts, between people with and without lung nodules at 3\xa0months and 6\xa0months. The committee heard that the ongoing Artificial intelligence and Big Data for Early Lung Cancer Diagnosis (IDEAL) study is exploring the quality of life of people with lung nodules on CT surveillance. The committee concluded that EarlyCDT Lung test results could have an impact on anxiety, but that no evidence is available to support this.\n\n## A linked-evidence modelling approach would be appropriate to estimate the impact of EarlyCDT Lung on long-term patient outcomes\n\nNo direct trial evidence was found on how EarlyCDT Lung impacts on long-term patient outcomes, such as lung cancer related mortality and morbidity, morbidity associated with other diagnostic tests or procedures, and overall and disease-free survival. The committee noted that this was an important factor to understand, but heard that a randomised control trial for assessing the impact of EarlyCDT Lung on patient outcomes would not be feasible because of the number of patients needed to power the study. The committee agreed that a linked-evidence modelling approach could be used to estimate the impact of EarlyCDT Lung on long-term patient outcomes. This method would link new diagnostic accuracy and decision impact data to existing clinical outcome data on lung nodules and lung cancer (see section 4.1).\n\n# Cost effectiveness\n\n## Current management practice for intermediate-risk nodules is undefined\n\nThe EAG's report highlighted variation in management practices and a lack of evidence around decisions in managing intermediate nodules. Under the British Thoracic Society's (BTS) guidelines for the investigation and management of pulmonary nodules (2015) people with nodules in the intermediate 10% to 70% risk group may be offered CT surveillance, biopsy or surgical excision. A clinical expert explained that in the BTS guidelines, the defined malignancy risk categories for initiating Brock and Herder risk assessment, and for guiding further testing and treatment, were mostly based on evidence graded at a level\xa03 (non-analytical studies; for example, case reports, case series). The committee recommended that an audit of existing data should be carried out to determine how these nodules are currently managed in NHS practice. It considered that the impact of EarlyCDT Lung and other tests would be difficult to ascertain without first understanding what happens in current clinical practice (see section 4.2).\n\n## The clinical consequences of CT surveillance of lung nodules, such as stage progression, are uncertain\n\nThe committee noted that the potential benefit of EarlyCDT Lung is that it could identify malignant lung nodules earlier than standard tests such as CT surveillance. This could lead to earlier treatment and improved patient outcomes. It also noted that there was no evidence that stage progression of malignant nodules happens in the timeframe of CT surveillance. The EAG commented that modelling studies of lung cancer screening strategies often evaluate the likelihood of pre-clinical stage progression over time, but cautioned that the generalisability of this evidence is unclear. The committee noted that it is important to understand if and how lung nodules progress during CT surveillance. This information could then be used in a linked-evidence modelling approach to understand if EarlyCDT Lung could result in meaningful earlier diagnosis of malignant lung nodules. The committee discussed that this data should be available through existing databases and recommended that it could be obtained as part of a large audit (see section 4.2).\n\n## Data on patient and nodule characteristics and how different factors impact disease progression would be helpful for future modelling\n\nThe EAG report highlighted that better characterisation of the target population and nodule characteristics is needed for future assessments. It noted that the group of people with lung nodules is heterogeneous and different factors may impact on the speed of progression of malignant lung nodules. The committee agreed that this is important data to collect because it could be used in future modelling of the clinical and cost effectiveness of EarlyCDT Lung or other new tests in this area (see section 4.2).\n\n## EarlyCDT Lung is not recommended for routine use in the NHS\n\nThe committee acknowledged that the evidence to support the use of the EarlyCDT Lung to assess the malignancy risk of solid lung nodules is weak. So, the full benefits and potential harms of widespread use of EarlyCDT Lung testing cannot be reliably quantified. There is no robust data to show the clinical utility of EarlyCDT Lung testing, specifically:\n\nhow well it distinguishes between benign and malignant nodules\n\nhow it influences clinical decision making\n\nthe impact it has on longer-term clinical outcomes.The committee concluded that it was unable to recommend the widespread use of EarlyCDT Lung testing. It recommended that further research is needed to address the limitations in the evidence (see section 4.2).\n\n## A better understanding of the target population and the current diagnostic pathway is needed\n\nThe committee noted that a better understanding of the population with lung nodules and of the current diagnostic pathway is critical for supporting a linked-evidence model for EarlyCDT Lung and for other new technologies that would be used in the same pathway (see section 2.3). These issues include:\n\nHow patient and nodule characteristics impact disease progression (see section\xa03.11).\n\nHow intermediate-risk nodules are currently managed (see section\xa03.9).\n\nThe clinical consequences of CT surveillance of lung nodules (see\xa0section 3.10).\n\nThe prevalence, likelihood and impact of false-positive test results and overdiagnosis (see section\xa03.6).", 'Recommendations for further research': 'Further research is recommended on:\n\nThe accuracy of EarlyCDT Lung, and the validity of the risk models used to combine EarlyCDT Lung results with the Brock and the Herder risk models.\n\nThe impact of EarlyCDT Lung on clinical management decisions.\n\nA large retrospective audit is recommended to:\n\nUnderstand how patient and nodule characteristics impact on malignancy prevalence and disease progression.\n\nUnderstand current practice regarding clinical management of people with intermediate-risk lung nodules.\n\nDetermine the clinical consequences of CT surveillance, including the likelihood of disease progression during CT surveillance.\n\nDetermine the likelihood and impact of unnecessary biopsy or resection of indolent and benign nodules If existing data on these points is limited or not routinely collected, a prospective data collection should be undertaken to obtain it.'}
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https://www.nice.org.uk/guidance/dg46
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Evidence-based recommendations on EarlyCDT Lung for assessing the risk of lung cancer in solid lung nodules.
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2c05aa78a1c558e0ed54a80a055f59c578ed1443
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nice
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Pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma after stem cell transplant or at least 2 previous therapies
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Pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma after stem cell transplant or at least 2 previous therapies
Evidence-based recommendations on pembrolizumab (Keytruda) for relapsed or refractory classical Hodgkin lymphoma in people aged 3 and older who have had a stem cell transplant or at least 2 previous therapies.
# Recommendations
Pembrolizumab is recommended as an option for treating relapsed or refractory classical Hodgkin lymphoma in people aged 3 and older. It is recommended if they have had an autologous stem cell transplant that has not worked or they have had at least 2 previous therapies and an autologous stem cell transplant is not an option, and only if:
they have not had brentuximab vedotin and
the company provides pembrolizumab according to the commercial arrangement.
Why the committee made these recommendations
Pembrolizumab is an additional treatment option for people with relapsed or refractory classical Hodgkin lymphoma. Clinical trial evidence shows that pembrolizumab delays the condition getting worse. The effect of pembrolizumab on how long people live is not known because longer term evidence from the KEYNOTE‑204 trial is not available yet.
Pembrolizumab is a cost‑effective use of NHS resources for treating relapsed or refractory classical Hodgkin lymphoma in people who have had an autologous stem cell transplant that has not worked but have not had brentuximab vedotin and in people who have had at least 2 treatments, have not had an autologous stem cell transplant and have not had brentuximab vedotin. So, it is recommended for use in the NHS in these populations.# Information about pembrolizumab
# Marketing authorisation indication
Pembrolizumab (Keytruda, MSD) has a marketing authorisation in the UK 'as monotherapy for the treatment of adult and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least 2 prior therapies when ASCT is not a treatment option'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for pembrolizumab.
# Price
The list price is £2,630 for 1 × 100 mg vial (excluding VAT; BNF online accessed December 2021).
The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by MSD, reviews of these submissions by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## People with classical Hodgkin lymphoma would welcome an effective treatment option that is more tolerable
The patient expert and a committee member with personal experience of how the condition affects people's lives explained that classical Hodgkin lymphoma and its treatment substantially affects quality of life. They explained that the physical symptoms, which can include fatigue, breathlessness, nausea, fevers, night sweats, weight loss and severe itching, are also exacerbated by the emotional effect of the condition. People with classical Hodgkin lymphoma may experience depression, anxiety, isolation and loss of self‑esteem. Further consequences can include substantial financial impact because of the inability to work and an inability to care for children. The patient expert explained that pembrolizumab is a desirable treatment option, because it is more tolerable and more convenient than other treatments for classical Hodgkin lymphoma and does not need prolonged hospital stays. They explained that these are important factors for people with the condition. The committee recognised the potential benefits of pembrolizumab for people with classical Hodgkin lymphoma. It concluded that people would welcome a new effective treatment option, especially one that is well tolerated.
# Treatment pathway
## Pembrolizumab would offer an alternative treatment option to brentuximab vedotin for people who have had at least 2 previous treatments
Treatment for classical Hodgkin lymphoma which is relapsed or refractory to first-line chemotherapy is salvage chemotherapy. People whose condition has responded to salvage chemotherapy, and who are well enough, may have an autologous stem cell transplant. NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive Hodgkin lymphoma recommends brentuximab vedotin for people whose condition has relapsed after transplant, or who have had at least 2 previous therapies and for whom a stem cell transplant is not suitable. This broadly corresponds with the patient population for this appraisal. Pembrolizumab is recommended within the Cancer Drugs Fund as an option for people who have not had an autologous stem cell transplant and whose condition is relapsed or refractory to brentuximab vedotin (see NICE's technology appraisal guidance on pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma). The clinical experts noted that although most people are able to have pembrolizumab after brentuximab vedotin because of its availability though the Cancer Drugs Fund, the routinely commissioned standard care is multi‑agent chemotherapy. The clinical experts explained that some people may be offered an autologous or allogeneic stem cell transplant after third‑ or fourth‑line treatment depending on their fitness for transplant and how their condition has responded to previous lines of therapy. The committee noted that pembrolizumab has previously been appraised for use after brentuximab vedotin in NICE's technology appraisal guidance on pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma. However, its marketing authorisation has now been extended to allow its use as a third-line treatment option instead of brentuximab vedotin. The committee concluded that pembrolizumab would potentially offer an alternative to brentuximab vedotin for people who have had at least 2 previous lines of therapy, with or without a previous stem cell transplant.
# Clinical evidence
## KEYNOTE-204 subgroup data is generalisable to people who have had at least 2 previous treatments, with or without previous stem cell transplant
KEYNOTE‑204 is an open‑label, randomised controlled trial comparing pembrolizumab with brentuximab vedotin as a treatment for classical Hodgkin lymphoma in adults whose condition is relapsed or refractory to at least 1 previous multi-agent chemotherapy regimen. Participants in KEYNOTE‑204 were randomised after stratification into groups who had and had not had previous stem cell transplant. The committee noted that the marketing authorisation for pembrolizumab is narrower than the trial population and includes only people for whom autologous stem cell transplant has not been successful or who have had at least 2 previous treatments when autologous stem cell transplant is not an option. It noted that the population of interest was a subgroup of the whole KEYNOTE‑204 population. The committee noted that the comparator treatment in KEYNOTE‑204 is brentuximab vedotin and NICE recommends brentuximab vedotin for people who have had 2 or more previous treatments (see section 3.2), although it noted that brentuximab vedotin could be used for longer in KEYNOTE‑204 than allowed in its marketing authorisation. The clinical experts considered that the trial results for the subgroup corresponding to the marketing authorisation are generalisable to clinical practice. The committee concluded that the trial results for this subgroup are generalisable to NHS practice.
# Clinical effectiveness
## Pembrolizumab improves progression-free survival compared with brentuximab vedotin
The population in KEYNOTE‑204 who had at least 2 previous treatments, with or without previous stem cell transplant, showed longer median progression-free survival with pembrolizumab than brentuximab vedotin (median progression-free survival 54.7 weeks compared with 35.7 weeks ). The committee noted that the subgroups who had and had not had a previous stem cell transplant were not in the statistical analysis plan. However, analysis of these subgroups indicated that median progression‑free survival was longer with pembrolizumab than brentuximab vedotin in both groups. The clinical experts explained that pembrolizumab may not have the same relative benefit compared with brentuximab vedotin for people with and without previous transplant. This is because, in some people, the lymphoma will not have responded well enough to chemotherapy to allow a stem cell transplant and these people's condition may have a poorer response to further chemotherapy, including brentuximab vedotin, which is a targeted chemotherapy. Pembrolizumab is an immunotherapy with a different mechanism of action and is not expected to be affected by previous response to chemotherapy. The data also suggested that overall prognosis is poorer for people who have not had a previous stem cell transplant compared with those who had, with a shorter progression‑free survival in both the pembrolizumab and brentuximab vedotin arms in this group. The committee concluded that for people who had had at least 2 previous treatments with or without previous stem cell transplant, pembrolizumab improves progression‑free survival.
## KEYNOTE-204 overall survival data are not currently available and time to second progression data are immature
Overall survival data from KEYNOTE‑204 are immature and not currently available. Data from KEYNOTE‑204 show that time to second progression (time to disease progression while having the next anticancer treatment) is longer for people having pembrolizumab compared with brentuximab vedotin after 24 months follow up. However, the time to second progression data are immature and the ERG explained that this was a substantial limitation for its use as an indicator of overall survival benefit. The company highlighted that overall survival is a primary outcome in KEYNOTE‑204 and that data will be available in the future. The committee concluded that overall survival could not be estimated from the currently available data in KEYNOTE‑204 and other evidence sources would be necessary to estimate overall survival.
## Pembrolizumab may increase the number of people who might be able to have a stem cell transplant compared with brentuximab vedotin, but data are limited
KEYNOTE‑204 showed that a similar proportion of people in the pembrolizumab (20.3%) and brentuximab vedotin (22.4%) arms went on to have autologous stem cell transplant at any point during follow up. However, of the people who had a stem cell transplant in the brentuximab vedotin arm, some had also had PD‑1 inhibitor treatment (pembrolizumab or nivolumab) before a stem cell transplant was done. The committee was also aware that KEYNOTE‑204 was not designed to assess if pembrolizumab would result in more people having a stem cell transplant compared with brentuximab vedotin. The clinical experts stated that the population who had not had a previous stem cell transplant would include both people who were not fit enough to have a transplant and people whose condition had not responded well enough to chemotherapy to have a transplant. The group whose condition had not responded to chemotherapy may show improved disease response with a third treatment with a different mechanism of action, and therefore be able to have a subsequent stem cell transplant. They stated that although there was limited data, it was plausible that the proportions of people having a stem cell transplant after pembrolizumab will be greater than after brentuximab vedotin. The clinical experts explained that the rates of complete remission for pembrolizumab are comparable to those of brentuximab vedotin. However partial remission rates are higher and partial remission duration is usually longer with pembrolizumab, which may allow more stem cell transplants. The clinical experts also highlighted the possibility that pembrolizumab treatment increases toxicity to allogeneic stem cell transplant but noted that evidence on this is still emerging. They highlighted that this is only applicable to allogeneic stem cell transplant and that autologous stem cell transplant would usually be the preferred treatment option after pembrolizumab or brentuximab vedotin for people who are fit for transplant. The committee concluded that in practice, pembrolizumab may increase the number of people who are able to have an autologous stem cell transplant compared with brentuximab vedotin, but data is limited.
## NHS England policy is to fund medicines for children within a specialised service when NICE recommends a technology for adults
The committee was aware that the marketing authorisation for this indication includes children aged 3 and older, but that KEYNOTE‑204 only included adults. The single-arm study KEYNOTE‑015 assessed the safety and efficacy of pembrolizumab in children but the company did not include this data in its model. The company stated that this was because NHS England policy is to fund medicines for children within a specialised service if it is recommended for use in adults by a NICE technology appraisal (when the medicine has a licence for use in children and both the indication for use and the age of the child fall within those specified in the adult licence). The committee concluded that children should not be excluded from the recommendations in line with the marketing authorisation for this indication.
# Company's economic model
## The company's model structure is appropriate for decision making
The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of pembrolizumab compared with brentuximab vedotin. The 3 health states were progression-free survival, progressed disease and death. The committee discussed that previous appraisals for classical Hodgkin lymphoma had used a 4‑state model and included stem cell transplant as a health state. The company highlighted that pembrolizumab was not positioned as a 'bridge to transplant' in KEYNOTE‑204 and therefore used a 3‑state model. The company assumed equal rates of stem cell transplant in both the pembrolizumab and brentuximab vedotin arms in its model, including the costs of stem cell transplant, but did not model the impact of stem cell transplant on survival or quality of life. The clinical experts stated that pembrolizumab was likely to be used as a bridge to transplant in people whose disease responds adequately and who are fit enough (see section 3.6). The committee discussed that pembrolizumab may increase the number of people who are able to have a stem cell transplant (see section 3.6) but noted that the model did not capture the costs and benefits of pembrolizumab used as a bridge to transplant. However, it concluded that the company's model was adequate for decision making.
## It is appropriate to consider people who had and had not had a stem cell transplant separately
In its original submission, the company presented cost-effectiveness estimates for a pooled population of people who had and had not had a stem cell transplant, as well as estimates for people who had and who had not had a stem cell transplant separately. The company presented a model at technical engagement which only included a pooled population of people who have had 2 previous treatments either with or without previous stem cell transplant. The committee discussed that this was the population of interest from KEYNOTE‑204 (see section 3.3). However, the ERG suggested that people who had and had not had a stem cell transplant should be considered separately in the model. This is because the treatment pathway is different for these groups and the prognosis of these groups is also expected to be different. The ERG presented an economic analysis based on these subgroups and the company presented a separate analysis for people who had had 2 previous treatments without previous stem cell transplant in response to the appraisal consultation document. The clinical experts agreed that the subsequent treatment options for these subgroups differ and that prognosis is poorer for people who are not fit for transplant because of age or comorbidities. However, they noted that the group without previous stem cell transplant also included people who were considered fit for transplant but had been previously not been able to have one only because their disease had not responded well enough to chemotherapy, so did not necessarily have a poorer prognosis. The committee was aware that the estimates of costs included in the model may be affected by different subsequent treatment pathways. It concluded that it was appropriate to consider the subgroups of people who have had and have not had a previous stem cell transplant separately.
# Assumptions in the economic model
## For people who have not had a stem cell transplant, the routinely available treatment after brentuximab vedotin is multi-agent chemotherapy
The ERG highlighted that different subsequent treatments are offered after third‑line treatment has not worked, depending on if a person has had a previous stem cell transplant (see section 3.9). The clinical experts explained that:
People who have previously had a stem cell transplant and had brentuximab vedotin as third‑line treatment would usually be offered nivolumab.
People who have not previously had a stem cell transplant and had brentuximab vedotin as third‑line treatment would currently be offered pembrolizumab, which is available through the Cancer Drugs Fund. The committee was aware of NICE's position statement that drugs available through the Cancer Drugs Fund should not be included in economic models. The clinical experts explained that in the absence of pembrolizumab, multi‑agent chemotherapy is the only option for subsequent treatment in routine commissioning. They highlighted that the choice of multi‑agent chemotherapy differs, but that single agent bendamustine, which was included in the company's model at the first committee meeting, is no longer considered suitable. In response to the appraisal consultation document, the company updated its model for this subgroup and included subsequent treatments in line with those described by the clinical experts.
If pembrolizumab were available as a third‑line treatment, brentuximab vedotin would be likely to be given as the next treatment, both for people who have, and have not had a previous stem cell transplant.The committee concluded that the company's updated approach to modelling subsequent treatments using multi‑agent chemotherapy after brentuximab vedotin was appropriate for people who have had 2 previous treatments without a previous stem cell transplant.
## Overall survival estimates are uncertain, but Gopal et al. (2015) is a reasonable source of data for people who have had a stem cell transplant
Overall survival data from KEYNOTE‑204 are not available (see section 3.5). In its analysis of the pooled population of people who have had 2 previous treatments with and without stem cell transplant (see section 3.9), the company used overall survival data in its model from Gopal et al., a single-arm trial of brentuximab vedotin in people with a previous stem cell transplant. The company applied overall survival data from Gopal et al. to the pembrolizumab and brentuximab vedotin arms in the model, assuming equal overall survival with both treatments. The ERG stated that Gopal et al. was appropriate to estimate overall survival for people who have had a previous stem cell transplant because the participants in Gopal et al. had all had previous stem cell transplant and a median of 2.5 previous lines of therapy. The committee considered that KEYNOTE‑204 overall survival data would be preferable to using external data sources, but this was not yet available. It discussed that the company's assumption of equal overall survival with both treatments for this group was likely to be conservative and noted that the company did not provide further analysis for this subgroup in response to the appraisal consultation document. The committee concluded that in the absence of overall survival data from KEYNOTE-204, overall survival estimates are uncertain but Gopal et al. is a reasonable source for people who have had a previous stem cell transplant.
## It is likely that pembrolizumab is associated with an overall survival benefit for people who have not had a previous stem cell transplant
At the first committee meeting, the company assumed equal overall survival in both treatment arms and modelled this using data from Gopal et al. (2015) for a pooled population of people who have had at least 2 previous treatments with and without stem cell transplant (see section 3.11). In response to the appraisal consultation document, the company addressed only the population who had not had stem cell transplant and updated its model to include an overall survival benefit for this group. The company stated that it agreed with the committee's conclusion at the first committee meeting that its initial approach of assuming equal overall survival was conservative, given that there was a progression-free survival benefit for pembrolizumab compared with brentuximab vedotin in KEYNOTE‑204. Assuming equivalent overall survival meant that people were modelled to die at a faster rate once the disease progressed if they had pembrolizumab than if they had brentuximab vedotin before progression. The clinical experts did not consider this to be plausible, noting people may actually live longer with progressed disease after pembrolizumab than after brentuximab vedotin because pembrolizumab can have disease modifying effects which last after disease progression. The clinical experts stated that the potential for pembrolizumab to increase the proportion of people who would go on to have potentially curative stem cell transplant (see section 3.6) would also be expected to improve overall survival with pembrolizumab compared with brentuximab vedotin. The committee concluded that although there was no trial overall survival data, it was plausible that there would be an overall survival benefit of pembrolizumab compared with brentuximab vedotin in people who had not had a stem cell transplant.
## The size of overall survival benefit for people without previous stem cell transplant is highly uncertain
To estimate overall survival for pembrolizumab the company used data from a stem cell ineligible cohort of KEYNOTE‑087, a single‑arm trial of pembrolizumab in people who had had at least 3 previous treatments (a later line of therapy than KEYNOTE‑204). An alternative estimate used data from the Systemic Anti-Cancer Therapy (SACT) database for people who had pembrolizumab as fourth‑line treatment, which is currently funded through the Cancer Drugs Fund. To estimate overall survival for brentuximab vedotin the company used data from Eyre et al. (2017), a UK‑based, retrospective observational study of brentuximab vedotin in people who had 2 previous treatments without previous stem cell transplant. The ERG highlighted that the KEYNOTE‑087 data was immature and highly uncertain as well as being in a later line of therapy than KEYNOTE‑204. The clinical experts stated that the overall survival benefit presented by the company comparing KEYNOTE‑087 with Eyre et al. was likely to be over‑estimated. The committee noted that using the SACT data to estimate overall survival in the pembrolizumab arm reduced the modelled overall survival benefit, giving a more plausible estimate. The committee concluded that the size of benefit for people without previous stem cell transplant is highly uncertain.
## Post-progression health-state utility values are uncertain
At the first committee meeting, the company presented health-related quality of life data from KEYNOTE‑204 for the pooled population who had had at least 2 previous treatments with and without previous stem cell transplant. This indicated that health-related quality of life in people whose condition progressed after having pembrolizumab is better than for people whose condition progressed after having brentuximab vedotin. The ERG noted that this was uncertain, because of small patient numbers and the data being collected over a short follow up of 30 days after stopping treatment. It highlighted that this time may not be long enough to capture the true progressed disease state utility values. Therefore, the ERG's preferred assumptions included equal post‑progression utilities for both arms, based on the values reported for brentuximab vedotin in the pooled population who have had at least 2 previous treatments with and without previous stem cell transplant. In response to the appraisal consultation document, the company updated its preferred assumption for the post‑progression utility value after pembrolizumab, using the post‑progression utility value from a trial of nivolumab. The updated value was lower than the post‑progression utility after pembrolizumab seen in KEYNOTE‑204 but was higher than the ERG's approach of assuming equal post‑progression utility values for pembrolizumab and brentuximab vedotin. The clinical experts explained that they may expect health‑related quality of life to be better in people whose condition progressed after having pembrolizumab compared with people whose condition progressed after having brentuximab vedotin. This is because brentuximab vedotin is associated with higher rates of side effects, including neuropathy, which can be debilitating and persist for several months in some people. They explained that the severity of side effects is associated with time on treatment, which is likely to be longer for people for whom stem cell transplant is not suitable. They explained that the side effects associated with pembrolizumab have less effect on quality of life. The committee agreed that some side effects of brentuximab vedotin may persist after stopping treatment, but it was difficult to quantify any expected difference in health‑related quality of life between the treatment arms over the long term because of the methods used to collect utility data in KEYNOTE‑204. It agreed that a better long‑term utility in the progressed state for pembrolizumab compared with brentuximab vedotin was unproven. It concluded that the post‑progression health‑state utility values for pembrolizumab are uncertain but that it was unlikely that the health‑state utility values estimated in KEYNOTE‑204 would persist for the whole period of progression. Therefore, the committee preferred the ERG's assumption of equal pembrolizumab and brentuximab vedotin post‑progression utilities, although it recognised this may be conservative.
## The company's approach to estimating the proportion of people who have subsequent treatment is appropriate
In response to the appraisal consultation document, the company updated its model to include a new approach to calculating the number of people who would have subsequent treatment in the population without previous stem cell treatment. This was calculated by considering the proportion of people whose disease had progressed but who had not died in each model cycle. Of these people, the proportion who would have subsequent treatment was assumed to reflect the proportion of people who had subsequent treatment in each arm of KEYNOTE‑204 (these data are academic in confidence and cannot be reported here). The clinical experts noted that the proportions of people having subsequent treatment in each arm of KEYNOTE‑204 was approximately what is seen in clinical practice. The committee concluded that the company's approach to estimating the proportion of people who have subsequent treatment, using data from KEYNOTE‑204, was appropriate.
# Cost-effectiveness estimate
## Pembrolizumab is less costly and more effective than brentuximab vedotin in people who have had a previous stem cell transplant
The committee agreed that its preferred approach was to consider people who have had and have not had a previous stem cell transplant separately (see section 3.9). The company presented separate analyses for this subgroup in its original submission. However, at the first committee meeting, after an update to the model at technical engagement, the company only presented cost‑effectiveness estimates for the pooled population of people with or without previous stem cell transplant. For people with previous stem cell transplant, the ERG exploratory analysis (and the analyses provided by the ERG using the relevant company assumptions from the original submission where these differed to the ERG's) indicated that pembrolizumab dominated brentuximab vedotin, that is pembrolizumab was cost saving and was associated with a greater quality‑adjusted life year gain than brentuximab vedotin. Pembrolizumab dominated brentuximab vedotin in all scenario analyses presented by the ERG for this subgroup.
## Pembrolizumab is cost effective in the subgroup without previous stem cell transplant if a relatively small overall survival benefit is assumed
In response to the appraisal consultation document, the company updated its model to include separate analysis of people who have had 2 previous treatments without stem cell transplant. The assumptions made by the company at the second committee meeting for this subgroup were:
multi‑agent chemotherapy is the subsequent treatment after brentuximab vedotin (see section 3.10)
using KEYNOTE‑087 to estimate overall survival for the pembrolizumab arm and Eyre et al. to estimate overall survival for the brentuximab vedotin arm, resulting in an overall survival benefit for pembrolizumab (see section 3.13)
using post-progression utility data from KEYNOTE‑204 for the brentuximab vedotin arm and post‑progression utility data from a trial of nivolumab for the pembrolizumab arm (see section 3.14)
calculating the number of people for whom subsequent treatment is suitable in each cycle based on progression‑free survival (see section 3.15)
using each arm of the KEYNOTE‑204 data to estimate the proportion of people having subsequent treatment after progression (see section 3.15).The company base case gave an incremental cost effectiveness ratio (ICER) of under £20,000 per quality-adjusted life year (QALY) gained. The exact ICERs cannot be reported because of confidential commercial arrangements for comparator and subsequent treatments.The ERG did not present its preferred assumptions for the subgroup of people who have had 2 previous treatments without previous stem cell transplant at the second committee meeting. Instead, it presented several scenario analyses for this subgroup, including a scenario which assumed equal overall survival in both arms, using data from Eyre et al. The committee recalled its conclusion that pembrolizumab is associated with an overall survival benefit but that the size of this is uncertain (see section 3.12 and section 3.13). At the request of the committee the ERG provided a threshold analysis, to show the effect of increasing the overall survival benefit in increments. It did this by applying a series of hazard ratios to the modelled overall survival with brentuximab vedotin to model overall survival scenarios with pembrolizumab. This analysis also included the following assumptions:
using multi‑agent chemotherapy as subsequent treatment after brentuximab vedotin
using the same post‑progression utility values in both treatment arms
calculating the number of people for whom subsequent treatment is suitable in each cycle based on progression‑free survival exits
using each arm of the KEYNOTE‑204 data to estimate the proportion of people having subsequent treatment after progression
using a 26‑week cut-point for extrapolating data on progression‑free survival and time on treatment.The committee concluded that the assumptions used by the ERG in its threshold analysis were appropriate. It considered the results of the threshold analysis, which showed that the ICER for pembrolizumab compared with brentuximab vedotin was under £30,000 per QALY gained if a relatively small overall survival benefit with pembrolizumab was assumed. The committee noted that the ICER was under £20,000 per QALY gained when the overall survival benefit seen in the company's analysis using SACT data for pembrolizumab was reached in the threshold analysis, which it considered to be the most plausible of the scenarios presented by the company (see section 3.13). The committee concluded that plausible assumptions of an overall survival benefit with pembrolizumab compared with brentuximab vedotin resulted in an ICER below £30,000 per QALY which represented a cost‑effective use of NHS resources.
## Pembrolizumab is recommended for treating classical Hodgkin lymphoma in people with previous stem cell transplant
The committee noted that all relevant analyses for the subgroup of people who have had a previous stem cell transplant showed that pembrolizumab dominated brentuximab vedotin (see section 3.16). The committee concluded that pembrolizumab was a cost‑effective use of NHS resources in this population. It recommended pembrolizumab as an option for treating relapsed or refractory classical Hodgkin lymphoma in people whose condition has relapsed after or is refractory to autologous stem cell transplant and have not had brentuximab vedotin, only if the company provides pembrolizumab according to the commercial arrangement.
## Pembrolizumab is recommended for treating classical Hodgkin lymphoma in people who have not had a previous stem cell transplant
The committee noted that the threshold analysis presented by the ERG showed that pembrolizumab could be considered cost effective when a relatively small overall survival benefit was assumed (see section 3.17). It concluded that pembrolizumab was associated with an overall survival benefit (see section 3.12) and therefore that it was likely that pembrolizumab was a cost‑effective use of NHS resources in this population. Therefore, the committee recommended pembrolizumab as an option for treating classical Hodgkin lymphoma in people for whom autologous stem cell transplant is not a treatment option and who have had at least 2 previous therapies which has not included brentuximab vedotin.
# Innovation
## The model is adequate to capture the benefits of pembrolizumab
The company considers pembrolizumab to be innovative. It suggested that using pembrolizumab as a third‑line treatment is a step-change in the management of classical Hodgkin lymphoma. The clinical experts agreed that PD‑L1 inhibitors such as pembrolizumab are innovative medicines. However, they highlighted that pembrolizumab and other PD‑L1 inhibitors are currently available at other stages in the treatment pathway. The committee noted that the company's model did not include the costs and benefits of using pembrolizumab as a bridge to transplant because the company did not consider it would be used in this way. It concluded that it had not been presented with evidence of any additional benefits from pembrolizumab as third‑line treatment that had not already been included.
# Equalities issues
It was highlighted during the appraisal consultation that there was potential for the draft recommendation (which did not recommend pembrolizumab for people who have had 2 previous treatments without previous stem cell transplant) to affect older people disproportionately negatively. This is because stem cell transplants are more likely to be unsuitable for older people. The committee noted that suitability of a stem cell transplant was dependent on a person's fitness but also if their condition had responded to chemotherapy, and suitability of transplant was not defined on the basis of age. The committee concluded that its final recommendation recommended pembrolizumab for people who could and could not have a stem cell transplant and therefore would not disadvantage people who could not have stem cell transplant.
|
{'Recommendations': 'Pembrolizumab is recommended as an option for treating relapsed or refractory classical Hodgkin lymphoma in people aged\xa03\xa0and older. It is recommended if they have had an autologous stem cell transplant that has not worked or they have had at least 2 previous therapies and an autologous stem cell transplant is not an option, and only if:\n\nthey have not had brentuximab vedotin and\n\nthe company provides pembrolizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nPembrolizumab is an additional treatment option for people with relapsed or refractory classical Hodgkin lymphoma. Clinical trial evidence shows that pembrolizumab delays the condition getting worse. The effect of pembrolizumab on how long people live is not known because longer term evidence from the KEYNOTE‑204 trial is not available yet.\n\nPembrolizumab is a cost‑effective use of NHS resources for treating relapsed or refractory classical Hodgkin lymphoma in people who have had an autologous stem cell transplant that has not worked but have not had brentuximab vedotin and in people who have had at least 2\xa0treatments, have not had an autologous stem cell transplant and have not had brentuximab vedotin. So, it is recommended for use in the NHS in these populations.', 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, MSD) has a marketing authorisation in the UK 'as monotherapy for the treatment of adult and paediatric patients aged 3\xa0years and older with relapsed or refractory classical Hodgkin lymphoma who have failed autologous stem cell transplant (ASCT) or following at least 2\xa0prior therapies when ASCT is not a treatment option'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe list price is £2,630 for 1\xa0×\xa0100\xa0mg vial (excluding VAT; BNF online accessed December 2021).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by MSD, reviews of these submissions by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## People with classical Hodgkin lymphoma would welcome an effective treatment option that is more tolerable\n\nThe patient expert and a committee member with personal experience of how the condition affects people's lives explained that classical Hodgkin lymphoma and its treatment substantially affects quality of life. They explained that the physical symptoms, which can include fatigue, breathlessness, nausea, fevers, night sweats, weight loss and severe itching, are also exacerbated by the emotional effect of the condition. People with classical Hodgkin lymphoma may experience depression, anxiety, isolation and loss of self‑esteem. Further consequences can include substantial financial impact because of the inability to work and an inability to care for children. The patient expert explained that pembrolizumab is a desirable treatment option, because it is more tolerable and more convenient than other treatments for classical Hodgkin lymphoma and does not need prolonged hospital stays. They explained that these are important factors for people with the condition. The committee recognised the potential benefits of pembrolizumab for people with classical Hodgkin lymphoma. It concluded that people would welcome a new effective treatment option, especially one that is well tolerated.\n\n# Treatment pathway\n\n## Pembrolizumab would offer an alternative treatment option to brentuximab vedotin for people who have had at least 2\xa0previous treatments\n\nTreatment for classical Hodgkin lymphoma which is relapsed or refractory to first-line chemotherapy is salvage chemotherapy. People whose condition has responded to salvage chemotherapy, and who are well enough, may have an autologous stem cell transplant. NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive Hodgkin lymphoma recommends brentuximab vedotin for people whose condition has relapsed after transplant, or who have had at least 2\xa0previous therapies and for whom a stem cell transplant is not suitable. This broadly corresponds with the patient population for this appraisal. Pembrolizumab is recommended within the Cancer Drugs Fund as an option for people who have not had an autologous stem cell transplant and whose condition is relapsed or refractory to brentuximab vedotin (see NICE's technology appraisal guidance on pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma). The clinical experts noted that although most people are able to have pembrolizumab after brentuximab vedotin because of its availability though the Cancer Drugs Fund, the routinely commissioned standard care is multi‑agent chemotherapy. The clinical experts explained that some people may be offered an autologous or allogeneic stem cell transplant after third‑ or fourth‑line treatment depending on their fitness for transplant and how their condition has responded to previous lines of therapy. The committee noted that pembrolizumab has previously been appraised for use after brentuximab vedotin in NICE's technology appraisal guidance on pembrolizumab for treating relapsed or refractory classical Hodgkin lymphoma. However, its marketing authorisation has now been extended to allow its use as a third-line treatment option instead of brentuximab vedotin. The committee concluded that pembrolizumab would potentially offer an alternative to brentuximab vedotin for people who have had at least 2 previous lines of therapy, with or without a previous stem cell transplant.\n\n# Clinical evidence\n\n## KEYNOTE-204 subgroup data is generalisable to people who have had at least 2 previous treatments, with or without previous stem cell transplant\n\nKEYNOTE‑204 is an open‑label, randomised controlled trial comparing pembrolizumab with brentuximab vedotin as a treatment for classical Hodgkin lymphoma in adults whose condition is relapsed or refractory to at least 1\xa0previous multi-agent chemotherapy regimen. Participants in KEYNOTE‑204 were randomised after stratification into groups who had and had not had previous stem cell transplant. The committee noted that the marketing authorisation for pembrolizumab is narrower than the trial population and includes only people for whom autologous stem cell transplant has not been successful or who have had at least 2\xa0previous treatments when autologous stem cell transplant is not an option. It noted that the population of interest was a subgroup of the whole KEYNOTE‑204 population. The committee noted that the comparator treatment in KEYNOTE‑204 is brentuximab vedotin and NICE recommends brentuximab vedotin for people who have had 2 or more previous treatments (see section\xa03.2), although it noted that brentuximab vedotin could be used for longer in KEYNOTE‑204 than allowed in its marketing authorisation. The clinical experts considered that the trial results for the subgroup corresponding to the marketing authorisation are generalisable to clinical practice. The committee concluded that the trial results for this subgroup are generalisable to NHS practice.\n\n# Clinical effectiveness\n\n## Pembrolizumab improves progression-free survival compared with brentuximab vedotin\n\nThe population in KEYNOTE‑204 who had at least 2\xa0previous treatments, with or without previous stem cell transplant, showed longer median progression-free survival with pembrolizumab than brentuximab vedotin (median progression-free survival 54.7\xa0weeks [95% confidence interval 37.7 to 84.3] compared with 35.7\xa0weeks [95% confidence interval 24.4 to 38.1]). The committee noted that the subgroups who had and had not had a previous stem cell transplant were not in the statistical analysis plan. However, analysis of these subgroups indicated that median progression‑free survival was longer with pembrolizumab than brentuximab vedotin in both groups. The clinical experts explained that pembrolizumab may not have the same relative benefit compared with brentuximab vedotin for people with and without previous transplant. This is because, in some people, the lymphoma will not have responded well enough to chemotherapy to allow a stem cell transplant and these people's condition may have a poorer response to further chemotherapy, including brentuximab vedotin, which is a targeted chemotherapy. Pembrolizumab is an immunotherapy with a different mechanism of action and is not expected to be affected by previous response to chemotherapy. The data also suggested that overall prognosis is poorer for people who have not had a previous stem cell transplant compared with those who had, with a shorter progression‑free survival in both the pembrolizumab and brentuximab vedotin arms in this group. The committee concluded that for people who had had at least 2\xa0previous treatments with or without previous stem cell transplant, pembrolizumab improves progression‑free survival.\n\n## KEYNOTE-204 overall survival data are not currently available and time to second progression data are immature\n\nOverall survival data from KEYNOTE‑204 are immature and not currently available. Data from KEYNOTE‑204 show that time to second progression (time to disease progression while having the next anticancer treatment) is longer for people having pembrolizumab compared with brentuximab vedotin after 24\xa0months follow up. However, the time to second progression data are immature and the ERG explained that this was a substantial limitation for its use as an indicator of overall survival benefit. The company highlighted that overall survival is a primary outcome in KEYNOTE‑204 and that data will be available in the future. The committee concluded that overall survival could not be estimated from the currently available data in KEYNOTE‑204 and other evidence sources would be necessary to estimate overall survival.\n\n## Pembrolizumab may increase the number of people who might be able to have a stem cell transplant compared with brentuximab vedotin, but data are limited\n\nKEYNOTE‑204 showed that a similar proportion of people in the pembrolizumab (20.3%) and brentuximab vedotin (22.4%) arms went on to have autologous stem cell transplant at any point during follow up. However, of the people who had a stem cell transplant in the brentuximab vedotin arm, some had also had PD‑1 inhibitor treatment (pembrolizumab or nivolumab) before a stem cell transplant was done. The committee was also aware that KEYNOTE‑204 was not designed to assess if pembrolizumab would result in more people having a stem cell transplant compared with brentuximab vedotin. The clinical experts stated that the population who had not had a previous stem cell transplant would include both people who were not fit enough to have a transplant and people whose condition had not responded well enough to chemotherapy to have a transplant. The group whose condition had not responded to chemotherapy may show improved disease response with a third treatment with a different mechanism of action, and therefore be able to have a subsequent stem cell transplant. They stated that although there was limited data, it was plausible that the proportions of people having a stem cell transplant after pembrolizumab will be greater than after brentuximab vedotin. The clinical experts explained that the rates of complete remission for pembrolizumab are comparable to those of brentuximab vedotin. However partial remission rates are higher and partial remission duration is usually longer with pembrolizumab, which may allow more stem cell transplants. The clinical experts also highlighted the possibility that pembrolizumab treatment increases toxicity to allogeneic stem cell transplant but noted that evidence on this is still emerging. They highlighted that this is only applicable to allogeneic stem cell transplant and that autologous stem cell transplant would usually be the preferred treatment option after pembrolizumab or brentuximab vedotin for people who are fit for transplant. The committee concluded that in practice, pembrolizumab may increase the number of people who are able to have an autologous stem cell transplant compared with brentuximab vedotin, but data is limited.\n\n## NHS England policy is to fund medicines for children within a specialised service when NICE recommends a technology for adults\n\nThe committee was aware that the marketing authorisation for this indication includes children aged 3\xa0and older, but that KEYNOTE‑204 only included adults. The single-arm study KEYNOTE‑015 assessed the safety and efficacy of pembrolizumab in children but the company did not include this data in its model. The company stated that this was because NHS England policy is to fund medicines for children within a specialised service if it is recommended for use in adults by a NICE technology appraisal (when the medicine has a licence for use in children and both the indication for use and the age of the child fall within those specified in the adult licence). The committee concluded that children should not be excluded from the recommendations in line with the marketing authorisation for this indication.\n\n# Company's economic model\n\n## The company's model structure is appropriate for decision making\n\nThe company presented a 3‑state partitioned survival model to estimate the cost effectiveness of pembrolizumab compared with brentuximab vedotin. The 3\xa0health states were progression-free survival, progressed disease and death. The committee discussed that previous appraisals for classical Hodgkin lymphoma had used a 4‑state model and included stem cell transplant as a health state. The company highlighted that pembrolizumab was not positioned as a 'bridge to transplant' in KEYNOTE‑204 and therefore used a 3‑state model. The company assumed equal rates of stem cell transplant in both the pembrolizumab and brentuximab vedotin arms in its model, including the costs of stem cell transplant, but did not model the impact of stem cell transplant on survival or quality of life. The clinical experts stated that pembrolizumab was likely to be used as a bridge to transplant in people whose disease responds adequately and who are fit enough (see section\xa03.6). The committee discussed that pembrolizumab may increase the number of people who are able to have a stem cell transplant (see section\xa03.6) but noted that the model did not capture the costs and benefits of pembrolizumab used as a bridge to transplant. However, it concluded that the company's model was adequate for decision making.\n\n## It is appropriate to consider people who had and had not had a stem cell transplant separately\n\nIn its original submission, the company presented cost-effectiveness estimates for a pooled population of people who had and had not had a stem cell transplant, as well as estimates for people who had and who had not had a stem cell transplant separately. The company presented a model at technical engagement which only included a pooled population of people who have had 2\xa0previous treatments either with or without previous stem cell transplant. The committee discussed that this was the population of interest from KEYNOTE‑204 (see section\xa03.3). However, the ERG suggested that people who had and had not had a stem cell transplant should be considered separately in the model. This is because the treatment pathway is different for these groups and the prognosis of these groups is also expected to be different. The ERG presented an economic analysis based on these subgroups and the company presented a separate analysis for people who had had 2\xa0previous treatments without previous stem cell transplant in response to the appraisal consultation document. The clinical experts agreed that the subsequent treatment options for these subgroups differ and that prognosis is poorer for people who are not fit for transplant because of age or comorbidities. However, they noted that the group without previous stem cell transplant also included people who were considered fit for transplant but had been previously not been able to have one only because their disease had not responded well enough to chemotherapy, so did not necessarily have a poorer prognosis. The committee was aware that the estimates of costs included in the model may be affected by different subsequent treatment pathways. It concluded that it was appropriate to consider the subgroups of people who have had and have not had a previous stem cell transplant separately.\n\n# Assumptions in the economic model\n\n## For people who have not had a stem cell transplant, the routinely available treatment after brentuximab vedotin is multi-agent chemotherapy\n\nThe ERG highlighted that different subsequent treatments are offered after third‑line treatment has not worked, depending on if a person has had a previous stem cell transplant (see section\xa03.9). The clinical experts explained that:\n\nPeople who have previously had a stem cell transplant and had brentuximab vedotin as third‑line treatment would usually be offered nivolumab.\n\nPeople who have not previously had a stem cell transplant and had brentuximab vedotin as third‑line treatment would currently be offered pembrolizumab, which is available through the Cancer Drugs Fund. The committee was aware of NICE's position statement that drugs available through the Cancer Drugs Fund should not be included in economic models. The clinical experts explained that in the absence of pembrolizumab, multi‑agent chemotherapy is the only option for subsequent treatment in routine commissioning. They highlighted that the choice of multi‑agent chemotherapy differs, but that single agent bendamustine, which was included in the company's model at the first committee meeting, is no longer considered suitable. In response to the appraisal consultation document, the company updated its model for this subgroup and included subsequent treatments in line with those described by the clinical experts.\n\nIf pembrolizumab were available as a third‑line treatment, brentuximab vedotin would be likely to be given as the next treatment, both for people who have, and have not had a previous stem cell transplant.The committee concluded that the company's updated approach to modelling subsequent treatments using multi‑agent chemotherapy after brentuximab vedotin was appropriate for people who have had 2\xa0previous treatments without a previous stem cell transplant.\n\n## Overall survival estimates are uncertain, but Gopal et al. (2015) is a reasonable source of data for people who have had a stem cell transplant\n\nOverall survival data from KEYNOTE‑204 are not available (see section\xa03.5). In its analysis of the pooled population of people who have had 2\xa0previous treatments with and without stem cell transplant (see section\xa03.9), the company used overall survival data in its model from Gopal et al., a single-arm trial of brentuximab vedotin in people with a previous stem cell transplant. The company applied overall survival data from Gopal et al. to the pembrolizumab and brentuximab vedotin arms in the model, assuming equal overall survival with both treatments. The ERG stated that Gopal et al. was appropriate to estimate overall survival for people who have had a previous stem cell transplant because the participants in Gopal et al. had all had previous stem cell transplant and a median of 2.5 previous lines of therapy. The committee considered that KEYNOTE‑204 overall survival data would be preferable to using external data sources, but this was not yet available. It discussed that the company's assumption of equal overall survival with both treatments for this group was likely to be conservative and noted that the company did not provide further analysis for this subgroup in response to the appraisal consultation document. The committee concluded that in the absence of overall survival data from KEYNOTE-204, overall survival estimates are uncertain but Gopal et al. is a reasonable source for people who have had a previous stem cell transplant.\n\n## It is likely that pembrolizumab is associated with an overall survival benefit for people who have not had a previous stem cell transplant\n\nAt the first committee meeting, the company assumed equal overall survival in both treatment arms and modelled this using data from Gopal et al. (2015) for a pooled population of people who have had at least 2\xa0previous treatments with and without stem cell transplant (see section\xa03.11). In response to the appraisal consultation document, the company addressed only the population who had not had stem cell transplant and updated its model to include an overall survival benefit for this group. The company stated that it agreed with the committee's conclusion at the first committee meeting that its initial approach of assuming equal overall survival was conservative, given that there was a progression-free survival benefit for pembrolizumab compared with brentuximab vedotin in KEYNOTE‑204. Assuming equivalent overall survival meant that people were modelled to die at a faster rate once the disease progressed if they had pembrolizumab than if they had brentuximab vedotin before progression. The clinical experts did not consider this to be plausible, noting people may actually live longer with progressed disease after pembrolizumab than after brentuximab vedotin because pembrolizumab can have disease modifying effects which last after disease progression. The clinical experts stated that the potential for pembrolizumab to increase the proportion of people who would go on to have potentially curative stem cell transplant (see section\xa03.6) would also be expected to improve overall survival with pembrolizumab compared with brentuximab vedotin. The committee concluded that although there was no trial overall survival data, it was plausible that there would be an overall survival benefit of pembrolizumab compared with brentuximab vedotin in people who had not had a stem cell transplant.\n\n## The size of overall survival benefit for people without previous stem cell transplant is highly uncertain\n\nTo estimate overall survival for pembrolizumab the company used data from a stem cell ineligible cohort of KEYNOTE‑087, a single‑arm trial of pembrolizumab in people who had had at least 3\xa0previous treatments (a later line of therapy than KEYNOTE‑204). An alternative estimate used data from the Systemic Anti-Cancer Therapy (SACT) database for people who had pembrolizumab as fourth‑line treatment, which is currently funded through the Cancer Drugs Fund. To estimate overall survival for brentuximab vedotin the company used data from Eyre et al. (2017), a UK‑based, retrospective observational study of brentuximab vedotin in people who had 2\xa0previous treatments without previous stem cell transplant. The ERG highlighted that the KEYNOTE‑087 data was immature and highly uncertain as well as being in a later line of therapy than KEYNOTE‑204. The clinical experts stated that the overall survival benefit presented by the company comparing KEYNOTE‑087 with Eyre et al. was likely to be over‑estimated. The committee noted that using the SACT data to estimate overall survival in the pembrolizumab arm reduced the modelled overall survival benefit, giving a more plausible estimate. The committee concluded that the size of benefit for people without previous stem cell transplant is highly uncertain.\n\n## Post-progression health-state utility values are uncertain\n\nAt the first committee meeting, the company presented health-related quality of life data from KEYNOTE‑204 for the pooled population who had had at least 2\xa0previous treatments with and without previous stem cell transplant. This indicated that health-related quality of life in people whose condition progressed after having pembrolizumab is better than for people whose condition progressed after having brentuximab vedotin. The ERG noted that this was uncertain, because of small patient numbers and the data being collected over a short follow up of 30\xa0days after stopping treatment. It highlighted that this time may not be long enough to capture the true progressed disease state utility values. Therefore, the ERG's preferred assumptions included equal post‑progression utilities for both arms, based on the values reported for brentuximab vedotin in the pooled population who have had at least 2\xa0previous treatments with and without previous stem cell transplant. In response to the appraisal consultation document, the company updated its preferred assumption for the post‑progression utility value after pembrolizumab, using the post‑progression utility value from a trial of nivolumab. The updated value was lower than the post‑progression utility after pembrolizumab seen in KEYNOTE‑204 but was higher than the ERG's approach of assuming equal post‑progression utility values for pembrolizumab and brentuximab vedotin. The clinical experts explained that they may expect health‑related quality of life to be better in people whose condition progressed after having pembrolizumab compared with people whose condition progressed after having brentuximab vedotin. This is because brentuximab vedotin is associated with higher rates of side effects, including neuropathy, which can be debilitating and persist for several months in some people. They explained that the severity of side effects is associated with time on treatment, which is likely to be longer for people for whom stem cell transplant is not suitable. They explained that the side effects associated with pembrolizumab have less effect on quality of life. The committee agreed that some side effects of brentuximab vedotin may persist after stopping treatment, but it was difficult to quantify any expected difference in health‑related quality of life between the treatment arms over the long term because of the methods used to collect utility data in KEYNOTE‑204. It agreed that a better long‑term utility in the progressed state for pembrolizumab compared with brentuximab vedotin was unproven. It concluded that the post‑progression health‑state utility values for pembrolizumab are uncertain but that it was unlikely that the health‑state utility values estimated in KEYNOTE‑204 would persist for the whole period of progression. Therefore, the committee preferred the ERG's assumption of equal pembrolizumab and brentuximab vedotin post‑progression utilities, although it recognised this may be conservative.\n\n## The company's approach to estimating the proportion of people who have subsequent treatment is appropriate\n\nIn response to the appraisal consultation document, the company updated its model to include a new approach to calculating the number of people who would have subsequent treatment in the population without previous stem cell treatment. This was calculated by considering the proportion of people whose disease had progressed but who had not died in each model cycle. Of these people, the proportion who would have subsequent treatment was assumed to reflect the proportion of people who had subsequent treatment in each arm of KEYNOTE‑204 (these data are academic in confidence and cannot be reported here). The clinical experts noted that the proportions of people having subsequent treatment in each arm of KEYNOTE‑204 was approximately what is seen in clinical practice. The committee concluded that the company's approach to estimating the proportion of people who have subsequent treatment, using data from KEYNOTE‑204, was appropriate.\n\n# Cost-effectiveness estimate\n\n## Pembrolizumab is less costly and more effective than brentuximab vedotin in people who have had a previous stem cell transplant\n\nThe committee agreed that its preferred approach was to consider people who have had and have not had a previous stem cell transplant separately (see section\xa03.9). The company presented separate analyses for this subgroup in its original submission. However, at the first committee meeting, after an update to the model at technical engagement, the company only presented cost‑effectiveness estimates for the pooled population of people with or without previous stem cell transplant. For people with previous stem cell transplant, the ERG exploratory analysis (and the analyses provided by the ERG using the relevant company assumptions from the original submission where these differed to the ERG's) indicated that pembrolizumab dominated brentuximab vedotin, that is pembrolizumab was cost saving and was associated with a greater quality‑adjusted life year gain than brentuximab vedotin. Pembrolizumab dominated brentuximab vedotin in all scenario analyses presented by the ERG for this subgroup.\n\n## Pembrolizumab is cost effective in the subgroup without previous stem cell transplant if a relatively small overall survival benefit is assumed\n\nIn response to the appraisal consultation document, the company updated its model to include separate analysis of people who have had 2\xa0previous treatments without stem cell transplant. The assumptions made by the company at the second committee meeting for this subgroup were:\n\nmulti‑agent chemotherapy is the subsequent treatment after brentuximab vedotin (see section\xa03.10)\n\nusing KEYNOTE‑087 to estimate overall survival for the pembrolizumab arm and Eyre et al. to estimate overall survival for the brentuximab vedotin arm, resulting in an overall survival benefit for pembrolizumab (see section\xa03.13)\n\nusing post-progression utility data from KEYNOTE‑204 for the brentuximab vedotin arm and post‑progression utility data from a trial of nivolumab for the pembrolizumab arm (see section\xa03.14)\n\ncalculating the number of people for whom subsequent treatment is suitable in each cycle based on progression‑free survival (see section\xa03.15)\n\nusing each arm of the KEYNOTE‑204 data to estimate the proportion of people having subsequent treatment after progression (see section\xa03.15).The company base case gave an incremental cost effectiveness ratio (ICER) of under £20,000 per quality-adjusted life year (QALY) gained. The exact ICERs cannot be reported because of confidential commercial arrangements for comparator and subsequent treatments.The ERG did not present its preferred assumptions for the subgroup of people who have had 2\xa0previous treatments without previous stem cell transplant at the second committee meeting. Instead, it presented several scenario analyses for this subgroup, including a scenario which assumed equal overall survival in both arms, using data from Eyre et al. The committee recalled its conclusion that pembrolizumab is associated with an overall survival benefit but that the size of this is uncertain (see section\xa03.12 and section 3.13). At the request of the committee the ERG provided a threshold analysis, to show the effect of increasing the overall survival benefit in increments. It did this by applying a series of hazard ratios to the modelled overall survival with brentuximab vedotin to model overall survival scenarios with pembrolizumab. This analysis also included the following assumptions:\n\nusing multi‑agent chemotherapy as subsequent treatment after brentuximab vedotin\n\nusing the same post‑progression utility values in both treatment arms\n\ncalculating the number of people for whom subsequent treatment is suitable in each cycle based on progression‑free survival exits\n\nusing each arm of the KEYNOTE‑204 data to estimate the proportion of people having subsequent treatment after progression\n\nusing a 26‑week cut-point for extrapolating data on progression‑free survival and time on treatment.The committee concluded that the assumptions used by the ERG in its threshold analysis were appropriate. It considered the results of the threshold analysis, which showed that the ICER for pembrolizumab compared with brentuximab vedotin was under £30,000 per QALY gained if a relatively small overall survival benefit with pembrolizumab was assumed. The committee noted that the ICER was under £20,000 per QALY gained when the overall survival benefit seen in the company's analysis using SACT data for pembrolizumab was reached in the threshold analysis, which it considered to be the most plausible of the scenarios presented by the company (see section\xa03.13). The committee concluded that plausible assumptions of an overall survival benefit with pembrolizumab compared with brentuximab vedotin resulted in an ICER below £30,000 per QALY which represented a cost‑effective use of NHS resources.\n\n## Pembrolizumab is recommended for treating classical Hodgkin lymphoma in people with previous stem cell transplant\n\nThe committee noted that all relevant analyses for the subgroup of people who have had a previous stem cell transplant showed that pembrolizumab dominated brentuximab vedotin (see section\xa03.16). The committee concluded that pembrolizumab was a cost‑effective use of NHS resources in this population. It recommended pembrolizumab as an option for treating relapsed or refractory classical Hodgkin lymphoma in people whose condition has relapsed after or is refractory to autologous stem cell transplant and have not had brentuximab vedotin, only if the company provides pembrolizumab according to the commercial arrangement.\n\n## Pembrolizumab is recommended for treating classical Hodgkin lymphoma in people who have not had a previous stem cell transplant\n\nThe committee noted that the threshold analysis presented by the ERG showed that pembrolizumab could be considered cost effective when a relatively small overall survival benefit was assumed (see section\xa03.17). It concluded that pembrolizumab was associated with an overall survival benefit (see section\xa03.12) and therefore that it was likely that pembrolizumab was a cost‑effective use of NHS resources in this population. Therefore, the committee recommended pembrolizumab as an option for treating classical Hodgkin lymphoma in people for whom autologous stem cell transplant is not a treatment option and who have had at least 2\xa0previous therapies which has not included brentuximab vedotin.\n\n# Innovation\n\n## The model is adequate to capture the benefits of pembrolizumab\n\nThe company considers pembrolizumab to be innovative. It suggested that using pembrolizumab as a third‑line treatment is a step-change in the management of classical Hodgkin lymphoma. The clinical experts agreed that PD‑L1 inhibitors such as pembrolizumab are innovative medicines. However, they highlighted that pembrolizumab and other PD‑L1 inhibitors are currently available at other stages in the treatment pathway. The committee noted that the company's model did not include the costs and benefits of using pembrolizumab as a bridge to transplant because the company did not consider it would be used in this way. It concluded that it had not been presented with evidence of any additional benefits from pembrolizumab as third‑line treatment that had not already been included.\n\n# Equalities issues\n\nIt was highlighted during the appraisal consultation that there was potential for the draft recommendation (which did not recommend pembrolizumab for people who have had 2\xa0previous treatments without previous stem cell transplant) to affect older people disproportionately negatively. This is because stem cell transplants are more likely to be unsuitable for older people. The committee noted that suitability of a stem cell transplant was dependent on a person's fitness but also if their condition had responded to chemotherapy, and suitability of transplant was not defined on the basis of age. The committee concluded that its final recommendation recommended pembrolizumab for people who could and could not have a stem cell transplant and therefore would not disadvantage people who could not have stem cell transplant."}
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https://www.nice.org.uk/guidance/ta772
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Evidence-based recommendations on pembrolizumab (Keytruda) for relapsed or refractory classical Hodgkin lymphoma in people aged 3 and older who have had a stem cell transplant or at least 2 previous therapies.
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ea6c2229fda03aa6307bce58af4a0978a5701673
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nice
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Pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous non-small-cell lung cancer
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Pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous non-small-cell lung cancer
Evidence-based recommendations on pembrolizumab (Keytruda) with carboplatin and paclitaxel for adults with untreated metastatic squamous non-small-cell lung cancer.
# Recommendations
Pembrolizumab with carboplatin and paclitaxel is recommended as an option for untreated metastatic squamous non-small-cell lung cancer (NSCLC) in adults, only if
their tumours express PD‑L1 with a tumour proportion score of 0% to 49%
their tumours express PD‑L1 with a tumour proportion score of 50% or more and they need urgent clinical intervention
it is stopped at 2 years of uninterrupted treatment or earlier if their disease progresses and
the company provides pembrolizumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with pembrolizumab plus carboplatin and paclitaxel that was started in the Cancer Drugs Fund before this guidance was published. For those people, pembrolizumab plus carboplatin and paclitaxel will be funded by the company until the patient and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous NSCLC.
Initial treatment for metastatic squamous NSCLC depends on PD‑L1 tumour proportion score. People whose tumours have a PD‑L1 tumour proportion score of 0% to 49%, usually have cisplatin or carboplatin plus either gemcitabine, paclitaxel or vinorelbine (platinum-based combination chemotherapy). People whose tumours have a PD‑L1 tumour proportion score of 50% or more usually have pembrolizumab alone.
Clinical trial evidence shows that pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel (pembrolizumab combination therapy) increases how long people with metastatic squamous NSCLC live compared with placebo plus carboplatin and paclitaxel or nab-paclitaxel.
Pembrolizumab combination therapy meets NICE's criteria to be considered a life-extending treatment at the end of life in both PD‑L1 tumour proportion score subgroups. The cost-effectiveness estimates in people whose tumours express PD‑L1 with a tumour proportion score of 0% to 49% were within what NICE considers a good use of NHS resources. For people whose tumours have a PD‑L1 tumour proportion score of 50% or more and who need an urgent clinical intervention (for example, because their cancer may cause major airway blockage), the cost-effectiveness estimates were not certain. However, they are likely to be within what NICE considers a good use of NHS resources, so pembrolizumab combination is recommended in both groups.# Information about pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel
# Marketing authorisation indication
Pembrolizumab (Keytruda, Merck Sharp & Dohme) plus carboplatin and paclitaxel or nab-paclitaxel is indicated for 'the first-line treatment of metastatic squamous non-small-cell lung carcinoma in adults'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for pembrolizumab.
# Price
Pembrolizumab solution for infusion costs £2,630 per 100‑mg vial (excluding VAT; BNF online, accessed August 2021).
The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Merck Sharp and Dohme, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal of pembrolizumab with carboplatin and paclitaxel or nab‑paclitaxel (from now referred to as pembrolizumab combination therapy) for untreated metastatic squamous non-small-cell lung cancer (NSCLC). Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the KEYNOTE‑407 trial about overall survival in people with untreated metastatic squamous NSCLC. It was required to do this for the overall population and by PD‑L1 tumour proportion score subgroups.
The appraisal committee was aware that no additional safety data from KEYNOTE‑407 was presented for this Cancer Drugs Fund review. But it agreed this was unlikely to affect the cost-effectiveness estimates.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see the ERG report, table 1, page 7). It took these into account in its decision making.
# Clinical need
## Pembrolizumab combination therapy would be a welcome additional treatment option for untreated metastatic squamous NSCLC
People with squamous NSCLC often have a poor quality of life, and a potential extension to life is important to them. Outcomes tend to be worse with squamous NSCLC than with non-squamous NSCLC because people have more smoking-related comorbidities. For people with squamous NSCLC whose tumours express PD‑L1 with a tumour proportion score of 0% to 49%, outcomes are particularly poor. This is because the only first-line treatment is platinum-based combination chemotherapy, if it is tolerated. In the original appraisal, the clinical experts explained that for people whose tumours express PD‑L1 at 50% or more, most clinicians would use pembrolizumab monotherapy to avoid chemotherapy toxicity. But they added that some people who need urgent clinical intervention (for example, people with impending major airway obstruction) may benefit from initial combination therapy with pembrolizumab and chemotherapy. The committee concluded that pembrolizumab combination therapy would be a welcome additional treatment option for untreated metastatic squamous NSCLC.
## Treatment and prognosis will differ by PD‑L1 status so subgroups based on PD‑L1 status should be considered separately
Treatment for lung cancer is defined by histology (non-squamous or squamous NSCLC) and PD‑L1 tumour proportion score. This is in line with NICE's guideline on lung cancer: diagnosis and management. First-line management of metastatic squamous NSCLC in clinical practice is platinum-based combination chemotherapy (that is, cisplatin or carboplatin and either gemcitabine, paclitaxel or vinorelbine) for people whose tumours express PD‑L1 at less than 50%. In NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC, pembrolizumab monotherapy is recommended only for people whose tumours express PD‑L1 at 50% or more. At consultation, clinical feedback stated that in clinical practice people would be assessed and treatment decisions would be made based on the 3 PD‑L1 tumour proportion scores (that is, PD‑L1 tumour proportion scores of less than 1%,1% to 49% and 50% or more). The committee was aware of the different treatment options for people whose tumours express PD‑L1 at different levels (see section 3.1). It was satisfied that prognosis may be dependent on the 3 PD‑L1 subgroups but that treatment options may not be. It concluded that subgroups based on PD‑L1 tumour proportion scores of 0% to 49% and 50% or more should be considered separately.
# Clinical management
## Pembrolizumab combination therapy should be considered in the same groups that had access in the Cancer Drugs Fund
Pembrolizumab monotherapy is the standard first-line treatment option for people whose cancer has a PD‑L1 tumour proportion score of 50% or more. The company, in its original submission, did an indirect treatment comparison of pembrolizumab combination therapy and pembrolizumab monotherapy using data from KEYNOTE‑407 and KEYNOTE‑042. KEYNOTE‑042 was a trial including 1,274 people with PD‑L1‑positive tumours that compared pembrolizumab monotherapy with platinum-based chemotherapy. After consultation the company clarified that it was seeking continued access to pembrolizumab combination only for those groups that had access in the Cancer Drugs Fund. That is,
everyone with a PD‑L1 tumour proportion score of 0% to 49% and
people with a PD‑L1 tumour proportion score of 50% or more who need urgent clinical intervention (defined in the Cancer Drugs Fund as people who 'require an urgent clinical response so as to justify the use of the combination of pembrolizumab, carboplatin and paclitaxel rather than pembrolizumab monotherapy'). The company stated the comparator was chemotherapy for people with a PD‑L1 tumour proportion score of 50% or more who would benefit from urgent clinical intervention. This was in line with the comparator in KEYNOTE-407. It considered the company's indirect treatment comparison to be no longer relevant. The clinical lead for the Cancer Drugs Fund noted that prescribing data in the Cancer Drugs Fund showed that out of the 1,015 people who received pembrolizumab combination, 113 (11%) had a PD‑L1 tumour proportion score of 50% or more and needed urgent clinical intervention. The committee heard that for this group the aim of pembrolizumab combination treatment is for chemotherapy to shrink the tumour, which is compressing the airway, so the person can benefit from pembrolizumab later. The ERG noted that data from KEYNOTE-407 was based on the broader group with PD‑L1 tumour proportion scores of 50% or more and did not reflect the company's intended population of those who need urgent clinical intervention. The committee were satisfied that the smaller subgroup was appropriate to consider. Clinical advice suggested that this group did benefit from pembrolizumab combination therapy. The committee concluded pembrolizumab combination therapy should be considered for the same groups that had access in the Cancer Drugs Fund. This includes people with tumours that have a PD‑L1 tumour proportion scores of 50% or more who need urgent clinical intervention.
# Clinical evidence
## Intention-to-treat results do not reflect clinical practice and decisions about clinical effectiveness should be based on PD‑L1 status
The main clinical evidence for pembrolizumab combination therapy came from KEYNOTE‑407, a randomised placebo-controlled trial. It included 559 adults with untreated advanced or metastatic squamous NSCLC with an Eastern Cooperative Oncology Group performance status of 0 or 1. Pembrolizumab combination therapy was compared with placebo plus carboplatin and paclitaxel or nab-paclitaxel (from now, standard chemotherapy) as a first-line treatment. In NHS clinical practice, carboplatin plus gemcitabine is the most commonly used chemotherapy regimen for people whose tumours express PD‑L1 at less than 50%. At technical engagement, the company provided additional overall-survival data from a later follow up of KEYNOTE‑407 (data cut September 2020). Median overall survival was 17.2 months for pembrolizumab combination therapy and 11.6 months for standard chemotherapy (hazard ratio 0.71, 95% confidence interval 0.59 to 0.86). Median progression-free survival was 8.0 months for pembrolizumab combination therapy and 5.1 months for standard chemotherapy (HR 0.59, 95% CI 0.49 to 0.71). The committee agreed that overall- and progression-free survival data from the final analysis and additional data cuts were more mature than those from the interim analysis used in the original appraisal. It recognised that pembrolizumab combination therapy improved overall and progression-free survival compared with standard chemotherapy in the intention‑to‑treat population. However, it acknowledged that the results are not generalisable to clinical practice. This was because the treatments used in the study were different to those used in the NHS, depending on the PD‑L1 tumour proportion score. The committee concluded that the clinical results used in the intention-to-treat population did not reflect clinical practice. It further concluded that decisions about clinical effectiveness should be based on PD‑L1 status (that is, PD‑L1 tumour proportion scores of 0% to 49% and 50% or more in those who need urgent clinical intervention).
## People in the PD‑L1 subgroups would also benefit from pembrolizumab combination therapy
The company presented clinical-effectiveness results for the PD‑L1 subgroups in its submission. The committee was aware that, in the protocol for KEYNOTE‑407, people were stratified to treatment arms by a PD‑L1 tumour proportion score of at least 1% and less than 1%. However, people were enrolled regardless of PD‑L1 status and were spread across 3 PD‑L1 tumour proportion score subgroups (less than 1%, 1% to 49%, and 50% or more). The final analysis of KEYNOTE‑407 (data cut May 2019) showed a reduction in risk of death of:
% for people with a PD‑L1 tumour proportion score of less than 1% (HR 0.79, 95% CI 0.56 to 1.11)
% for people with PD‑L1 tumour proportion scores of 1% to 49% (HR 0.59, 95% CI 0.42 to 0.84)
% for people with a PD‑L1 tumour proportion score of 50% or more (HR 0.79; the confidence intervals and median overall- and progression-free survival values are academic in confidence so cannot be reported here).The committee noted the results suggested pembrolizumab combination therapy was effective at reducing risk of death in people with PD‑L1 tumour proportion scores of 1% to 49%. However, it noted that these results were not conclusive. The results for people with PD‑L1 tumour proportion scores of less than 1% and 50% or more were less statistically certain. At consultation the company provided additional overall- and progression-free survival data from the September 2020 data cut of KEYNOTE-407. Although the values are academic in confidence and so cannot be reported directly, the company suggested this meant the evidence base is sufficiently robust and mature enough to ensure cost-effectiveness estimates are no longer associated with meaningful uncertainty. The committee noted that the confidence intervals for overall survival crossed 1.0 in the PD‑L1 subgroups of less than 1% and for those with PD‑L1 scores of at least 50% or more. This suggested that there may not be a difference between pembrolizumab combination therapy and standard care in these groups. The results showed that 26.6% of those having pembrolizumab combination therapy were still alive at the September 2020 data cut from KEYNOTE‑407, and 18.1% of those having standard chemotherapy had survived without their cancer progressing. The committee concluded that people in the PD‑L1 subgroups would also benefit from pembrolizumab combination therapy.
# The company's economic model
## The company's updated economic model is appropriate
The company's economic analysis was based on the ERG's preferred analysis that was used in the original appraisal. This used the more conservative clinical estimates around progression-free survival as agreed by the committee (termed the 'ERG's pessimistic analysis 6b'). In its submission to the Cancer Drugs Fund review, the company made several changes to its updated model. These included the following amendments, which it applied to the May 2019 data cut of KEYNOTE‑407 and updated to the September 2020 cut after consultation:
Log-logistic parametric models were used to extrapolate overall survival in each treatment group.
A hybrid approach was used that included Kaplan–Meier estimates followed by log-normal extrapolation models with a 26‑week cut-off point to extrapolate progression-free survival in each treatment group.
A generalised gamma extrapolation model (shortened to a maximum treatment duration of 35 cycles) was used to model time to treatment discontinuation for pembrolizumab, and Kaplan–Meier estimates were updated for the standard care group.
The probabilities of having second-line treatments were updated. Also, the data used to model assumptions around the duration of second-line atezolizumab and pembrolizumab in the standard care group included the OAK and KEYNOTE‑010 trials.
Health utilities were defined according to the model health states. The progression-free state was based on KEYNOTE‑407 and the post-progression state was based on the TOPICAL trial with adjustment for the number of people having second-line treatment.The committee agreed that, overall, these amendments were in line with the terms of engagement for the Cancer Drugs Fund review. It also agreed that the company's updated model was generally robust enough for decision making.
## The 0% to 49% PD‑L1 subgroup should be weighted by the Cancer Drug Fund usage
The committee recalled that its preference was to consider the PD‑L1 subgroups based on those with tumour proportion scores of 0% to 49% and those with 50% or more who need urgent clinical intervention (see section 3.2 and section 3.3). After consultation the company agreed this was appropriate. The committee was aware that because the KEYNOTE-407 trial did not include a prespecified subgroup of people whose tumours express PD‑L1 at less than 50%, there was no evidence on the effectiveness of pembrolizumab combination therapy in this group. Therefore, the ERG weighted the life years gained, quality-adjusted life years (QALYs) and costs from the company's model with the proportions from the KEYNOTE-407 groups with PD‑L1 expression of less than 1% and 1% to 49%. After the first committee meeting, the company noted that recent prescribing data had identified differences in the proportions using pembrolizumab combination therapy in the trial compared with those in NHS clinical practice. It suggested that the market research prescribing data was the most accurate source to weight the 0% to 49% PD‑L1 subgroup. This showed that pembrolizumab combination therapy was used in NHS clinical practice by 22% of those with PD‑L1 tumour proportion scores of less than 1% and 68% of those with tumour proportion scores of 1% to 49%. In KEYNOTE-40, 35.5% of patients receiving pembrolizumab combination therapy had a PD-L1 tumour proportion scores less than 1% and 37.8% had tumour proportion scores of 1% to 49%. At the second committee meeting the clinical lead for the Cancer Drugs Fund explained that 48% of those with PD‑L1 tumour proportion scores of less than 1% and 41% of those with tumour proportion scores of 1% to 49% had accessed pembrolizumab combination therapy in the Cancer Drugs Fund. The committee considered the 3 data sources and agreed that the Cancer Drugs Fund was the most accurate source of prescribing data because it was based upon real-world use of pembrolizumab combination therapy. This data showed the total number of people who had received treatment with pembrolizumab combination therapy for metastatic squamous NSCLC in the NHS. It concluded the Cancer Drugs Fund prescribing data is the most appropriate source to weight the 0% to 49% PD‑L1 subgroup.
## The company's choice of parametric models for overall and progression-free survival are appropriate for decision making
In the original appraisal, the company and the ERG used various modelling approaches to estimate long-term survival in the pembrolizumab combination therapy and the comparator arms. The company fitted a hybrid model using Kaplan–Meier data from the interim analysis of KEYNOTE‑407 and additional data from the Surveillance, Epidemiology, and End Results (SEER) database. The committee had concluded that the company's modelled overall survival in the pembrolizumab combination therapy arm was too optimistic. It preferred the ERG's log-logistic extrapolation in each treatment arm with no cut-off points. This was because data in the SEER database had not included second-line immunotherapy treatments. In its submission to the Cancer Drugs Fund review, the company fitted a log-logistic model to the May 2019 data cut of KEYNOTE‑407 with no cut-off points to the data for each treatment group. The company justified this choice because it was in line with the committee's preferred analyses from the original appraisal. It also had one of the best goodness-of-fit statistics, and the most clinically plausible 5‑year and 10‑year overall-survival estimates. The committee noticed that, overall, the Weibull extrapolation model had one of the best statistical fits. However, it considered that the differences were marginal. For progression-free survival, the company fitted the same hybrid model it used in the original appraisal, updated with the May 2019 data cut off. At the first committee meeting the company provided additional survival follow-up data (based on a cut-off date of September 2020) to reinforce the overall- and progression-free survival estimates. The company did not initially incorporate the Kaplan–Meier estimates using the most recent data cut-off plots into its economic model. The ERG was able to provide these updated overall-survival extrapolations using the latest cut-off data. However, it was not able to do so to update progression-free survival because that had been based on a hybrid model, which the company had not updated. The ERG carried out additional sensitivity analyses using alternative parametric survival models. The committee recognised that all the estimates were subject to uncertainty. It also noted that using the alternative parametric survival models did influence the incremental cost-effectiveness ratio (ICER) for pembrolizumab combination therapy. The committee noted that, with the exception of the log-normal extrapolation model, the ICER would increase if any other extrapolation model was used to model both overall and progression-free survival. However, the ICER was less sensitive to the choice of progression-free survival model. After consultation the company updated its economic model for the 3 PD‑L1 subgroups. It used the September 2020 data cut from KEYNOTE-407, justifying its choice of extrapolation model for the PD‑L1 subgroups with tumour proportion scores of less than 1%, 1% to 49%, and 50% or more based on goodness-of-fit assessments. The ERG noted that the company's consultation response had not considered the plausibility of the chosen model. However, at the second committee meeting, the company clarified that the clinical plausibility of the extrapolation models had been considered in its original submission during the committee's decision making for NICE's original technology appraisal for pembrolizumab combination therapy with carboplatin and paclitaxel for untreated metastatic squamous NSCLC. The committee concluded the company's choice of parametric models to extrapolate overall and progression-free survival was appropriate for decision making.
## Costs of subsequent treatment included in the economic model should reflect the treatments in KEYNOTE‑407
The company's updated economic model submitted to the Cancer Drugs Fund review assumed that the costs of subsequent immunotherapies applied to everyone having standard care and subsequent-line treatment. This was in line with the committee's preferred assumptions from the original appraisal about subsequent-line immunotherapy in the standard chemotherapy group. But, the ERG noted that this was inconsistent with the experience of people in KEYNOTE‑407, in which a few people had chemotherapy alone as subsequent treatment. It also noted that the model overestimated the costs of second-line immunotherapy in the standard care group, which would underestimate the ICER for pembrolizumab combination therapy. The ERG used an alternative approach in its preferred base case, in which the costs of chemotherapy were only applied to people who had subsequent-line treatment. This included the people in KEYNOTE‑407 who had subsequent chemotherapy. The clinical experts explained that this did not reflect clinical practice. The committee noted that, although including costs for subsequent-line chemotherapy differed from usual clinical practice, it preferred the consistent approach used by the ERG. At consultation, the company recognised there were problems with each approach taken. It considered that using KEYNOTE-407 data on subsequent treatments might undervalue the cost-effectiveness of pembrolizumab combination therapy. But, it stated, it would accept using the 'within-trial' approach adopted by the ERG. The committee agreed that the costs of subsequent treatment included in the economic model should reflect the treatments in KEYNOTE‑407.
## A treatment effect lasting 5 years for both overall and progression-free survival is appropriate for decision making
In the original appraisal, the committee's preferred analysis included a 2‑year treatment stopping rule and a treatment effect lasting between 3 years and 5 years. In its submission to the Cancer Drugs Fund review, the company proposed a 5‑year duration of treatment benefit for overall survival in its base case. It suggested that there was no direct evidence to support the suggestion that the treatment benefit will wane 5 years after stopping treatment. However, it chose this for consistency with previous immunotherapies. The company included scenario analyses exploring the effects of 3‑year and 4‑year durations of treatment effect. The ERG noted that the waning of treatment effect in the company's base case had only been applied to progression-free survival in the subgroup of people with PD‑L1 tumour proportion scores of 50% or more. So, it applied the waning of treatment effect to both overall and progression-free survival in its preferred base case. The committee noted that including waning of treatment effect on progression-free survival for the intention-to-treat population did not have a large effect on the ICER. At its first meeting, the committee considered the company's and ERG's preferred assumptions alongside decisions made in previous appraisals of immunotherapies and agreed there was no new evidence presented to change its position from the original appraisal. So, it concluded that, for consistency with previous appraisals of immunotherapies for NSCLC, a treatment effect lasting between 3 years and 5 years after starting treatment was appropriate for decision making. In its response to consultation, the company stated its new data cut from September 2020 of KEYNOTE-407, showing a follow up beyond 3 years did not support the committee's preference on waning of treatment effect. The company updated its economic analyses to include a treatment effect for overall survival up to 5 years but assumed a lifetime treatment effect for progression-free survival. The ERG noted the Kaplan–Meier data from the September 2020 data cut -off of KEYNOTE-407 and suggested there may be high levels of censoring and both treatment groups had few overall-survival events at later time points. The data did not show whether the treatment effect would continue for longer than 4 years. Although alternative analyses such as using empirical hazard functions and log cumulative hazards may have assessed whether the treatment effects persisted longer term, these had not been used. The committee agreed the longer-term data of KEYNOTE-407 showed the treatment effect of pembrolizumab combination therapy probably did not wane before 4 years. It was satisfied with the company's assumption for overall survival but it was unclear about the company's rationale about whether the treatment effect for progression-free survival would persist for a lifetime duration. It considered that treatment waning is usually an assumption that is applied when the available data is immature, and so cannot show what happens when people stop having treatment. However, it had agreed the KEYNOTE-407 was now more mature and it was reasonable to assume that the treatment effect for progression-free survival would follow a similar trajectory to overall survival. For this reason the committee concluded that a treatment effect lasting 5 years for both overall and progression-free survival is appropriate for decision making.
## Time to treatment stopping for both groups should be modelled using cumulative probabilities from the Kaplan–Meier estimates
The company considered various survival-extrapolation models fitted to the final data cut of KEYNOTE-407 to model time to stopping treatment for the pembrolizumab combination arm. It chose to use the generalised gamma distribution in its base case, based on goodness-of-fit statistics. The company did not fit parametric models for the comparator group. But, in line with the company model for the original appraisal, it used Kaplan–Meier estimates based on the observed cumulative probabilities of staying on treatment. These were taken from the final data cut of KEYNOTE‑407. The ERG had no concerns with this approach for the standard care group. But, it considered the extrapolation modelling approach used for the pembrolizumab arm did not fit the data well. It chose to use the cumulative probabilities from the Kaplan–Meier estimates in its preferred base-case analysis. The committee agreed that the methods used to model time to stopping treatment in the ERG's base case were preferable to fitting survival models that did not represent the data well. For this reason, the committee concluded that time to stopping treatment for both treatment groups should be modelled using cumulative probabilities from the Kaplan–Meier estimates.
# End of life
## The extension-to-life criterion is likely met for both PD‑L1 subgroups
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a NICE technology appraisal committee should satisfy itself that all of the following criteria have been met:
The treatment is indicated for patients with a short life expectancy, normally less than 24 months.
There is sufficient evidence to indicate that the treatment offers an extension to life, normally at least an additional 3 months, compared with current NHS treatment.The committee recognised that the overall-survival data from the latest data cut showed the survival benefit with pembrolizumab combination therapy was maintained (HR 0.71) in the intention-to-treat population. This suggests a median overall-survival benefit of 5.6 months with pembrolizumab combination therapy compared with standard care. However, the survival benefit based on the May 2019 data cut of KEYNOTE-407 was more uncertain for the PD‑L1 subgroups. The hazard ratios for overall survival were higher in the subgroup with a PD‑L1 tumour proportion score of 50% or more (HR 0.79). At the second committee meeting the committee considered the new evidence on the PD‑L1 subgroups provided by the company from the September 2020 data cut of KEYNOTE-407. The committee agreed, there was a clinical unmet need for people in the 50% or more PD‑L1 subgroup, who have additional complications that require an urgent clinical response. By definition, this group would need urgent clinical intervention and would likely be particularly unwell. They would therefore need a treatment that would prolong their life, which is likely to exceed 3 months. For people in the 0% to 49% PD‑L1 subgroup, the committee noted that using the company's latest model with the Cancer Drug Fund prescribing data to inform the weighting, suggested an extension to life of at least 3 months. It concluded that pembrolizumab combination therapy would likely meet the extension-to-life criterion for people with a PD‑L1 tumour proportion score of 0% to 49% and for those with a PD‑L1 tumour proportion score of 50% or more who need urgent clinical intervention.
## The short-life-expectancy criterion is likely met
For the short-life-expectancy criterion, the company noted that the most recent data from KEYNOTE‑407 (data cut September 2020) reported a median overall survival of 11.6 months for the standard care arm for the intention-to-treat population. The company model predicted a mean overall survival with standard care of 27.1 months. Based on the most recent overall-survival data, it noted that its economic model predicted that only 28.5% of people in the intention-to-treat population having standard chemotherapy would be alive at 24 months. The company noted that survival with current therapies in NICE's ongoing technology appraisal for nivolumab with ipilimumab and chemotherapy for untreated metastatic NSCLC is less than 24 months for people with squamous histology and a PD‑L1 tumour proportion score of less than 50%. This had been supported by the clinical experts involved in that technology appraisal, who confirmed that treatment options in the NHS would vary by histology and PD‑L1 status. At the second committee meeting, the company accepted that NICE's end of life criteria should be considered based on the PD‑L1 subgroups of 0% to 49% and 50% or more in those who need urgent clinical intervention. The committee noted that the company's updated base case using the September 2020 data cut and weighted using the percentage usage from the Cancer Drugs Fund, suggested that people on standard chemotherapy would live approximately 2 years. It concluded that the short-life-expectancy criterion was likely met for both subgroups.
# Cost-effectiveness estimates
## An acceptable ICER is £50,000 per QALY gained
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee's preferred assumptions included:
log-logistic extrapolation fitted to overall survival in both treatment arms
a hybrid model fitted for progression-free survival in both treatment arms
cumulative probabilities from the Kaplan–Meier estimates fitted to time to treatment discontinuation data in both arms
utilities based on pre- or post-progression status
a stopping rule and costs applied for 35 cycles
duration of subsequent treatments in line with the company submission to the Cancer Drugs Fund review and updated distribution of subsequent-line therapies in line with subsequent treatments in KEYNOTE‑407
a treatment effect for both overall and progression-free survival lasting 5 years after starting treatment
weighting the cost-effectiveness results of the less than 1% and 1% to 49% PD‑L1 subgroups using the Cancer Drugs Fund prescribing data.The committee considered its conclusion that the end of life criteria is likely met for both PD‑L1 subgroups (see section 3.12 and section 3.13). Therefore, it agreed that an acceptable ICER would be £50,000 per QALY gained.
## Pembrolizumab combination is recommended for routine use in the 0% to 49% PD‑L1 subgroup
The committee considered the results of its preferred analysis for the 0% to 49% PD‑L1 subgroup, reweighted using the prescribing data from the Cancer Drugs Fund. The ICER was below £50,000 per QALY gained. The committee concluded that pembrolizumab combination is recommended for routine use in people whose tumours express PD‑L1 with a tumour proportion score of 0% to 49%.
## Pembrolizumab combination is recommended for routine use in the 50% or more PD‑L1 subgroup who need urgent clinical intervention
The committee considered the results of its preferred analysis for the 50% or more PD‑L1 subgroup who need urgent clinical intervention. The ICER was below £50,00 per QALY gained. It noted it had not seen any direct or indirect evidence specifically for the 50% or more PD‑L1 subgroup who need urgent clinical intervention. It considered there was a high unmet need for this group because there is a lack of other treatment options available and because this group are likely to have a very short life expectancies. It considered the ICER was likely to be a cost-effective use of NHS resources, despite the lack of a robust evidence in the subgroup. For this reason, the committee concluded that pembrolizumab combination therapy is recommended for routine use in the NHS for people whose tumours have a PD‑L1 tumour proportion score of 50% or more and who need urgent clinical intervention.
# Other factors
## There are no equalities issues, and all relevant benefits are captured in the QALY
At consultation, the company highlighted that people with squamous NSCLC could have poorer outcomes because of smoking-related comorbidities. It suggested this was likely to have an impact on people in lower socioeconomic groups because rates of smoking are higher in these populations. The committee noted it had no evidence to suggest outcomes would differ for this group of people compared with people who had other cancers. The committee concluded there are no equalities issues and all relevant benefits of the technology were captured in the QALY.
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{'Recommendations': "Pembrolizumab with carboplatin and paclitaxel is recommended as an option for untreated metastatic squamous non-small-cell lung cancer (NSCLC) in adults, only if\n\ntheir tumours express PD‑L1 with a tumour proportion score of 0% to 49%\n\ntheir tumours express PD‑L1 with a tumour proportion score of 50% or more and they need urgent clinical intervention\n\nit is stopped at 2\xa0years of uninterrupted treatment or earlier if their disease progresses and\n\nthe company provides pembrolizumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with pembrolizumab plus carboplatin and paclitaxel that was started in the Cancer Drugs Fund before this guidance was published. For those people, pembrolizumab plus carboplatin and paclitaxel will be funded by the company until the patient and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for pembrolizumab with carboplatin and paclitaxel for untreated metastatic squamous NSCLC.\n\nInitial treatment for metastatic squamous NSCLC depends on PD‑L1 tumour proportion score. People whose tumours have a PD‑L1 tumour proportion score of 0% to 49%, usually have cisplatin or carboplatin plus either gemcitabine, paclitaxel or vinorelbine (platinum-based combination chemotherapy). People whose tumours have a PD‑L1 tumour proportion score of 50% or more usually have pembrolizumab alone.\n\nClinical trial evidence shows that pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel (pembrolizumab combination therapy) increases how long people with metastatic squamous NSCLC live compared with placebo plus carboplatin and paclitaxel or nab-paclitaxel.\n\nPembrolizumab combination therapy meets NICE's criteria to be considered a life-extending treatment at the end of life in both PD‑L1 tumour proportion score subgroups. The cost-effectiveness estimates in people whose tumours express PD‑L1 with a tumour proportion score of 0% to 49% were within what NICE considers a good use of NHS resources. For people whose tumours have a PD‑L1 tumour proportion score of 50% or more and who need an urgent clinical intervention (for example, because their cancer may cause major airway blockage), the cost-effectiveness estimates were not certain. However, they are likely to be within what NICE considers a good use of NHS resources, so pembrolizumab combination is recommended in both groups.", 'Information about pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, Merck Sharp & Dohme) plus carboplatin and paclitaxel or nab-paclitaxel is indicated for 'the first-line treatment of metastatic squamous non-small-cell lung carcinoma in adults'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nPembrolizumab solution for infusion costs £2,630 per 100‑mg vial (excluding VAT; BNF online, accessed August 2021).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Merck Sharp and Dohme, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal of pembrolizumab with carboplatin and paclitaxel or nab‑paclitaxel (from now referred to as pembrolizumab combination therapy) for untreated metastatic squamous non-small-cell lung cancer (NSCLC). Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the KEYNOTE‑407 trial about overall survival in people with untreated metastatic squamous NSCLC. It was required to do this for the overall population and by PD‑L1 tumour proportion score subgroups.\n\nThe appraisal committee was aware that no additional safety data from KEYNOTE‑407 was presented for this Cancer Drugs Fund review. But it agreed this was unlikely to affect the cost-effectiveness estimates.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see the ERG report, table\xa01, page\xa07). It took these into account in its decision making.\n\n# Clinical need\n\n## Pembrolizumab combination therapy would be a welcome additional treatment option for untreated metastatic squamous NSCLC\n\nPeople with squamous NSCLC often have a poor quality of life, and a potential extension to life is important to them. Outcomes tend to be worse with squamous NSCLC than with non-squamous NSCLC because people have more smoking-related comorbidities. For people with squamous NSCLC whose tumours express PD‑L1 with a tumour proportion score of 0% to 49%, outcomes are particularly poor. This is because the only first-line treatment is platinum-based combination chemotherapy, if it is tolerated. In the original appraisal, the clinical experts explained that for people whose tumours express PD‑L1 at 50% or more, most clinicians would use pembrolizumab monotherapy to avoid chemotherapy toxicity. But they added that some people who need urgent clinical intervention (for example, people with impending major airway obstruction) may benefit from initial combination therapy with pembrolizumab and chemotherapy. The committee concluded that pembrolizumab combination therapy would be a welcome additional treatment option for untreated metastatic squamous NSCLC.\n\n## Treatment and prognosis will differ by PD‑L1 status so subgroups based on PD‑L1 status should be considered separately\n\nTreatment for lung cancer is defined by histology (non-squamous or squamous NSCLC) and PD‑L1 tumour proportion score. This is in line with NICE's guideline on lung cancer: diagnosis and management. First-line management of metastatic squamous NSCLC in clinical practice is platinum-based combination chemotherapy (that is, cisplatin or carboplatin and either gemcitabine, paclitaxel or vinorelbine) for people whose tumours express PD‑L1 at less than 50%. In NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC, pembrolizumab monotherapy is recommended only for people whose tumours express PD‑L1 at 50% or more. At consultation, clinical feedback stated that in clinical practice people would be assessed and treatment decisions would be made based on the 3\xa0PD‑L1 tumour proportion scores (that is, PD‑L1 tumour proportion scores of less than 1%,1% to 49% and 50% or more). The committee was aware of the different treatment options for people whose tumours express PD‑L1 at different levels (see section\xa03.1). It was satisfied that prognosis may be dependent on the 3 PD‑L1 subgroups but that treatment options may not be. It concluded that subgroups based on PD‑L1 tumour proportion scores of 0% to 49% and 50% or more should be considered separately.\n\n# Clinical management\n\n## Pembrolizumab combination therapy should be considered in the same groups that had access in the Cancer Drugs Fund\n\nPembrolizumab monotherapy is the standard first-line treatment option for people whose cancer has a PD‑L1 tumour proportion score of 50% or more. The company, in its original submission, did an indirect treatment comparison of pembrolizumab combination therapy and pembrolizumab monotherapy using data from KEYNOTE‑407 and KEYNOTE‑042. KEYNOTE‑042 was a trial including 1,274 people with PD‑L1‑positive tumours that compared pembrolizumab monotherapy with platinum-based chemotherapy. After consultation the company clarified that it was seeking continued access to pembrolizumab combination only for those groups that had access in the Cancer Drugs Fund. That is,\n\neveryone with a PD‑L1 tumour proportion score of 0% to 49% and\n\npeople with a PD‑L1 tumour proportion score of 50% or more who need urgent clinical intervention (defined in the Cancer Drugs Fund as people who 'require an urgent clinical response [for example, impending major airway obstruction] so as to justify the use of the combination of pembrolizumab, carboplatin and paclitaxel rather than pembrolizumab monotherapy'). The company stated the comparator was chemotherapy for people with a PD‑L1 tumour proportion score of 50% or more who would benefit from urgent clinical intervention. This was in line with the comparator in KEYNOTE-407. It considered the company's indirect treatment comparison to be no longer relevant. The clinical lead for the Cancer Drugs Fund noted that prescribing data in the Cancer Drugs Fund showed that out of the 1,015 people who received pembrolizumab combination, 113 (11%) had a PD‑L1 tumour proportion score of 50% or more and needed urgent clinical intervention. The committee heard that for this group the aim of pembrolizumab combination treatment is for chemotherapy to shrink the tumour, which is compressing the airway, so the person can benefit from pembrolizumab later. The ERG noted that data from KEYNOTE-407 was based on the broader group with PD‑L1 tumour proportion scores of 50% or more and did not reflect the company's intended population of those who need urgent clinical intervention. The committee were satisfied that the smaller subgroup was appropriate to consider. Clinical advice suggested that this group did benefit from pembrolizumab combination therapy. The committee concluded pembrolizumab combination therapy should be considered for the same groups that had access in the Cancer Drugs Fund. This includes people with tumours that have a PD‑L1 tumour proportion scores of 50% or more who need urgent clinical intervention.\n\n# Clinical evidence\n\n## Intention-to-treat results do not reflect clinical practice and decisions about clinical effectiveness should be based on PD‑L1 status\n\nThe main clinical evidence for pembrolizumab combination therapy came from KEYNOTE‑407, a randomised placebo-controlled trial. It included 559\xa0adults with untreated advanced or metastatic squamous NSCLC with an Eastern Cooperative Oncology Group performance status of 0\xa0or\xa01. Pembrolizumab combination therapy was compared with placebo plus carboplatin and paclitaxel or nab-paclitaxel (from now, standard chemotherapy) as a first-line treatment. In NHS clinical practice, carboplatin plus gemcitabine is the most commonly used chemotherapy regimen for people whose tumours express PD‑L1 at less than 50%. At technical engagement, the company provided additional overall-survival data from a later follow up of KEYNOTE‑407 (data cut September 2020). Median overall survival was 17.2\xa0months for pembrolizumab combination therapy and 11.6\xa0months for standard chemotherapy (hazard ratio [HR]\xa00.71, 95%\xa0confidence interval [CI] 0.59\xa0to\xa00.86). Median progression-free survival was 8.0\xa0months for pembrolizumab combination therapy and 5.1\xa0months for standard chemotherapy (HR\xa00.59, 95%\xa0CI 0.49\xa0to 0.71). The committee agreed that overall- and progression-free survival data from the final analysis and additional data cuts were more mature than those from the interim analysis used in the original appraisal. It recognised that pembrolizumab combination therapy improved overall and progression-free survival compared with standard chemotherapy in the intention‑to‑treat population. However, it acknowledged that the results are not generalisable to clinical practice. This was because the treatments used in the study were different to those used in the NHS, depending on the PD‑L1 tumour proportion score. The committee concluded that the clinical results used in the intention-to-treat population did not reflect clinical practice. It further concluded that decisions about clinical effectiveness should be based on PD‑L1 status (that is, PD‑L1 tumour proportion scores of 0% to 49% and 50% or more in those who need urgent clinical intervention).\n\n## People in the PD‑L1 subgroups would also benefit from pembrolizumab combination therapy\n\nThe company presented clinical-effectiveness results for the PD‑L1 subgroups in its submission. The committee was aware that, in the protocol for KEYNOTE‑407, people were stratified to treatment arms by a PD‑L1 tumour proportion score of at least 1% and less than 1%. However, people were enrolled regardless of PD‑L1 status and were spread across 3\xa0PD‑L1 tumour proportion score subgroups (less than 1%, 1% to 49%, and 50% or more). The final analysis of KEYNOTE‑407 (data cut May 2019) showed a reduction in risk of death of:\n\n% for people with a PD‑L1 tumour proportion score of less than 1% (HR\xa00.79, 95%\xa0CI 0.56\xa0to\xa01.11)\n\n% for people with PD‑L1 tumour proportion scores of 1% to 49% (HR\xa00.59, 95%\xa0CI 0.42\xa0to\xa00.84)\n\n% for people with a PD‑L1 tumour proportion score of 50% or more (HR\xa00.79; the confidence intervals and median overall- and progression-free survival values are academic in confidence so cannot be reported here).The committee noted the results suggested pembrolizumab combination therapy was effective at reducing risk of death in people with PD‑L1 tumour proportion scores of 1% to 49%. However, it noted that these results were not conclusive. The results for people with PD‑L1 tumour proportion scores of less than 1% and 50% or more were less statistically certain. At consultation the company provided additional overall- and progression-free survival data from the September 2020 data cut of KEYNOTE-407. Although the values are academic in confidence and so cannot be reported directly, the company suggested this meant the evidence base is sufficiently robust and mature enough to ensure cost-effectiveness estimates are no longer associated with meaningful uncertainty. The committee noted that the confidence intervals for overall survival crossed 1.0 in the PD‑L1 subgroups of less than 1% and for those with PD‑L1 scores of at least 50% or more. This suggested that there may not be a difference between pembrolizumab combination therapy and standard care in these groups. The results showed that 26.6% of those having pembrolizumab combination therapy were still alive at the September 2020 data cut from KEYNOTE‑407, and 18.1% of those having standard chemotherapy had survived without their cancer progressing. The committee concluded that people in the PD‑L1 subgroups would also benefit from pembrolizumab combination therapy.\n\n# The company's economic model\n\n## The company's updated economic model is appropriate\n\nThe company's economic analysis was based on the ERG's preferred analysis that was used in the original appraisal. This used the more conservative clinical estimates around progression-free survival as agreed by the committee (termed the 'ERG's pessimistic analysis\xa06b'). In its submission to the Cancer Drugs Fund review, the company made several changes to its updated model. These included the following amendments, which it applied to the May 2019 data cut of KEYNOTE‑407 and updated to the September 2020 cut after consultation:\n\nLog-logistic parametric models were used to extrapolate overall survival in each treatment group.\n\nA hybrid approach was used that included Kaplan–Meier estimates followed by log-normal extrapolation models with a 26‑week cut-off point to extrapolate progression-free survival in each treatment group.\n\nA generalised gamma extrapolation model (shortened to a maximum treatment duration of 35\xa0cycles) was used to model time to treatment discontinuation for pembrolizumab, and Kaplan–Meier estimates were updated for the standard care group.\n\nThe probabilities of having second-line treatments were updated. Also, the data used to model assumptions around the duration of second-line atezolizumab and pembrolizumab in the standard care group included the OAK and KEYNOTE‑010 trials.\n\nHealth utilities were defined according to the model health states. The progression-free state was based on KEYNOTE‑407 and the post-progression state was based on the TOPICAL trial with adjustment for the number of people having second-line treatment.The committee agreed that, overall, these amendments were in line with the terms of engagement for the Cancer Drugs Fund review. It also agreed that the company's updated model was generally robust enough for decision making.\n\n## The 0% to 49% PD‑L1 subgroup should be weighted by the Cancer Drug Fund usage\n\nThe committee recalled that its preference was to consider the PD‑L1 subgroups based on those with tumour proportion scores of 0% to 49% and those with 50% or more who need urgent clinical intervention (see section\xa03.2 and section\xa03.3). After consultation the company agreed this was appropriate. The committee was aware that because the KEYNOTE-407 trial did not include a prespecified subgroup of people whose tumours express PD‑L1 at less than 50%, there was no evidence on the effectiveness of pembrolizumab combination therapy in this group. Therefore, the ERG weighted the life years gained, quality-adjusted life years (QALYs) and costs from the company's model with the proportions from the KEYNOTE-407 groups with PD‑L1 expression of less than 1% and 1% to 49%. After the first committee meeting, the company noted that recent prescribing data had identified differences in the proportions using pembrolizumab combination therapy in the trial compared with those in NHS clinical practice. It suggested that the market research prescribing data was the most accurate source to weight the 0% to 49% PD‑L1 subgroup. This showed that pembrolizumab combination therapy was used in NHS clinical practice by 22% of those with PD‑L1 tumour proportion scores of less than 1% and 68% of those with tumour proportion scores of 1% to 49%. In KEYNOTE-40, 35.5% of patients receiving pembrolizumab combination therapy had a PD-L1 tumour proportion scores less than 1% and 37.8% had tumour proportion scores of 1% to 49%. At the second committee meeting the clinical lead for the Cancer Drugs Fund explained that 48% of those with PD‑L1 tumour proportion scores of less than 1% and 41% of those with tumour proportion scores of 1% to 49% had accessed pembrolizumab combination therapy in the Cancer Drugs Fund. The committee considered the 3\xa0data sources and agreed that the Cancer Drugs Fund was the most accurate source of prescribing data because it was based upon real-world use of pembrolizumab combination therapy. This data showed the total number of people who had received treatment with pembrolizumab combination therapy for metastatic squamous NSCLC in the NHS. It concluded the Cancer Drugs Fund prescribing data is the most appropriate source to weight the 0% to 49% PD‑L1 subgroup.\n\n## The company's choice of parametric models for overall and progression-free survival are appropriate for decision making\n\nIn the original appraisal, the company and the ERG used various modelling approaches to estimate long-term survival in the pembrolizumab combination therapy and the comparator arms. The company fitted a hybrid model using Kaplan–Meier data from the interim analysis of KEYNOTE‑407 and additional data from the Surveillance, Epidemiology, and End Results (SEER) database. The committee had concluded that the company's modelled overall survival in the pembrolizumab combination therapy arm was too optimistic. It preferred the ERG's log-logistic extrapolation in each treatment arm with no cut-off points. This was because data in the SEER database had not included second-line immunotherapy treatments. In its submission to the Cancer Drugs Fund review, the company fitted a log-logistic model to the May 2019 data cut of KEYNOTE‑407 with no cut-off points to the data for each treatment group. The company justified this choice because it was in line with the committee's preferred analyses from the original appraisal. It also had one of the best goodness-of-fit statistics, and the most clinically plausible 5‑year and 10‑year overall-survival estimates. The committee noticed that, overall, the Weibull extrapolation model had one of the best statistical fits. However, it considered that the differences were marginal. For progression-free survival, the company fitted the same hybrid model it used in the original appraisal, updated with the May 2019 data cut off. At the first committee meeting the company provided additional survival follow-up data (based on a cut-off date of September 2020) to reinforce the overall- and progression-free survival estimates. The company did not initially incorporate the Kaplan–Meier estimates using the most recent data cut-off plots into its economic model. The ERG was able to provide these updated overall-survival extrapolations using the latest cut-off data. However, it was not able to do so to update progression-free survival because that had been based on a hybrid model, which the company had not updated. The ERG carried out additional sensitivity analyses using alternative parametric survival models. The committee recognised that all the estimates were subject to uncertainty. It also noted that using the alternative parametric survival models did influence the incremental cost-effectiveness ratio (ICER) for pembrolizumab combination therapy. The committee noted that, with the exception of the log-normal extrapolation model, the ICER would increase if any other extrapolation model was used to model both overall and progression-free survival. However, the ICER was less sensitive to the choice of progression-free survival model. After consultation the company updated its economic model for the 3\xa0PD‑L1 subgroups. It used the September 2020 data cut from KEYNOTE-407, justifying its choice of extrapolation model for the PD‑L1 subgroups with tumour proportion scores of less than 1%, 1% to 49%, and 50% or more based on goodness-of-fit assessments. The ERG noted that the company's consultation response had not considered the plausibility of the chosen model. However, at the second committee meeting, the company clarified that the clinical plausibility of the extrapolation models had been considered in its original submission during the committee's decision making for NICE's original technology appraisal for pembrolizumab combination therapy with carboplatin and paclitaxel for untreated metastatic squamous NSCLC. The committee concluded the company's choice of parametric models to extrapolate overall and progression-free survival was appropriate for decision making.\n\n## Costs of subsequent treatment included in the economic model should reflect the treatments in KEYNOTE‑407\n\nThe company's updated economic model submitted to the Cancer Drugs Fund review assumed that the costs of subsequent immunotherapies applied to everyone having standard care and subsequent-line treatment. This was in line with the committee's preferred assumptions from the original appraisal about subsequent-line immunotherapy in the standard chemotherapy group. But, the ERG noted that this was inconsistent with the experience of people in KEYNOTE‑407, in which a few people had chemotherapy alone as subsequent treatment. It also noted that the model overestimated the costs of second-line immunotherapy in the standard care group, which would underestimate the ICER for pembrolizumab combination therapy. The ERG used an alternative approach in its preferred base case, in which the costs of chemotherapy were only applied to people who had subsequent-line treatment. This included the people in KEYNOTE‑407 who had subsequent chemotherapy. The clinical experts explained that this did not reflect clinical practice. The committee noted that, although including costs for subsequent-line chemotherapy differed from usual clinical practice, it preferred the consistent approach used by the ERG. At consultation, the company recognised there were problems with each approach taken. It considered that using KEYNOTE-407 data on subsequent treatments might undervalue the cost-effectiveness of pembrolizumab combination therapy. But, it stated, it would accept using the 'within-trial' approach adopted by the ERG. The committee agreed that the costs of subsequent treatment included in the economic model should reflect the treatments in KEYNOTE‑407.\n\n## A treatment effect lasting 5\xa0years for both overall and progression-free survival is appropriate for decision making\n\nIn the original appraisal, the committee's preferred analysis included a 2‑year treatment stopping rule and a treatment effect lasting between 3\xa0years and 5\xa0years. In its submission to the Cancer Drugs Fund review, the company proposed a 5‑year duration of treatment benefit for overall survival in its base case. It suggested that there was no direct evidence to support the suggestion that the treatment benefit will wane 5\xa0years after stopping treatment. However, it chose this for consistency with previous immunotherapies. The company included scenario analyses exploring the effects of 3‑year and 4‑year durations of treatment effect. The ERG noted that the waning of treatment effect in the company's base case had only been applied to progression-free survival in the subgroup of people with PD‑L1 tumour proportion scores of 50% or more. So, it applied the waning of treatment effect to both overall and progression-free survival in its preferred base case. The committee noted that including waning of treatment effect on progression-free survival for the intention-to-treat population did not have a large effect on the ICER. At its first meeting, the committee considered the company's and ERG's preferred assumptions alongside decisions made in previous appraisals of immunotherapies and agreed there was no new evidence presented to change its position from the original appraisal. So, it concluded that, for consistency with previous appraisals of immunotherapies for NSCLC, a treatment effect lasting between 3\xa0years and 5\xa0years after starting treatment was appropriate for decision making. In its response to consultation, the company stated its new data cut from September 2020 of KEYNOTE-407, showing a follow\xa0up beyond 3\xa0years did not support the committee's preference on waning of treatment effect. The company updated its economic analyses to include a treatment effect for overall survival up to 5\xa0years but assumed a lifetime treatment effect for progression-free survival. The ERG noted the Kaplan–Meier data from the September 2020 data cut -off of KEYNOTE-407 and suggested there may be high levels of censoring and both treatment groups had few overall-survival events at later time\xa0points. The data did not show whether the treatment effect would continue for longer than 4\xa0years. Although alternative analyses such as using empirical hazard functions and log cumulative hazards may have assessed whether the treatment effects persisted longer term, these had not been used. The committee agreed the longer-term data of KEYNOTE-407 showed the treatment effect of pembrolizumab combination therapy probably did not wane before 4\xa0years. It was satisfied with the company's assumption for overall survival but it was unclear about the company's rationale about whether the treatment effect for progression-free survival would persist for a lifetime duration. It considered that treatment waning is usually an assumption that is applied when the available data is immature, and so cannot show what happens when people stop having treatment. However, it had agreed the KEYNOTE-407 was now more mature and it was reasonable to assume that the treatment effect for progression-free survival would follow a similar trajectory to overall survival. For this reason the committee concluded that a treatment effect lasting 5\xa0years for both overall and progression-free survival is appropriate for decision\xa0making.\n\n## Time to treatment stopping for both groups should be modelled using cumulative probabilities from the Kaplan–Meier estimates\n\nThe company considered various survival-extrapolation models fitted to the final data cut of KEYNOTE-407 to model time to stopping treatment for the pembrolizumab combination arm. It chose to use the generalised gamma distribution in its base case, based on goodness-of-fit statistics. The company did not fit parametric models for the comparator group. But, in line with the company model for the original appraisal, it used Kaplan–Meier estimates based on the observed cumulative probabilities of staying on treatment. These were taken from the final data cut of KEYNOTE‑407. The ERG had no concerns with this approach for the standard care group. But, it considered the extrapolation modelling approach used for the pembrolizumab arm did not fit the data well. It chose to use the cumulative probabilities from the Kaplan–Meier estimates in its preferred base-case analysis. The committee agreed that the methods used to model time to stopping treatment in the ERG's base case were preferable to fitting survival models that did not represent the data well. For this reason, the committee concluded that time to stopping treatment for both treatment groups should be modelled using cumulative probabilities from the Kaplan–Meier estimates.\n\n# End of life\n\n## The extension-to-life criterion is likely met for both PD‑L1 subgroups\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. This states that a NICE technology appraisal committee should satisfy itself that all of the following criteria have been met:\n\nThe treatment is indicated for patients with a short life expectancy, normally less than 24\xa0months.\n\nThere is sufficient evidence to indicate that the treatment offers an extension to life, normally at least an additional 3\xa0months, compared with current NHS treatment.The committee recognised that the overall-survival data from the latest data cut showed the survival benefit with pembrolizumab combination therapy was maintained (HR\xa00.71) in the intention-to-treat population. This suggests a median overall-survival benefit of 5.6\xa0months with pembrolizumab combination therapy compared with standard care. However, the survival benefit based on the May 2019 data cut of KEYNOTE-407 was more uncertain for the PD‑L1 subgroups. The hazard ratios for overall survival were higher in the subgroup with a PD‑L1 tumour proportion score of 50% or more (HR\xa00.79). At the second committee meeting the committee considered the new evidence on the PD‑L1 subgroups provided by the company from the September 2020 data cut of KEYNOTE-407. The committee agreed, there was a clinical unmet need for people in the 50% or more PD‑L1 subgroup, who have additional complications that require an urgent clinical response. By definition, this group would need urgent clinical intervention and would likely be particularly unwell. They would therefore need a treatment that would prolong their life, which is likely to exceed 3 months. For people in the 0% to 49% PD‑L1 subgroup, the committee noted that using the company's latest model with the Cancer Drug Fund prescribing data to inform the weighting, suggested an extension to life of at least 3\xa0months. It concluded that pembrolizumab combination therapy would likely meet the extension-to-life criterion for people with a PD‑L1 tumour proportion score of 0% to 49% and for those with a PD‑L1 tumour proportion score of 50% or more who need urgent clinical intervention.\n\n## The short-life-expectancy criterion is likely met\n\nFor the short-life-expectancy criterion, the company noted that the most recent data from KEYNOTE‑407 (data cut September 2020) reported a median overall survival of 11.6\xa0months for the standard care arm for the intention-to-treat population. The company model predicted a mean overall survival with standard care of 27.1\xa0months. Based on the most recent overall-survival data, it noted that its economic model predicted that only 28.5% of people in the intention-to-treat population having standard chemotherapy would be alive at 24\xa0months. The company noted that survival with current therapies in NICE's ongoing technology appraisal for nivolumab with ipilimumab and chemotherapy for untreated metastatic NSCLC is less than 24\xa0months for people with squamous histology and a PD‑L1 tumour proportion score of less than 50%. This had been supported by the clinical experts involved in that technology appraisal, who confirmed that treatment options in the NHS would vary by histology and PD‑L1 status. At the second committee meeting, the company accepted that NICE's end of life criteria should be considered based on the PD‑L1 subgroups of 0% to 49% and 50% or more in those who need urgent clinical intervention. The committee noted that the company's updated base case using the September 2020 data cut and weighted using the percentage usage from the Cancer Drugs Fund, suggested that people on standard chemotherapy would live approximately 2\xa0years. It concluded that the short-life-expectancy criterion was likely met for both subgroups.\n\n# Cost-effectiveness estimates\n\n## An acceptable ICER is £50,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee's preferred assumptions included:\n\nlog-logistic extrapolation fitted to overall survival in both treatment arms\n\na hybrid model fitted for progression-free survival in both treatment arms\n\ncumulative probabilities from the Kaplan–Meier estimates fitted to time to treatment discontinuation data in both arms\n\nutilities based on pre- or post-progression status\n\na stopping rule and costs applied for 35\xa0cycles\n\nduration of subsequent treatments in line with the company submission to the Cancer Drugs Fund review and updated distribution of subsequent-line therapies in line with subsequent treatments in KEYNOTE‑407\n\na treatment effect for both overall and progression-free survival lasting 5\xa0years after starting treatment\n\nweighting the cost-effectiveness results of the less than 1% and 1% to 49% PD‑L1 subgroups using the Cancer Drugs Fund prescribing data.The committee considered its conclusion that the end of life criteria is likely met for both PD‑L1 subgroups (see section\xa03.12 and section\xa03.13). Therefore, it agreed that an acceptable ICER would be £50,000 per QALY gained.\n\n## Pembrolizumab combination is recommended for routine use in the 0% to 49% PD‑L1 subgroup\n\nThe committee considered the results of its preferred analysis for the 0% to 49% PD‑L1 subgroup, reweighted using the prescribing data from the Cancer Drugs Fund. The ICER was below £50,000 per QALY gained. The committee concluded that pembrolizumab combination is recommended for routine use in people whose tumours express PD‑L1 with a tumour proportion score of 0% to 49%.\n\n## Pembrolizumab combination is recommended for routine use in the 50% or more PD‑L1 subgroup who need urgent clinical intervention\n\nThe committee considered the results of its preferred analysis for the 50% or more PD‑L1 subgroup who need urgent clinical intervention. The ICER was below £50,00 per QALY gained. It noted it had not seen any direct or indirect evidence specifically for the 50% or more PD‑L1 subgroup who need urgent clinical intervention. It considered there was a high unmet need for this group because there is a lack of other treatment options available and because this group are likely to have a very short life expectancies. It considered the ICER was likely to be a cost-effective use of NHS resources, despite the lack of a robust evidence in the subgroup. For this reason, the committee concluded that pembrolizumab combination therapy is recommended for routine use in the NHS for people whose tumours have a PD‑L1 tumour proportion score of 50% or more and who need urgent clinical intervention.\n\n# Other factors\n\n## There are no equalities issues, and all relevant benefits are captured in the QALY\n\nAt consultation, the company highlighted that people with squamous NSCLC could have poorer outcomes because of smoking-related comorbidities. It suggested this was likely to have an impact on people in lower socioeconomic groups because rates of smoking are higher in these populations. The committee noted it had no evidence to suggest outcomes would differ for this group of people compared with people who had other cancers. The committee concluded there are no equalities issues and all relevant benefits of the technology were captured in the QALY."}
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https://www.nice.org.uk/guidance/ta770
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Evidence-based recommendations on pembrolizumab (Keytruda) with carboplatin and paclitaxel for adults with untreated metastatic squamous non-small-cell lung cancer.
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46feea5287119d0b27f9720ee56a9d632d92e6b7
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nice
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Microwave ablation for primary or metastatic cancer in the lung
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Microwave ablation for primary or metastatic cancer in the lung
Evidence-based recommendations on microwave ablation for primary or metastatic cancer in the lung in adults. This involves inserting a probe into the lung, through the skin of the chest, to send microwaves into the cancer cells. This produces heat, aiming to destroy the cancer (ablation).
# Recommendations
Evidence on the safety of microwave ablation for treating primary lung cancer and metastases in the lung is adequate but shows it can cause infrequent serious complications. Evidence on its efficacy shows it reduces tumour size. But the evidence on improvement in survival, long-term outcomes and quality of life is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Further research should be randomised controlled trials or disease registry studies. It should report patient selection, disease progression and quality of life, and take account of the effectiveness of managing oligometastatic disease in patients.
Clinicians who want to use microwave ablation to treat primary lung cancer and metastases in the lung should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Make sure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Make sure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.
Regularly review data on outcomes and safety for this procedure.
People with primary or metastatic lung cancer should be referred to an appropriately constituted multidisciplinary team.
The procedure should only be done in specialist centres by clinicians with specific training in this procedure.# The condition, current treatments and procedure
# The condition
Lung cancer is one of the most common types of cancer. The symptoms often do not appear until the disease is at an advanced stage, and the prognosis is generally poor. Cancer that begins in the lungs is called primary lung cancer. There are 2 main types of primary lung cancer: small-cell lung cancer (which is fast growing and can spread quickly) and non-small-cell lung cancer (which usually grows and spreads slowly; this includes squamous cell carcinoma, adenocarcinoma and large-cell carcinoma).
Cancer that starts in one part of the body and spreads via the blood stream to the lungs is known as secondary lung cancer (also called metastatic lung cancer or lung metastasis). Common tumours that metastasise to the lungs include breast cancer, colon cancer, prostate cancer, sarcoma, bladder cancer, neuroblastoma and Wilm's tumour.
# Current treatments
NICE's guideline on lung cancer describes the treatment of non-small-cell and small-cell lung cancer. The choice of treatment for primary or metastatic cancer in the lung depends on the type, size, position and stage of the cancer, and the patient's overall health. Common treatments for primary or metastatic cancer in the lung include surgery, chemotherapy, radiotherapy, or a combination of these. Other treatments include photodynamic therapy, thermal ablation, immunotherapy and biological therapy.
# The procedure
The procedure is usually done using general anaesthesia, and occasionally using local anaesthesia and sedation. Under imaging guidance, a small probe is advanced through the chest wall and into each targeted lesion. It delivers high-frequency microwave energy to rapidly agitate water molecules in the tissues. This converts energy into heat, which causes tumour necrosis. Patients with larger tumours or multiple lesions may have multiple pulses of energy delivered within a treatment session or have a staged treatment with multiple sessions.
This procedure aims to destroy tumour cells and create localised areas of tissue necrosis with minimal damage to surrounding normal tissues. Microwave ablation is a minimally invasive procedure. It usually lasts 1 to 2 hours with only 5 to 10 minutes of active ablation time.
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{'Recommendations': "Evidence on the safety of microwave ablation for treating primary lung cancer and metastases in the lung is adequate but shows it can cause infrequent serious complications. Evidence on its efficacy shows it reduces tumour size. But the evidence on improvement in survival, long-term outcomes and quality of life is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nFurther research should be randomised controlled trials or disease registry studies. It should report patient selection, disease progression and quality of life, and take account of the effectiveness of managing oligometastatic disease in patients.\n\nClinicians who want to use microwave ablation to treat primary lung cancer and metastases in the lung should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nMake sure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nMake sure systems are in place that support clinicians to collect and report data on outcomes and safety for everyone having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPeople with primary or metastatic lung cancer should be referred to an appropriately constituted multidisciplinary team.\n\nThe procedure should only be done in specialist centres by clinicians with specific training in this procedure.", 'The condition, current treatments and procedure': "# The condition\n\nLung cancer is one of the most common types of cancer. The symptoms often do not appear until the disease is at an advanced stage, and the prognosis is generally poor. Cancer that begins in the lungs is called primary lung cancer. There are 2 main types of primary lung cancer: small-cell lung cancer (which is fast growing and can spread quickly) and non-small-cell lung cancer (which usually grows and spreads slowly; this includes squamous cell carcinoma, adenocarcinoma and large-cell carcinoma).\n\nCancer that starts in one part of the body and spreads via the blood stream to the lungs is known as secondary lung cancer (also called metastatic lung cancer or lung metastasis). Common tumours that metastasise to the lungs include breast cancer, colon cancer, prostate cancer, sarcoma, bladder cancer, neuroblastoma and Wilm's tumour.\n\n# Current treatments\n\nNICE's guideline on lung cancer describes the treatment of non-small-cell and small-cell lung cancer. The choice of treatment for primary or metastatic cancer in the lung depends on the type, size, position and stage of the cancer, and the patient's overall health. Common treatments for primary or metastatic cancer in the lung include surgery, chemotherapy, radiotherapy, or a combination of these. Other treatments include photodynamic therapy, thermal ablation, immunotherapy and biological therapy.\n\n# The procedure\n\nThe procedure is usually done using general anaesthesia, and occasionally using local anaesthesia and sedation. Under imaging guidance, a small probe is advanced through the chest wall and into each targeted lesion. It delivers high-frequency microwave energy to rapidly agitate water molecules in the tissues. This converts energy into heat, which causes tumour necrosis. Patients with larger tumours or multiple lesions may have multiple pulses of energy delivered within a treatment session or have a staged treatment with multiple sessions.\n\nThis procedure aims to destroy tumour cells and create localised areas of tissue necrosis with minimal damage to surrounding normal tissues. Microwave ablation is a minimally invasive procedure. It usually lasts 1 to 2\xa0hours with only 5 to 10\xa0minutes of active ablation time."}
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https://www.nice.org.uk/guidance/ipg716
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Evidence-based recommendations on microwave ablation for primary or metastatic cancer in the lung in adults. This involves inserting a probe into the lung, through the skin of the chest, to send microwaves into the cancer cells. This produces heat, aiming to destroy the cancer (ablation).
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a485b6d6527e02c3716ed4f5b4298ef29027781d
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nice
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Palforzia for treating peanut allergy in children and young people
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Palforzia for treating peanut allergy in children and young people
Evidence-based recommendations on Palforzia for treating peanut allergy in children and young people.
# Recommendations
Palforzia is recommended, within its marketing authorisation, as an option for treating peanut allergy in children aged 4 to 17. It can be continued in people who turn 18 while on treatment. Palforzia should be used with a peanut-avoidant diet.
Why the committee made these recommendations
For people with peanut allergy, strictly avoiding peanuts and being ready to respond to an emergency are the main ways to protect against reactions to accidental exposure.
Clinical trial evidence shows that Palforzia improves tolerance to peanut protein compared with placebo when precise amounts are used in a food challenge test. And it is likely that Palforzia improves people's quality of life once they are having a stable dose. People are likely to need to take Palforzia or regularly include peanuts in their diet to maintain the tolerance they gained. It is uncertain how long people would continue treatment, but few are likely to need to continue Palforzia for the rest of their lives.
The most likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Also, additional benefits of Palforzia may not have been captured in the cost-effectiveness results. So, Palforzia is recommended.# Information about Palforzia
# Marketing authorisation indication
Palforzia is indicated 'for the treatment of patients aged 4 to 17 years with a confirmed diagnosis of peanut allergy. Palforzia may be continued in patients aged 18 years or older. Palforzia should be used in conjunction with a peanut-avoidant diet'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for palforzia.
# Price
The list price of Palforzia is £10.12 per day. A flat price is applied for each Palforzia dose (range 0.5 mg to 300 mg).# Committee discussion
The appraisal committee considered evidence submitted by Aimmune Therapeutics UK Ltd, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# Clinical need and treatment pathway
## Peanut allergy burdens patients and their carers
Peanut allergy is one of the most common food allergies in children, affecting between 0.5% and 2% of children in the UK. Severe reactions, notably anaphylaxis, can be life threatening, although deaths from peanut allergy-related anaphylaxis are very rare in the UK. Symptoms can have a rapid onset. They can include angioedema (facial swelling), respiratory symptoms (wheezing), conjunctivitis, oral allergy syndrome (lip or tongue swelling), rhinitis (blocked nose) and urticaria (blotchy red rash). It is not possible to predict the likelihood or severity of future allergic reactions based on previous reactions. Patient experts explained that peanut allergy affects 'all aspects of daily life' and 'can cause extreme anxiety' for children and young people with the allergy and their carers. It can have implications for shopping and preparing food, weaning infants, eating out, travelling, seasonal events, education, socialising and work. Parents may experience anxiety, in particular around the time their children start secondary school or leave home. The committee concluded that peanut allergy burdens patients and their carers.
## There is a need for preventive treatment options for peanut allergy
The goal of treatment for peanut allergy is preventive, that is, to reduce the frequency and severity of allergic reactions and improve quality of life, to lessen anxiety and to normalise activities of daily living. The main preventive strategy for peanut allergy is strictly avoiding peanuts and being ready to respond to an emergency. Symptomatic treatment of mild reactions to accidental peanut exposure includes antihistamines, whereas severe anaphylactic reactions need emergency treatment including self-administered adrenaline. Clinical experts explained that strictly avoiding peanuts cannot be considered the only option, and active preventive treatments are needed to reduce the risks of accidental peanut exposure. They noted that most accidental exposures involve less than 300 mg of peanut protein. Tolerating this amount, equivalent to roughly 1.5 peanuts, would give 'bite protection' from small accidental exposures to peanut and would be a 'meaningful outcome'. Tolerating 1,000 mg of peanut protein is considered to be 'highly clinically significant'. The committee concluded that clinicians and people affected by peanut allergy would welcome a treatment option that would reduce the risks of accidental peanut exposure and improve quality of life of children with peanut allergy and their carers.
## Lifetime treatment with Palforzia or regularly including peanuts in the diet is needed to maintain tolerance
Palforzia is an oral immunotherapy, consisting of peanut protein, as a defatted powder of Arachis hypogaea L. It is given through a 'structured dosing' approach, starting from a dose level as low as 0.5 mg, and gradually increasing. This allows people to build tolerance to peanut protein over time. Strict peanut avoidance and emergency preparedness continue during treatment. The experts explained that Palforzia allows for precise and reproducible dosing of 'minuscule amounts' of peanut protein, which is not possible with dietary peanut. However, according to the clinical experts, once people tolerate higher doses of peanut protein, they can start to include peanuts in their diet to maintain their tolerance instead of continuing treatment with Palforzia. This is not reflected in the marketing authorisation for Palforzia, which notes that daily maintenance is required to maintain the tolerance and clinical effects of Palforzia. Yet, it also states that no recommendation can be made about the duration of treatment beyond 24 months, and that the effect of stopping treatment on maintenance of clinical efficacy has not been evaluated. The clinical experts explained that people not regularly including peanuts in their diet after Palforzia treatment may lose tolerance and will need to return to strictly avoiding peanuts and being prepared for emergencies. They added that whether or not people keep peanuts in their diet after Palforzia treatment may be linked to taste aversion, motivation, adverse effects, restrictions around meals and exercise, and support received. The patient experts anticipated that people will be highly motivated to include peanuts in their diet after committing to Palforzia treatment, but noted that some may be averse to the taste of peanuts. Moreover, there may be psychological stress and anxiety associated with eating a food that people have diligently avoided and greatly feared for many years. The patient experts explained that people with peanut allergy and their carers may require additional psychological support during the transition. The committee concluded that people would need lifetime treatment with Palforzia or to regularly include peanuts in their diet to maintain tolerance to peanuts.
## Strict peanut avoidance is the most appropriate comparator
Palforzia is used 'in conjunction with a peanut-avoidant diet', in line with its marketing authorisation. The company selected strict peanut avoidance as the only comparator for Palforzia. The committee agreed, concluding that strict peanut avoidance was the most appropriate comparator for Palforzia.
# Clinical evidence
## An oral food challenge is clinically relevant and an appropriate surrogate end point
The committee recalled that 1 of the treatment goals is to reduce the risks associated with accidental peanut exposure (see section 3.2). Reactions to accidental exposures are uncommon, with 1 study suggesting an annual incidence of around 12%. Therefore, clinical trials use oral food challenges as a surrogate end point. In an oral food challenge, people are given increasing doses of precise amounts of peanut protein to assess their tolerance to the allergen. Their maximum tolerated dose, or 'tolerability threshold', is the highest dose tolerated with no more than mild symptoms. Having some tolerance to peanut protein can protect from risks of accidental exposure to peanut. The committee recalled that tolerating 1,000 mg peanut protein is considered clinically significant. The committee agreed that tolerance to peanut protein measured during oral food challenge is clinically relevant, and reflects an appropriate surrogate end point for assessing the efficacy of Palforzia.
## Palforzia was studied in 2 phase 3 trials that are generalisable to NHS practice
Palforzia was studied in 2 randomised controlled trials conducted in North America and Europe, including the UK. All people had peanut allergy confirmed by peanut-specific immunoglobulin E (IgE) reactivity and skin prick test. All participants had an entry food challenge at screening to select people who had dose-limiting symptoms to peanut protein at a dose of 100 mg or less in PALISADE, and 300 mg or less in ARTEMIS. PALISADE enrolled people aged 4 to 55 years (n=496), and ARTEMIS enrolled people aged 4 to 17 years (n=175). People were randomised to receive Palforzia while avoiding peanuts, or placebo while avoiding peanuts. Treatment with Palforzia was given in 3 phases:
An 'escalation phase', which consisted of 5 dose levels (0.5 mg to 6 mg), all given on day 1 of treatment.
An 'up-dosing phase', which had 11 dose levels lasting 2 weeks each (3 mg to 300 mg).
A 'maintenance phase', in which people received 300 mg once daily for 24 to 28 weeks in PALISADE and 12 weeks in ARTEMIS.Peanut desensitisation was measured in an exit food challenge at the end of maintenance treatment. The primary end point in ARTEMIS and PALISADE in Europe was the proportion of people who tolerated at least 1,000 mg peanut protein with no more than mild symptoms, whereas in PALISADE in North America, it was the proportion of people who tolerated at least 600 mg peanut protein. People completing maintenance treatment and tolerating at least 300 mg peanut protein in the food challenge could enrol in PALISADE follow-on, an open-label observational study, and continue the Palforzia maintenance dose for a further 28 to 56 weeks, after which there was an additional food challenge. The clinical experts explained that the baseline characteristics of people enrolled in PALISADE and ARTEMIS aligned with those of people with peanut allergy seen in NHS practice. They also explained that people in NHS practice would follow the same dosing schedule as in the trials. The committee concluded that PALISADE and ARTEMIS are generalisable to NHS practice.
## Palforzia improves tolerance to peanut protein compared with placebo
Compared with placebo, Palforzia increased the proportion of people who could tolerate at least 1,000 mg peanut protein. Among people aged 4 to 17 years, the proportion of people tolerating at least 1,000 mg peanut protein was:
% of people randomised to Palforzia versus 2.4% of people randomised to placebo in PALISADE (absolute treatment difference 48.7%; 95% confidence interval 38.0% to 57.7%; p<0.0001)
% versus 2.3% of people, respectively, in ARTEMIS (absolute treatment difference 56.0%; 95% confidence interval 44.1% to 65.2%; p<0.0001).These findings were supported by the key secondary outcomes of tolerating at least 600 mg or at least 300 mg peanut protein. The committee concluded that Palforzia improved tolerance to peanut protein in people aged 4 to 17 years with peanut allergy compared with placebo.
## There is no direct clinical trial evidence that Palforzia reduces the frequency and severity of reactions to accidental peanut exposure
The committee recalled that reactions to accidental peanut exposure are uncommon (see section 3.5). It noted that these reactions, including severe anaphylactic reactions needing treatment with adrenaline, infrequently occurred in the Palforzia trials. It also noted that there were no proven differences in this outcome between the Palforzia and placebo groups. The company considers the exact rates to be confidential so they cannot be reported here. The committee appreciated that avoiding anaphylaxis from accidental exposure to peanuts is a goal of treatment with Palforzia, but also that treatment with Palforzia increases the risk of anaphylactic reactions as an adverse event of treatment (see section 3.9). A clinical expert noted that although there is no direct evidence that Palforzia 'prevents anaphylaxis' following accidental exposure, there is evidence from clinical trials that the maximum severity of symptoms at the exit oral food challenge was lower with Palforzia than with placebo. The committee concluded that there is no direct clinical trial evidence that Palforzia reduces the frequency and severity of reactions to accidental peanut exposure.
## Palforzia may increase the risk of treatment-related anaphylactic reactions, but the risk of severe anaphylaxis is low
People who had Palforzia had more adverse events affecting the gastrointestinal tract, respiratory tract, skin, and immune system than those who received placebo. Severe or serious treatment-emergent adverse events were rare. The committee noted that mild and moderate anaphylactic reactions as an adverse event of treatment (not because of accidental peanut exposure) were more common with Palforzia than with placebo, but severe anaphylactic reactions were rare – only 1 patient in the Palforzia group and 2 patients in the placebo group had severe anaphylaxis in PALISADE, and none in ARTEMIS. In both trials, more people on Palforzia stopped treatment because of treatment-emergent adverse events than did people taking placebo. The committee concluded that Palforzia may increase the risk of treatment-related reactions, although the risk of severe anaphylaxis is low.
## The committee would prefer a meta-analysis, but this would not have a meaningful impact on the results
The company explained that it attempted a meta-analysis of Palforzia clinical trial data but did not consider it robust because of differences in study design between PALISADE and ARTEMIS. These differences included trial location (North America and Europe versus Europe only), age of participants (4 to 55 years versus 4 to 17 years), severity of peanut allergy (reactions to 100 mg or less versus 300 mg or less in the entry food challenge test), and duration of maintenance treatment (24 to 28 weeks versus 12 weeks). The ERG explained that despite these differences, the company could have done a network meta-analysis, a simple meta-analysis, or used individual participant data. The ERG also noted that the company did not consider a phase 2 study, the ARC001 trial. The company explained that it excluded this study because it had only 55 participants and was done solely in the US. The ERG accepted that including this study would not add much insight. The committee agreed with the ERG that despite differences between trials, there were several ways in which the company could have done a meta-analysis of trial data. It noted that meta-analysis would have allowed it to assess heterogeneity and uncertainty in the treatment effect. The committee concluded that it would have preferred to have seen the results of a meta-analysis, but accepted this would be unlikely to have any meaningful impact on the results presented.
# Cost-effectiveness evidence
## The company's economic model is suitable for decision making
The company used a Markov state transition model to estimate the cost effectiveness of Palforzia plus avoiding peanuts compared with avoiding peanuts only. The model structure had 5 phases: escalation, up‑dosing, maintenance, extension and extrapolation. After maintenance, health states were based on the amount of peanut protein tolerated in an oral food challenge. Simulated people who tolerated 300 mg or more peanut protein could also move to an 'include peanuts in diet' health state. From all health states, people could move to 'spontaneous tolerance' with the lifetime probability of 5%, or 'death' health states. The committee concluded that the model structure and health states were reasonable, and suitable for decision making.
## It is reasonable to assume no survival benefit from Palforzia
The model assumed that peanut allergy does not increase the risk of death compared with that of the general population. The company modelled the risk of death from UK life tables for the general population. The company assumed that Palforzia had no effect on the risk of dying. All gains in quality-adjusted life years (QALYs) were from improvements in quality of life for patients and their carers. The committee recalled that deaths from peanut allergy are very rare in the UK. However, the committee considered it possible that Palforzia could decrease that risk and noted that the assumption of no survival gain may be conservative (see section 3.22). The committee concluded that it is reasonable to assume no survival benefit of Palforzia in the model.
## The model does not reflect that in the NHS some people may need an oral food challenge before starting Palforzia
The company based its model on results from PALISADE; ARTEMIS was used in a scenario analysis. In PALISADE, everyone had an oral food challenge before they entered the trial to confirm they were sensitive to less than 100 mg peanut protein. However, the company and the ERG models excluded an oral food challenge before starting Palforzia. The committee noted that the company's trial results for people with confirmed severe peanut allergy may not apply to an unscreened NHS population, some of whom might have developed tolerance spontaneously, or be sensitive to higher doses of peanut protein than people in the trial. The British Society of Allergy and Clinical Immunology 'strongly recommended' doing a food challenge before starting Palforzia in the NHS to confirm whether a peanut allergy is still present, and to determine its severity. The clinical experts explained that re-testing for peanut allergy with a skin prick test and/or IgE testing already forms part of routine care to check for tolerance that sometimes develops spontaneously. It is also done to remind teenagers of their allergy – older children may not have experienced a reaction to peanuts since they were much younger and may not remember being allergic. The clinical experts noted that up to half of people may need a food challenge to determine whether treatment with Palforzia is suitable for them. They also noted that people with recent severe reactions to small amounts of peanut protein from accidental exposure would not need a food challenge. The committee acknowledged that the model did not include a food challenge before starting treatment with Palforzia. The committee concluded that the model does not reflect the likely need for oral food challenge before starting Palforzia in the NHS.
## The model does not reflect that most people would not need an oral food challenge after Palforzia treatment in NHS practice
The company and ERG models included a single oral food challenge for people taking Palforzia, at around 2 years, and none for people avoiding peanuts only. The clinical experts confirmed that people who avoid peanuts are not usually offered food challenges in NHS practice. They also confirmed that if a food challenge were needed after Palforzia, they would offer one only after 1 to 2 years of treatment. They explained that fewer than 20% of people would need a food challenge to determine tolerance after treatment with Palforzia. This is because taking maintenance doses of Palforzia is a de facto food challenge, and if people take 300 mg Palforzia every day, they will be able to tolerate the same amount of peanut protein. Therefore, most people could start including peanuts in their diets without the oral food challenge. The committee concluded that the model does not reflect that most people would not need an oral food challenge after Palforzia treatment in NHS practice.
## Few people are likely to continue treatment with Palforzia lifelong in NHS practice, and the model overestimates this
In the model, people who tolerate at least 300 mg peanut protein in the oral food challenge after approximately 2 years of treatment can:
stay on Palforzia lifelong and continue avoiding peanuts
start including peanuts in their diet permanently
start including peanuts in their diet, but then switch back to avoiding peanuts. The company estimated the likelihood of being in each of these 3 groups based on a consensus clinical opinion. The company considers these estimates confidential so they cannot be reported here. The ERG acknowledged that the company used reasonable methods to reach these estimates but highlighted that they are not evidence based and are uncertain. The patient experts explained that people who have committed to 2 years' treatment with Palforzia will be highly motivated to maintain tolerance, start dietary peanuts and adhere to a diet that includes peanuts. The clinical experts agreed that most people would be happy to start including peanuts in their diet, although some may then stop. The clinical experts explained that only people with borderline tolerance to 300 mg peanut protein may need to continue treatment with Palforzia. They expected this would be fewer than 5% of people who had completed maintenance treatment with Palforzia. The committee noted that this proportion was lower than the company assumed in its model. The committee concluded that fewer people than modelled are likely to continue treatment with Palforzia lifelong in NHS practice.
# Utility values
## The utility values for people with peanut allergy are uncertain
The company conducted a de novo utility study to estimate quality of life in children and young people with peanut allergy using the EQ‑5D‑Y (the youth EQ‑5D), and for their carers using EQ‑5D. The company pooled data from various sources and populations to obtain utility estimates, including:
-nline surveys completed by young people aged 12 to 17 with peanut allergy themselves ('self-reported utilities'); none of whom had prior treatment with Palforzia
-nline surveys completed by carers on behalf of their children aged 4 to 11 with peanut allergy ('proxy-reported utilities'); none of the children had prior treatment with Palforzia
interviews with carers reporting utilities on behalf of their children aged 4 to 11 with peanut allergy; none of the children had prior treatment with Palforzia
'Palforzia surveys': surveys among people who have had prior treatment with Palforzia, of which 2 were self-reported by young people aged 12 to 17, and 5 were proxy-reported by parents of children aged 4 to 11 with peanut allergy.The company pooled data from all these populations and sources (n=157) to inform its cost-effectiveness modelling. The ERG preferred to use only self-reported data from young people who had not had prior treatment with Palforzia (n=38). The ERG was concerned that carers may project some of the negative impact on their own quality of life when reporting proxy utility values for children. This risks double counting the negative impact on carers, because the company included carer disutility separately in its model (see section 3.17). Furthermore, the ERG explained that the company's survey among people who have had Palforzia, or their carers, may have been biased, because they might have not remembered what their (or their children's) quality of life was before or during the treatment. The committee noted the large difference between the utility values estimated by the company and the ERG. It agreed with the ERG that utility values from the Palforzia survey were not plausible. It also noted that the difference between the company and ERG approaches seemed to be driven mainly by differences in methods of data collection, rather than whether utilities were self- or proxy-reported. The committee agreed it was unclear which utility values better reflected quality of life of people with peanut allergy in NHS practice. The committee concluded that the utility values were uncertain and agreed to consider both the ERG-preferred approach and the pooled sample from all treatment-naive people, that is, excluding those from the Palforzia survey (n=150).
## The model adequately reflects utility values for carers of children with peanut allergy
The patient and clinical experts explained that carers often 'carry the mental load' of peanut allergy day to day. The model included carer disutility until people with peanut allergy reached 18 years of age. The utility values for carers were collected in the company's de novo utility study, using EQ‑5D (see section 3.16). The company assumed that on average, there was more than 1 carer per child (the company considers the exact number to be confidential so it cannot be reported here). The ERG agreed it was reasonable to include carer quality of life in the model, but highlighted that the number of carers per child is uncertain. The committee noted that the number of carers per child assumed by the company was in line with other technology appraisals that included carers' quality of life. The committee concluded that including carers' quality of life in the model is appropriate, and that the methods used by the company to capture this were acceptable.
## It is reasonable to assume the utility gains for children with peanut allergy and their carers can be realised without oral food challenge
The company and ERG assumed that treatment with Palforzia during escalation and up‑dosing has a negative impact on quality of life of children with peanut allergy and their carers. However, once people start maintenance treatment, there is a small gain in quality of life compared with baseline. Any further gains are then realised only after the oral food challenge, and are linked to the tolerance level reached, with higher benefit related to higher tolerance levels. The ERG explained this is because utility values associated with a change in tolerance level are realised only after the results of a food challenge become known. Both the ERG and company models also assumed that people who avoid peanuts but do not take Palforzia do not have any oral food challenge and therefore have no gains in quality of life. That is, the model assumed they have the same baseline quality of life throughout the model time horizon. The clinical experts explained that people on Palforzia could have quality-of-life benefits without an oral food challenge because they know they can tolerate a 300 mg dose of peanut protein, and can start including peanuts in their diet. The committee recalled that tolerating 300 mg peanut protein gives 'bite protection' (see section 3.2). It also recalled that taking maintenance doses of Palforzia is a de facto food challenge and people could start including peanuts in their diet after reaching tolerance to 300 mg peanut protein. The committee concluded that utility gains for children with peanut allergy and their carers related to Palforzia treatment can be realised without an oral food challenge.
# Costs
## The model should have included the costs related to setting up oral immunotherapy services in NHS food allergy clinics
The committee noted that treatment with Palforzia is resource intensive because patients must attend a clinic prepared to treat anaphylaxis for initial dose escalation and the first dose of each new up‑dosing level. The ERG confirmed that the company's model captures costs related to staff time and resources needed to deliver Palforzia during these clinic visits. The clinical experts explained that food allergy clinics are mainly run as diagnostic services; extending into delivering oral immunotherapy would demand additional investment, particularly in capacity and training of staff. The company confirmed that its model did not include costs related to the 'set up' needed to provide oral immunotherapy in food allergy clinics. The committee noted that NICE's guide to the methods of technology appraisal specifies that 'if introduction of the technology requires changes in infrastructure, costs or savings should be included in the analysis'. The committee concluded that the model should have included all costs related to setting up oral immunotherapy treatment in NHS practice.
## The costs of reactions to accidental peanut exposure and treatment-related adverse events are adequately captured in the model
The ERG's and company's final models included all treatment-related adverse events that could affect costs or benefits of Palforzia. Both assumed that an ambulance and accident and emergency visit may be needed for all anaphylactic reactions regardless of their severity or cause – that is, whether caused by Palforzia or accidental exposure to peanuts. The clinical experts agreed that all patients with anaphylaxis should receive the same care, regardless of cause. The committee concluded that the company and ERG captured the costs of reactions to accidental peanut exposure and treatment-related adverse events in their models.
# Cost-effectiveness estimates
## Palforzia is a cost-effective use of NHS resources
The committee noted that company and ERG base-case models differed only in their approach to estimating utility values (see section 3.16). In a deterministic pairwise analysis, the company base-case incremental cost-effectiveness ratio (ICER) was £23,745 per QALY gained compared with avoiding peanuts only. The ERG deterministic base case was £36,565 per QALY gained. Corresponding probabilistic ICERs were £25,940 and £39,716 per QALY gained, respectively, compared with avoiding peanuts only. However, the committee noted that neither the ERG nor company base cases fully captured its preferences that:
up to 50% of people may need an oral food challenge before starting Palforzia in NHS practice to confirm peanut allergy (see section 3.13)
fewer than 20% of people would need an oral food challenge after Palforzia treatment to determine if they can start introducing peanuts into the diet, instead of continuing Palforzia (see section 3.14)
fewer than 5% of people would be expected to continue treatment with Palforzia lifelong in NHS practice (see section 3.15)
utility values for people with peanut allergy are highly uncertain; therefore, both the ERG-preferred utilities from only adolescent self-reported, treatment-naive sample (n=38) and pooled utilities from all people naive to treatment (n=150) should be considered (see section 3.16)
Palforzia can have a positive impact on quality of life of people with peanut allergy and their carers without an oral food challenge (see section 3.18)
all costs related to setting up oral immunotherapy treatment in NHS practice should be included (see section 3.19).The committee therefore considered a number of scenario analyses done by the ERG. It noted that assuming a food challenge before starting treatment with Palforzia had a minimal impact on the ERG base-case ICER, increasing it to £37,059 per QALY gained. Although it did not see a scenario assuming lower use of oral food challenge after treatment with Palforzia, it agreed it would also be likely to have a minimal impact on the ICERs. The committee noted that the choice of utility values and the proportion of people continuing treatment lifelong had the biggest impact on the cost-effectiveness estimates. Using utility values from the 150 treatment-naive people in the sample decreased the ERG base-case ICER to £27,735 per QALY gained. Assuming nobody continues Palforzia lifelong decreased the ERG base-case ICER to below £20,000 per QALY gained. The committee noted it did not see any scenario analyses assuming 5% people would continue Palforzia lifelong, but agreed that ICERs would slightly increase compared with scenarios assuming nobody continues Palforzia lifelong. When using utilities from the full sample of 150 treatment-naive people, the ICERs would be lower than £20,000 per QALY gained. The committee therefore agreed that the most plausible ICERs, when excluding the costs of setting up oral immunotherapy treatment in NHS practice, would be around £20,000 per QALY gained. The committee further noted it did not see any scenario analyses including all costs related to setting up oral immunotherapy treatment in NHS practice, in line with its preferred assumptions, and that it may be difficult to estimate the impact on the cost-effectiveness estimates. However, the committee agreed there may be some benefits of Palforzia not captured in the company and ERG models (see section 3.22). It also recalled that peanut allergy is a burden for children and their carers (see section 3.1). Therefore, the committee concluded that Palforzia is likely to be a cost-effective use of NHS resources, and therefore recommended it for routine NHS use.
# Innovation and equality
## Palforzia is innovative and may have some benefits that are not adequately captured in the model
The committee agreed with the clinical experts and the company that Palforzia is a 'potential step change' in treating peanut allergy and as such is innovative. It further noted some potential benefits that may not have been captured in the modelling:
The company's model assumed no survival benefit from Palforzia (see section 3.12), so if even 1 death from anaphylaxis is prevented by Palforzia, this would be an additional benefit for people with peanut allergy and the NHS.
Even if people do not continue to benefit from treatment for their whole life, for example if they return to avoiding peanuts later in life, they may still have benefited from treatment and peanut tolerance during important years as a young adult, when they are growing up, gaining independence and travelling.The committee concluded that Palforzia is innovative and may have some benefits that were not adequately captured in the model, and took this into account in its decision making.
## There are no equalities issues that can be addressed in the guidance
The committee recalled that Palforzia has a marketing authorisation for treatment of peanut allergy in people aged 4 to 17 and those who turned 18 while on treatment (see section 2.1). This means most adults with peanut allergy will have no access to treatment. However, the committee noted that its remit only allows it to appraise a technology within its marketing authorisation.
The committee recalled that treatment with Palforzia is resource intensive because patients must attend a clinic prepared to treat anaphylaxis for initial dose escalation and the first dose of each new up‑dosing level, in line with its marketing authorisation (see section 3.19). The patient and clinical experts explained that there may be unequal access to specialist allergy clinics in England because of geographic location or socioeconomic status. The committee considered these issues but noted they are related to implementing guidance in NHS practice and therefore outside of its remit. The committee concluded there are no equalities issues that can be addressed in the guidance.
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{'Recommendations': "Palforzia is recommended, within its marketing authorisation, as an option for treating peanut allergy in children aged 4\xa0to\xa017. It can be continued in people who turn\xa018 while on treatment. Palforzia should be used with a peanut-avoidant diet.\n\nWhy the committee made these recommendations\n\nFor people with peanut allergy, strictly avoiding peanuts and being ready to respond to an emergency are the main ways to protect against reactions to accidental exposure.\n\nClinical trial evidence shows that Palforzia improves tolerance to peanut protein compared with placebo when precise amounts are used in a food challenge test. And it is likely that Palforzia improves people's quality of life once they are having a stable dose. People are likely to need to take Palforzia or regularly include peanuts in their diet to maintain the tolerance they gained. It is uncertain how long people would continue treatment, but few are likely to need to continue Palforzia for the rest of their lives.\n\nThe most likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Also, additional benefits of Palforzia may not have been captured in the cost-effectiveness results. So, Palforzia is recommended.", 'Information about Palforzia': "# Marketing authorisation indication\n\nPalforzia is indicated 'for the treatment of patients aged 4\xa0to\xa017\xa0years with a confirmed diagnosis of peanut allergy. Palforzia may be continued in patients aged 18\xa0years or older. Palforzia should be used in conjunction with a peanut-avoidant diet'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for palforzia.\n\n# Price\n\nThe list price of Palforzia is £10.12 per day. A flat price is applied for each Palforzia dose (range 0.5\xa0mg to 300\xa0mg).", 'Committee discussion': "The appraisal committee considered evidence submitted by Aimmune Therapeutics UK Ltd, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical need and treatment pathway\n\n## Peanut allergy burdens patients and their carers\n\nPeanut allergy is one of the most common food allergies in children, affecting between 0.5% and 2% of children in the UK. Severe reactions, notably anaphylaxis, can be life threatening, although deaths from peanut allergy-related anaphylaxis are very rare in the UK. Symptoms can have a rapid onset. They can include angioedema (facial swelling), respiratory symptoms (wheezing), conjunctivitis, oral allergy syndrome (lip or tongue swelling), rhinitis (blocked nose) and urticaria (blotchy red rash). It is not possible to predict the likelihood or severity of future allergic reactions based on previous reactions. Patient experts explained that peanut allergy affects 'all aspects of daily life' and 'can cause extreme anxiety' for children and young people with the allergy and their carers. It can have implications for shopping and preparing food, weaning infants, eating out, travelling, seasonal events, education, socialising and work. Parents may experience anxiety, in particular around the time their children start secondary school or leave home. The committee concluded that peanut allergy burdens patients and their carers.\n\n## There is a need for preventive treatment options for peanut allergy\n\nThe goal of treatment for peanut allergy is preventive, that is, to reduce the frequency and severity of allergic reactions and improve quality of life, to lessen anxiety and to normalise activities of daily living. The main preventive strategy for peanut allergy is strictly avoiding peanuts and being ready to respond to an emergency. Symptomatic treatment of mild reactions to accidental peanut exposure includes antihistamines, whereas severe anaphylactic reactions need emergency treatment including self-administered adrenaline. Clinical experts explained that strictly avoiding peanuts cannot be considered the only option, and active preventive treatments are needed to reduce the risks of accidental peanut exposure. They noted that most accidental exposures involve less than 300\xa0mg of peanut protein. Tolerating this amount, equivalent to roughly 1.5\xa0peanuts, would give 'bite protection' from small accidental exposures to peanut and would be a 'meaningful outcome'. Tolerating 1,000\xa0mg of peanut protein is considered to be 'highly clinically significant'. The committee concluded that clinicians and people affected by peanut allergy would welcome a treatment option that would reduce the risks of accidental peanut exposure and improve quality of life of children with peanut allergy and their carers.\n\n## Lifetime treatment with Palforzia or regularly including peanuts in the diet is needed to maintain tolerance\n\nPalforzia is an oral immunotherapy, consisting of peanut protein, as a defatted powder of Arachis hypogaea\xa0L. It is given through a 'structured dosing' approach, starting from a dose level as low as 0.5\xa0mg, and gradually increasing. This allows people to build tolerance to peanut protein over time. Strict peanut avoidance and emergency preparedness continue during treatment. The experts explained that Palforzia allows for precise and reproducible dosing of 'minuscule amounts' of peanut protein, which is not possible with dietary peanut. However, according to the clinical experts, once people tolerate higher doses of peanut protein, they can start to include peanuts in their diet to maintain their tolerance instead of continuing treatment with Palforzia. This is not reflected in the marketing authorisation for Palforzia, which notes that daily maintenance is required to maintain the tolerance and clinical effects of Palforzia. Yet, it also states that no recommendation can be made about the duration of treatment beyond 24\xa0months, and that the effect of stopping treatment on maintenance of clinical efficacy has not been evaluated. The clinical experts explained that people not regularly including peanuts in their diet after Palforzia treatment may lose tolerance and will need to return to strictly avoiding peanuts and being prepared for emergencies. They added that whether or not people keep peanuts in their diet after Palforzia treatment may be linked to taste aversion, motivation, adverse effects, restrictions around meals and exercise, and support received. The patient experts anticipated that people will be highly motivated to include peanuts in their diet after committing to Palforzia treatment, but noted that some may be averse to the taste of peanuts. Moreover, there may be psychological stress and anxiety associated with eating a food that people have diligently avoided and greatly feared for many years. The patient experts explained that people with peanut allergy and their carers may require additional psychological support during the transition. The committee concluded that people would need lifetime treatment with Palforzia or to regularly include peanuts in their diet to maintain tolerance to peanuts.\n\n## Strict peanut avoidance is the most appropriate comparator\n\nPalforzia is used 'in conjunction with a peanut-avoidant diet', in line with its marketing authorisation. The company selected strict peanut avoidance as the only comparator for Palforzia. The committee agreed, concluding that strict peanut avoidance was the most appropriate comparator for Palforzia.\n\n# Clinical evidence\n\n## An oral food challenge is clinically relevant and an appropriate surrogate end point\n\nThe committee recalled that 1\xa0of the treatment goals is to reduce the risks associated with accidental peanut exposure (see section\xa03.2). Reactions to accidental exposures are uncommon, with 1\xa0study suggesting an annual incidence of around 12%. Therefore, clinical trials use oral food challenges as a surrogate end point. In an oral food challenge, people are given increasing doses of precise amounts of peanut protein to assess their tolerance to the allergen. Their maximum tolerated dose, or 'tolerability threshold', is the highest dose tolerated with no more than mild symptoms. Having some tolerance to peanut protein can protect from risks of accidental exposure to peanut. The committee recalled that tolerating 1,000\xa0mg peanut protein is considered clinically significant. The committee agreed that tolerance to peanut protein measured during oral food challenge is clinically relevant, and reflects an appropriate surrogate end point for assessing the efficacy of Palforzia.\n\n## Palforzia was studied in 2 phase\xa03 trials that are generalisable to NHS practice\n\nPalforzia was studied in 2\xa0randomised controlled trials conducted in North America and Europe, including the UK. All people had peanut allergy confirmed by peanut-specific immunoglobulin\xa0E (IgE) reactivity and skin prick test. All participants had an entry food challenge at screening to select people who had dose-limiting symptoms to peanut protein at a dose of 100\xa0mg or less in PALISADE, and 300\xa0mg or less in ARTEMIS. PALISADE enrolled people aged 4\xa0to\xa055\xa0years (n=496), and ARTEMIS enrolled people aged 4\xa0to\xa017\xa0years (n=175). People were randomised to receive Palforzia while avoiding peanuts, or placebo while avoiding peanuts. Treatment with Palforzia was given in 3\xa0phases:\n\nAn 'escalation phase', which consisted of 5\xa0dose levels (0.5\xa0mg to 6\xa0mg), all given on day\xa01 of treatment.\n\nAn 'up-dosing phase', which had 11\xa0dose levels lasting 2\xa0weeks each (3\xa0mg to 300\xa0mg).\n\nA 'maintenance phase', in which people received 300\xa0mg once daily for 24\xa0to 28\xa0weeks in PALISADE and 12\xa0weeks in ARTEMIS.Peanut desensitisation was measured in an exit food challenge at the end of maintenance treatment. The primary end point in ARTEMIS and PALISADE in Europe was the proportion of people who tolerated at least 1,000\xa0mg peanut protein with no more than mild symptoms, whereas in PALISADE in North America, it was the proportion of people who tolerated at least 600\xa0mg peanut protein. People completing maintenance treatment and tolerating at least 300\xa0mg peanut protein in the food challenge could enrol in PALISADE follow-on, an open-label observational study, and continue the Palforzia maintenance dose for a further 28\xa0to 56\xa0weeks, after which there was an additional food challenge. The clinical experts explained that the baseline characteristics of people enrolled in PALISADE and ARTEMIS aligned with those of people with peanut allergy seen in NHS practice. They also explained that people in NHS practice would follow the same dosing schedule as in the trials. The committee concluded that PALISADE and ARTEMIS are generalisable to NHS practice.\n\n## Palforzia improves tolerance to peanut protein compared with placebo\n\nCompared with placebo, Palforzia increased the proportion of people who could tolerate at least 1,000\xa0mg peanut protein. Among people aged 4\xa0to\xa017\xa0years, the proportion of people tolerating at least 1,000\xa0mg peanut protein was:\n\n% of people randomised to Palforzia versus 2.4% of people randomised to placebo in PALISADE (absolute treatment difference 48.7%; 95% confidence interval 38.0% to 57.7%; p<0.0001)\n\n% versus 2.3% of people, respectively, in ARTEMIS (absolute treatment difference 56.0%; 95% confidence interval 44.1% to 65.2%; p<0.0001).These findings were supported by the key secondary outcomes of tolerating at least 600\xa0mg or at least 300\xa0mg peanut protein. The committee concluded that Palforzia improved tolerance to peanut protein in people aged 4\xa0to\xa017\xa0years with peanut allergy compared with placebo.\n\n## There is no direct clinical trial evidence that Palforzia reduces the frequency and severity of reactions to accidental peanut exposure\n\nThe committee recalled that reactions to accidental peanut exposure are uncommon (see section\xa03.5). It noted that these reactions, including severe anaphylactic reactions needing treatment with adrenaline, infrequently occurred in the Palforzia trials. It also noted that there were no proven differences in this outcome between the Palforzia and placebo groups. The company considers the exact rates to be confidential so they cannot be reported here. The committee appreciated that avoiding anaphylaxis from accidental exposure to peanuts is a goal of treatment with Palforzia, but also that treatment with Palforzia increases the risk of anaphylactic reactions as an adverse event of treatment (see section\xa03.9). A clinical expert noted that although there is no direct evidence that Palforzia 'prevents anaphylaxis' following accidental exposure, there is evidence from clinical trials that the maximum severity of symptoms at the exit oral food challenge was lower with Palforzia than with placebo. The committee concluded that there is no direct clinical trial evidence that Palforzia reduces the frequency and severity of reactions to accidental peanut exposure.\n\n## Palforzia may increase the risk of treatment-related anaphylactic reactions, but the risk of severe anaphylaxis is low\n\nPeople who had Palforzia had more adverse events affecting the gastrointestinal tract, respiratory tract, skin, and immune system than those who received placebo. Severe or serious treatment-emergent adverse events were rare. The committee noted that mild and moderate anaphylactic reactions as an adverse event of treatment (not because of accidental peanut exposure) were more common with Palforzia than with placebo, but severe anaphylactic reactions were rare – only 1\xa0patient in the Palforzia group and 2\xa0patients in the placebo group had severe anaphylaxis in PALISADE, and none in ARTEMIS. In both trials, more people on Palforzia stopped treatment because of treatment-emergent adverse events than did people taking placebo. The committee concluded that Palforzia may increase the risk of treatment-related reactions, although the risk of severe anaphylaxis is low.\n\n## The committee would prefer a meta-analysis, but this would not have a meaningful impact on the results\n\nThe company explained that it attempted a meta-analysis of Palforzia clinical trial data but did not consider it robust because of differences in study design between PALISADE and ARTEMIS. These differences included trial location (North America and Europe versus Europe only), age of participants (4\xa0to 55\xa0years versus 4\xa0to\xa017\xa0years), severity of peanut allergy (reactions to 100\xa0mg or less versus 300\xa0mg or less in the entry food challenge test), and duration of maintenance treatment (24\xa0to 28\xa0weeks versus 12\xa0weeks). The ERG explained that despite these differences, the company could have done a network meta-analysis, a simple meta-analysis, or used individual participant data. The ERG also noted that the company did not consider a phase\xa02 study, the ARC001 trial. The company explained that it excluded this study because it had only 55\xa0participants and was done solely in the US. The ERG accepted that including this study would not add much insight. The committee agreed with the ERG that despite differences between trials, there were several ways in which the company could have done a meta-analysis of trial data. It noted that meta-analysis would have allowed it to assess heterogeneity and uncertainty in the treatment effect. The committee concluded that it would have preferred to have seen the results of a meta-analysis, but accepted this would be unlikely to have any meaningful impact on the results presented.\n\n# Cost-effectiveness evidence\n\n## The company's economic model is suitable for decision making\n\nThe company used a Markov state transition model to estimate the cost effectiveness of Palforzia plus avoiding peanuts compared with avoiding peanuts only. The model structure had 5\xa0phases: escalation, up‑dosing, maintenance, extension and extrapolation. After maintenance, health states were based on the amount of peanut protein tolerated in an oral food challenge. Simulated people who tolerated 300\xa0mg or more peanut protein could also move to an 'include peanuts in diet' health state. From all health states, people could move to 'spontaneous tolerance' with the lifetime probability of 5%, or 'death' health states. The committee concluded that the model structure and health states were reasonable, and suitable for decision making.\n\n## It is reasonable to assume no survival benefit from Palforzia\n\nThe model assumed that peanut allergy does not increase the risk of death compared with that of the general population. The company modelled the risk of death from UK life tables for the general population. The company assumed that Palforzia had no effect on the risk of dying. All gains in quality-adjusted life years (QALYs) were from improvements in quality of life for patients and their carers. The committee recalled that deaths from peanut allergy are very rare in the UK. However, the committee considered it possible that Palforzia could decrease that risk and noted that the assumption of no survival gain may be conservative (see section\xa03.22). The committee concluded that it is reasonable to assume no survival benefit of Palforzia in the model.\n\n## The model does not reflect that in the NHS some people may need an oral food challenge before starting Palforzia\n\nThe company based its model on results from PALISADE; ARTEMIS was used in a scenario analysis. In PALISADE, everyone had an oral food challenge before they entered the trial to confirm they were sensitive to less than 100\xa0mg peanut protein. However, the company and the ERG models excluded an oral food challenge before starting Palforzia. The committee noted that the company's trial results for people with confirmed severe peanut allergy may not apply to an unscreened NHS population, some of whom might have developed tolerance spontaneously, or be sensitive to higher doses of peanut protein than people in the trial. The British Society of Allergy and Clinical Immunology 'strongly recommended' doing a food challenge before starting Palforzia in the NHS to confirm whether a peanut allergy is still present, and to determine its severity. The clinical experts explained that re-testing for peanut allergy with a skin prick test and/or IgE testing already forms part of routine care to check for tolerance that sometimes develops spontaneously. It is also done to remind teenagers of their allergy – older children may not have experienced a reaction to peanuts since they were much younger and may not remember being allergic. The clinical experts noted that up to half of people may need a food challenge to determine whether treatment with Palforzia is suitable for them. They also noted that people with recent severe reactions to small amounts of peanut protein from accidental exposure would not need a food challenge. The committee acknowledged that the model did not include a food challenge before starting treatment with Palforzia. The committee concluded that the model does not reflect the likely need for oral food challenge before starting Palforzia in the NHS.\n\n## The model does not reflect that most people would not need an oral food challenge after Palforzia treatment in NHS practice\n\nThe company and ERG models included a single oral food challenge for people taking Palforzia, at around 2\xa0years, and none for people avoiding peanuts only. The clinical experts confirmed that people who avoid peanuts are not usually offered food challenges in NHS practice. They also confirmed that if a food challenge were needed after Palforzia, they would offer one only after 1\xa0to 2\xa0years of treatment. They explained that fewer than 20% of people would need a food challenge to determine tolerance after treatment with Palforzia. This is because taking maintenance doses of Palforzia is a de facto food challenge, and if people take 300\xa0mg Palforzia every day, they will be able to tolerate the same amount of peanut protein. Therefore, most people could start including peanuts in their diets without the oral food challenge. The committee concluded that the model does not reflect that most people would not need an oral food challenge after Palforzia treatment in NHS practice.\n\n## Few people are likely to continue treatment with Palforzia lifelong in NHS practice, and the model overestimates this\n\nIn the model, people who tolerate at least 300\xa0mg peanut protein in the oral food challenge after approximately 2\xa0years of treatment can:\n\nstay on Palforzia lifelong and continue avoiding peanuts\n\nstart including peanuts in their diet permanently\n\nstart including peanuts in their diet, but then switch back to avoiding peanuts. The company estimated the likelihood of being in each of these 3\xa0groups based on a consensus clinical opinion. The company considers these estimates confidential so they cannot be reported here. The ERG acknowledged that the company used reasonable methods to reach these estimates but highlighted that they are not evidence based and are uncertain. The patient experts explained that people who have committed to 2\xa0years' treatment with Palforzia will be highly motivated to maintain tolerance, start dietary peanuts and adhere to a diet that includes peanuts. The clinical experts agreed that most people would be happy to start including peanuts in their diet, although some may then stop. The clinical experts explained that only people with borderline tolerance to 300\xa0mg peanut protein may need to continue treatment with Palforzia. They expected this would be fewer than 5% of people who had completed maintenance treatment with Palforzia. The committee noted that this proportion was lower than the company assumed in its model. The committee concluded that fewer people than modelled are likely to continue treatment with Palforzia lifelong in NHS practice.\n\n# Utility values\n\n## The utility values for people with peanut allergy are uncertain\n\nThe company conducted a de novo utility study to estimate quality of life in children and young people with peanut allergy using the EQ‑5D‑Y (the youth EQ‑5D), and for their carers using EQ‑5D. The company pooled data from various sources and populations to obtain utility estimates, including:\n\nonline surveys completed by young people aged 12\xa0to\xa017 with peanut allergy themselves ('self-reported utilities'); none of whom had prior treatment with Palforzia\n\nonline surveys completed by carers on behalf of their children aged 4\xa0to\xa011 with peanut allergy ('proxy-reported utilities'); none of the children had prior treatment with Palforzia\n\ninterviews with carers reporting utilities on behalf of their children aged 4\xa0to\xa011 with peanut allergy; none of the children had prior treatment with Palforzia\n\n'Palforzia surveys': surveys among people who have had prior treatment with Palforzia, of which 2\xa0were self-reported by young people aged 12\xa0to\xa017, and 5\xa0were proxy-reported by parents of children aged 4\xa0to\xa011 with peanut allergy.The company pooled data from all these populations and sources (n=157) to inform its cost-effectiveness modelling. The ERG preferred to use only self-reported data from young people who had not had prior treatment with Palforzia (n=38). The ERG was concerned that carers may project some of the negative impact on their own quality of life when reporting proxy utility values for children. This risks double counting the negative impact on carers, because the company included carer disutility separately in its model (see section\xa03.17). Furthermore, the ERG explained that the company's survey among people who have had Palforzia, or their carers, may have been biased, because they might have not remembered what their (or their children's) quality of life was before or during the treatment. The committee noted the large difference between the utility values estimated by the company and the ERG. It agreed with the ERG that utility values from the Palforzia survey were not plausible. It also noted that the difference between the company and ERG approaches seemed to be driven mainly by differences in methods of data collection, rather than whether utilities were self- or proxy-reported. The committee agreed it was unclear which utility values better reflected quality of life of people with peanut allergy in NHS practice. The committee concluded that the utility values were uncertain and agreed to consider both the ERG-preferred approach and the pooled sample from all treatment-naive people, that is, excluding those from the Palforzia survey (n=150).\n\n## The model adequately reflects utility values for carers of children with peanut allergy\n\nThe patient and clinical experts explained that carers often 'carry the mental load' of peanut allergy day to day. The model included carer disutility until people with peanut allergy reached 18\xa0years of age. The utility values for carers were collected in the company's de novo utility study, using EQ‑5D (see section\xa03.16). The company assumed that on average, there was more than 1\xa0carer per child (the company considers the exact number to be confidential so it cannot be reported here). The ERG agreed it was reasonable to include carer quality of life in the model, but highlighted that the number of carers per child is uncertain. The committee noted that the number of carers per child assumed by the company was in line with other technology appraisals that included carers' quality of life. The committee concluded that including carers' quality of life in the model is appropriate, and that the methods used by the company to capture this were acceptable.\n\n## It is reasonable to assume the utility gains for children with peanut allergy and their carers can be realised without oral food challenge\n\nThe company and ERG assumed that treatment with Palforzia during escalation and up‑dosing has a negative impact on quality of life of children with peanut allergy and their carers. However, once people start maintenance treatment, there is a small gain in quality of life compared with baseline. Any further gains are then realised only after the oral food challenge, and are linked to the tolerance level reached, with higher benefit related to higher tolerance levels. The ERG explained this is because utility values associated with a change in tolerance level are realised only after the results of a food challenge become known. Both the ERG and company models also assumed that people who avoid peanuts but do not take Palforzia do not have any oral food challenge and therefore have no gains in quality of life. That is, the model assumed they have the same baseline quality of life throughout the model time horizon. The clinical experts explained that people on Palforzia could have quality-of-life benefits without an oral food challenge because they know they can tolerate a 300\xa0mg dose of peanut protein, and can start including peanuts in their diet. The committee recalled that tolerating 300\xa0mg peanut protein gives 'bite protection' (see section\xa03.2). It also recalled that taking maintenance doses of Palforzia is a de facto food challenge and people could start including peanuts in their diet after reaching tolerance to 300\xa0mg peanut protein. The committee concluded that utility gains for children with peanut allergy and their carers related to Palforzia treatment can be realised without an oral food challenge.\n\n# Costs\n\n## The model should have included the costs related to setting up oral immunotherapy services in NHS food allergy clinics\n\nThe committee noted that treatment with Palforzia is resource intensive because patients must attend a clinic prepared to treat anaphylaxis for initial dose escalation and the first dose of each new up‑dosing level. The ERG confirmed that the company's model captures costs related to staff time and resources needed to deliver Palforzia during these clinic visits. The clinical experts explained that food allergy clinics are mainly run as diagnostic services; extending into delivering oral immunotherapy would demand additional investment, particularly in capacity and training of staff. The company confirmed that its model did not include costs related to the 'set up' needed to provide oral immunotherapy in food allergy clinics. The committee noted that NICE's guide to the methods of technology appraisal specifies that 'if introduction of the technology requires changes in infrastructure, costs or savings should be included in the analysis'. The committee concluded that the model should have included all costs related to setting up oral immunotherapy treatment in NHS practice.\n\n## The costs of reactions to accidental peanut exposure and treatment-related adverse events are adequately captured in the model\n\nThe ERG's and company's final models included all treatment-related adverse events that could affect costs or benefits of Palforzia. Both assumed that an ambulance and accident and emergency visit may be needed for all anaphylactic reactions regardless of their severity or cause – that is, whether caused by Palforzia or accidental exposure to peanuts. The clinical experts agreed that all patients with anaphylaxis should receive the same care, regardless of cause. The committee concluded that the company and ERG captured the costs of reactions to accidental peanut exposure and treatment-related adverse events in their models.\n\n# Cost-effectiveness estimates\n\n## Palforzia is a cost-effective use of NHS resources\n\nThe committee noted that company and ERG base-case models differed only in their approach to estimating utility values (see section\xa03.16). In a deterministic pairwise analysis, the company base-case incremental cost-effectiveness ratio (ICER) was £23,745 per QALY gained compared with avoiding peanuts only. The ERG deterministic base case was £36,565 per QALY gained. Corresponding probabilistic ICERs were £25,940 and £39,716 per QALY gained, respectively, compared with avoiding peanuts only. However, the committee noted that neither the ERG nor company base cases fully captured its preferences that:\n\nup to 50% of people may need an oral food challenge before starting Palforzia in NHS practice to confirm peanut allergy (see section\xa03.13)\n\nfewer than 20% of people would need an oral food challenge after Palforzia treatment to determine if they can start introducing peanuts into the diet, instead of continuing Palforzia (see section\xa03.14)\n\nfewer than 5% of people would be expected to continue treatment with Palforzia lifelong in NHS practice (see section\xa03.15)\n\nutility values for people with peanut allergy are highly uncertain; therefore, both the ERG-preferred utilities from only adolescent self-reported, treatment-naive sample (n=38) and pooled utilities from all people naive to treatment (n=150) should be considered (see section\xa03.16)\n\nPalforzia can have a positive impact on quality of life of people with peanut allergy and their carers without an oral food challenge (see section\xa03.18)\n\nall costs related to setting up oral immunotherapy treatment in NHS practice should be included (see section\xa03.19).The committee therefore considered a number of scenario analyses done by the ERG. It noted that assuming a food challenge before starting treatment with Palforzia had a minimal impact on the ERG base-case ICER, increasing it to £37,059 per QALY gained. Although it did not see a scenario assuming lower use of oral food challenge after treatment with Palforzia, it agreed it would also be likely to have a minimal impact on the ICERs. The committee noted that the choice of utility values and the proportion of people continuing treatment lifelong had the biggest impact on the cost-effectiveness estimates. Using utility values from the 150\xa0treatment-naive people in the sample decreased the ERG base-case ICER to £27,735 per QALY gained. Assuming nobody continues Palforzia lifelong decreased the ERG base-case ICER to below £20,000 per QALY gained. The committee noted it did not see any scenario analyses assuming 5% people would continue Palforzia lifelong, but agreed that ICERs would slightly increase compared with scenarios assuming nobody continues Palforzia lifelong. When using utilities from the full sample of 150\xa0treatment-naive people, the ICERs would be lower than £20,000 per QALY gained. The committee therefore agreed that the most plausible ICERs, when excluding the costs of setting up oral immunotherapy treatment in NHS practice, would be around £20,000 per QALY gained. The committee further noted it did not see any scenario analyses including all costs related to setting up oral immunotherapy treatment in NHS practice, in line with its preferred assumptions, and that it may be difficult to estimate the impact on the cost-effectiveness estimates. However, the committee agreed there may be some benefits of Palforzia not captured in the company and ERG models (see section\xa03.22). It also recalled that peanut allergy is a burden for children and their carers (see section\xa03.1). Therefore, the committee concluded that Palforzia is likely to be a cost-effective use of NHS resources, and therefore recommended it for routine NHS use.\n\n# Innovation and equality\n\n## Palforzia is innovative and may have some benefits that are not adequately captured in the model\n\nThe committee agreed with the clinical experts and the company that Palforzia is a 'potential step change' in treating peanut allergy and as such is innovative. It further noted some potential benefits that may not have been captured in the modelling:\n\nThe company's model assumed no survival benefit from Palforzia (see section\xa03.12), so if even 1\xa0death from anaphylaxis is prevented by Palforzia, this would be an additional benefit for people with peanut allergy and the NHS.\n\nEven if people do not continue to benefit from treatment for their whole life, for example if they return to avoiding peanuts later in life, they may still have benefited from treatment and peanut tolerance during important years as a young adult, when they are growing up, gaining independence and travelling.The committee concluded that Palforzia is innovative and may have some benefits that were not adequately captured in the model, and took this into account in its decision making.\n\n## There are no equalities issues that can be addressed in the guidance\n\nThe committee recalled that Palforzia has a marketing authorisation for treatment of peanut allergy in people aged 4\xa0to\xa017 and those who turned\xa018 while on treatment (see section\xa02.1). This means most adults with peanut allergy will have no access to treatment. However, the committee noted that its remit only allows it to appraise a technology within its marketing authorisation.\n\nThe committee recalled that treatment with Palforzia is resource intensive because patients must attend a clinic prepared to treat anaphylaxis for initial dose escalation and the first dose of each new up‑dosing level, in line with its marketing authorisation (see section\xa03.19). The patient and clinical experts explained that there may be unequal access to specialist allergy clinics in England because of geographic location or socioeconomic status. The committee considered these issues but noted they are related to implementing guidance in NHS practice and therefore outside of its remit. The committee concluded there are no equalities issues that can be addressed in the guidance."}
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https://www.nice.org.uk/guidance/ta769
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Evidence-based recommendations on Palforzia for treating peanut allergy in children and young people.
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e479fd46e25618016145d61a617bf0921ad3e7d3
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nice
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Daratumumab in combination for untreated multiple myeloma when a stem cell transplant is suitable
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Daratumumab in combination for untreated multiple myeloma when a stem cell transplant is suitable
Evidence-based recommendations on daratumumab (Darzalex) with bortezomib, thalidomide and dexamethasone for untreated multiple myeloma when a stem cell transplant is suitable.
# Recommendations
Daratumumab plus bortezomib, thalidomide and dexamethasone is recommended, within its marketing authorisation, as induction and consolidation treatment for untreated multiple myeloma in adults, when an autologous stem cell transplant is suitable. It is recommended only if the company provides daratumumab according to the commercial arrangement.
Why the committee made these recommendations
Before having an autologous stem cell transplant, most people with untreated multiple myeloma have bortezomib plus thalidomide and dexamethasone as the first treatment. This appraisal looks at adding daratumumab to bortezomib plus thalidomide and dexamethasone (daratumumab in combination) before transplant (induction) and for a short time after transplant (consolidation).
Clinical trial results show that, compared with bortezomib plus thalidomide and dexamethasone, daratumumab in combination increases how long people live and extends the time before the condition worsens.
The cost-effectiveness estimates are within what NICE considers acceptable. So, daratumumab in combination is recommended.# Information about daratumumab
# Marketing authorisation indication
Daratumumab (Darzalex, Janssen–Cilag) in combination with bortezomib, thalidomide and dexamethasone, is indicated 'for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for daratumumab.
# Price
The list price for daratumumab is £4,320 per 1,800‑mg vial of solution for injection intended for fixed-dose subcutaneous administration (excluding VAT; BNF online, accessed November 2021). It is also available as a concentrate for solution for intravenous infusion with a list price of £360 per 100‑mg vial, and £1,440 per 400‑mg vial (excluding VAT; BNF online, accessed November 2021). The company has a commercial arrangement. This makes daratumumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.
The list price for bortezomib is £762.38 per 3.5‑mg vial (excluding VAT; BNF online, accessed November 2021). There is a discount for bortezomib agreed with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.
The list price for thalidomide is £298.48 per 28‑pack of 50 mg capsules (excluding VAT; BNF online, accessed November 2021).
There is a nationally available discount for dexamethasone with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.# Committee discussion
The appraisal committee met 3 times to consider evidence submitted by Janssen–Cilag, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage that preceded the first committee meeting:
the uncertainty in the hazard ratios from the company's meta-analysis on the relationship between minimal residual disease status and survival outcomes (issue 1, see ERG report, page 14)
the most appropriate definition of minimal residual disease negativity (issue 2, see ERG report, page 15)
the most plausible extrapolations of long-term survival for people having bortezomib plus thalidomide and dexamethasone (issue 4, see ERG report, page 17)
the uncertainty around the treatment effect of daratumumab plus bortezomib, thalidomide and dexamethasone (daratumumab in combination) on progression-free survival and overall survival, based on the company's landmark analysis (issue 5, see ERG report, page 18)
how long the treatment effect of daratumumab in combination lasts (issue 6, see ERG report, page 19).
The committee also considered that maintenance with lenalidomide should be included as a subsequent treatment in the modelling.
# New treatment option
## People with untreated multiple myeloma would welcome a new option for first-line treatment
Patient experts explained that multiple myeloma is a relapsing and remitting disease and can include severe symptoms. The first remission is often the 'best' remission because people are at their fittest. With each line of treatment, some people stop treatment because they become too ill or have complications. Therefore, the patient experts believed that the most effective treatments should be given as early as possible in the treatment pathway. Patients need new treatment options that improve response and offer a longer remission, as well as limit or delay complications associated with multiple myeloma. The patient experts noted that more people having daratumumab in combination have no minimal residual disease (a measure of residual tumour cells in bone marrow) than those having other treatments. This signifies a deep response. They considered that daratumumab in combination is well tolerated. The committee concluded that people with untreated multiple myeloma would welcome well-tolerated new treatment options that give a longer period of remission and improve survival.
# Treatment pathway
## When an autologous stem cell transplant is suitable, people usually have induction treatment followed by high-dose chemotherapy before transplant
Around 1 in 3 people newly diagnosed with multiple myeloma in the UK will be eligible for an autologous stem cell transplant. For this population, first-line treatment consists of induction treatment to stabilise the disease, high-dose chemotherapy (usually melphalan) followed by an autologous stem cell transplant to deepen response and prolong progression-free survival. Consolidation treatment, which also aims to improve depth of response and involves offering the treatment used at induction again for a short period, is not standard NHS practice. NICE recommend lenalidomide as maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma in adults, with the aim of increasing the length of remission. After relapse, people will progress onto subsequent lines of treatment. The committee concluded that when an autologous stem cell transplant is suitable, people will usually have induction treatment followed by high-dose chemotherapy before their transplant.
## Bortezomib plus thalidomide and dexamethasone is the most relevant comparator reflecting NHS practice, and has similar efficacy and costs to bortezomib plus cyclophosphamide and dexamethasone
The committee was aware that the NICE scope included the following 4 comparators to reflect NHS practice: bortezomib plus dexamethasone; bortezomib plus dexamethasone and thalidomide; bortezomib plus cyclophosphamide and dexamethasone; and cyclophosphamide plus thalidomide and dexamethasone. The committee understood that the company had included only bortezomib plus dexamethasone and thalidomide as a comparator in its original economic model, but had added bortezomib plus dexamethasone in response to consultation after the first committee meeting. Clinical experts advised that when an autologous stem cell transplant is suitable, most people with untreated multiple myeloma would have an induction (first treatment) regimen of bortezomib plus thalidomide and dexamethasone. When thalidomide is not tolerated or is contraindicated, clinicians usually offer bortezomib plus dexamethasone and cyclophosphamide. Cyclophosphamide plus thalidomide and dexamethasone is rarely offered. The clinical experts noted that bortezomib plus thalidomide and dexamethasone has comparable efficacy to bortezomib plus cyclophosphamide and dexamethasone. They explained that both 'triple regimens' (3 drugs) induce a deeper response than the 'double regimen' (2 drugs) of bortezomib plus dexamethasone. The clinical experts explained that they may offer bortezomib plus dexamethasone to patients who do not tolerate a triple regimen, but these patients would be unlikely to be offered an autologous stem cell transplant. Consequently, bortezomib plus dexamethasone is rarely offered to people for whom a stem cell transplant would be suitable, a requirement of this appraisal. The committee understood that the company did not include bortezomib plus cyclophosphamide and dexamethasone as a comparator in its economic model. The company discussed that its rationale for not including bortezomib plus cyclophosphamide and dexamethasone was because they thought it had similar efficacy and costs to bortezomib plus thalidomide and dexamethasone. The committee considered that there was uncertainty in the company's matching-adjusted indirect comparison comparing bortezomib plus cyclophosphamide and dexamethasone to bortezomib plus thalidomide and dexamethasone (see section 3.11). The committee concluded that bortezomib plus thalidomide and dexamethasone was the most relevant comparator, with similar efficacy and costs to bortezomib plus cyclophosphamide and dexamethasone.
## Consolidation treatment including daratumumab can be incorporated into NHS practice
Consolidation treatment follows induction treatment and autologous stem cell transplant and is not standard NHS practice (see section 3.2) but was included in the company's clinical trial (see section 3.6). Specifically, treatment with daratumumab in combination involved 4 cycles of induction treatment followed by high-dose chemotherapy, followed by an autologous stem cell transplant, and then 2 cycles of consolidation treatment. The marketing authorisation reflects using the treatment before and after transplant, but the clinical experts reiterated that it was not standard clinical practice in the NHS. Instead, 6 rather than 4 cycles of induction treatment are usually offered before transplant, and none after transplant. The clinical experts stated they would be keen to offer consolidation if the evidence supported it. They considered that consolidation could be incorporated into NHS practice and implemented with few challenges. The committee concluded that consolidation treatment with daratumumab in combination could be incorporated into NHS practice.
## Maintenance with lenalidomide is widely used in clinical practice, and should be incorporated into the economic model
In its original submission, the company's economic model did not include maintenance treatment with lenalidomide after an autologous stem cell transplant. This was because at the time of the company's submission, NICE was still appraising lenalidomide maintenance and it was not standard clinical practice. However, after NICE's technology appraisal guidance on lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma, the clinical experts explained that lenalidomide maintenance is now widely used in practice and this was likely to increase further. The clinical experts noted that there is no clinical evidence evaluating the efficacy of lenalidomide maintenance after daratumumab in combination. They noted that clinical trials separately test induction and maintenance regimens. The committee acknowledged that the lack of clinical evidence exploring using lenalidomide maintenance after daratumumab in combination made incorporating it into the model challenging, but not impossible. It concluded that the model should reflect NHS practice and include both costs and benefits of lenalidomide maintenance.
## Adding daratumumab to bortezomib plus thalidomide and dexamethasone improves progression-free and overall survival
The CASSIOPEIA trial provides the clinical evidence for daratumumab in combination for untreated multiple myeloma when an autologous stem cell transplant is suitable. This was a phase 3, open-label, randomised trial based in 111 European sites. Patients included 1,085 adults aged up to 65 with untreated multiple myeloma eligible for an autologous stem cell transplant randomised 1:1 to either daratumumab in combination (experimental arm) or bortezomib plus thalidomide and dexamethasone (control arm). The protocol stipulated that people in both arms have 4 cycles of induction treatment with the above regimens, followed by an autologous stem cell transplant and a further 2 cycles of consolidation treatment. The primary outcome was the proportion of people with a stringent complete disease response within 100 days after an autologous stem cell transplant. The committee was aware that the company chose not to model this primary outcome in its cost-effectiveness analyses (see section 3.12). Secondary outcomes included overall survival, progression-free survival, and the proportion of patients without minimal residual disease. At the primary data cut (and final analysis for the primary outcome) after a median follow up of 18.8 months, 28.9% of patients in the experimental arm and 20.3% of patients in the control arm had a stringent complete response after consolidation (odds ratio 1.60, 95% confidence interval 1.21 to 2.12). The company also presented survival results from 2 later data cuts with a median follow up of 29.2 months and 44.5 months, respectively. At the earlier of the 2 data cuts, the hazard ratios for progression-free survival and overall survival were 0.50 (95% CI 0.38 to 0.65) and 0.52 (95% CI 0.33 to 0.85), respectively, favouring the experimental arm. The company submitted the results of the latest data cut as confidential.
CASSIOPEIA also has an ongoing second part, in which people whose disease at least partially responded after consolidation are eligible to take part. These people are re-randomised to maintenance treatment either with daratumumab monotherapy or observation until disease progression. However, maintenance treatment with daratumumab monotherapy is not currently included in the marketing authorisation and does not represent NHS practice. The committee recognised that the CASSIOPEIA results do not reflect NHS practice. The company adjusted the results of progression-free survival and overall survival from CASSIOPEIA for people switching to maintenance treatment with daratumumab monotherapy using a pre-specified inverse probability weighting method, which produced similar results to the unadjusted analysis. The committee concluded that adding daratumumab to bortezomib plus thalidomide and dexamethasone improved progression-free survival and overall survival.
## The inverse probability of censoring weighting (IPCW)-adjusted landmark analysis is appropriate to adjust for daratumumab monotherapy
The company presented a landmark analysis to explore the relationship between minimal residual disease status and survival. Minimal residual disease negativity in the bone marrow (determined by bone marrow aspiration) was assessed at 2 timepoints in CASSIOPEIA. The first was after patients completed induction treatment, and the second after they completed consolidation treatment (around 100 days after an autologous stem cell transplant). The company used only the data from people alive at the post-consolidation assessment (the 'landmark' timepoint). It split the data by a patient's minimal residual disease status (negative or positive), and for each group calculated hazard ratios for progression-free survival and overall survival for people having daratumumab in combination compared with those having bortezomib plus thalidomide and dexamethasone. Taking these calculated hazard ratios for people with and without minimal residual disease, the company then used them to extrapolate long-term progression-free and overall survival in the economic model (see section 3.12). At technical engagement before the committee's first meeting, the company updated the landmark analysis using the latest data cut from CASSIOPEIA, but could not use inverse probability weighting to adjust the results of the updated landmark analysis for re-randomising patients to daratumumab maintenance (which would not happen in practice; see section 3.6). The company justified this, noting that the landmark analysis was not pre-specified in the trial protocol and that it could not yet access the individual patient data from the second part of CASSIOPEIA because the trial was still blinded. Instead, the company adjusted the landmark analysis by censoring the data from all people re-randomised to daratumumab maintenance. The results of this censored analysis showed that adding daratumumab to bortezomib plus thalidomide and dexamethasone improved progression-free survival and overall survival, independent of minimal residual disease status. The ERG noted that the results of the landmark analysis were inconsistent with those from the intention-to-treat (ITT) data adjusted using inverse probability weighting. The ERG considered that this was likely because of bias introduced by the company's censoring approach. The committee agreed that the results of the landmark analysis may be biased because of informative censoring. However, it deemed that the direction of the bias was unclear and affected both treatment arms. After the first committee meeting, the company accessed the individual patient data it needed to adjust the results of its landmark analysis for re-randomisation to daratumumab maintenance using an inverse probability of censoring weighting (IPCW) approach. The results of the IPCW-adjusted landmark analysis were broadly comparable with the censoring-adjusted landmark analysis for progression-free survival. However, the hazard ratio improved slightly for overall survival for daratumumab in combination compared with bortezomib plus thalidomide and dexamethasone for people with minimal residual disease and worsened for people without minimal residual disease. The ERG commented that although it could not validate the analysis, the IPCW-adjusted landmark analysis appeared reasonable. At the third committee meeting, the company explained that it considered residual confounding unlikely because people in phase 2 of the trial were re-randomised before having maintenance treatment or observation. The committee concluded that the company's IPCW-adjusted landmark analysis is likely to be less biased than the censoring-adjusted landmark analysis and more appropriate for decision making.
## Minimal residual disease negativity is likely to predict survival outcomes better than stringent complete response
The committee was aware that the company extrapolated progression-free survival and overall survival in its economic model based on the presence (positivity) or absence (negativity) of minimal residual disease at the landmark timepoint (see section 3.8). The clinical experts stated that, although minimal residual disease is not routinely measured in clinical practice and does not guide treatment choices, minimal residual disease negativity compared with minimal residual disease positivity is associated with better progression-free survival and overall survival. The committee queried why the company chose to split the patients in the model by minimal residual disease (a secondary outcome in CASSIOPEIA) rather than stringent complete response (the primary outcome in CASSIOPEIA). The company explained that when it designed CASSIOPEIA, stringent complete response was considered by the oncology community to be the most informative outcome. However, according to the company, minimal residual disease is now considered better than stringent complete response in assessing depth of response. The company acknowledged that minimal residual disease status was yet to be accepted by regulators as a primary outcome in multiple myeloma trials. The ERG agreed that having no minimal residual disease is likely to predict survival outcomes better than a stringent complete response. The committee was aware that in NICE's technology appraisal guidance on daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma, the committee had concluded that the relationship between minimal residual disease and long-term overall survival was not well established and could not inform the economic model. However, it understood that there was now greater clinical support for the link between minimal residual disease negativity and survival outcomes. The committee would have preferred to see further evidence to support the company's assertion that minimal residual disease status better predicts progression-free survival and overall survival than does stringent complete response. Based on the clinical experts' input, the committee concluded that in the company's approach to modelling long-term survival (see section 3.12), it was reasonable to split patients into those with and without minimal residual disease.
# Adverse events
## The adverse event profile of daratumumab in combination is acceptable
The company considered that overall, the adverse event profile of treatments was similar between groups in CASSIOPEIA. However, the committee noted the higher frequency of nausea, neutropenia, thrombocytopenia, lymphopenia and cough reported in the experimental arm. According to the company, the increased rate of neutropenia in people having daratumumab in combination was not associated with an increased risk of neutropenic fever. The company noted that, at a median follow up of 18.8 months, infusion-related reactions of any grade associated with daratumumab in combination happened in around 35% of patients. The adverse events were manageable, with a frequency of severe (grade 3 or 4) events (3.5%), rates of stopping treatment (0.6%) and no fatal events. The company added that it anticipated that the subcutaneous formulation of daratumumab would have a lower incidence of infusion-related reactions. The clinical experts noted that overall, daratumumab has limited and manageable adverse effects. The committee concluded that the adverse event profile of daratumumab in combination was acceptable.
# Indirect comparisons
## Results of the company's matching-adjusted indirect comparisons are uncertain
There are no trials directly comparing daratumumab in combination with bortezomib plus dexamethasone, with or without cyclophosphamide. Therefore, the company did matching-adjusted indirect comparisons and used these to estimate the relative effectiveness of the 2 regimens. The company also estimated the relative effectiveness of bortezomib plus thalidomide and dexamethasone, compared with bortezomib plus dexamethasone, with or without cyclophosphamide. For bortezomib plus cyclophosphamide and dexamethasone, the company used data from GMMG‑MM5, a randomised trial comparing this regimen with doxorubicin plus dexamethasone. For bortezomib plus dexamethasone, the company used data from IFM 2005‑01, a randomised trial comparing this regimen with vincristine plus doxorubicin and dexamethasone. The company adjusted the patient-level data from CASSIOPEIA to match the study-level baseline patient characteristics from GMMG‑MM5 and IFM 2005‑01. The comparisons were unanchored because there was no common comparator between the studies. The company did not use the results of the indirect comparisons to inform the economic model directly, but rather to support the omission of some comparators from the model (see section 3.3). The ERG could not verify that the company had correctly implemented the matching-adjusted indirect comparisons, nor check the results because the company did not provide the ERG with individual patient data from CASSIOPEIA. The ERG added that it would have preferred to see a scenario analysis using a simulated treatment comparison. The committee understood that for the comparison with bortezomib plus cyclophosphamide and dexamethasone, the sample size was smaller, and that adjusting for more covariates would further reduce the effective sample size. The committee also noted that comparing bortezomib plus thalidomide and dexamethasone with bortezomib plus cyclophosphamide and dexamethasone generated wide confidence intervals. It concluded that there was uncertainty around whether the indirect comparisons supported the clinical experts' opinion on the relative efficacy of the different comparators (see section 3.3).
# The company's economic model
## The company's approach to modelling long-term survival, using a landmark analysis, is acceptable for decision making
The company presented a partitioned survival model comprising 3 health states (pre-progression, progressive disease and death) to estimate the cost effectiveness of daratumumab in combination compared with bortezomib plus thalidomide and dexamethasone. The company developed survival models to predict survival beyond the end of the CASSIOPEIA trial over a lifetime time horizon. It explored a conventional approach of fitting parametric models to the ITT (whole trial population) data from CASSIOPEIA but considered the predicted overall survival varied widely by the different distributions. In its original submission, the company chose not to provide cost-effectiveness results based on these analyses because it believed that they would have been very uncertain. Instead, the company used the Kaplan–Meier curves from CASSIOPEIA up to the landmark timepoint (see section 3.8). The company split the people still alive at this timepoint into those with and without minimal residual disease. It then took a 5‑step approach to modelling long-term progression-free survival and overall survival:
Step 1: For people with minimal residual disease who had bortezomib plus thalidomide and dexamethasone, the company fitted separate parametric distributions to the post-landmark data from CASSIOPEIA to model progression-free survival and overall survival (see section 3.15).
Step 2: The company did a meta-analysis to estimate the relationship between minimal residual disease and survival for people for whom a stem cell transplant is suitable and who have standard care (see section 3.13). From this, it calculated 2 hazard ratios. The first reflected the association between minimal residual disease status and overall survival, and the second the association between minimal residual disease status and progression-free survival.
Step 3: The company applied the hazard ratios from step 2 to the parametric curves for people with minimal residual disease who had bortezomib plus thalidomide and dexamethasone (from step 1), to calculate progression-free survival and overall survival curves for people without minimal residual disease having the same treatment.
Step 4: The company applied the hazard ratios from the landmark analysis (see section 3.8) to the survival curves for people having bortezomib plus thalidomide and dexamethasone (from steps 1 and 3) to calculate the curves for people having daratumumab in combination, split by minimal residual disease status.
Step 5: Finally, the company weighted the survival curves for all patients in each arm split by minimal residual disease status based on the proportion of people with and without minimal residual disease at the landmark timepoint.The ERG agreed with the company that the overall survival data from CASSIOPEIA was too immature for parametric distributions fitted to the ITT data to be robust. In the first meeting, the committee noted the uncertainties associated with the different elements of the company's approach; these included the choice of extrapolations for people with minimal residual disease who had bortezomib plus thalidomide and dexamethasone (see section 3.15), and the results of the meta-analysis (see section 3.13) and landmark analysis (see section 3.8). In its first meeting, the committee was unsure if the company's approach to the long-term survival modelling reduced the uncertainty. It would have preferred that a scenario be provided using a conventional approach of fitting models directly to the ITT data from CASSIOPEIA. In response to consultation, the company updated its economic model to include a scenario with standard parametric models fitted directly to the IPCW-adjusted ITT data from the first part of CASSIOPEIA. The company selected a Weibull model for progression-free survival and overall survival for both treatment arms. The committee considered that both of the company's approaches to survival modelling had uncertainty, but noted that the cost-effectiveness results were similar between the 2. It concluded that the company's original approach of using a landmark analysis split by minimal residual disease status was acceptable to model long-term survival.
## The meta-analysis on the relationship between minimal residual disease status and survival is uncertain, but minimally affects results
To inform the survival curves for people without minimal residual disease having bortezomib plus thalidomide and dexamethasone, the company did a meta-analysis exploring the relationship between minimal residual disease and survival for people having any treatment representing standard care. The results showed improved progression-free survival and overall survival in people without minimal residual disease compared with those with minimal residual disease. The company modelled this using hazard ratios, which needed the proportional hazards assumption (that is, that the relative risk of an event was fixed irrespective of time) to be met. The ERG considered that there was some uncertainty with the hazard ratios from the meta-analysis. This was because the included studies differed with respect to baseline International Staging System scores (which signify prognosis), as well as the treatments representing standard care. The ERG also observed that the assessments of progression-free survival and overall survival started at different timepoints across the studies. However, the company commented that no events were reported across the studies before the start of assessment, so this should not have affected the results. The committee was uncertain if the effect of minimal residual disease on survival outcomes would stay constant over time, as was needed for the proportional hazard's assumption. However, it understood that the hazard ratios for people with and without minimal residual disease were not a key driver of the cost-effectiveness results.
## It is likely people without residual disease would have a complete response over time and the company's definition of minimal residual disease is appropriate
The ERG found that the definition of minimal residual disease varied across the studies the company included in its meta-analysis. Some studies included the criteria of the International Myeloma Working Group (IMWG), which states people must have a conventional complete disease response. However, in CASSIOPEIA, minimal residual disease was assessed regardless of conventional complete response. The ERG noted that there were more people without minimal residual disease in CASSIOPEIA than there were with a conventional complete disease response. At technical engagement, the company updated its meta-analysis to include only studies in which minimal residual disease had been defined regardless of conventional complete response. This had broadly similar results to the company's original meta-analysis. The ERG would have preferred that the company also provide a scenario in which it applied a consistent definition of minimal residual disease according to the IMWG criteria (that is, needing a conventional complete response). The ERG noted that in CASSIOPEIA, the absolute rates of minimal residual disease negativity were much lower when using the IMWG definition. This would affect the survival extrapolations in the model, and change the weight attributed to the curves for people with and without minimal residual disease in each treatment arm. The committee noted that a scenario provided by the ERG with post-consolidation minimal residual negativity rates defined according to the IMWG definition considerably impacted the cost-effectiveness results. The clinical experts explained that all people without minimal residual disease would eventually have a conventional complete response but agreed that there was sometimes a delay between the 2 outcomes. The committee accepted that people without minimal residual disease would have a conventional complete response over time, and that the definition used in the company's economic model (regardless of conventional complete response) was likely to be appropriate.
# Modelling survival
## Modelled survival for people who have bortezomib plus thalidomide and dexamethasone should be based on IPCW-adjusted landmark analyses
The company extrapolated progression-free survival and overall survival for people with minimal residual disease who have bortezomib plus thalidomide and dexamethasone using parametric distributions fitted to the post-landmark data from CASSIOPEIA. The company used this patient group because it had the highest number of events and therefore the most mature data. The committee discussed if limiting the analysis to people who had survived to the landmark time would bias the results, but the company explained that very few patients in CASSIOPEIA had died before this point. The company adjusted the extrapolations of survival to account for people switching to maintenance with daratumumab monotherapy in CASSIOPEIA using a censoring approach and an IPCW approach (see section 3.8). In the model presented at the first committee meeting, the company fitted the parametric distributions to the censoring-adjusted landmark analysis data. However, the ERG was concerned that the censoring of people re-randomised to maintenance with daratumumab monotherapy would bias the overall survival results (see section 3.8). This was because people who had maintenance treatment in CASSIOPEIA had to have disease with at least a partial response after consolidation, and therefore a better prognosis. The committee agreed with the ERG that the company's censoring approach would likely underestimate survival for patients having bortezomib plus thalidomide and dexamethasone. In response to consultation, the company provided a revised base-case analysis that used the data from the updated IPCW-adjusted landmark analysis (see section 3.8). In its revised base case, the company extrapolated survival for people with minimal residual disease having bortezomib plus thalidomide and dexamethasone using a Gompertz distribution for progression-free survival and an exponential distribution for overall survival. The company considered that its revised analysis likely overestimated overall survival for people having bortezomib plus thalidomide and dexamethasone. It suggested that this was because people in CASSIOPEIA had consolidation treatment, which was not currently part of NHS practice (see section 3.4). Consolidation treatment could have produced a deeper response than induction treatment alone, and therefore longer survival. The ERG considered that the extrapolations used by the company in its revised base case reasonably fit the CASSIOPEIA trial data. However, the ERG agreed with the company that the predictions of overall survival exceeded those from clinical experts. The ERG suggested that this could be because of the nature of the population and interventions in the trial, and the use of a constant hazard ratio to estimate overall survival for people without minimal residual disease. The committee recalled that the company's revised IPCW-adjusted landmark analysis was likely less subject to bias than the censoring-adjusted landmark analysis (see section 3.8). The committee also appreciated in its third meeting that the re-randomisation in the CASSIOPEIA trial would minimise residual confounding in adjusted analyses because of the randomisation. It concluded that survival for people having bortezomib plus thalidomide and dexamethasone should be modelled using curves fitted to the IPCW-adjusted data from the landmark analysis.
## The estimate of long-term survival for people who have bortezomib plus thalidomide and dexamethasone reflects clinical practice
At the third committee meeting, the company reiterated its belief that the model overestimates survival for people who have bortezomib plus thalidomide and dexamethasone so any cost-effectiveness results underestimate cost effectiveness. The company noted that the revised base case now included lenalidomide maintenance (see section 3.5) and that the predicted survival rate at 5 years in the model exceeded that seen in the Myeloma XI trial. The ERG explained that validating modelled extrapolations with clinical opinion and data from external sources does not entirely resolve uncertainty. The committee considered the results from: the company's revised base case, CASSIOPEIA, the GIMEMA study and Myeloma XI. It noted that the differences between the survival estimates in the company's revised base case and those seen in the Myeloma XI trial were relatively small. The committee concluded that estimates for long-term survival for people who have bortezomib plus thalidomide and dexamethasone are likely to reflect clinical practice.
## The duration of the treatment effect for daratumumab in combination is unknown, but it is reasonable to assume it will be maintained long term
Treatment effect waning refers to if the relative treatment effect of daratumumab is likely to reduce over time after people stop taking it. The company's original base case included a lifetime treatment effect with daratumumab. The company believed that there was no evidence to suggest if, or when, the treatment effect of daratumumab would wane over time. It noted that the latest data cut from CASSIOPEIA, with a median follow up of almost 4 years, continued to show a relative benefit for daratumumab. The company presented evidence that people who have daratumumab have deeper responses, which is associated with improved survival outcomes. The company presented evidence from the GIMEMA‑MMY‑3006 trial, which investigated the efficacy of bortezomib plus dexamethasone compared with bortezomib plus dexamethasone and thalidomide in people with previously untreated symptomatic and measurable myeloma. The company explained that the results support maintaining a treatment effect driven by deeper responses. Clinical experts explained that they expect a similar effect for daratumumab in combination. The ERG noted that there was limited evidence to support a lifetime treatment effect with daratumumab in combination, and that the company's assumption was optimistic. It presented scenarios where the treatment effect lasted only 5 years, and a scenario where the treatment effect declined between 5 and 10 years and stopped at 10 years. The ERG modelled this by setting the disease progression and mortality rates of daratumumab in combination as equal to that of bortezomib plus dexamethasone and thalidomide from the set timepoint, for example, 5 years, onwards. The committee understood that including a treatment effect that wanes in the model considerably affects the cost-effectiveness results. At the first committee meeting, the committee agreed that it was reasonable to consider scenarios in which the treatment effect declined between 5 and 10 years. In response to consultation, the company presented scenarios for treatment waning but continued to assume a lifetime treatment effect for daratumumab in combination in its base case. At the second committee meeting, the clinical lead for the Cancer Drugs Fund noted that results from CASSIOPEIA part 2 suggested the effect of adding daratumumab to bortezomib plus thalidomide and dexamethasone had not waned. The committee considered the possibility that because people have first-line daratumumab in combination for a fixed, short-treatment duration, its treatment effect may be less likely to wane than if they had it for longer. This is because the entire benefit of first-line daratumumab in combination would have been delivered, followed by high-dose chemotherapy, and there would be no opportunity for a gradual loss of effect over time. At the third committee meeting, the company presented a revised base case that assumed a lifetime treatment effect for daratumumab in combination but included treatment waning for subsequent lenalidomide maintenance therapy (as per the preferred assumptions from NICE's technology appraisal guidance on lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma; see section 3.5). The company reiterated that the long-term outcomes for people who had daratumumab in combination were driven by a deeper post-consolidation response and not a conventional treatment effect. The ERG explained that the model structure 'hard wires' a treatment effect and that the evidence from CASSIOPEIA for additional survival benefits within the minimal residual disease groups are uncertain with wide confidence intervals. The clinical lead for the Cancer Drugs Fund explained that having daratumumab in combination could deliver a long or even lifetime treatment effect. He explained that people who have daratumumab in combination are more likely to achieve minimal residual disease negative status after induction and that evidence suggests these people are likely to experience better long-term outcomes after chemotherapy and autologous stem cell transplant. The committee acknowledged that it was clinically plausible that people who had daratumumab in combination would have a different natural history of disease after treatment, but recalled the uncertainty around the additional survival benefits within the minimal residual disease groups. The committee considered that the scenarios exploring treatment waning showed different survival outcomes for people who had daratumumab in combination and which showed the range of possible cost-effectiveness estimates. However, the committee concluded that, based on the evidence presented to it, it was reasonable to assume that the effect of deepening a response would be maintained over a lifetime for daratumumab in combination.
# Lenalidomide maintenance
## Previous treatment with daratumumab in combination is likely to extend maintenance therapy with lenalidomide and extend survival
The committee requested that the company include lenalidomide maintenance treatment after consolidation with or without daratumumab in the company's economic modelling (see section 3.5). At the second committee meeting, the company included the costs of lenalidomide maintenance but did not include any benefit of lenalidomide maintenance. At the third committee meeting, the company presented its revised base-case and scenario analyses, which included both costs and benefits of lenalidomide maintenance. The company based the duration of lenalidomide maintenance treatment on the median time to stopping lenalidomide seen in the subgroup of the Myeloma XI trial for whom a transplant was suitable. Myeloma XI was a phase 3 trial and the key clinical evidence was from NICE's technology appraisal guidance on lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma, which compared lenalidomide maintenance treatment with observation. The company modelled an 'uplift' (improvement) in progression-free survival for this appraisal using the observed hazard ratio by minimal residual disease status in the Myeloma XI trial. The company assumed no survival benefits associated with lenalidomide maintenance in its revised base case; the costs and survival benefits of lenalidomide maintenance were equal for both arms. The company also provided a scenario analysis that included a longer treatment duration on lenalidomide maintenance for the subgroup who were minimal residual disease negative in the daratumumab in combination arm. In a scenario analysis, this subgroup had 18 additional cycles of lenalidomide maintenance and a survival benefit for both progression-free and overall survival. The company modelled this by improving the hazard ratios by 20% in the minimal residual disease negative subgroup in the daratumumab in combination arm. The clinical lead for the Cancer Drugs Fund explained that adding daratumumab to induction and consolidation treatment would likely increase the duration of lenalidomide maintenance and so it was reasonable to assume it prolonged overall survival. The committee considered that the company's scenario analysis was more likely to reflect clinical practice. The ERG noted that the duration of additional treatment and any associated benefits were uncertain because of limited evidence. The ERG provided additional scenario analyses that tested the sensitivity of results to the duration and associated benefits of lenalidomide maintenance after daratumumab in combination. The committee noted that amending the duration or additional benefit of lenalidomide maintenance after daratumumab in combination modestly affected the incremental cost-effectiveness ratio (ICER), and concluded that the company scenario that included a 20% improvement in the hazard ratios for overall and progression-free survival was reasonable for decision making.
# Age at the start of induction treatment
## The age of patients at the start of induction treatment should reflect UK epidemiological evidence
The company used a mean age of 56.6 years at the start of induction treatment in its economic model, taken from CASSIOPEIA. The ERG considered that this did not reflect NHS clinical practice, because CASSIOPEIA excluded patients aged over 65. Evidence from Public Health England suggests that many people with newly diagnosed multiple myeloma eligible for transplant are aged over 65. The committee concluded in its first committee meeting that the mean age from the Public Health England data better reflected NHS practice and should be used in the economic model. The company revised its base case for the second committee meeting to include a mean age at the start of induction from the Public Health England data.
# Costs of subsequent treatments
## Panobinostat plus bortezomib and dexamethasone should not be included as a treatment at third or fourth line
The company's model included the costs of second-, third- and fourth-line treatments given after first-line induction and consolidation treatment. The NICE Cancer Drugs Fund position statement specifies that companies should not include treatments recommended for use in the Cancer Drugs Fund in their economic modelling because they do not yet reflect routine NHS practice or may not be commissioned in future. To reflect this, the company omitted treatments recommended for use in the Cancer Drugs Fund. It further assumed that around 45% of people would have panobinostat plus bortezomib and dexamethasone as their third-line treatment. However, the ERG understood that this regimen is rarely used in third or fourth line because it is poorly tolerated and is mainly used in later lines. The clinical experts agreed, stating that they avoid offering panobinostat plus bortezomib and dexamethasone. The committee concluded that panobinostat plus bortezomib and dexamethasone should not be included as a third- or fourth-line treatment in the model. The company revised its base case at consultation to omit panobinostat plus bortezomib and dexamethasone as a third- or fourth-line treatment.
# Cost-effectiveness results
## Daratumumab in combination is cost effective when compared with bortezomib, thalidomide and dexamethasone
The committee recalled that its preferred assumptions were:
including lenalidomide maintenance to reflect NHS practice (see section 3.5 and section 3.18)
using a landmark analysis adjusted for re-randomisation to daratumumab maintenance using the company's IPCW approach (see section 3.8)
basing the long-term survival modelling on the company's approach using a landmark analysis, split by minimal residual disease status (see section 3.12)
using the IPCW-adjusted landmark analysis to model survival for people having bortezomib plus thalidomide and dexamethasone (see section 3.15)
modelling a daratumumab lifetime treatment effect (see section 3.17)
using a mean age at the start of induction treatment based on evidence from Public Health England (see section 3.19)
-mitting panobinostat plus bortezomib and dexamethasone as a treatment at third or fourth line (see section 3.20).The committee agreed that the most plausible ICER was within the range NICE normally considers an acceptable use of NHS resources, that is £20,000 to £30,000 per quality-adjusted life year (QALY) gained. The figure cannot be reported because it includes confidential discounts for daratumumab, bortezomib, dexamethasone and some of the treatments offered second line and beyond. The committee concluded that daratumumab in combination is a cost-effective use of NHS resources compared with bortezomib plus thalidomide and dexamethasone.
# Equalities and innovation
The ERG raised 2 potential equalities issues. The first was that daratumumab in combination should not be restricted to people aged up to 65, which reflects the inclusion criteria in CASSIOPEIA. The second was that multiple myeloma is more common in men than women, and it also has a higher incidence in people of African or Caribbean family background. The committee did not restrict its discussion to an age-restricted population. Issues related to differences in prevalence or incidence of a disease are not equality issues if they do not affect access to a technology.
The company stated that daratumumab in combination was innovative because it has a different mechanism of action from other available treatments. The committee agreed that although the technology would likely improve survival, there were no additional gains in health-related quality of life over those already included. In response to consultation, patient experts explained that they believed daratumumab was innovative. They suggested that people having daratumumab in combination may benefit psychologically from knowing they have a higher chance of achieving minimal residual disease negative status. However, the committee concluded that it had not been presented with evidence to change its view that there were no additional gains in health-related quality of life over those already included in the QALY calculations.
# Conclusion
## Daratumumab in combination is recommended for routine use in the NHS
Daratumumab in combination is more clinically effective than standard care, bortezomib plus thalidomide and dexamethasone for untreated multiple myeloma when a stem cell transplant is suitable. The committee agreed that the most plausible ICER for daratumumab in combination compared with bortezomib plus thalidomide and dexamethasone was within the range considered to be a cost-effective use of NHS resources. It concluded that daratumumab in combination should be recommended for routine use as an option for untreated multiple myeloma when a stem cell transplant is suitable.
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{'Recommendations': 'Daratumumab plus bortezomib, thalidomide and dexamethasone is recommended, within its marketing authorisation, as induction and consolidation treatment for untreated multiple myeloma in adults, when an autologous stem cell transplant is suitable. It is recommended only if the company provides daratumumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nBefore having an autologous stem cell transplant, most people with untreated multiple myeloma have bortezomib plus thalidomide and dexamethasone as the first treatment. This appraisal looks at adding daratumumab to bortezomib plus thalidomide and dexamethasone (daratumumab in combination) before transplant (induction) and for a short time after transplant (consolidation).\n\nClinical trial results show that, compared with bortezomib plus thalidomide and dexamethasone, daratumumab in combination increases how long people live and extends the time before the condition worsens.\n\nThe cost-effectiveness estimates are within what NICE considers acceptable. So, daratumumab in combination is recommended.', 'Information about daratumumab': "# Marketing authorisation indication\n\nDaratumumab (Darzalex, Janssen–Cilag) in combination with bortezomib, thalidomide and dexamethasone, is indicated 'for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for daratumumab.\n\n# Price\n\nThe list price for daratumumab is £4,320 per 1,800‑mg vial of solution for injection intended for fixed-dose subcutaneous administration (excluding VAT; BNF online, accessed November 2021). It is also available as a concentrate for solution for intravenous infusion with a list price of £360 per 100‑mg vial, and £1,440 per 400‑mg vial (excluding VAT; BNF online, accessed November 2021). The company has a commercial arrangement. This makes daratumumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.\n\nThe list price for bortezomib is £762.38 per 3.5‑mg vial (excluding VAT; BNF online, accessed November 2021). There is a discount for bortezomib agreed with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.\n\nThe list price for thalidomide is £298.48 per 28‑pack of 50\xa0mg capsules (excluding VAT; BNF online, accessed November\xa02021).\n\nThere is a nationally available discount for dexamethasone with the Commercial Medicines Unit. The prices agreed through the framework are commercial in confidence.", 'Committee discussion': "The appraisal committee met 3\xa0times to consider evidence submitted by Janssen–Cilag, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage that preceded the first committee meeting:\n\nthe uncertainty in the hazard ratios from the company's meta-analysis on the relationship between minimal residual disease status and survival outcomes (issue\xa01, see ERG report, page\xa014)\n\nthe most appropriate definition of minimal residual disease negativity (issue\xa02, see ERG report, page\xa015)\n\nthe most plausible extrapolations of long-term survival for people having bortezomib plus thalidomide and dexamethasone (issue\xa04, see ERG report, page\xa017)\n\nthe uncertainty around the treatment effect of daratumumab plus bortezomib, thalidomide and dexamethasone (daratumumab in combination) on progression-free survival and overall survival, based on the company's landmark analysis (issue\xa05, see ERG report, page\xa018)\n\nhow long the treatment effect of daratumumab in combination lasts (issue\xa06, see ERG report, page\xa019).\n\nThe committee also considered that maintenance with lenalidomide should be included as a subsequent treatment in the modelling.\n\n# New treatment option\n\n## People with untreated multiple myeloma would welcome a new option for first-line treatment\n\nPatient experts explained that multiple myeloma is a relapsing and remitting disease and can include severe symptoms. The first remission is often the 'best' remission because people are at their fittest. With each line of treatment, some people stop treatment because they become too ill or have complications. Therefore, the patient experts believed that the most effective treatments should be given as early as possible in the treatment pathway. Patients need new treatment options that improve response and offer a longer remission, as well as limit or delay complications associated with multiple myeloma. The patient experts noted that more people having daratumumab in combination have no minimal residual disease (a measure of residual tumour cells in bone marrow) than those having other treatments. This signifies a deep response. They considered that daratumumab in combination is well tolerated. The committee concluded that people with untreated multiple myeloma would welcome well-tolerated new treatment options that give a longer period of remission and improve survival.\n\n# Treatment pathway\n\n## When an autologous stem cell transplant is suitable, people usually have induction treatment followed by high-dose chemotherapy before transplant\n\nAround 1\xa0in 3\xa0people newly diagnosed with multiple myeloma in the UK will be eligible for an autologous stem cell transplant. For this population, first-line treatment consists of induction treatment to stabilise the disease, high-dose chemotherapy (usually melphalan) followed by an autologous stem cell transplant to deepen response and prolong progression-free survival. Consolidation treatment, which also aims to improve depth of response and involves offering the treatment used at induction again for a short period, is not standard NHS practice. NICE recommend lenalidomide as maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma in adults, with the aim of increasing the length of remission. After relapse, people will progress onto subsequent lines of treatment. The committee concluded that when an autologous stem cell transplant is suitable, people will usually have induction treatment followed by high-dose chemotherapy before their transplant.\n\n## Bortezomib plus thalidomide and dexamethasone is the most relevant comparator reflecting NHS practice, and has similar efficacy and costs to bortezomib plus cyclophosphamide and dexamethasone\n\nThe committee was aware that the NICE scope included the following 4\xa0comparators to reflect NHS practice: bortezomib plus dexamethasone; bortezomib plus dexamethasone and thalidomide; bortezomib plus cyclophosphamide and dexamethasone; and cyclophosphamide plus thalidomide and dexamethasone. The committee understood that the company had included only bortezomib plus dexamethasone and thalidomide as a comparator in its original economic model, but had added bortezomib plus dexamethasone in response to consultation after the first committee meeting. Clinical experts advised that when an autologous stem cell transplant is suitable, most people with untreated multiple myeloma would have an induction (first treatment) regimen of bortezomib plus thalidomide and dexamethasone. When thalidomide is not tolerated or is contraindicated, clinicians usually offer bortezomib plus dexamethasone and cyclophosphamide. Cyclophosphamide plus thalidomide and dexamethasone is rarely offered. The clinical experts noted that bortezomib plus thalidomide and dexamethasone has comparable efficacy to bortezomib plus cyclophosphamide and dexamethasone. They explained that both 'triple regimens' (3\xa0drugs) induce a deeper response than the 'double regimen' (2\xa0drugs) of bortezomib plus dexamethasone. The clinical experts explained that they may offer bortezomib plus dexamethasone to patients who do not tolerate a triple regimen, but these patients would be unlikely to be offered an autologous stem cell transplant. Consequently, bortezomib plus dexamethasone is rarely offered to people for whom a stem cell transplant would be suitable, a requirement of this appraisal. The committee understood that the company did not include bortezomib plus cyclophosphamide and dexamethasone as a comparator in its economic model. The company discussed that its rationale for not including bortezomib plus cyclophosphamide and dexamethasone was because they thought it had similar efficacy and costs to bortezomib plus thalidomide and dexamethasone. The committee considered that there was uncertainty in the company's matching-adjusted indirect comparison comparing bortezomib plus cyclophosphamide and dexamethasone to bortezomib plus thalidomide and dexamethasone (see section\xa03.11). The committee concluded that bortezomib plus thalidomide and dexamethasone was the most relevant comparator, with similar efficacy and costs to bortezomib plus cyclophosphamide and dexamethasone.\n\n## Consolidation treatment including daratumumab can be incorporated into NHS practice\n\nConsolidation treatment follows induction treatment and autologous stem cell transplant and is not standard NHS practice (see section\xa03.2) but was included in the company's clinical trial (see section\xa03.6). Specifically, treatment with daratumumab in combination involved 4\xa0cycles of induction treatment followed by high-dose chemotherapy, followed by an autologous stem cell transplant, and then 2\xa0cycles of consolidation treatment. The marketing authorisation reflects using the treatment before and after transplant, but the clinical experts reiterated that it was not standard clinical practice in the NHS. Instead, 6\xa0rather than 4\xa0cycles of induction treatment are usually offered before transplant, and none after transplant. The clinical experts stated they would be keen to offer consolidation if the evidence supported it. They considered that consolidation could be incorporated into NHS practice and implemented with few challenges. The committee concluded that consolidation treatment with daratumumab in combination could be incorporated into NHS practice.\n\n## Maintenance with lenalidomide is widely used in clinical practice, and should be incorporated into the economic model\n\nIn its original submission, the company's economic model did not include maintenance treatment with lenalidomide after an autologous stem cell transplant. This was because at the time of the company's submission, NICE was still appraising lenalidomide maintenance and it was not standard clinical practice. However, after NICE's technology appraisal guidance on lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma, the clinical experts explained that lenalidomide maintenance is now widely used in practice and this was likely to increase further. The clinical experts noted that there is no clinical evidence evaluating the efficacy of lenalidomide maintenance after daratumumab in combination. They noted that clinical trials separately test induction and maintenance regimens. The committee acknowledged that the lack of clinical evidence exploring using lenalidomide maintenance after daratumumab in combination made incorporating it into the model challenging, but not impossible. It concluded that the model should reflect NHS practice and include both costs and benefits of lenalidomide maintenance.\n\n## Adding daratumumab to bortezomib plus thalidomide and dexamethasone improves progression-free and overall survival\n\nThe CASSIOPEIA trial provides the clinical evidence for daratumumab in combination for untreated multiple myeloma when an autologous stem cell transplant is suitable. This was a phase\xa03, open-label, randomised trial based in 111\xa0European sites. Patients included 1,085\xa0adults aged up to\xa065 with untreated multiple myeloma eligible for an autologous stem cell transplant randomised 1:1 to either daratumumab in combination (experimental arm) or bortezomib plus thalidomide and dexamethasone (control arm). The protocol stipulated that people in both arms have 4\xa0cycles of induction treatment with the above regimens, followed by an autologous stem cell transplant and a further 2\xa0cycles of consolidation treatment. The primary outcome was the proportion of people with a stringent complete disease response within 100\xa0days after an autologous stem cell transplant. The committee was aware that the company chose not to model this primary outcome in its cost-effectiveness analyses (see section\xa03.12). Secondary outcomes included overall survival, progression-free survival, and the proportion of patients without minimal residual disease. At the primary data cut (and final analysis for the primary outcome) after a median follow up of 18.8\xa0months, 28.9% of patients in the experimental arm and 20.3% of patients in the control arm had a stringent complete response after consolidation (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.21 to 2.12). The company also presented survival results from 2\xa0later data cuts with a median follow up of 29.2\xa0months and 44.5\xa0months, respectively. At the earlier of the 2\xa0data cuts, the hazard ratios for progression-free survival and overall survival were 0.50 (95% CI 0.38 to 0.65) and 0.52 (95% CI 0.33 to 0.85), respectively, favouring the experimental arm. The company submitted the results of the latest data cut as confidential.\n\nCASSIOPEIA also has an ongoing second part, in which people whose disease at least partially responded after consolidation are eligible to take part. These people are re-randomised to maintenance treatment either with daratumumab monotherapy or observation until disease progression. However, maintenance treatment with daratumumab monotherapy is not currently included in the marketing authorisation and does not represent NHS practice. The committee recognised that the CASSIOPEIA results do not reflect NHS practice. The company adjusted the results of progression-free survival and overall survival from CASSIOPEIA for people switching to maintenance treatment with daratumumab monotherapy using a pre-specified inverse probability weighting method, which produced similar results to the unadjusted analysis. The committee concluded that adding daratumumab to bortezomib plus thalidomide and dexamethasone improved progression-free survival and overall survival.\n\n## The inverse probability of censoring weighting (IPCW)-adjusted landmark analysis is appropriate to adjust for daratumumab monotherapy\n\nThe company presented a landmark analysis to explore the relationship between minimal residual disease status and survival. Minimal residual disease negativity in the bone marrow (determined by bone marrow aspiration) was assessed at 2\xa0timepoints in CASSIOPEIA. The first was after patients completed induction treatment, and the second after they completed consolidation treatment (around 100\xa0days after an autologous stem cell transplant). The company used only the data from people alive at the post-consolidation assessment (the 'landmark' timepoint). It split the data by a patient's minimal residual disease status (negative or positive), and for each group calculated hazard ratios for progression-free survival and overall survival for people having daratumumab in combination compared with those having bortezomib plus thalidomide and dexamethasone. Taking these calculated hazard ratios for people with and without minimal residual disease, the company then used them to extrapolate long-term progression-free and overall survival in the economic model (see section\xa03.12). At technical engagement before the committee's first meeting, the company updated the landmark analysis using the latest data cut from CASSIOPEIA, but could not use inverse probability weighting to adjust the results of the updated landmark analysis for re-randomising patients to daratumumab maintenance (which would not happen in practice; see section\xa03.6). The company justified this, noting that the landmark analysis was not pre-specified in the trial protocol and that it could not yet access the individual patient data from the second part of CASSIOPEIA because the trial was still blinded. Instead, the company adjusted the landmark analysis by censoring the data from all people re-randomised to daratumumab maintenance. The results of this censored analysis showed that adding daratumumab to bortezomib plus thalidomide and dexamethasone improved progression-free survival and overall survival, independent of minimal residual disease status. The ERG noted that the results of the landmark analysis were inconsistent with those from the intention-to-treat (ITT) data adjusted using inverse probability weighting. The ERG considered that this was likely because of bias introduced by the company's censoring approach. The committee agreed that the results of the landmark analysis may be biased because of informative censoring. However, it deemed that the direction of the bias was unclear and affected both treatment arms. After the first committee meeting, the company accessed the individual patient data it needed to adjust the results of its landmark analysis for re-randomisation to daratumumab maintenance using an inverse probability of censoring weighting (IPCW) approach. The results of the IPCW-adjusted landmark analysis were broadly comparable with the censoring-adjusted landmark analysis for progression-free survival. However, the hazard ratio improved slightly for overall survival for daratumumab in combination compared with bortezomib plus thalidomide and dexamethasone for people with minimal residual disease and worsened for people without minimal residual disease. The ERG commented that although it could not validate the analysis, the IPCW-adjusted landmark analysis appeared reasonable. At the third committee meeting, the company explained that it considered residual confounding unlikely because people in phase\xa02 of the trial were re-randomised before having maintenance treatment or observation. The committee concluded that the company's IPCW-adjusted landmark analysis is likely to be less biased than the censoring-adjusted landmark analysis and more appropriate for decision making.\n\n## Minimal residual disease negativity is likely to predict survival outcomes better than stringent complete response\n\nThe committee was aware that the company extrapolated progression-free survival and overall survival in its economic model based on the presence (positivity) or absence (negativity) of minimal residual disease at the landmark timepoint (see section\xa03.8). The clinical experts stated that, although minimal residual disease is not routinely measured in clinical practice and does not guide treatment choices, minimal residual disease negativity compared with minimal residual disease positivity is associated with better progression-free survival and overall survival. The committee queried why the company chose to split the patients in the model by minimal residual disease (a secondary outcome in CASSIOPEIA) rather than stringent complete response (the primary outcome in CASSIOPEIA). The company explained that when it designed CASSIOPEIA, stringent complete response was considered by the oncology community to be the most informative outcome. However, according to the company, minimal residual disease is now considered better than stringent complete response in assessing depth of response. The company acknowledged that minimal residual disease status was yet to be accepted by regulators as a primary outcome in multiple myeloma trials. The ERG agreed that having no minimal residual disease is likely to predict survival outcomes better than a stringent complete response. The committee was aware that in NICE's technology appraisal guidance on daratumumab with bortezomib and dexamethasone for previously treated multiple myeloma, the committee had concluded that the relationship between minimal residual disease and long-term overall survival was not well established and could not inform the economic model. However, it understood that there was now greater clinical support for the link between minimal residual disease negativity and survival outcomes. The committee would have preferred to see further evidence to support the company's assertion that minimal residual disease status better predicts progression-free survival and overall survival than does stringent complete response. Based on the clinical experts' input, the committee concluded that in the company's approach to modelling long-term survival (see section\xa03.12), it was reasonable to split patients into those with and without minimal residual disease.\n\n# Adverse events\n\n## The adverse event profile of daratumumab in combination is acceptable\n\nThe company considered that overall, the adverse event profile of treatments was similar between groups in CASSIOPEIA. However, the committee noted the higher frequency of nausea, neutropenia, thrombocytopenia, lymphopenia and cough reported in the experimental arm. According to the company, the increased rate of neutropenia in people having daratumumab in combination was not associated with an increased risk of neutropenic fever. The company noted that, at a median follow up of 18.8\xa0months, infusion-related reactions of any grade associated with daratumumab in combination happened in around 35% of patients. The adverse events were manageable, with a frequency of severe (grade\xa03 or\xa04) events (3.5%), rates of stopping treatment (0.6%) and no fatal events. The company added that it anticipated that the subcutaneous formulation of daratumumab would have a lower incidence of infusion-related reactions. The clinical experts noted that overall, daratumumab has limited and manageable adverse effects. The committee concluded that the adverse event profile of daratumumab in combination was acceptable.\n\n# Indirect comparisons\n\n## Results of the company's matching-adjusted indirect comparisons are uncertain\n\nThere are no trials directly comparing daratumumab in combination with bortezomib plus dexamethasone, with or without cyclophosphamide. Therefore, the company did matching-adjusted indirect comparisons and used these to estimate the relative effectiveness of the 2\xa0regimens. The company also estimated the relative effectiveness of bortezomib plus thalidomide and dexamethasone, compared with bortezomib plus dexamethasone, with or without cyclophosphamide. For bortezomib plus cyclophosphamide and dexamethasone, the company used data from GMMG‑MM5, a randomised trial comparing this regimen with doxorubicin plus dexamethasone. For bortezomib plus dexamethasone, the company used data from IFM\xa02005‑01, a randomised trial comparing this regimen with vincristine plus doxorubicin and dexamethasone. The company adjusted the patient-level data from CASSIOPEIA to match the study-level baseline patient characteristics from GMMG‑MM5 and IFM\xa02005‑01. The comparisons were unanchored because there was no common comparator between the studies. The company did not use the results of the indirect comparisons to inform the economic model directly, but rather to support the omission of some comparators from the model (see section\xa03.3). The ERG could not verify that the company had correctly implemented the matching-adjusted indirect comparisons, nor check the results because the company did not provide the ERG with individual patient data from CASSIOPEIA. The ERG added that it would have preferred to see a scenario analysis using a simulated treatment comparison. The committee understood that for the comparison with bortezomib plus cyclophosphamide and dexamethasone, the sample size was smaller, and that adjusting for more covariates would further reduce the effective sample size. The committee also noted that comparing bortezomib plus thalidomide and dexamethasone with bortezomib plus cyclophosphamide and dexamethasone generated wide confidence intervals. It concluded that there was uncertainty around whether the indirect comparisons supported the clinical experts' opinion on the relative efficacy of the different comparators (see section\xa03.3).\n\n# The company's economic model\n\n## The company's approach to modelling long-term survival, using a landmark analysis, is acceptable for decision making\n\nThe company presented a partitioned survival model comprising 3\xa0health states (pre-progression, progressive disease and death) to estimate the cost effectiveness of daratumumab in combination compared with bortezomib plus thalidomide and dexamethasone. The company developed survival models to predict survival beyond the end of the CASSIOPEIA trial over a lifetime time horizon. It explored a conventional approach of fitting parametric models to the ITT (whole trial population) data from CASSIOPEIA but considered the predicted overall survival varied widely by the different distributions. In its original submission, the company chose not to provide cost-effectiveness results based on these analyses because it believed that they would have been very uncertain. Instead, the company used the Kaplan–Meier curves from CASSIOPEIA up to the landmark timepoint (see section\xa03.8). The company split the people still alive at this timepoint into those with and without minimal residual disease. It then took a 5‑step approach to modelling long-term progression-free survival and overall survival:\n\nStep 1: For people with minimal residual disease who had bortezomib plus thalidomide and dexamethasone, the company fitted separate parametric distributions to the post-landmark data from CASSIOPEIA to model progression-free survival and overall survival (see section\xa03.15).\n\nStep 2: The company did a meta-analysis to estimate the relationship between minimal residual disease and survival for people for whom a stem cell transplant is suitable and who have standard care (see section\xa03.13). From this, it calculated 2\xa0hazard ratios. The first reflected the association between minimal residual disease status and overall survival, and the second the association between minimal residual disease status and progression-free survival.\n\nStep 3: The company applied the hazard ratios from step\xa02 to the parametric curves for people with minimal residual disease who had bortezomib plus thalidomide and dexamethasone (from step\xa01), to calculate progression-free survival and overall survival curves for people without minimal residual disease having the same treatment.\n\nStep 4: The company applied the hazard ratios from the landmark analysis (see section\xa03.8) to the survival curves for people having bortezomib plus thalidomide and dexamethasone (from steps\xa01 and\xa03) to calculate the curves for people having daratumumab in combination, split by minimal residual disease status.\n\nStep 5: Finally, the company weighted the survival curves for all patients in each arm split by minimal residual disease status based on the proportion of people with and without minimal residual disease at the landmark timepoint.The ERG agreed with the company that the overall survival data from CASSIOPEIA was too immature for parametric distributions fitted to the ITT data to be robust. In the first meeting, the committee noted the uncertainties associated with the different elements of the company's approach; these included the choice of extrapolations for people with minimal residual disease who had bortezomib plus thalidomide and dexamethasone (see section\xa03.15), and the results of the meta-analysis (see section\xa03.13) and landmark analysis (see section\xa03.8). In its first meeting, the committee was unsure if the company's approach to the long-term survival modelling reduced the uncertainty. It would have preferred that a scenario be provided using a conventional approach of fitting models directly to the ITT data from CASSIOPEIA. In response to consultation, the company updated its economic model to include a scenario with standard parametric models fitted directly to the IPCW-adjusted ITT data from the first part of CASSIOPEIA. The company selected a Weibull model for progression-free survival and overall survival for both treatment arms. The committee considered that both of the company's approaches to survival modelling had uncertainty, but noted that the cost-effectiveness results were similar between the\xa02. It concluded that the company's original approach of using a landmark analysis split by minimal residual disease status was acceptable to model long-term survival.\n\n## The meta-analysis on the relationship between minimal residual disease status and survival is uncertain, but minimally affects results\n\nTo inform the survival curves for people without minimal residual disease having bortezomib plus thalidomide and dexamethasone, the company did a meta-analysis exploring the relationship between minimal residual disease and survival for people having any treatment representing standard care. The results showed improved progression-free survival and overall survival in people without minimal residual disease compared with those with minimal residual disease. The company modelled this using hazard ratios, which needed the proportional hazards assumption (that is, that the relative risk of an event was fixed irrespective of time) to be met. The ERG considered that there was some uncertainty with the hazard ratios from the meta-analysis. This was because the included studies differed with respect to baseline International Staging System scores (which signify prognosis), as well as the treatments representing standard care. The ERG also observed that the assessments of progression-free survival and overall survival started at different timepoints across the studies. However, the company commented that no events were reported across the studies before the start of assessment, so this should not have affected the results. The committee was uncertain if the effect of minimal residual disease on survival outcomes would stay constant over time, as was needed for the proportional hazard's assumption. However, it understood that the hazard ratios for people with and without minimal residual disease were not a key driver of the cost-effectiveness results.\n\n## It is likely people without residual disease would have a complete response over time and the company's definition of minimal residual disease is appropriate\n\nThe ERG found that the definition of minimal residual disease varied across the studies the company included in its meta-analysis. Some studies included the criteria of the International Myeloma Working Group (IMWG), which states people must have a conventional complete disease response. However, in CASSIOPEIA, minimal residual disease was assessed regardless of conventional complete response. The ERG noted that there were more people without minimal residual disease in CASSIOPEIA than there were with a conventional complete disease response. At technical engagement, the company updated its meta-analysis to include only studies in which minimal residual disease had been defined regardless of conventional complete response. This had broadly similar results to the company's original meta-analysis. The ERG would have preferred that the company also provide a scenario in which it applied a consistent definition of minimal residual disease according to the IMWG criteria (that is, needing a conventional complete response). The ERG noted that in CASSIOPEIA, the absolute rates of minimal residual disease negativity were much lower when using the IMWG definition. This would affect the survival extrapolations in the model, and change the weight attributed to the curves for people with and without minimal residual disease in each treatment arm. The committee noted that a scenario provided by the ERG with post-consolidation minimal residual negativity rates defined according to the IMWG definition considerably impacted the cost-effectiveness results. The clinical experts explained that all people without minimal residual disease would eventually have a conventional complete response but agreed that there was sometimes a delay between the 2\xa0outcomes. The committee accepted that people without minimal residual disease would have a conventional complete response over time, and that the definition used in the company's economic model (regardless of conventional complete response) was likely to be appropriate.\n\n# Modelling survival\n\n## Modelled survival for people who have bortezomib plus thalidomide and dexamethasone should be based on IPCW-adjusted landmark analyses\n\nThe company extrapolated progression-free survival and overall survival for people with minimal residual disease who have bortezomib plus thalidomide and dexamethasone using parametric distributions fitted to the post-landmark data from CASSIOPEIA. The company used this patient group because it had the highest number of events and therefore the most mature data. The committee discussed if limiting the analysis to people who had survived to the landmark time would bias the results, but the company explained that very few patients in CASSIOPEIA had died before this point. The company adjusted the extrapolations of survival to account for people switching to maintenance with daratumumab monotherapy in CASSIOPEIA using a censoring approach and an IPCW approach (see section\xa03.8). In the model presented at the first committee meeting, the company fitted the parametric distributions to the censoring-adjusted landmark analysis data. However, the ERG was concerned that the censoring of people re-randomised to maintenance with daratumumab monotherapy would bias the overall survival results (see section\xa03.8). This was because people who had maintenance treatment in CASSIOPEIA had to have disease with at least a partial response after consolidation, and therefore a better prognosis. The committee agreed with the ERG that the company's censoring approach would likely underestimate survival for patients having bortezomib plus thalidomide and dexamethasone. In response to consultation, the company provided a revised base-case analysis that used the data from the updated IPCW-adjusted landmark analysis (see section\xa03.8). In its revised base case, the company extrapolated survival for people with minimal residual disease having bortezomib plus thalidomide and dexamethasone using a Gompertz distribution for progression-free survival and an exponential distribution for overall survival. The company considered that its revised analysis likely overestimated overall survival for people having bortezomib plus thalidomide and dexamethasone. It suggested that this was because people in CASSIOPEIA had consolidation treatment, which was not currently part of NHS practice (see section\xa03.4). Consolidation treatment could have produced a deeper response than induction treatment alone, and therefore longer survival. The ERG considered that the extrapolations used by the company in its revised base case reasonably fit the CASSIOPEIA trial data. However, the ERG agreed with the company that the predictions of overall survival exceeded those from clinical experts. The ERG suggested that this could be because of the nature of the population and interventions in the trial, and the use of a constant hazard ratio to estimate overall survival for people without minimal residual disease. The committee recalled that the company's revised IPCW-adjusted landmark analysis was likely less subject to bias than the censoring-adjusted landmark analysis (see section\xa03.8). The committee also appreciated in its third meeting that the re-randomisation in the CASSIOPEIA trial would minimise residual confounding in adjusted analyses because of the randomisation. It concluded that survival for people having bortezomib plus thalidomide and dexamethasone should be modelled using curves fitted to the IPCW-adjusted data from the landmark analysis.\n\n## The estimate of long-term survival for people who have bortezomib plus thalidomide and dexamethasone reflects clinical practice\n\nAt the third committee meeting, the company reiterated its belief that the model overestimates survival for people who have bortezomib plus thalidomide and dexamethasone so any cost-effectiveness results underestimate cost effectiveness. The company noted that the revised base case now included lenalidomide maintenance (see section\xa03.5) and that the predicted survival rate at 5\xa0years in the model exceeded that seen in the Myeloma\xa0XI trial. The ERG explained that validating modelled extrapolations with clinical opinion and data from external sources does not entirely resolve uncertainty. The committee considered the results from: the company's revised base case, CASSIOPEIA, the GIMEMA study and Myeloma\xa0XI. It noted that the differences between the survival estimates in the company's revised base case and those seen in the Myeloma\xa0XI trial were relatively small. The committee concluded that estimates for long-term survival for people who have bortezomib plus thalidomide and dexamethasone are likely to reflect clinical practice.\n\n## The duration of the treatment effect for daratumumab in combination is unknown, but it is reasonable to assume it will be maintained long term\n\nTreatment effect waning refers to if the relative treatment effect of daratumumab is likely to reduce over time after people stop taking it. The company's original base case included a lifetime treatment effect with daratumumab. The company believed that there was no evidence to suggest if, or when, the treatment effect of daratumumab would wane over time. It noted that the latest data cut from CASSIOPEIA, with a median follow up of almost 4\xa0years, continued to show a relative benefit for daratumumab. The company presented evidence that people who have daratumumab have deeper responses, which is associated with improved survival outcomes. The company presented evidence from the GIMEMA‑MMY‑3006 trial, which investigated the efficacy of bortezomib plus dexamethasone compared with bortezomib plus dexamethasone and thalidomide in people with previously untreated symptomatic and measurable myeloma. The company explained that the results support maintaining a treatment effect driven by deeper responses. Clinical experts explained that they expect a similar effect for daratumumab in combination. The ERG noted that there was limited evidence to support a lifetime treatment effect with daratumumab in combination, and that the company's assumption was optimistic. It presented scenarios where the treatment effect lasted only 5\xa0years, and a scenario where the treatment effect declined between 5\xa0and 10\xa0years and stopped at 10\xa0years. The ERG modelled this by setting the disease progression and mortality rates of daratumumab in combination as equal to that of bortezomib plus dexamethasone and thalidomide from the set timepoint, for example, 5\xa0years, onwards. The committee understood that including a treatment effect that wanes in the model considerably affects the cost-effectiveness results. At the first committee meeting, the committee agreed that it was reasonable to consider scenarios in which the treatment effect declined between 5\xa0and 10\xa0years. In response to consultation, the company presented scenarios for treatment waning but continued to assume a lifetime treatment effect for daratumumab in combination in its base case. At the second committee meeting, the clinical lead for the Cancer Drugs Fund noted that results from CASSIOPEIA part\xa02 suggested the effect of adding daratumumab to bortezomib plus thalidomide and dexamethasone had not waned. The committee considered the possibility that because people have first-line daratumumab in combination for a fixed, short-treatment duration, its treatment effect may be less likely to wane than if they had it for longer. This is because the entire benefit of first-line daratumumab in combination would have been delivered, followed by high-dose chemotherapy, and there would be no opportunity for a gradual loss of effect over time. At the third committee meeting, the company presented a revised base case that assumed a lifetime treatment effect for daratumumab in combination but included treatment waning for subsequent lenalidomide maintenance therapy (as per the preferred assumptions from NICE's technology appraisal guidance on lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma; see section\xa03.5). The company reiterated that the long-term outcomes for people who had daratumumab in combination were driven by a deeper post-consolidation response and not a conventional treatment effect. The ERG explained that the model structure 'hard wires' a treatment effect and that the evidence from CASSIOPEIA for additional survival benefits within the minimal residual disease groups are uncertain with wide confidence intervals. The clinical lead for the Cancer Drugs Fund explained that having daratumumab in combination could deliver a long or even lifetime treatment effect. He explained that people who have daratumumab in combination are more likely to achieve minimal residual disease negative status after induction and that evidence suggests these people are likely to experience better long-term outcomes after chemotherapy and autologous stem cell transplant. The committee acknowledged that it was clinically plausible that people who had daratumumab in combination would have a different natural history of disease after treatment, but recalled the uncertainty around the additional survival benefits within the minimal residual disease groups. The committee considered that the scenarios exploring treatment waning showed different survival outcomes for people who had daratumumab in combination and which showed the range of possible cost-effectiveness estimates. However, the committee concluded that, based on the evidence presented to it, it was reasonable to assume that the effect of deepening a response would be maintained over a lifetime for daratumumab in combination.\n\n# Lenalidomide maintenance\n\n## Previous treatment with daratumumab in combination is likely to extend maintenance therapy with lenalidomide and extend survival\n\nThe committee requested that the company include lenalidomide maintenance treatment after consolidation with or without daratumumab in the company's economic modelling (see section\xa03.5). At the second committee meeting, the company included the costs of lenalidomide maintenance but did not include any benefit of lenalidomide maintenance. At the third committee meeting, the company presented its revised base-case and scenario analyses, which included both costs and benefits of lenalidomide maintenance. The company based the duration of lenalidomide maintenance treatment on the median time to stopping lenalidomide seen in the subgroup of the Myeloma\xa0XI trial for whom a transplant was suitable. Myeloma\xa0XI was a phase\xa03 trial and the key clinical evidence was from NICE's technology appraisal guidance on lenalidomide maintenance treatment after an autologous stem cell transplant for newly diagnosed multiple myeloma, which compared lenalidomide maintenance treatment with observation. The company modelled an 'uplift' (improvement) in progression-free survival for this appraisal using the observed hazard ratio by minimal residual disease status in the Myeloma\xa0XI trial. The company assumed no survival benefits associated with lenalidomide maintenance in its revised base case; the costs and survival benefits of lenalidomide maintenance were equal for both arms. The company also provided a scenario analysis that included a longer treatment duration on lenalidomide maintenance for the subgroup who were minimal residual disease negative in the daratumumab in combination arm. In a scenario analysis, this subgroup had 18\xa0additional cycles of lenalidomide maintenance and a survival benefit for both progression-free and overall survival. The company modelled this by improving the hazard ratios by 20% in the minimal residual disease negative subgroup in the daratumumab in combination arm. The clinical lead for the Cancer Drugs Fund explained that adding daratumumab to induction and consolidation treatment would likely increase the duration of lenalidomide maintenance and so it was reasonable to assume it prolonged overall survival. The committee considered that the company's scenario analysis was more likely to reflect clinical practice. The ERG noted that the duration of additional treatment and any associated benefits were uncertain because of limited evidence. The ERG provided additional scenario analyses that tested the sensitivity of results to the duration and associated benefits of lenalidomide maintenance after daratumumab in combination. The committee noted that amending the duration or additional benefit of lenalidomide maintenance after daratumumab in combination modestly affected the incremental cost-effectiveness ratio (ICER), and concluded that the company scenario that included a 20% improvement in the hazard ratios for overall and progression-free survival was reasonable for decision making.\n\n# Age at the start of induction treatment\n\n## The age of patients at the start of induction treatment should reflect UK epidemiological evidence\n\nThe company used a mean age of 56.6\xa0years at the start of induction treatment in its economic model, taken from CASSIOPEIA. The ERG considered that this did not reflect NHS clinical practice, because CASSIOPEIA excluded patients aged over\xa065. Evidence from Public Health England suggests that many people with newly diagnosed multiple myeloma eligible for transplant are aged over\xa065. The committee concluded in its first committee meeting that the mean age from the Public Health England data better reflected NHS practice and should be used in the economic model. The company revised its base case for the second committee meeting to include a mean age at the start of induction from the Public Health England data.\n\n# Costs of subsequent treatments\n\n## Panobinostat plus bortezomib and dexamethasone should not be included as a treatment at third or fourth line\n\nThe company's model included the costs of second-, third- and fourth-line treatments given after first-line induction and consolidation treatment. The NICE Cancer Drugs Fund position statement specifies that companies should not include treatments recommended for use in the Cancer Drugs Fund in their economic modelling because they do not yet reflect routine NHS practice or may not be commissioned in future. To reflect this, the company omitted treatments recommended for use in the Cancer Drugs Fund. It further assumed that around 45% of people would have panobinostat plus bortezomib and dexamethasone as their third-line treatment. However, the ERG understood that this regimen is rarely used in third or fourth line because it is poorly tolerated and is mainly used in later lines. The clinical experts agreed, stating that they avoid offering panobinostat plus bortezomib and dexamethasone. The committee concluded that panobinostat plus bortezomib and dexamethasone should not be included as a third- or fourth-line treatment in the model. The company revised its base case at consultation to omit panobinostat plus bortezomib and dexamethasone as a third- or fourth-line treatment.\n\n# Cost-effectiveness results\n\n## Daratumumab in combination is cost effective when compared with bortezomib, thalidomide and dexamethasone\n\nThe committee recalled that its preferred assumptions were:\n\nincluding lenalidomide maintenance to reflect NHS practice (see section\xa03.5 and section\xa03.18)\n\nusing a landmark analysis adjusted for re-randomisation to daratumumab maintenance using the company's IPCW approach (see section\xa03.8)\n\nbasing the long-term survival modelling on the company's approach using a landmark analysis, split by minimal residual disease status (see section\xa03.12)\n\nusing the IPCW-adjusted landmark analysis to model survival for people having bortezomib plus thalidomide and dexamethasone (see section\xa03.15)\n\nmodelling a daratumumab lifetime treatment effect (see section\xa03.17)\n\nusing a mean age at the start of induction treatment based on evidence from Public Health England (see section\xa03.19)\n\nomitting panobinostat plus bortezomib and dexamethasone as a treatment at third or fourth line (see section\xa03.20).The committee agreed that the most plausible ICER was within the range NICE normally considers an acceptable use of NHS resources, that is £20,000 to £30,000 per quality-adjusted life year (QALY) gained. The figure cannot be reported because it includes confidential discounts for daratumumab, bortezomib, dexamethasone and some of the treatments offered second line and beyond. The committee concluded that daratumumab in combination is a cost-effective use of NHS resources compared with bortezomib plus thalidomide and dexamethasone.\n\n# Equalities and innovation\n\nThe ERG raised 2\xa0potential equalities issues. The first was that daratumumab in combination should not be restricted to people aged up to\xa065, which reflects the inclusion criteria in CASSIOPEIA. The second was that multiple myeloma is more common in men than women, and it also has a higher incidence in people of African or Caribbean family background. The committee did not restrict its discussion to an age-restricted population. Issues related to differences in prevalence or incidence of a disease are not equality issues if they do not affect access to a technology.\n\nThe company stated that daratumumab in combination was innovative because it has a different mechanism of action from other available treatments. The committee agreed that although the technology would likely improve survival, there were no additional gains in health-related quality of life over those already included. In response to consultation, patient experts explained that they believed daratumumab was innovative. They suggested that people having daratumumab in combination may benefit psychologically from knowing they have a higher chance of achieving minimal residual disease negative status. However, the committee concluded that it had not been presented with evidence to change its view that there were no additional gains in health-related quality of life over those already included in the QALY calculations.\n\n# Conclusion\n\n## Daratumumab in combination is recommended for routine use in the NHS\n\nDaratumumab in combination is more clinically effective than standard care, bortezomib plus thalidomide and dexamethasone for untreated multiple myeloma when a stem cell transplant is suitable. The committee agreed that the most plausible ICER for daratumumab in combination compared with bortezomib plus thalidomide and dexamethasone was within the range considered to be a cost-effective use of NHS resources. It concluded that daratumumab in combination should be recommended for routine use as an option for untreated multiple myeloma when a stem cell transplant is suitable."}
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https://www.nice.org.uk/guidance/ta763
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Evidence-based recommendations on daratumumab (Darzalex) with bortezomib, thalidomide and dexamethasone for untreated multiple myeloma when a stem cell transplant is suitable.
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f08d5bb3e461f5b06f2bec50007e823dae4fb34f
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nice
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Fremanezumab for preventing migraine
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Fremanezumab for preventing migraine
Evidence-based recommendations on fremanezumab (Ajovy) for preventing migraine in adults.
# Recommendations
Fremanezumab is recommended as an option for preventing migraine in adults, only if:
they have 4 or more migraine days a month
at least 3 preventive drug treatments have failed and
the company provides it according to the commercial arrangement.
Stop fremanezumab after 12 weeks of treatment if:
in episodic migraine (fewer than 15 headache days a month), the frequency does not reduce by at least 50%
in chronic migraine (15 headache days a month or more with at least 8 of those having features of migraine), the frequency does not reduce by at least 30%.
These recommendations are not intended to affect treatment with fremanezumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatments for preventing chronic or episodic migraine include beta-blockers, antidepressants and anticonvulsant drugs. If chronic migraine does not respond to at least 3 preventive drug treatments, botulinum toxin type A or best supportive care (treatment for the migraine symptoms) is offered. If episodic migraine does not respond to at least 3 preventive drug treatments, best supportive care is offered.
For people whose migraine has not responded to at least 3 oral preventive treatments, clinical trial evidence shows that fremanezumab works better than best supportive care in both episodic and chronic migraine. However, it is unclear if fremanezumab works better than botulinum toxin type A.
For chronic migraine, assuming fremanezumab works better than botulinum toxin type A, the most likely cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources. So it is recommended for chronic migraine. For episodic migraine, the estimates of cost effectiveness are even lower, so it is recommended for episodic migraine. Fremanezumab treatment should be stopped if it is not working well enough after 12 weeks.# Information about fremanezumab
# Marketing authorisation indication
Fremanezumab (Ajovy, Teva Pharmaceuticals) is indicated for 'prophylaxis of migraine in adults who have at least 4 migraine days per month'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for fremanezumab.
# Price
The price of fremanezumab is £450.00 per 225‑mg injection (£1,350 per 675 mg) excluding VAT; BNF online, accessed November 2021. The company has a commercial arrangement. This makes fremanezumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Teva UK Limited, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.
As part of the rapid review of the previous appraisal of fremanezumab (TA631), the appraisal committee considered further evidence submitted by the company for episodic migraine, and a review of this submission by the ERG. See the committee papers for full details.
# The condition
## Migraine has a substantial effect on health-related quality of life
Migraine attacks usually last between 4 hours and 72 hours and involve throbbing head pain of moderate to severe intensity, which can be highly disabling. The patient experts explained that they are often accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound or other sensory stimuli, numbness, confusion, loss of concentration and speech issues. Migraine can adversely affect quality of life, affecting people's ability to do their usual activities, including work. Some people with migraine have severe depression and suicidal thoughts. All of these can slow personal and professional development so that people feel they have unachieved potential. Chronic migraine is defined as 15 or more headache days a month with at least 8 of those having features of migraine. Episodic migraine is defined as less than 15 headache days a month. A clinical expert explained that the severity of the condition can vary over time. The committee concluded that migraine, particularly chronic migraine, is a debilitating condition that substantially affects both physical and psychological aspects of quality of life and employment.
# Treatment pathway and comparators
## At least 3 oral preventive treatments are tried before more specialist treatment is considered
The clinical experts explained that the aim of treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. The committee was aware that in chronic migraine, a 30% reduction in migraine frequency is considered a clinically meaningful response to treatment. In episodic migraine, a 50% reduction is considered a clinically meaningful response. If clinical response is less than this, or the person is not able to have an adequate dosage for long enough or has adverse events, treatment is stopped and another oral preventive treatment is tried. The clinical experts explained that it is important for people to try a range of oral preventive treatments before considering more specialist treatment, such as botulinum toxin type A (for chronic migraine) or fremanezumab. A clinical expert noted that at least 5 different oral preventive treatments were available for migraine but that not all of these would be tried before offering fremanezumab. The clinical experts agreed that fremanezumab would usually be offered after 3 failed oral preventive treatments. This was because there was no clear evidence that using oral preventives after this was of benefit, and side effects may outweigh any benefits. The committee understood that some clinicians may choose to offer a fourth or fifth oral preventive before offering more specialist treatments. It concluded that an adequate trial of at least 3 oral preventive treatments represents usual NHS practice before more specialist treatment is considered. It further concluded that a clinically meaningful response was a 30% reduction (for chronic migraine) or a 50% reduction (for episodic migraine) in migraine frequency.
## The most relevant comparators are best supportive care for episodic migraine and botulinum toxin type A and best supportive care for chronic migraine
The company's submission focused on people with migraine for whom at least 3 previous preventive treatments had failed (defined as lack of a clinically meaningful response, intolerance to the treatment or the treatment was contraindicated or unsuitable). The company considered that fremanezumab would likely be used in NHS clinical practice at this point because of the unmet need for additional treatment options after 3 preventive treatments had failed. The company presented evidence for fremanezumab's clinical effectiveness compared with placebo for episodic migraine and compared with placebo and botulinum toxin type A for chronic migraine. The company considered that placebo was representative of best supportive care, because it comprised acute treatments that people would have for their migraine symptoms when preventive treatments had not worked. The committee recalled its discussion about using oral preventive treatments after 3 had failed (see section 3.2) and agreed that best supportive care was the most appropriate comparator in episodic migraine. It recognised that best supportive care would not reduce the frequency or severity of migraine and would increase the risk of medication overuse headache. It also recalled that botulinum toxin type A is recommended for people with chronic migraine whose condition has not responded to at least 3 prior preventive therapies. However, the committee was also aware that some people who are eligible for botulinum toxin type A are unable to have it or have to wait a long time for it. This is because few UK clinics are offering this treatment, and there are long waiting lists for it. The committee concluded that both botulinum toxin type A and best supportive care were relevant comparators in chronic migraine.
## High-frequency episodic migraine is not a clinically distinct subgroup
The company defined high-frequency episodic migraine as between 8 and 14 monthly headache days. The ERG noted that the company's high-frequency episodic migraine definition was not in line with other definitions in the literature (10 to 14 and 11 to 14 monthly headache days), highlighting that there was no consensus on the definition. The clinical experts explained that there is no internationally recognised classification of high-frequency episodic migraine and that it is not a clearly defined clinical subgroup. They also noted that the definition of high-frequency episodic migraine is arbitrary, and a person's quality of life is negatively affected irrespective of which type of migraine they have. The committee concluded that high-frequency episodic migraine is not a distinct subgroup and agreed not to consider it further.
# Clinical evidence
## The FOCUS trial provides the most relevant clinical evidence for the population of interest
The company's systematic literature review identified 3 double-blind randomised controlled trials evaluating fremanezumab:
FOCUS: in people whose migraine had inadequately responded to 2 to 4 previous classes of preventive treatment
HALO EM: in people with episodic migraine when fewer than 2 classes of preventive treatment had failed
HALO CM: in people with chronic migraine when fewer than 2 classes of preventive treatment had failed.All trials compared fremanezumab (dosage of 675 mg every 3 months or 225 mg monthly) with placebo in adults aged 18 to 70 years across multiple international centres. The HALO and FOCUS trials were 16 weeks long, including a 4‑week run‑in period and a 12‑week treatment period. Long-term safety and efficacy data were collected in the HALO extension study, which included people from HALO EM and HALO CM for a further 12 months. The committee recalled that fremanezumab would be considered as a treatment option after 3 oral preventive treatments had failed (see section 3.2 and section 3.3). It concluded that the subgroup of people from FOCUS for whom 3 preventive treatments had failed provided the most relevant data for the population of interest.
## FOCUS does not fully reflect the people who may be eligible for fremanezumab in clinical practice
The committee considered the generalisability of FOCUS to NHS clinical practice. FOCUS excluded people who had the most severe, unremitting headaches, clinically significant comorbidities or clinically significant psychiatric issues. Therefore, it agreed that people enrolled in FOCUS were on average healthier than people who may be eligible for fremanezumab in clinical practice. The committee also considered whether inadequate treatment response, as defined in FOCUS, reflected what would be considered treatment failure in clinical practice. FOCUS defined an inadequate treatment response as a lack of clinically meaningful improvement after at least 3 months of therapy, intolerance to the treatment or the treatment was contraindicated or unsuitable. The clinical experts explained that a contraindication would not necessarily represent a treatment failure. But the company clarified that only about 2% of recorded treatment failures were because of a contraindication. The committee also noted that some people may have had a clinically meaningful response to an oral preventive treatment before stopping because of adverse events. It also noted that valproic acid was not frequently used in the UK for migraine prevention, although about 1 in 3 people in FOCUS had previously had it. The committee concluded that FOCUS may not fully reflect those eligible for fremanezumab in clinical practice.
## Differences in fremanezumab dosage between the trials and the marketing authorisation are unlikely to affect the generalisability of the results
The committee understood that people with chronic migraine in the 225 mg monthly fremanezumab treatment group in both FOCUS and HALO CM had a 675 mg loading dose. It considered whether this loading dose could bias the clinical-effectiveness results for this group. The company noted that a loading dose was not included in fremanezumab's marketing authorisation because the 675 mg quarterly and 225 mg monthly dosages have equal efficacy. It also noted that having no loading dose simplified dosing, therefore benefiting patients and clinicians. The committee concluded that differences in dosing between the FOCUS and HALO CM trials and the marketing authorisation would not likely affect the generalisability of the results to clinical practice.
## Fremanezumab is clinically effective compared with placebo for episodic and chronic migraine
The company presented clinical-effectiveness results from FOCUS for the subgroup of people for whom 3 or 4 preventive migraine therapies failed to produce clinically meaningful improvement, were not tolerated, or were contraindicated or unsuitable. The baseline to week 12 subgroup results from FOCUS showed:
fremanezumab reduced the number of monthly migraine days more than placebo for episodic and chronic migraine
more people on fremanezumab had a reduction of at least 50% in the average monthly number of migraine days compared with placebo for episodic migraine
more people on fremanezumab had a reduction of at least 30% in the average monthly number of migraine days compared with placebo for chronic migraine
fremanezumab reduced the monthly number of days with acute headache medication more than placebo for both episodic and chronic migraine.The committee recalled that the company's subgroup analysis from FOCUS may not fully reflect the population of interest (see section 3.5), but agreed that this subgroup provided the most relevant clinical evidence. It also noted that the results were taken from a post-hoc subgroup analysis, which it agreed reduced the robustness of the findings. It concluded that the subgroup results showed that fremanezumab is an effective treatment compared with placebo for people with episodic or chronic migraine when 3 or 4 preventive treatments have failed.
## The long-term comparative effectiveness of fremanezumab is unknown
The duration of the blinded phase in the trials was 12 weeks for FOCUS, HALO EM and HALO CM. The company provided supporting data for fremanezumab's long-term effectiveness from the uncontrolled open-label HALO extension study. The committee recalled that the population in the HALO studies was less relevant than the population in FOCUS to the population of interest (see section 3.5), but acknowledged that no long-term evidence was available from FOCUS. People who had fremanezumab in HALO EM and HALO CM had the option to continue on a stable dose in the extension study, whereas those who had placebo could opt to be randomly assigned to either 675 mg fremanezumab quarterly or 225 mg monthly (with a 675 mg loading dose in HALO CM). The committee recognised that although the HALO extension study provided some longer-term clinical-effectiveness evidence for people having fremanezumab, comparative effectiveness could not be estimated because the extension study did not include a placebo group. The committee recognised that because not everyone in the trials continued to the extension phase, there was an additional risk of bias. This was because it considered that people not having benefit were more likely to drop out. The company said that the results suggested that treatment effectiveness was maintained long term with no evidence of waning. It noted similar results for people who previously had fremanezumab in HALO EM and HALO CM to those who had previously had placebo, and consistency in results between the 2 fremanezumab dosages (675 mg quarterly and 225 mg monthly). These results were considered academic in confidence by the company and cannot be reported here. The committee concluded that the long-term benefits of fremanezumab compared with best supportive care remained uncertain.
## Fremanezumab may be clinically effective for chronic migraine after 3 preventive treatments and botulinum toxin type A have failed
Clinical experts advised that botulinum toxin type A is ineffective for about 1 in 3 people with chronic migraine, based on real-world studies. The committee recalled that this group of people has high unmet need because of high disease burden and no further treatment options. At consultation, the company submitted additional evidence on the clinical effectiveness of fremanezumab compared with best supportive care for people with chronic migraine after 3 preventive treatments and botulinum toxin type A have failed. The evidence was based on a post-hoc subgroup analysis of FOCUS. The baseline to week 12 results showed improvements in key outcomes (as listed in section 3.8), which were in line with the results for the subgroup of people for whom 3 or 4 preventive migraine therapies failed (see section 3.8). They were considered academic in confidence by the company and cannot be reported here. The ERG highlighted the small population size in this analysis. It noted that the clinical-effectiveness evidence was weak and should be treated with caution. The company also submitted supporting analyses for 2 additional slightly larger populations:
people for whom 3 or more treatments have failed, one of which was botulinum toxin type A
all people with chronic migraine for whom botulinum toxin type A has failed, regardless of the number of prior therapies.The results of these analyses were in line with the main subgroup analysis. The committee noted that the company's analysis was exploratory. But it concluded that fremanezumab appeared to be clinically effective compared with best supportive care for chronic migraine after 3 preventive treatments and botulinum toxin type A have failed.
# Indirect treatment comparison
## It is uncertain whether fremanezumab is more clinically effective than botulinum toxin type A
There was no direct evidence comparing fremanezumab with botulinum toxin type A for chronic migraine. So the company did an indirect comparison using data from:
FOCUS for fremanezumab
study 295, which compared erenumab and placebo
PREEMPT1 and PREEMPT2, which compared botulinum toxin type A with placebo.The company noted that data from study 295 was included only to strengthen the network and not to include erenumab as an additional comparator. However, the ERG noted that adding this study does not strengthen or weaken the network in any way and so it was not expected to affect the network meta-analysis results. The comparison was in the subgroup for whom 3 or 4 previous treatments had failed (as defined in section 3.2). It compared the reduction in monthly migraine days in people on fremanezumab with the reduction in monthly headache days in people on botulinum toxin type A. It also compared the proportion of people on fremanezumab with at least a 50% reduction in monthly migraine days at 12 weeks with the proportion of people on botulinum toxin type A with at least a 50% reduction in monthly headache days at 24 weeks. Differences in outcomes and time points reflected the differences in primary outcomes and timing of assessments between the FOCUS and PREEMPT trials. The results of the comparison numerically favoured fremanezumab, but these findings were not statistically significant in people for whom at least 3 preventive treatments had failed (results are academic in confidence and cannot be reported here). Because the results were not statistically significant, fremanezumab could be more effective or less effective than botulinum toxin type A. The company used placebo as the common comparator, but it was administered differently:
as either a single subcutaneous injection every month or 3 subcutaneous injections every quarter in the fremanezumab trial
as intramuscular injections into 31 to 39 different sites on the head and neck in the botulinum toxin type A trials.The committee thought the differences in administration may have influenced the placebo responses, which were substantially different in the trials. It also considered the difference between monthly migraine days with fremanezumab and monthly headache days with botulinum toxin type A. The clinical experts explained that headache days and migraine days both affected quality of life but changes in monthly migraine days were more important because migraines are more severe. The committee thought that because these were separately reported as clinically distinct outcomes, they should not be considered the same. The clinical experts acknowledged that there was UK real-world evidence supporting the effectiveness, tolerability and safety of botulinum toxin type A. The committee acknowledged this and recognised the same evidence was not available for fremanezumab (as for most new treatment options). Given the concern over the analysis and the lack of statistically significant results, the committee concluded that there was a high degree of uncertainty about whether fremanezumab was more clinically effective than botulinum toxin type A for chronic migraine. It agreed it was appropriate to consider a scenario in which equivalent efficacy was assumed and another in which the results of the network meta-analysis were incorporated.
# Quality of life
## The Migraine-Specific Quality of Life Questionnaire is more sensitive to changes in quality of life caused by migraine than the EQ-5D-5L
Health-related quality-of-life data was collected in FOCUS using the Migraine-Specific Quality of Life Questionnaire (MSQ) and the EQ‑5D‑5L. The committee was aware that in NICE's reference case and current position statement on the EQ‑5D‑5L, the EQ‑5D‑3L is preferred for base-case analyses. The company considered that the EQ‑5D‑5L was not sensitive to changes in quality of life with migraine because the questionnaire had to be completed on appointment days. This meant that it only captured quality-of-life data for people who were able to attend appointments. A person having a migraine on the day of their appointment would likely rearrange it and the effect of that migraine on quality of life would not be captured. The clinical experts explained that in clinical practice, they use the Headache Impact Test (HIT6) and Migraine Disability Assessment Test (MIDAS) to measure quality of life, so it was not known whether MSQ was the best available measure of quality of life. The company highlighted that the MSQ included a 4‑week recall period, which ensured the effect of migraine on quality of life was captured. The committee concluded that the rationale for using MSQ data was reasonable because the EQ‑5D‑5L was not sufficiently sensitive to changes in quality of life caused by migraine.
# The company's economic model
## The company's economic model is appropriate for decision making
The company modelled the assessment period of 12 weeks (24 weeks for botulinum toxin type A) as a decision tree, and the post-assessment period as a Markov model. Episodic and chronic migraine were analysed separately, with each analysis using a dedicated set of input parameters. In the decision tree phase, people were grouped into those whose migraine:
responded (defined as a 50% reduction for episodic migraine or a 30% reduction for chronic migraine in monthly migraine days from baseline) and who remained on treatment
did not respond and who stopped treatment.The Markov phase was used to model the distribution of monthly migraine days in each health state: no response (on treatment); response (on treatment); discontinue (off treatment). The committee concluded that the structure of the company's economic model was appropriate for decision making.
# Modelling long-term treatment effectiveness
## A lifetime time horizon is necessary to capture all relevant costs and benefits associated with fremanezumab
The company's base-case model included a time horizon of 10 years. The company explained that it expected all meaningful differences in costs and quality-adjusted life years (QALYs) between treatments to be captured in this time horizon. It also noted that because there is no long-term natural history data, any long-term modelling beyond 10 years would be highly uncertain. The ERG highlighted that a time horizon of 10 years was a problem for predicting long-term safety and efficacy. However, it agreed with the company that extending the time horizon increased the uncertainty in extrapolating short-term evidence, and because of this it considered 10 years to be a reasonable time horizon. The committee understood that extending the time horizon could increase the uncertainty. But it noted that arbitrarily capping the time horizon could also increase uncertainty because long-term costs and benefits were not captured. It acknowledged that, although the average age of the subgroup from FOCUS was over 40 years, people much younger than this would have treatment in clinical practice. Therefore, it agreed this should be taken into account in the model time horizon. The committee concluded that it preferred a lifetime time horizon to ensure that all relevant costs and benefits associated with fremanezumab were captured. For the rapid review, the company used a lifetime time horizon in its updated model.
## The fremanezumab all-cause discontinuation rate is higher than expected and could affect the cost-effectiveness results
The company's model included a separate health state for people who stopped treatment. The discontinuation rate applied after each model cycle (4 weeks) was based on the number of people on fremanezumab who dropped out of the HALO extension study. The committee considered that the discontinuation rate (from all causes) was relatively high for what it understood to be a clinically effective and well-tolerated treatment. The ERG noted that the discontinuation rate in the HALO extension study was higher than that seen in the extension studies of another anti-calcitonin gene-related peptide (CGRP), erenumab (NICE has published guidance on erenumab for preventing migraine). The clinical experts noted that the additional injections given in the HALO trials to preserve the blinding of treatment allocation could explain why more people dropped out. The patient experts highlighted that most people would tolerate injections if the treatment was effective. The committee agreed that additional injections alone were unlikely to explain the higher-than-expected discontinuation rates. It also noted that the HALO extension study from which the discontinuation rate was calculated was an open-label study. This meant that treatment allocation was not blinded, so additional sham injections would not be necessary. It acknowledged that because treatment costs stop after discontinuation, an inflated discontinuation rate would affect the cost-effectiveness results. The committee concluded that the discontinuation rate was higher than expected and this could affect the cost-effectiveness results.
## The company's post-discontinuation assumptions are overly optimistic
The ERG explained that assuming migraine frequency would revert to that of best supportive care after discontinuation from all causes was overly optimistic. This is because the migraine frequency of people having best supportive care was determined by the response to placebo in the clinical trials. It noted that this response was similar to that of people on fremanezumab. It also considered it unrealistic that a substantial treatment effect would be maintained indefinitely for people who are no longer having fremanezumab treatment. The clinical experts highlighted that there was no long-term evidence in people who have stopped treatment, but agreed that it seemed implausible that a substantial treatment benefit would be maintained. The committee agreed that this assumption was overly optimistic because an implausibly large benefit was maintained and costs were stopped. To account for this, the ERG did a scenario analysis. In this, people reverted to baseline migraine days after fremanezumab discontinuation (from all causes), and the treatment effect for people whose migraine responded to best supportive care diminished to baseline over 1 year. The committee agreed that this scenario was more in line with how the clinical experts expected treatment effectiveness could change after stopping treatment. The committee concluded that the company's post-discontinuation assumptions were overly optimistic. It agreed that it would consider the ERG's scenario in which people revert to baseline monthly migraine days after stopping fremanezumab, botulinum toxin type A or best supportive care.
## Applying a negative stopping rule is appropriate
The company's model included a negative stopping rule. So in the model, people whose migraine did not respond to treatment (a reduction in monthly migraine days from baseline of less than 50% for episodic migraine or less than 30% for chronic migraine) stopped treatment after assessment at 12 weeks (24 weeks for botulinum toxin type A). The committee concluded that it was appropriate to include a negative stopping rule at 12 weeks in the economic model if there was no response to treatment. It accepted the company's approach to modelling this. It agreed that any treatment benefit seen while on treatment (during the initial 12 weeks) would not be maintained after stopping the treatment.
## Positive stopping rule assumptions are not appropriate
The company's model applied a positive stopping rule by assuming 20% of people whose migraine responded to treatment would discontinue every 64 weeks (52‑week treatment period and 12‑week response assessment). After this period, treatment effect was maintained, but treatment costs were stopped indefinitely. The patient expert explained that, from their own experience, once fremanezumab was stopped, the benefit was maintained for only a short time before migraines returned to their pretreatment frequency and severity. The committee recalled that there was a lack of long-term effectiveness evidence for fremanezumab in the population of interest (see section 3.9). It recognised that there was no evidence but agreed it was unrealistic to assume that the treatment effect would be maintained indefinitely after stopping treatment. It also noted that any report of long-term treatment effectiveness could be affected by natural variation in the condition. The committee acknowledged that without long-term natural history data, this could not be fully understood. In response to consultation, the company revised its positive stopping rule. The proposed new stopping rule assumed that 15% of people whose migraine responded to treatment would stop every year. It also assumed that once treatment stopped, migraine frequency returned to pretreatment levels within 1 year. The committee was aware that clinical experts considered that successful treatment with fremanezumab would not be continued indefinitely (see section 3.2). The company did not provide any positive stopping criteria for chronic or episodic migraine. However, the committee noted clinical expert comments at consultation suggesting that people with chronic migraine would stop treatment when their migraines had reduced to 10 migraine days a month for at least 3 months. The committee was aware that no comments were received about positive stopping criteria in episodic migraine. Therefore, taking account of what it had heard from the clinical experts, the committee considered that there are no clear criteria for when people should stop treatment and understood that a positive stopping rule could be challenging to implement in clinical practice. It recognised that people may not be willing to stop treatment that is beneficial for them. It also recalled that no positive stopping criteria were used in FOCUS. Therefore, the committee concluded that it was not appropriate to apply the company's positive stopping rule in the model. But it acknowledged that treatment may not continue indefinitely after successful treatment and took this into account for decision making.
# Utility values in the economic model
## The company's approach to calculating model utility values is reasonable but still uncertain
The utility values used in the model were generated from mapping MSQ results to the EQ‑5D‑3L using the Gillard et al. (2012) algorithm. The committee understood that the MSQ data was based on the full trial population, and not just on those for whom 3 or 4 treatments had failed. It also understood that the patient characteristics could not be included in the mapping algorithm because of data limitations. It agreed that this could limit the robustness of the mapped EQ‑5D‑3L utility values used in the economic model. It also noted concerns about the reliability of the utility values given the uncertainty of using data from the broader, full trial population. It noted that the mapping algorithm led to implausibly low utility values for certain patient populations, as confirmed by the clinical experts. The ERG explained that the company did not provide enough detail on how the utility values were extracted and mapped to assess their robustness. The committee concluded that the company's approach to calculating model utility values was reasonable but noted that the values were uncertain because of data limitations.
## The company's original approach to additional on-treatment utility value benefits should not be included in the model
After mapping from MSQ to EQ‑5D‑3L, the company split the EQ‑5D utility values into 'on‑treatment' and 'off‑treatment' groups. Off‑treatment health state utility values were estimated using baseline (week 0) MSQ data. On‑treatment utility values were estimated from the week 4 and week 12 MSQ data. Off‑treatment utility values were applied for people on best supportive care and on‑treatment utility values were used for fremanezumab and botulinum toxin type A until people stopped treatment. The company highlighted that on‑treatment utility value benefits have been shown for people with migraine. It noted that applying treatment-specific utility values was consistent with the appraisal for botulinum toxin type A for chronic migraine. The ERG noted that the on‑ and off‑treatment utilities were not appropriately generated and applied in the model. It considered the company's approach was overly simplistic and did not account for possible improvements in quality of life related to being included in a clinical trial (placebo effect). It also explained that the on‑treatment utilities were not correctly applied in the model because of how the model was structured. The committee recalled that utility values were generated from MSQ data, which measured the impact of migraine on daily social and work-related activities, and emotional functioning. Therefore, it agreed that it was uncertain whether health-related quality-of-life benefits beyond those related to reducing monthly migraine days were not already adequately captured by the MSQ. It also noted that baseline (before treatment) fremanezumab utility values included a benefit over best supportive care, which it agreed was inconsistent with applying an on‑treatment utility value benefit. At the time of the original guidance (TA631; June 2020), the committee concluded that the company's additional on‑treatment utility value benefits should not be included in the economic model.
## There is a clinical rationale for using differential utilities for on- and off-treatment health states
Since the publication of the original guidance for this topic (TA631), NICE has published guidance on galcanezumab for preventing migraine and erenumab for preventing migraine. Both are anti-CGRP drugs for migraine in adults, like fremanezumab. In these appraisals, the committee was satisfied that it had seen enough evidence to support using differential utilities for the treatment being appraised. That is, using different utilities for people on and off fremanezumab, as a result of taking into account improvements in utilities beyond a reduction in the monthly migraine days measure. For the rapid review of fremanezumab, the company presented evidence to support using differential utility values in its economic modelling. It focused on episodic migraine (specifically when 3 preventive treatments had failed) because fremanezumab was not recommended for episodic migraine in TA631. The company's clinical experts advised that there are improvements in utilities beyond a reduction in the monthly migraine days measure, which does not fully capture the duration and severity of migraines, and other factors that influence quality of life. The company reasoned that quality of life is affected by migraine between attacks, not just during them, so quality-of-life impairment could extend beyond monthly migraine days alone. Using differential utilities reflects further treatment benefits, for example improvements in photophobia and disability levels, less severe migraine attacks, and quicker recovery time. The company explained that a migraine-specific quality-of-life questionnaire was used, which found a significant improvement in the different domains for fremanezumab compared with placebo, in the full FOCUS population and the population for whom 3 or more treatments had failed. The committee noted that a reduction in the monthly migraine days measure would not capture the benefits to people with migraine of being able to plan their lives and remain in employment. It acknowledged that better day-to-day functioning overall would lead to increased quality of life and utility values, and that a similar rationale had been accepted by the committee in other appraisals.
## The company's new approach to modelling differential utility for people on and off treatment is acceptable
The company's updated analyses for episodic migraine with 3 or more previous treatment failures used differential utilities, and the committee's preference for a normal distribution as in the NICE guidance on galcanezumab and erenumab. The company explained that in its regression analysis, fremanezumab treatment was a significant covariate in its preferred post-baseline model, and that its approach accounted for any placebo effect in the data. It did some face validity checks on the revised utility values generated by the new approach. The ERG believed the company's regression analysis seemed reasonable and consistent with previous migraine appraisals. However, the company did not provide a detailed statistical analysis plan. Because fremanezumab appeared to be a significant covariate, the ERG interpretation was that this may indicate fremanezumab has a utility benefit beyond reducing monthly migraine days alone. The ERG pointed out the similarities between the regression model used in the rapid review and those in the appraisals of galcanezumab and erenumab, which were used to justify the choice to use differential utilities for when people were on and off treatment. The ERG considered that the company's approach in its updated analysis addressed the limitations of previous regression models and used separate models for baseline and post-baseline quality-of-life data. The committee noted that the company should have provided a full statistical analysis plan alongside its updated analyses. It considered that fremanezumab may have a utility benefit beyond fewer monthly migraine days. So the committee concluded it was appropriate to take into account the company's updated analyses using differential utilities for its decision making in the rapid review.
# Costs in the economic model
## Costs used in the economic model are appropriate
The company based its resource use estimates on data from a European study of migraine burden by Vo et al. (2018). It noted a limitation of the study was that resource use estimates were based on monthly headache days, not migraine days, which it considered could underestimate the migraine cost burden. In the model, it assumed that resource use would be equivalent for both fremanezumab dosage schedules; monthly injections of 225 mg or 3 injections of 675 mg every quarter. The ERG noted that this could be a conservative assumption because quarterly administration is likely to be less resource intensive. The ERG also noted that resource use rates were not specific to the population of interest (that is, people who have had at least 3 failed preventive treatments) but based on the general migraine population. At consultation, the company submitted a revised base-case model, which included updated administration costs for botulinum toxin type A (£125 per administration as per the 2016/17 tariff; the corresponding cost for 2018/19 should be £116 but this has very limited impact on model results), as estimated by NICE and NHS England in their budget impact analysis. The committee concluded that, despite the limitations in the estimates of resource use, the costs included in the model were appropriate for decision making.
## Some people will need fremanezumab to be administered for them
The company assumed that fremanezumab could be self-administered by subcutaneous injection. At the technical engagement stage, the clinical experts suggested that most people would be capable of self-administering fremanezumab. However, 1 expert noted that disabled people or people with a learning disability, older people and those who have a phobia of needles may need help. They also noted that additional services may be needed to train people how to administer treatment. The committee concluded that it was unlikely that everyone having fremanezumab would be capable of self-administering treatment. It agreed that applying administration costs for 10% of people having fremanezumab was reasonable, but acknowledged that this had little effect on the model results.
# Cost-effectiveness estimates
## Because of the uncertainty, an acceptable ICER would be towards the lower end of the range normally considered cost effective for episodic migraine
NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted a high level of uncertainty, specifically:
the lack of long-term natural history data and the simplicity of the model (see section 3.14)
the sensitivity of the model to the time horizon and the different post-treatment discontinuation scenarios (see section 3.14 and section 3.18)
the sensitivity of the model to alternative utility value assumptions (see section 3.20).The committee also considered that the impact of introducing fremanezumab for episodic migraine on NHS resources may be higher than for chronic migraine. This is because episodic migraine is more common than chronic migraine. Therefore, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) for episodic migraine.
## Fremanezumab is cost effective for episodic migraine after 3 preventive treatments have failed
The committee recalled that it had concluded that people with high-frequency episodic migraine were not a distinct group, so it should not consider the cost-effectiveness analysis for this population further (see section 3.4). The company's revised base-case ICER for fremanezumab compared with best supportive care for episodic migraine was below the range NICE normally considers an acceptable use of NHS resources. For the rapid review, the company's revised base case included the committee's preferred assumptions from the time of the original guidance (TA631; June 2020):
model corrections
applying a lifetime (58 years) model time horizon (see section 3.14)
applying the ERG's post-discontinuation scenario (see section 3.16)
applying fremanezumab administration costs for 10% of people (see section 3.24).
removing a positive stopping rule (see section 3.18)
removing additional on‑treatment utility benefits (see section 3.20).It also included differential utilities for on and off treatment, as well as an updated commercial arrangement. Taking its preferences into account, the committee agreed that the most plausible ICER for fremanezumab compared with best supportive care for episodic migraine after 3 preventive treatments have failed was below £20,000 per QALY gained, which is less than the lower end of the range NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that fremanezumab was a cost-effective use of NHS resources for preventing episodic migraine after 3 preventive treatments have failed.
## Fremanezumab is cost effective for chronic migraine after 3 preventive treatments have failed
The committee was aware that many uncertainties associated with the episodic migraine evidence also applied to the chronic migraine evidence. However, it was aware that the eligible population and impact on NHS resources would be smaller for chronic migraine than for episodic migraine (see section 3.25). It also recalled that consultation comments from professional organisations and patient groups specifically highlighted the unmet need for the chronic migraine population. It therefore considered that an acceptable ICER would be within the range normally considered cost effective. The company's revised base-case fully incremental ICERs for fremanezumab compared with both best supportive care and botulinum toxin type A were within this range. The company's revised base case assumed the comparative effectiveness estimates from the network meta-analysis (see section 3.11) and the committee's preferred assumptions:
model corrections
applying a lifetime (58 years) model time horizon (see section 3.14)
applying the ERG's post-discontinuation scenario (see section 3.16)
applying fremanezumab administration costs for 10% of people (see section 3.24).However, the revised base case did not include these committee preferred assumptions:
removing a positive stopping rule (see section 3.18)
removing additional on‑treatment utility benefits (see section 3.20)
considering both a scenario of equal effectiveness of fremanezumab and botulinum toxin type A and a scenario using the results of the network meta-analysis (see section 3.11).The committee recalled that patient and expert groups told them of variable access and long waiting times for botulinum toxin type A treatment. It also recalled that both botulinum toxin type A and best supportive care were relevant comparators for people with chronic migraine (see section 3.3). Taking the committee's preferences into account, the ICER for fremanezumab compared with best supportive care was within the range NICE usually considers a cost-effective use of NHS resources. Taking its preferences into account and including equal effectiveness of fremanezumab and botulinum toxin type A, the committee noted that fremanezumab was dominated (more costly and less effective) by botulinum toxin type A. But the committee also noted that the difference in QALYs was very small and related to differences in the timing of the assessment for these 2 treatments (12 weeks for fremanezumab and 24 weeks for botulinum toxin type A) and subsequent discontinuation of the treatments. Therefore, it agreed the QALYs produced by the 2 treatments were likely similar. The committee noted that the total costs of fremanezumab were slightly higher than those of botulinum toxin type A over the lifetime model time horizon. The committee was aware that clinical experts considered that fremanezumab would likely cost less than botulinum toxin type A, but noted that no evidence was provided for this. Therefore, it agreed that the relative costs of the 2 therapies in NHS clinical practice were uncertain. It also considered that a small QALY benefit would be needed to produce an ICER within the range NICE usually considers a cost-effective use of NHS resources. The committee noted the results of 2 surveys done by the Migraine Trust, which showed that most patient and clinical experts consider anti-CGRP drugs to be either as effective as, or more effective than, botulinum toxin type A (see page 17 of the committee papers for the final appraisal document for TA631). The committee noted the methodological limitations of both surveys, which are considered to be low quality in the hierarchy of evidence. But it considered them as expert opinion, and agreed that it could be plausible that fremanezumab may have a small benefit over botulinum toxin type A. The committee noted that the analysis using clinical-effectiveness estimates from the network meta-analysis produced much bigger QALY benefits than this. When assuming the comparative effectiveness estimates from the network meta-analysis, the ICER for fremanezumab compared with botulinum toxin type A was within the range NICE usually considers a cost-effective use of NHS resources. Taking all the evidence into consideration, the committee concluded that, although there are still uncertainties with fremanezumab's clinical effectiveness and with the model, fremanezumab was likely to be a cost-effective use of NHS resources for preventing chronic migraine after 3 preventive treatments had failed.
## Fremanezumab is cost effective for chronic migraine after botulinum toxin type A has failed
The committee recalled that for the whole chronic migraine population, including the population for whom botulinum toxin type A had failed, fremanezumab was likely to be a cost-effective use of NHS resources for preventing chronic migraine after 3 preventive treatments had failed (see section 3.27). The committee considered the company's additional evidence submitted at consultation for people with chronic migraine only after 3 preventive treatments and botulinum toxin type A have failed. The committee concluded that the most plausible ICERs for fremanezumab compared with best supportive care were within the range normally considered a cost-effective use of NHS resources, using both company and committee preferred assumptions.
# Other factors
## There are no equalities issues that can be addressed in the guidance
The company and clinical and patient experts highlighted that migraine can be classed as a disability under the Equality Act (2010). Because migraine is most common in people of working age and affects more women than men, women may be disadvantaged in the workplace. In addition, there may be unequal access to specialist headache clinics in England. The committee considered these issues but concluded that no specific adjustments were needed to NICE's methods in this situation. No other equalities issues were raised after the original guidance for this topic was published (June 2020).
## There are no health-related benefits that are not captured in the analyses
The company suggested that fremanezumab should be considered as an innovative treatment on the grounds that anti-CGRP therapies represent a step change in the management of migraine. The committee concluded that the modelling had adequately captured the benefits of fremanezumab. But it also acknowledged that fremanezumab administration may be considered more convenient and less unpleasant than administration of botulinum toxin type A.
# Conclusion
## Fremanezumab for chronic migraine is recommended for use in the NHS
The committee recognised the substantial burden that migraine has on quality of life and day-to-day functioning. It acknowledged that this could lead to psychosocial issues (see section 3.1). The committee recalled that the most relevant comparators for chronic migraine were botulinum toxin type A and best supportive care (see section 3.3). It considered that fremanezumab was a clinically effective treatment compared with placebo (see section 3.8). However, the committee considered that it was uncertain whether fremanezumab was more clinically effective than botulinum toxin type A and agreed that it was appropriate to also consider equal effectiveness (see section 3.11). It considered the revised base case provided by the company at consultation, which included a confidential simple discount patient access scheme for fremanezumab. The committee noted that the most plausible ICER for fremanezumab compared with best supportive care was within the range NICE usually considers a cost-effective use of NHS resources. Although there was uncertainty around the relative treatment effects of fremanezumab and botulinum toxin type A, the committee considered it likely that fremanezumab was a cost-effective use of NHS resources. Therefore, the committee recommended fremanezumab for use in the NHS for preventing chronic migraine in adults after 3 preventive treatments have failed. This includes the chronic migraine population for whom treatment with botulinum toxin type A has failed. Treatment with fremanezumab should be stopped if migraine frequency does not reduce by at least 30% after 12 weeks of treatment.
## Fremanezumab for episodic migraine is recommended for use in the NHS
The committee recalled that the most relevant comparator for episodic migraine was best supportive care. It considered that the evidence showed that fremanezumab was clinically effective when compared with best supportive care. It also considered that the evidence in high-frequency episodic migraine was uncertain and did not consider it further because it is not a distinct subgroup. For the rapid review, the company presented new evidence supporting the use of differential utilities on and off treatment, specifically focusing on the population with episodic migraine after 3 preventive treatments have failed. It also submitted an updated commercial arrangement. The committee noted that the company should have provided a statistical analysis plan for the regression carried out. However, all the ICERs for scenarios using the updated model with differential utilities were less than £20,000 per QALY gained, and a scenario without differential utilities resulted in an ICER within the range usually considered an acceptable use of NHS resources. Therefore, the committee recommended fremanezumab for use in the NHS for preventing episodic migraines in adults after 3 preventive treatments have failed. Treatment with fremanezumab should be stopped if migraine frequency does not reduce by at least 50% after 12 weeks of treatment.
|
{'Recommendations': 'Fremanezumab is recommended as an option for preventing migraine in adults, only if:\n\nthey have 4\xa0or more migraine days a month\n\nat least 3\xa0preventive drug treatments have failed and\n\nthe company provides it according to the commercial arrangement.\n\nStop fremanezumab after 12\xa0weeks of treatment if:\n\nin episodic migraine (fewer than 15\xa0headache days a month), the frequency does not reduce by at least\xa050%\n\nin chronic migraine (15\xa0headache days a month or more with at least 8\xa0of those having features of migraine), the frequency does not reduce by at least\xa030%.\n\nThese recommendations are not intended to affect treatment with fremanezumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatments for preventing chronic or episodic migraine include beta-blockers, antidepressants and anticonvulsant drugs. If chronic migraine does not respond to at least 3\xa0preventive drug treatments, botulinum toxin type\xa0A or best supportive care (treatment for the migraine symptoms) is offered. If episodic migraine does not respond to at least 3\xa0preventive drug treatments, best supportive care is offered.\n\nFor people whose migraine has not responded to at least 3\xa0oral preventive treatments, clinical trial evidence shows that fremanezumab works better than best supportive care in both episodic and chronic migraine. However, it is unclear if fremanezumab works better than botulinum toxin type\xa0A.\n\nFor chronic migraine, assuming fremanezumab works better than botulinum toxin type\xa0A, the most likely cost-effectiveness estimates are within the range NICE normally considers an acceptable use of NHS resources. So it is recommended for chronic migraine. For episodic migraine, the estimates of cost effectiveness are even lower, so it is recommended for episodic migraine. Fremanezumab treatment should be stopped if it is not working well enough after 12\xa0weeks.', 'Information about fremanezumab': "# Marketing authorisation indication\n\nFremanezumab (Ajovy, Teva Pharmaceuticals) is indicated for 'prophylaxis of migraine in adults who have at least 4\xa0migraine days per month'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for fremanezumab.\n\n# Price\n\nThe price of fremanezumab is £450.00 per 225‑mg injection (£1,350 per 675\xa0mg) excluding VAT; BNF online, accessed November 2021. The company has a commercial arrangement. This makes fremanezumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Teva UK Limited, a review of this submission by the evidence review group (ERG), and the technical report developed through engagement with stakeholders. See the committee papers for full details of the evidence.\n\nAs part of the rapid review of the previous appraisal of fremanezumab (TA631), the appraisal committee considered further evidence submitted by the company for episodic migraine, and a review of this submission by the ERG. See the committee papers for full details.\n\n# The condition\n\n## Migraine has a substantial effect on health-related quality of life\n\nMigraine attacks usually last between 4\xa0hours and 72\xa0hours and involve throbbing head pain of moderate to severe intensity, which can be highly disabling. The patient experts explained that they are often accompanied by nausea, vomiting, sensitivity to light, sensitivity to sound or other sensory stimuli, numbness, confusion, loss of concentration and speech issues. Migraine can adversely affect quality of life, affecting people's ability to do their usual activities, including work. Some people with migraine have severe depression and suicidal thoughts. All of these can slow personal and professional development so that people feel they have unachieved potential. Chronic migraine is defined as 15\xa0or more headache days a month with at least 8\xa0of those having features of migraine. Episodic migraine is defined as less than 15\xa0headache days a month. A clinical expert explained that the severity of the condition can vary over time. The committee concluded that migraine, particularly chronic migraine, is a debilitating condition that substantially affects both physical and psychological aspects of quality of life and employment.\n\n# Treatment pathway and comparators\n\n## At least 3\xa0oral preventive treatments are tried before more specialist treatment is considered\n\nThe clinical experts explained that the aim of treatment is to reduce the frequency, severity or duration of migraine and improve quality of life. The committee was aware that in chronic migraine, a 30% reduction in migraine frequency is considered a clinically meaningful response to treatment. In episodic migraine, a 50% reduction is considered a clinically meaningful response. If clinical response is less than this, or the person is not able to have an adequate dosage for long enough or has adverse events, treatment is stopped and another oral preventive treatment is tried. The clinical experts explained that it is important for people to try a range of oral preventive treatments before considering more specialist treatment, such as botulinum toxin type\xa0A (for chronic migraine) or fremanezumab. A clinical expert noted that at least 5\xa0different oral preventive treatments were available for migraine but that not all of these would be tried before offering fremanezumab. The clinical experts agreed that fremanezumab would usually be offered after 3\xa0failed oral preventive treatments. This was because there was no clear evidence that using oral preventives after this was of benefit, and side effects may outweigh any benefits. The committee understood that some clinicians may choose to offer a fourth or fifth oral preventive before offering more specialist treatments. It concluded that an adequate trial of at least 3\xa0oral preventive treatments represents usual NHS practice before more specialist treatment is considered. It further concluded that a clinically meaningful response was a 30% reduction (for chronic migraine) or a 50% reduction (for episodic migraine) in migraine frequency.\n\n## The most relevant comparators are best supportive care for episodic migraine and botulinum toxin type\xa0A and best supportive care for chronic migraine\n\nThe company's submission focused on people with migraine for whom at least 3\xa0previous preventive treatments had failed (defined as lack of a clinically meaningful response, intolerance to the treatment or the treatment was contraindicated or unsuitable). The company considered that fremanezumab would likely be used in NHS clinical practice at this point because of the unmet need for additional treatment options after 3\xa0preventive treatments had failed. The company presented evidence for fremanezumab's clinical effectiveness compared with placebo for episodic migraine and compared with placebo and botulinum toxin type\xa0A for chronic migraine. The company considered that placebo was representative of best supportive care, because it comprised acute treatments that people would have for their migraine symptoms when preventive treatments had not worked. The committee recalled its discussion about using oral preventive treatments after 3\xa0had failed (see section\xa03.2) and agreed that best supportive care was the most appropriate comparator in episodic migraine. It recognised that best supportive care would not reduce the frequency or severity of migraine and would increase the risk of medication overuse headache. It also recalled that botulinum toxin type\xa0A is recommended for people with chronic migraine whose condition has not responded to at least 3\xa0prior preventive therapies. However, the committee was also aware that some people who are eligible for botulinum toxin type\xa0A are unable to have it or have to wait a long time for it. This is because few UK clinics are offering this treatment, and there are long waiting lists for it. The committee concluded that both botulinum toxin type\xa0A and best supportive care were relevant comparators in chronic migraine.\n\n## High-frequency episodic migraine is not a clinically distinct subgroup\n\nThe company defined high-frequency episodic migraine as between\xa08 and 14\xa0monthly headache days. The ERG noted that the company's high-frequency episodic migraine definition was not in line with other definitions in the literature (10\xa0to\xa014 and 11\xa0to\xa014 monthly headache days), highlighting that there was no consensus on the definition. The clinical experts explained that there is no internationally recognised classification of high-frequency episodic migraine and that it is not a clearly defined clinical subgroup. They also noted that the definition of high-frequency episodic migraine is arbitrary, and a person's quality of life is negatively affected irrespective of which type of migraine they have. The committee concluded that high-frequency episodic migraine is not a distinct subgroup and agreed not to consider it further.\n\n# Clinical evidence\n\n## The FOCUS trial provides the most relevant clinical evidence for the population of interest\n\nThe company's systematic literature review identified 3\xa0double-blind randomised controlled trials evaluating fremanezumab:\n\nFOCUS: in people whose migraine had inadequately responded to 2\xa0to\xa04 previous classes of preventive treatment\n\nHALO EM: in people with episodic migraine when fewer than 2\xa0classes of preventive treatment had failed\n\nHALO CM: in people with chronic migraine when fewer than 2\xa0classes of preventive treatment had failed.All trials compared fremanezumab (dosage of 675\xa0mg every 3\xa0months [quarterly] or 225\xa0mg monthly) with placebo in adults aged 18\xa0to 70\xa0years across multiple international centres. The HALO and FOCUS trials were 16\xa0weeks long, including a 4‑week run‑in period and a 12‑week treatment period. Long-term safety and efficacy data were collected in the HALO extension study, which included people from HALO EM and HALO CM for a further 12\xa0months. The committee recalled that fremanezumab would be considered as a treatment option after 3\xa0oral preventive treatments had failed (see section\xa03.2 and section\xa03.3). It concluded that the subgroup of people from FOCUS for whom 3\xa0preventive treatments had failed provided the most relevant data for the population of interest.\n\n## FOCUS does not fully reflect the people who may be eligible for fremanezumab in clinical practice\n\nThe committee considered the generalisability of FOCUS to NHS clinical practice. FOCUS excluded people who had the most severe, unremitting headaches, clinically significant comorbidities or clinically significant psychiatric issues. Therefore, it agreed that people enrolled in FOCUS were on average healthier than people who may be eligible for fremanezumab in clinical practice. The committee also considered whether inadequate treatment response, as defined in FOCUS, reflected what would be considered treatment failure in clinical practice. FOCUS defined an inadequate treatment response as a lack of clinically meaningful improvement after at least 3\xa0months of therapy, intolerance to the treatment or the treatment was contraindicated or unsuitable. The clinical experts explained that a contraindication would not necessarily represent a treatment failure. But the company clarified that only about 2% of recorded treatment failures were because of a contraindication. The committee also noted that some people may have had a clinically meaningful response to an oral preventive treatment before stopping because of adverse events. It also noted that valproic acid was not frequently used in the UK for migraine prevention, although about 1\xa0in\xa03\xa0people in FOCUS had previously had it. The committee concluded that FOCUS may not fully reflect those eligible for fremanezumab in clinical practice.\n\n## Differences in fremanezumab dosage between the trials and the marketing authorisation are unlikely to affect the generalisability of the results\n\nThe committee understood that people with chronic migraine in the 225\xa0mg monthly fremanezumab treatment group in both FOCUS and HALO CM had a 675\xa0mg loading dose. It considered whether this loading dose could bias the clinical-effectiveness results for this group. The company noted that a loading dose was not included in fremanezumab's marketing authorisation because the 675\xa0mg quarterly and 225\xa0mg monthly dosages have equal efficacy. It also noted that having no loading dose simplified dosing, therefore benefiting patients and clinicians. The committee concluded that differences in dosing between the FOCUS and HALO CM trials and the marketing authorisation would not likely affect the generalisability of the results to clinical practice.\n\n## Fremanezumab is clinically effective compared with placebo for episodic and chronic migraine\n\nThe company presented clinical-effectiveness results from FOCUS for the subgroup of people for whom 3\xa0or\xa04\xa0preventive migraine therapies failed to produce clinically meaningful improvement, were not tolerated, or were contraindicated or unsuitable. The baseline to week\xa012 subgroup results from FOCUS showed:\n\nfremanezumab reduced the number of monthly migraine days more than placebo for episodic and chronic migraine\n\nmore people on fremanezumab had a reduction of at least 50% in the average monthly number of migraine days compared with placebo for episodic migraine\n\nmore people on fremanezumab had a reduction of at least 30% in the average monthly number of migraine days compared with placebo for chronic migraine\n\nfremanezumab reduced the monthly number of days with acute headache medication more than placebo for both episodic and chronic migraine.The committee recalled that the company's subgroup analysis from FOCUS may not fully reflect the population of interest (see section\xa03.5), but agreed that this subgroup provided the most relevant clinical evidence. It also noted that the results were taken from a post-hoc subgroup analysis, which it agreed reduced the robustness of the findings. It concluded that the subgroup results showed that fremanezumab is an effective treatment compared with placebo for people with episodic or chronic migraine when 3\xa0or\xa04\xa0preventive treatments have failed.\n\n## The long-term comparative effectiveness of fremanezumab is unknown\n\nThe duration of the blinded phase in the trials was 12\xa0weeks for FOCUS, HALO EM and HALO CM. The company provided supporting data for fremanezumab's long-term effectiveness from the uncontrolled open-label HALO extension study. The committee recalled that the population in the HALO studies was less relevant than the population in FOCUS to the population of interest (see section\xa03.5), but acknowledged that no long-term evidence was available from FOCUS. People who had fremanezumab in HALO EM and HALO CM had the option to continue on a stable dose in the extension study, whereas those who had placebo could opt to be randomly assigned to either 675\xa0mg fremanezumab quarterly or 225\xa0mg monthly (with a 675\xa0mg loading dose in HALO CM). The committee recognised that although the HALO extension study provided some longer-term clinical-effectiveness evidence for people having fremanezumab, comparative effectiveness could not be estimated because the extension study did not include a placebo group. The committee recognised that because not everyone in the trials continued to the extension phase, there was an additional risk of bias. This was because it considered that people not having benefit were more likely to drop out. The company said that the results suggested that treatment effectiveness was maintained long term with no evidence of waning. It noted similar results for people who previously had fremanezumab in HALO EM and HALO CM to those who had previously had placebo, and consistency in results between the 2\xa0fremanezumab dosages (675\xa0mg quarterly and 225\xa0mg monthly). These results were considered academic in confidence by the company and cannot be reported here. The committee concluded that the long-term benefits of fremanezumab compared with best supportive care remained uncertain.\n\n## Fremanezumab may be clinically effective for chronic migraine after 3\xa0preventive treatments and botulinum toxin type\xa0A have failed\n\nClinical experts advised that botulinum toxin type\xa0A is ineffective for about 1\xa0in\xa03\xa0people with chronic migraine, based on real-world studies. The committee recalled that this group of people has high unmet need because of high disease burden and no further treatment options. At consultation, the company submitted additional evidence on the clinical effectiveness of fremanezumab compared with best supportive care for people with chronic migraine after 3\xa0preventive treatments and botulinum toxin type\xa0A have failed. The evidence was based on a post-hoc subgroup analysis of FOCUS. The baseline to week\xa012 results showed improvements in key outcomes (as listed in section\xa03.8), which were in line with the results for the subgroup of people for whom 3\xa0or\xa04\xa0preventive migraine therapies failed (see section\xa03.8). They were considered academic in confidence by the company and cannot be reported here. The ERG highlighted the small population size in this analysis. It noted that the clinical-effectiveness evidence was weak and should be treated with caution. The company also submitted supporting analyses for 2\xa0additional slightly larger populations:\n\npeople for whom 3\xa0or more treatments have failed, one of which was botulinum toxin type\xa0A\n\nall people with chronic migraine for whom botulinum toxin type\xa0A has failed, regardless of the number of prior therapies.The results of these analyses were in line with the main subgroup analysis. The committee noted that the company's analysis was exploratory. But it concluded that fremanezumab appeared to be clinically effective compared with best supportive care for chronic migraine after 3\xa0preventive treatments and botulinum toxin type\xa0A have failed.\n\n# Indirect treatment comparison\n\n## It is uncertain whether fremanezumab is more clinically effective than botulinum toxin type\xa0A\n\nThere was no direct evidence comparing fremanezumab with botulinum toxin type\xa0A for chronic migraine. So the company did an indirect comparison using data from:\n\nFOCUS for fremanezumab\n\nstudy\xa0295, which compared erenumab and placebo\n\nPREEMPT1 and PREEMPT2, which compared botulinum toxin type\xa0A with placebo.The company noted that data from study\xa0295 was included only to strengthen the network and not to include erenumab as an additional comparator. However, the ERG noted that adding this study does not strengthen or weaken the network in any way and so it was not expected to affect the network meta-analysis results. The comparison was in the subgroup for whom 3\xa0or 4\xa0previous treatments had failed (as defined in section\xa03.2). It compared the reduction in monthly migraine days in people on fremanezumab with the reduction in monthly headache days in people on botulinum toxin type\xa0A. It also compared the proportion of people on fremanezumab with at least a 50% reduction in monthly migraine days at 12\xa0weeks with the proportion of people on botulinum toxin type\xa0A with at least a 50% reduction in monthly headache days at 24\xa0weeks. Differences in outcomes and time points reflected the differences in primary outcomes and timing of assessments between the FOCUS and PREEMPT trials. The results of the comparison numerically favoured fremanezumab, but these findings were not statistically significant in people for whom at least 3\xa0preventive treatments had failed (results are academic in confidence and cannot be reported here). Because the results were not statistically significant, fremanezumab could be more effective or less effective than botulinum toxin type\xa0A. The company used placebo as the common comparator, but it was administered differently:\n\nas either a single subcutaneous injection every month or 3\xa0subcutaneous injections every quarter in the fremanezumab trial\n\nas intramuscular injections into 31\xa0to\xa039\xa0different sites on the head and neck in the botulinum toxin type\xa0A trials.The committee thought the differences in administration may have influenced the placebo responses, which were substantially different in the trials. It also considered the difference between monthly migraine days with fremanezumab and monthly headache days with botulinum toxin type\xa0A. The clinical experts explained that headache days and migraine days both affected quality of life but changes in monthly migraine days were more important because migraines are more severe. The committee thought that because these were separately reported as clinically distinct outcomes, they should not be considered the same. The clinical experts acknowledged that there was UK real-world evidence supporting the effectiveness, tolerability and safety of botulinum toxin type\xa0A. The committee acknowledged this and recognised the same evidence was not available for fremanezumab (as for most new treatment options). Given the concern over the analysis and the lack of statistically significant results, the committee concluded that there was a high degree of uncertainty about whether fremanezumab was more clinically effective than botulinum toxin type\xa0A for chronic migraine. It agreed it was appropriate to consider a scenario in which equivalent efficacy was assumed and another in which the results of the network meta-analysis were incorporated.\n\n# Quality of life\n\n## The Migraine-Specific Quality of Life Questionnaire is more sensitive to changes in quality of life caused by migraine than the EQ-5D-5L\n\nHealth-related quality-of-life data was collected in FOCUS using the Migraine-Specific Quality of Life Questionnaire (MSQ) and the EQ‑5D‑5L. The committee was aware that in NICE's reference case and current position statement on the EQ‑5D‑5L, the EQ‑5D‑3L is preferred for base-case analyses. The company considered that the EQ‑5D‑5L was not sensitive to changes in quality of life with migraine because the questionnaire had to be completed on appointment days. This meant that it only captured quality-of-life data for people who were able to attend appointments. A person having a migraine on the day of their appointment would likely rearrange it and the effect of that migraine on quality of life would not be captured. The clinical experts explained that in clinical practice, they use the Headache Impact Test (HIT6) and Migraine Disability Assessment Test (MIDAS) to measure quality of life, so it was not known whether MSQ was the best available measure of quality of life. The company highlighted that the MSQ included a 4‑week recall period, which ensured the effect of migraine on quality of life was captured. The committee concluded that the rationale for using MSQ data was reasonable because the EQ‑5D‑5L was not sufficiently sensitive to changes in quality of life caused by migraine.\n\n# The company's economic model\n\n## The company's economic model is appropriate for decision making\n\nThe company modelled the assessment period of 12\xa0weeks (24\xa0weeks for botulinum toxin type\xa0A) as a decision tree, and the post-assessment period as a Markov model. Episodic and chronic migraine were analysed separately, with each analysis using a dedicated set of input parameters. In the decision tree phase, people were grouped into those whose migraine:\n\nresponded (defined as a 50% reduction for episodic migraine or a 30% reduction for chronic migraine in monthly migraine days from baseline) and who remained on treatment\n\ndid not respond and who stopped treatment.The Markov phase was used to model the distribution of monthly migraine days in each health state: no response (on treatment); response (on treatment); discontinue (off treatment). The committee concluded that the structure of the company's economic model was appropriate for decision making.\n\n# Modelling long-term treatment effectiveness\n\n## A lifetime time horizon is necessary to capture all relevant costs and benefits associated with fremanezumab\n\nThe company's base-case model included a time horizon of 10\xa0years. The company explained that it expected all meaningful differences in costs and quality-adjusted life years (QALYs) between treatments to be captured in this time horizon. It also noted that because there is no long-term natural history data, any long-term modelling beyond 10\xa0years would be highly uncertain. The ERG highlighted that a time horizon of 10\xa0years was a problem for predicting long-term safety and efficacy. However, it agreed with the company that extending the time horizon increased the uncertainty in extrapolating short-term evidence, and because of this it considered 10\xa0years to be a reasonable time horizon. The committee understood that extending the time horizon could increase the uncertainty. But it noted that arbitrarily capping the time horizon could also increase uncertainty because long-term costs and benefits were not captured. It acknowledged that, although the average age of the subgroup from FOCUS was over 40\xa0years, people much younger than this would have treatment in clinical practice. Therefore, it agreed this should be taken into account in the model time horizon. The committee concluded that it preferred a lifetime time horizon to ensure that all relevant costs and benefits associated with fremanezumab were captured. For the rapid review, the company used a lifetime time horizon in its updated model.\n\n## The fremanezumab all-cause discontinuation rate is higher than expected and could affect the cost-effectiveness results\n\nThe company's model included a separate health state for people who stopped treatment. The discontinuation rate applied after each model cycle (4\xa0weeks) was based on the number of people on fremanezumab who dropped out of the HALO extension study. The committee considered that the discontinuation rate (from all causes) was relatively high for what it understood to be a clinically effective and well-tolerated treatment. The ERG noted that the discontinuation rate in the HALO extension study was higher than that seen in the extension studies of another anti-calcitonin gene-related peptide (CGRP), erenumab (NICE has published guidance on erenumab for preventing migraine). The clinical experts noted that the additional injections given in the HALO trials to preserve the blinding of treatment allocation could explain why more people dropped out. The patient experts highlighted that most people would tolerate injections if the treatment was effective. The committee agreed that additional injections alone were unlikely to explain the higher-than-expected discontinuation rates. It also noted that the HALO extension study from which the discontinuation rate was calculated was an open-label study. This meant that treatment allocation was not blinded, so additional sham injections would not be necessary. It acknowledged that because treatment costs stop after discontinuation, an inflated discontinuation rate would affect the cost-effectiveness results. The committee concluded that the discontinuation rate was higher than expected and this could affect the cost-effectiveness results.\n\n## The company's post-discontinuation assumptions are overly optimistic\n\nThe ERG explained that assuming migraine frequency would revert to that of best supportive care after discontinuation from all causes was overly optimistic. This is because the migraine frequency of people having best supportive care was determined by the response to placebo in the clinical trials. It noted that this response was similar to that of people on fremanezumab. It also considered it unrealistic that a substantial treatment effect would be maintained indefinitely for people who are no longer having fremanezumab treatment. The clinical experts highlighted that there was no long-term evidence in people who have stopped treatment, but agreed that it seemed implausible that a substantial treatment benefit would be maintained. The committee agreed that this assumption was overly optimistic because an implausibly large benefit was maintained and costs were stopped. To account for this, the ERG did a scenario analysis. In this, people reverted to baseline migraine days after fremanezumab discontinuation (from all causes), and the treatment effect for people whose migraine responded to best supportive care diminished to baseline over 1\xa0year. The committee agreed that this scenario was more in line with how the clinical experts expected treatment effectiveness could change after stopping treatment. The committee concluded that the company's post-discontinuation assumptions were overly optimistic. It agreed that it would consider the ERG's scenario in which people revert to baseline monthly migraine days after stopping fremanezumab, botulinum toxin type\xa0A or best supportive care.\n\n## Applying a negative stopping rule is appropriate\n\nThe company's model included a negative stopping rule. So in the model, people whose migraine did not respond to treatment (a reduction in monthly migraine days from baseline of less than 50% for episodic migraine or less than 30% for chronic migraine) stopped treatment after assessment at 12\xa0weeks (24\xa0weeks for botulinum toxin type\xa0A). The committee concluded that it was appropriate to include a negative stopping rule at 12\xa0weeks in the economic model if there was no response to treatment. It accepted the company's approach to modelling this. It agreed that any treatment benefit seen while on treatment (during the initial 12\xa0weeks) would not be maintained after stopping the treatment.\n\n## Positive stopping rule assumptions are not appropriate\n\nThe company's model applied a positive stopping rule by assuming 20% of people whose migraine responded to treatment would discontinue every 64\xa0weeks (52‑week treatment period and 12‑week response assessment). After this period, treatment effect was maintained, but treatment costs were stopped indefinitely. The patient expert explained that, from their own experience, once fremanezumab was stopped, the benefit was maintained for only a short time before migraines returned to their pretreatment frequency and severity. The committee recalled that there was a lack of long-term effectiveness evidence for fremanezumab in the population of interest (see section\xa03.9). It recognised that there was no evidence but agreed it was unrealistic to assume that the treatment effect would be maintained indefinitely after stopping treatment. It also noted that any report of long-term treatment effectiveness could be affected by natural variation in the condition. The committee acknowledged that without long-term natural history data, this could not be fully understood. In response to consultation, the company revised its positive stopping rule. The proposed new stopping rule assumed that 15% of people whose migraine responded to treatment would stop every year. It also assumed that once treatment stopped, migraine frequency returned to pretreatment levels within 1\xa0year. The committee was aware that clinical experts considered that successful treatment with fremanezumab would not be continued indefinitely (see section\xa03.2). The company did not provide any positive stopping criteria for chronic or episodic migraine. However, the committee noted clinical expert comments at consultation suggesting that people with chronic migraine would stop treatment when their migraines had reduced to 10\xa0migraine days a month for at least 3\xa0months. The committee was aware that no comments were received about positive stopping criteria in episodic migraine. Therefore, taking account of what it had heard from the clinical experts, the committee considered that there are no clear criteria for when people should stop treatment and understood that a positive stopping rule could be challenging to implement in clinical practice. It recognised that people may not be willing to stop treatment that is beneficial for them. It also recalled that no positive stopping criteria were used in FOCUS. Therefore, the committee concluded that it was not appropriate to apply the company's positive stopping rule in the model. But it acknowledged that treatment may not continue indefinitely after successful treatment and took this into account for decision making.\n\n# Utility values in the economic model\n\n## The company's approach to calculating model utility values is reasonable but still uncertain\n\nThe utility values used in the model were generated from mapping MSQ results to the EQ‑5D‑3L using the Gillard et al. (2012) algorithm. The committee understood that the MSQ data was based on the full trial population, and not just on those for whom 3\xa0or 4\xa0treatments had failed. It also understood that the patient characteristics could not be included in the mapping algorithm because of data limitations. It agreed that this could limit the robustness of the mapped EQ‑5D‑3L utility values used in the economic model. It also noted concerns about the reliability of the utility values given the uncertainty of using data from the broader, full trial population. It noted that the mapping algorithm led to implausibly low utility values for certain patient populations, as confirmed by the clinical experts. The ERG explained that the company did not provide enough detail on how the utility values were extracted and mapped to assess their robustness. The committee concluded that the company's approach to calculating model utility values was reasonable but noted that the values were uncertain because of data limitations.\n\n## The company's original approach to additional on-treatment utility value benefits should not be included in the model\n\nAfter mapping from MSQ to EQ‑5D‑3L, the company split the EQ‑5D utility values into 'on‑treatment' and 'off‑treatment' groups. Off‑treatment health state utility values were estimated using baseline (week\xa00) MSQ data. On‑treatment utility values were estimated from the week\xa04 and week\xa012 MSQ data. Off‑treatment utility values were applied for people on best supportive care and on‑treatment utility values were used for fremanezumab and botulinum toxin type\xa0A until people stopped treatment. The company highlighted that on‑treatment utility value benefits have been shown for people with migraine. It noted that applying treatment-specific utility values was consistent with the appraisal for botulinum toxin type\xa0A for chronic migraine. The ERG noted that the on‑ and off‑treatment utilities were not appropriately generated and applied in the model. It considered the company's approach was overly simplistic and did not account for possible improvements in quality of life related to being included in a clinical trial (placebo effect). It also explained that the on‑treatment utilities were not correctly applied in the model because of how the model was structured. The committee recalled that utility values were generated from MSQ data, which measured the impact of migraine on daily social and work-related activities, and emotional functioning. Therefore, it agreed that it was uncertain whether health-related quality-of-life benefits beyond those related to reducing monthly migraine days were not already adequately captured by the MSQ. It also noted that baseline (before treatment) fremanezumab utility values included a benefit over best supportive care, which it agreed was inconsistent with applying an on‑treatment utility value benefit. At the time of the original guidance (TA631; June 2020), the committee concluded that the company's additional on‑treatment utility value benefits should not be included in the economic model.\n\n## There is a clinical rationale for using differential utilities for on- and off-treatment health states\n\nSince the publication of the original guidance for this topic (TA631), NICE has published guidance on galcanezumab for preventing migraine and erenumab for preventing migraine. Both are anti-CGRP drugs for migraine in adults, like fremanezumab. In these appraisals, the committee was satisfied that it had seen enough evidence to support using differential utilities for the treatment being appraised. That is, using different utilities for people on and off fremanezumab, as a result of taking into account improvements in utilities beyond a reduction in the monthly migraine days measure. For the rapid review of fremanezumab, the company presented evidence to support using differential utility values in its economic modelling. It focused on episodic migraine (specifically when 3\xa0preventive treatments had failed) because fremanezumab was not recommended for episodic migraine in TA631. The company's clinical experts advised that there are improvements in utilities beyond a reduction in the monthly migraine days measure, which does not fully capture the duration and severity of migraines, and other factors that influence quality of life. The company reasoned that quality of life is affected by migraine between attacks, not just during them, so quality-of-life impairment could extend beyond monthly migraine days alone. Using differential utilities reflects further treatment benefits, for example improvements in photophobia and disability levels, less severe migraine attacks, and quicker recovery time. The company explained that a migraine-specific quality-of-life questionnaire was used, which found a significant improvement in the different domains for fremanezumab compared with placebo, in the full FOCUS population and the population for whom 3\xa0or more treatments had failed. The committee noted that a reduction in the monthly migraine days measure would not capture the benefits to people with migraine of being able to plan their lives and remain in employment. It acknowledged that better day-to-day functioning overall would lead to increased quality of life and utility values, and that a similar rationale had been accepted by the committee in other appraisals.\n\n## The company's new approach to modelling differential utility for people on and off treatment is acceptable\n\nThe company's updated analyses for episodic migraine with 3\xa0or more previous treatment failures used differential utilities, and the committee's preference for a normal distribution as in the NICE guidance on galcanezumab and erenumab. The company explained that in its regression analysis, fremanezumab treatment was a significant covariate in its preferred post-baseline model, and that its approach accounted for any placebo effect in the data. It did some face validity checks on the revised utility values generated by the new approach. The ERG believed the company's regression analysis seemed reasonable and consistent with previous migraine appraisals. However, the company did not provide a detailed statistical analysis plan. Because fremanezumab appeared to be a significant covariate, the ERG interpretation was that this may indicate fremanezumab has a utility benefit beyond reducing monthly migraine days alone. The ERG pointed out the similarities between the regression model used in the rapid review and those in the appraisals of galcanezumab and erenumab, which were used to justify the choice to use differential utilities for when people were on and off treatment. The ERG considered that the company's approach in its updated analysis addressed the limitations of previous regression models and used separate models for baseline and post-baseline quality-of-life data. The committee noted that the company should have provided a full statistical analysis plan alongside its updated analyses. It considered that fremanezumab may have a utility benefit beyond fewer monthly migraine days. So the committee concluded it was appropriate to take into account the company's updated analyses using differential utilities for its decision making in the rapid review.\n\n# Costs in the economic model\n\n## Costs used in the economic model are appropriate\n\nThe company based its resource use estimates on data from a European study of migraine burden by Vo et al. (2018). It noted a limitation of the study was that resource use estimates were based on monthly headache days, not migraine days, which it considered could underestimate the migraine cost burden. In the model, it assumed that resource use would be equivalent for both fremanezumab dosage schedules; monthly injections of 225\xa0mg or 3\xa0injections of 675\xa0mg every quarter. The ERG noted that this could be a conservative assumption because quarterly administration is likely to be less resource intensive. The ERG also noted that resource use rates were not specific to the population of interest (that is, people who have had at least 3\xa0failed preventive treatments) but based on the general migraine population. At consultation, the company submitted a revised base-case model, which included updated administration costs for botulinum toxin type\xa0A (£125 per administration as per the 2016/17 tariff; the corresponding cost for 2018/19 should be £116 but this has very limited impact on model results), as estimated by NICE and NHS England in their budget impact analysis. The committee concluded that, despite the limitations in the estimates of resource use, the costs included in the model were appropriate for decision making.\n\n## Some people will need fremanezumab to be administered for them\n\nThe company assumed that fremanezumab could be self-administered by subcutaneous injection. At the technical engagement stage, the clinical experts suggested that most people would be capable of self-administering fremanezumab. However, 1\xa0expert noted that disabled people or people with a learning disability, older people and those who have a phobia of needles may need help. They also noted that additional services may be needed to train people how to administer treatment. The committee concluded that it was unlikely that everyone having fremanezumab would be capable of self-administering treatment. It agreed that applying administration costs for 10% of people having fremanezumab was reasonable, but acknowledged that this had little effect on the model results.\n\n# Cost-effectiveness estimates\n\n## Because of the uncertainty, an acceptable ICER would be towards the lower end of the range normally considered cost effective for episodic migraine\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted a high level of uncertainty, specifically:\n\nthe lack of long-term natural history data and the simplicity of the model (see section\xa03.14)\n\nthe sensitivity of the model to the time horizon and the different post-treatment discontinuation scenarios (see section\xa03.14 and section\xa03.18)\n\nthe sensitivity of the model to alternative utility value assumptions (see section\xa03.20).The committee also considered that the impact of introducing fremanezumab for episodic migraine on NHS resources may be higher than for chronic migraine. This is because episodic migraine is more common than chronic migraine. Therefore, the committee agreed that an acceptable ICER would be towards the lower end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) for episodic migraine.\n\n## Fremanezumab is cost effective for episodic migraine after 3\xa0preventive treatments have failed\n\nThe committee recalled that it had concluded that people with high-frequency episodic migraine were not a distinct group, so it should not consider the cost-effectiveness analysis for this population further (see section\xa03.4). The company's revised base-case ICER for fremanezumab compared with best supportive care for episodic migraine was below the range NICE normally considers an acceptable use of NHS resources. For the rapid review, the company's revised base case included the committee's preferred assumptions from the time of the original guidance (TA631; June 2020):\n\nmodel corrections\n\napplying a lifetime (58\xa0years) model time horizon (see section\xa03.14)\n\napplying the ERG's post-discontinuation scenario (see section\xa03.16)\n\napplying fremanezumab administration costs for 10% of people (see section\xa03.24).\n\nremoving a positive stopping rule (see section\xa03.18)\n\nremoving additional on‑treatment utility benefits (see section\xa03.20).It also included differential utilities for on and off treatment, as well as an updated commercial arrangement. Taking its preferences into account, the committee agreed that the most plausible ICER for fremanezumab compared with best supportive care for episodic migraine after 3\xa0preventive treatments have failed was below £20,000 per QALY gained, which is less than the lower end of the range NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that fremanezumab was a cost-effective use of NHS resources for preventing episodic migraine after 3\xa0preventive treatments have failed.\n\n## Fremanezumab is cost effective for chronic migraine after 3\xa0preventive treatments have failed\n\nThe committee was aware that many uncertainties associated with the episodic migraine evidence also applied to the chronic migraine evidence. However, it was aware that the eligible population and impact on NHS resources would be smaller for chronic migraine than for episodic migraine (see section\xa03.25). It also recalled that consultation comments from professional organisations and patient groups specifically highlighted the unmet need for the chronic migraine population. It therefore considered that an acceptable ICER would be within the range normally considered cost effective. The company's revised base-case fully incremental ICERs for fremanezumab compared with both best supportive care and botulinum toxin type\xa0A were within this range. The company's revised base case assumed the comparative effectiveness estimates from the network meta-analysis (see section\xa03.11) and the committee's preferred assumptions:\n\nmodel corrections\n\napplying a lifetime (58\xa0years) model time horizon (see section\xa03.14)\n\napplying the ERG's post-discontinuation scenario (see section\xa03.16)\n\napplying fremanezumab administration costs for 10% of people (see section\xa03.24).However, the revised base case did not include these committee preferred assumptions:\n\nremoving a positive stopping rule (see section\xa03.18)\n\nremoving additional on‑treatment utility benefits (see section\xa03.20)\n\nconsidering both a scenario of equal effectiveness of fremanezumab and botulinum toxin type\xa0A and a scenario using the results of the network meta-analysis (see section\xa03.11).The committee recalled that patient and expert groups told them of variable access and long waiting times for botulinum toxin type\xa0A treatment. It also recalled that both botulinum toxin type\xa0A and best supportive care were relevant comparators for people with chronic migraine (see section\xa03.3). Taking the committee's preferences into account, the ICER for fremanezumab compared with best supportive care was within the range NICE usually considers a cost-effective use of NHS resources. Taking its preferences into account and including equal effectiveness of fremanezumab and botulinum toxin type\xa0A, the committee noted that fremanezumab was dominated (more costly and less effective) by botulinum toxin type\xa0A. But the committee also noted that the difference in QALYs was very small and related to differences in the timing of the assessment for these 2\xa0treatments (12\xa0weeks for fremanezumab and 24\xa0weeks for botulinum toxin type\xa0A) and subsequent discontinuation of the treatments. Therefore, it agreed the QALYs produced by the 2\xa0treatments were likely similar. The committee noted that the total costs of fremanezumab were slightly higher than those of botulinum toxin type\xa0A over the lifetime model time horizon. The committee was aware that clinical experts considered that fremanezumab would likely cost less than botulinum toxin type\xa0A, but noted that no evidence was provided for this. Therefore, it agreed that the relative costs of the 2\xa0therapies in NHS clinical practice were uncertain. It also considered that a small QALY benefit would be needed to produce an ICER within the range NICE usually considers a cost-effective use of NHS resources. The committee noted the results of 2\xa0surveys done by the Migraine Trust, which showed that most patient and clinical experts consider anti-CGRP drugs to be either as effective as, or more effective than, botulinum toxin type\xa0A (see page\xa017 of the committee papers for the final appraisal document for TA631). The committee noted the methodological limitations of both surveys, which are considered to be low quality in the hierarchy of evidence. But it considered them as expert opinion, and agreed that it could be plausible that fremanezumab may have a small benefit over botulinum toxin type\xa0A. The committee noted that the analysis using clinical-effectiveness estimates from the network meta-analysis produced much bigger QALY benefits than this. When assuming the comparative effectiveness estimates from the network meta-analysis, the ICER for fremanezumab compared with botulinum toxin type\xa0A was within the range NICE usually considers a cost-effective use of NHS resources. Taking all the evidence into consideration, the committee concluded that, although there are still uncertainties with fremanezumab's clinical effectiveness and with the model, fremanezumab was likely to be a cost-effective use of NHS resources for preventing chronic migraine after 3\xa0preventive treatments had failed.\n\n## Fremanezumab is cost effective for chronic migraine after botulinum toxin type\xa0A has failed\n\nThe committee recalled that for the whole chronic migraine population, including the population for whom botulinum toxin type\xa0A had failed, fremanezumab was likely to be a cost-effective use of NHS resources for preventing chronic migraine after 3\xa0preventive treatments had failed (see section\xa03.27). The committee considered the company's additional evidence submitted at consultation for people with chronic migraine only after 3\xa0preventive treatments and botulinum toxin type\xa0A have failed. The committee concluded that the most plausible ICERs for fremanezumab compared with best supportive care were within the range normally considered a cost-effective use of NHS resources, using both company and committee preferred assumptions.\n\n# Other factors\n\n## There are no equalities issues that can be addressed in the guidance\n\nThe company and clinical and patient experts highlighted that migraine can be classed as a disability under the Equality Act (2010). Because migraine is most common in people of working age and affects more women than men, women may be disadvantaged in the workplace. In addition, there may be unequal access to specialist headache clinics in England. The committee considered these issues but concluded that no specific adjustments were needed to NICE's methods in this situation. No other equalities issues were raised after the original guidance for this topic was published (June 2020).\n\n## There are no health-related benefits that are not captured in the analyses\n\nThe company suggested that fremanezumab should be considered as an innovative treatment on the grounds that anti-CGRP therapies represent a step change in the management of migraine. The committee concluded that the modelling had adequately captured the benefits of fremanezumab. But it also acknowledged that fremanezumab administration may be considered more convenient and less unpleasant than administration of botulinum toxin type\xa0A.\n\n# Conclusion\n\n## Fremanezumab for chronic migraine is recommended for use in the NHS\n\nThe committee recognised the substantial burden that migraine has on quality of life and day-to-day functioning. It acknowledged that this could lead to psychosocial issues (see section\xa03.1). The committee recalled that the most relevant comparators for chronic migraine were botulinum toxin type\xa0A and best supportive care (see section\xa03.3). It considered that fremanezumab was a clinically effective treatment compared with placebo (see section\xa03.8). However, the committee considered that it was uncertain whether fremanezumab was more clinically effective than botulinum toxin type\xa0A and agreed that it was appropriate to also consider equal effectiveness (see section\xa03.11). It considered the revised base case provided by the company at consultation, which included a confidential simple discount patient access scheme for fremanezumab. The committee noted that the most plausible ICER for fremanezumab compared with best supportive care was within the range NICE usually considers a cost-effective use of NHS resources. Although there was uncertainty around the relative treatment effects of fremanezumab and botulinum toxin type\xa0A, the committee considered it likely that fremanezumab was a cost-effective use of NHS resources. Therefore, the committee recommended fremanezumab for use in the NHS for preventing chronic migraine in adults after 3\xa0preventive treatments have failed. This includes the chronic migraine population for whom treatment with botulinum toxin type\xa0A has failed. Treatment with fremanezumab should be stopped if migraine frequency does not reduce by at least 30% after 12\xa0weeks of treatment.\n\n## Fremanezumab for episodic migraine is recommended for use in the NHS\n\nThe committee recalled that the most relevant comparator for episodic migraine was best supportive care. It considered that the evidence showed that fremanezumab was clinically effective when compared with best supportive care. It also considered that the evidence in high-frequency episodic migraine was uncertain and did not consider it further because it is not a distinct subgroup. For the rapid review, the company presented new evidence supporting the use of differential utilities on and off treatment, specifically focusing on the population with episodic migraine after 3\xa0preventive treatments have failed. It also submitted an updated commercial arrangement. The committee noted that the company should have provided a statistical analysis plan for the regression carried out. However, all the ICERs for scenarios using the updated model with differential utilities were less than £20,000 per QALY gained, and a scenario without differential utilities resulted in an ICER within the range usually considered an acceptable use of NHS resources. Therefore, the committee recommended fremanezumab for use in the NHS for preventing episodic migraines in adults after 3\xa0preventive treatments have failed. Treatment with fremanezumab should be stopped if migraine frequency does not reduce by at least 50% after 12\xa0weeks of treatment."}
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https://www.nice.org.uk/guidance/ta764
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Evidence-based recommendations on fremanezumab (Ajovy) for preventing migraine in adults.
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04072ddeb3372e6e7ea40731e08132255bbfd050
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nice
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Venetoclax with azacitidine for untreated acute myeloid leukaemia when intensive chemotherapy is unsuitable
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Venetoclax with azacitidine for untreated acute myeloid leukaemia when intensive chemotherapy is unsuitable
Evidence-based recommendations on venetoclax (Venclyxto) with azacitidine for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable.
# Recommendations
Venetoclax with azacitidine is recommended, within its marketing authorisation, as an option for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable. It is recommended only if the company provides venetoclax according to the commercial arrangement.
Why the committee made these recommendations
When intensive chemotherapy is unsuitable, treatment for untreated acute myeloid leukaemia is usually azacitidine or low dose cytarabine. The clinical trial evidence shows that people having venetoclax plus azacitidine live longer than people having azacitidine or low dose cytarabine alone.
Venetoclax with azacitidine meets NICE's criteria for a life-extending treatment at the end of life. The cost-effectiveness results are uncertain because it is not clear how many people who have venetoclax plus azacitidine might be considered cured. However, the likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Therefore, venetoclax plus azacitidine is recommended.# Information about venetoclax
# Marketing authorisation indication
Venetoclax (Venclyxto, AbbVie) in combination with a hypomethylating agent is indicated for 'the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for venetoclax.
# Price
The cost of venetoclax is £299.34 for 7×100 mg tablets (excluding VAT; BNF online accessed September 2021). The cost of azacitidine is £220 per 100‑mg vial (excluding VAT; BNF online accessed September 2021). The company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The general population mortality adjustment should be removed from the transition to the progression/relapse health state in the model (issue 2, see ERG report, section 4.2.6).
The company's updated approach to modelling time to treatment discontinuation is acceptable (issue 3, see ERG report, section 4.2.6).
It is acceptable in this case for adverse event data in the model to be sourced from a separate study to the VIALE trials, because it is unlikely to have a big impact on the cost-effectiveness results (issue 4, see ERG report, section 4.2.7).
It is acceptable in this case for treatment-independent utility values in the model to be derived from pooled data from both VIALE‑A and VIALE‑C, because it is unlikely to have a big impact on the cost-effectiveness results (issue 4, see ERG report, section 4.2.7).
Seven days' wastage for venetoclax should be included in the model to account for tablets that are prescribed but not used because of treatment discontinuation or death during a cycle (issue 6, see ERG report, section 4.2.8).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed issues 1, 5 and an additional issue identified at technical engagement, issue 7, which were outstanding after the technical engagement stage.
# New treatment option
## People with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option
Intensive chemotherapy is unsuitable for about 40% of people with untreated acute myeloid leukaemia. This may be because of fitness status, age or presence of comorbidities. The patient expert explained that patients in this group feel that treatment options for them are very limited. They value increased survival as much as increased quality of life, and the possibility of long-term remission with venetoclax plus azacitidine is appealing. Clinical experts also stated that there is a significant unmet need for new treatments for this population because outcomes with currently available treatments are poor. Venetoclax is an oral treatment that can be taken at home, so the time patients need to be in hospital might be significantly reduced. Patients would also appreciate being able to manage side effects at home when possible. The committee concluded that people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option.
# Comparators
## Splitting the trial population by blast cell count is necessary to compare venetoclax plus azacitidine with the relevant comparators but increases uncertainty
The evidence for venetoclax came from a randomised controlled trial, VIALE‑A (n=431), which compared venetoclax plus azacitidine with azacitidine alone in people with untreated acute myeloid leukaemia who could not have intensive chemotherapy because of age or comorbidities. The clinical experts considered that the population in the trial would be generalisable to people who would be eligible for venetoclax plus azacitidine in England. In the NHS in England, when intensive chemotherapy is unsuitable, acute myeloid leukaemia is treated with either azacitidine or low dose cytarabine. NICE's technology appraisal guidance on azacitidine recommends azacitidine only for acute myeloid leukaemia with 20% to 30% bone marrow blasts (from here, blasts). In practice, this means that low dose cytarabine is used for acute myeloid leukaemia with over 30% blasts. Therefore, the company did a post hoc subgroup analysis to split the trial population by blast count. It used the data from the subgroup with 20% to 30% blasts to compare venetoclax plus azacitidine with azacitidine alone. Another randomised controlled trial, VIALE‑C (n=211), compared venetoclax and low dose cytarabine with low dose cytarabine alone in the same overall population as VIALE‑A. To compare venetoclax plus azacitidine with low dose cytarabine in the group with over 30% blasts, the company used the over 30% blasts subgroup data on venetoclax plus azacitidine from VIALE‑A, and data on low dose cytarabine from a subgroup with over 30% blasts from VIALE‑C. The committee concluded that it was necessary to use the subgroup data to compare venetoclax plus azacitidine with the relevant comparators in clinical practice in England, but that the subgroup analysis increased uncertainty in the results.
# Clinical efficacy
## Venetoclax plus azacitidine increases overall survival compared with azacitidine or low dose cytarabine alone
The post hoc subgroup analysis splitting the trial population by blast count showed that venetoclax plus azacitidine increased overall survival compared with azacitidine alone in the subgroup with 20% to 30% blasts, but the increase was not statistically significant. The company noted that the VIALE trials were not powered to identify clinical benefit in these subgroups. The company considers the exact results to be academic in confidence, so they cannot be reported here. The post hoc analysis comparing venetoclax plus azacitidine (from VIALE‑A) with low dose cytarabine (from VIALE‑C) in the group with over 30% blasts showed that venetoclax plus azacitidine increased overall survival compared with low dose cytarabine, and that this increase was statistically significant. The company considers the exact results to be academic in confidence so they cannot be reported here. The company also did a network meta-analysis and propensity score matching to compare results across the 2 trials in the group with over 30% blasts and noted that the results were similar to those of the unadjusted comparison. The committee concluded that venetoclax plus azacitidine increases overall survival compared with azacitidine or low dose cytarabine alone.
# Economic model
## The company's economic model included a cure health state
The company presented a cohort-level state transition model to assess the cost effectiveness of venetoclax plus azacitidine. The model included 5 health states: remission, non-remission, cure, progressive disease/relapse and death. In the company's original model, patients having venetoclax who were alive after 2 years of being in the remission health state moved into the cure state. Patients having azacitidine alone could not transition to the cure state.
## The evidence for including a cure state in the model is uncertain, but it is plausible that some people may be cured
The company stated that the VIALE‑A results showed that complete remission rates with venetoclax plus azacitidine were similar to those seen in patients over 60 receiving intensive chemotherapy, and that rates of sustained deep remission were higher with venetoclax plus azacitidine than with azacitidine alone. It argued that there was an established relationship between complete remission and long-term survival, and that it was therefore plausible to assume that some patients having venetoclax plus azacitidine could be considered cured. It cited clinical advice that the rate of relapse after 2 years in remission is low and commented that there was a plateau in the Kaplan–Meier curve at 2 years. The ERG noted that there was a lack of long-term data to validate a cure assumption because the maximum follow up in VIALE‑A was 2.56 years. It highlighted that, historically, non-intensive treatments such as azacitidine and low dose cytarabine have not been considered curative in this population, and that the Kaplan–Meier curve was based on very few patients by 2 years. The clinical experts stated that it was plausible that there could be a proportion of patients who are cured after having venetoclax, but that it was difficult to specify a time frame, and there was a lack of evidence to inform this. At technical engagement, a professional organisation highlighted a small study by Chyn Chua et al. comparing stopping venetoclax treatment while in remission, with continuing it until relapse. It considered that the results suggested that venetoclax could be stopped after 2 years in remission without a negative impact on outcomes. However, the committee noted that in this study, a number of relapses occurred after 2 years. At consultation, the authors of the study commented that most of the late relapses were associated with new molecular or cytogenetic abnormalities, suggesting they were not relapses of the original disease. The company highlighted that a cure assumption had been included in NICE's technology appraisal guidance on gilteritinib for treating relapsed or refractory acute myeloid leukaemia. However, the committee noted that this appraisal was in a different population and that although the committee had accepted a cure assumption applied to all patients alive at between 2 and 3 years in the gilteritinib model, a substantial proportion of people in the trial had received a stem cell transplant. The committee also noted that the cure assumption in the gilteritinib model applied to both the gilteritinib and salvage chemotherapy arms, whereas in the venetoclax model it only applied to the venetoclax arm. The committee agreed that any cure state in the venetoclax model should have been applied to both arms. However, the ERG presented scenario analyses applying the cure state to the azacitidine and low dose cytarabine arms, and this only had a small impact on the cost-effectiveness results. At consultation, the company updated its base-case model so that people moved into the cure state after 3 years of being in remission, instead of 2 years. It also presented scenario analyses in which only a proportion of people in remission transitioned to the cure state. The rest remained in the remission state with a continuing disease-related risk of relapse and death. The ERG presented further scenario analyses with alternative proportions and noted that the cost-effectiveness results were not sensitive to the different proportions explored in these scenarios. The clinical experts estimated that 10% to 20% of people having venetoclax plus azacitidine may reach 3 years without a relapse and that 80% to 90% of these people would then never have a relapse. They explained that around 30% of people in this population have acute myeloid leukaemia with an NPM1, IDH1 or IDH2 mutation, and that these patients may be more likely to be cured. At the first committee meeting, the committee noted that cure fractions estimated from a mixture cure model may have been helpful to provide some basis for validating the proportion of patients remaining in the remission health state over time. At consultation, the company presented the proportion of people remaining in remission at various time points, based on removing the cure state and applying mixture cure models to separate transitions (from remission to relapse and from remission to death) to validate the proportion of the overall cohort who were in remission at different time points. The committee noted that it would have preferred to see the cure fraction reported from a mixture cure model fitted to the overall population. The committee concluded that the evidence for including a cure state in the model was uncertain, but that it was plausible that some people could be considered cured.
## Using the remission state utility value in the cure state does not affect the cost-effectiveness results
In the cure health state, patients were assumed to have the same utility value as that of the general population. The clinical experts stated that most people would return to the same level of quality of life after treatment as could be expected in the general population, but that a small number would not. The committee did not consider it plausible that patients in the cure state would experience the same level of quality of life as the general population. However, at consultation, the company stated that because of the age of patients in the model at the point of cure, the age-adjusted general population utility was always lower than the remission health state utility. Therefore, using the remission utility value in the cure state, capped by general population utility, had no effect on the cost-effectiveness results. The committee accepted that using the remission state utility value in the cure state did not affect the cost-effectiveness results.
## The company's updated assumptions about the proportions of people having subsequent gilteritinib are acceptable
In the company's original model, 3% of people in the venetoclax plus azacitidine arm had gilteritinib after venetoclax plus azacitidine, and all others who had subsequent treatment had hydroxycarbamide. The ERG suggested this proportion should be higher, based on clinical advice. At technical engagement, clinical experts and professional groups agreed that around 10% of people may have FLT3‑mutation‑positive disease and be eligible for gilteritinib after venetoclax plus azacitidine, azacitidine alone or low dose cytarabine. The company cited clinical advice that suggested more people who had venetoclax with azacitidine would be able to have subsequent treatment with gilteritinib than people who had azacitidine alone, because it was more likely their disease would go into complete remission. The company updated its base case to include 5% of people having gilteritinib after venetoclax plus azacitidine, and 3% having gilteritinib after azacitidine or low dose cytarabine. It also presented a scenario analysis showing that increasing the proportions to 15% after venetoclax plus azacitidine, and 10% after azacitidine or low dose cytarabine, had a small impact on the cost-effectiveness results. The ERG's clinical expert considered that the company's updated base-case assumptions were plausible. The committee agreed that the company's updated base-case assumptions were acceptable to use in the model.
## The company's updated modelling of dose intensity reflects clinical practice
The dose of venetoclax in the summary of product characteristics in VIALE‑A and in the company's model was 400 mg daily, after treatment initiation. The company applied a dose intensity of 50% to venetoclax in its model, based on clinical advice that the amount of venetoclax received by patients in the VIALE‑A trial was higher than would be expected in clinical practice in England. At technical engagement, clinical experts stated that in clinical practice in England, almost all patients with acute myeloid leukaemia would have concomitant treatment with azoles such as posaconazole as antifungal prophylaxis. Azoles are strong CYP3A inhibitors, which affect the metabolism of venetoclax and increase its plasma level. Therefore, in line with the summary of product characteristics advice on managing potential venetoclax interactions with CYP3A inhibitors, the dose of venetoclax used in clinical practice would be much lower than in the trial, usually 100 mg a day rather than 400 mg. The clinical experts also stated that they would often only give venetoclax for 14 days from the second cycle onwards, rather than 28 days, to limit toxicity. The company highlighted the summary of product characteristics for venetoclax, which notes that in most cases, this should be considered once the person's disease is in remission. The committee agreed that the dose intensity of venetoclax in the NHS in England would likely be 25% of the full licensed dose for the first cycle, and 12.5% from cycle 2 onwards. In response to consultation, the company updated its model to use a dose intensity for venetoclax of 25% for the first cycle and 12.5% from cycle 2 onwards. It presented a pharmacokinetic study that showed that a 100 mg dose of venetoclax given with a strong CYP3A inhibitor led to drug exposure between that of a 400 mg dose and the safe maximum dose of 1,200 mg per day. The company also presented a post hoc analysis of VIALE‑A data showing that complete remission rates were similar when an adjusted dose was given with a CYP3A inhibitor, compared with the licensed dose and no CYP3A inhibitor. The committee concluded that the company's updated modelling was appropriate and reflected clinical practice.
# End of life
## Venetoclax meets the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in the VIALE trials for people having azacitidine in the 20% to 30% blast count group and low dose cytarabine in the over 30% blast count group was under 24 months. The company considers the exact figures to be academic in confidence and so they cannot be reported here. The mean undiscounted life years in the model were 1.83 years for the azacitidine (20% to 30% blast count) arm and 0.84 years for the low dose cytarabine (over 30% blast count) arm. The committee agreed that the short life expectancy criterion was met. The increases in median overall survival from the trials for venetoclax plus azacitidine compared with azacitidine alone in the 20% to 30% blast count group and compared with low dose cytarabine in the over 30% blast count group were over 3 months. The company considers the exact figures to be academic in confidence so they cannot be reported here. The mean incremental undiscounted life years in the model were over 3 months across all scenarios for venetoclax plus azacitidine compared with azacitidine alone (20% to 30% blast count) and for venetoclax plus azacitidine compared with low dose cytarabine (over 30% blast count). The committee agreed that the extension to life criterion was met. It therefore concluded that venetoclax plus azacitidine met the criteria to be considered a life-extending treatment at the end of life.
# Cost-effectiveness results
## All the plausible ICERs presented are below £50,000 per QALY gained
All analyses included the patient access scheme for venetoclax. After technical engagement, the company's base-case incremental cost-effectiveness ratio (ICER) was £24,824 per quality-adjusted life year (QALY) gained for venetoclax plus azacitidine compared with azacitidine alone in the 20% to 30% blasts population, and £41,481 per QALY gained compared with low dose cytarabine in the over 30% blasts population. This included a cure point at 2 years. In its exploratory analyses, the ERG preferred to use alternative costs for adverse events in the model, to account for long-stay admissions. It also corrected an error in the cost of subsequent treatment. After consultation, the company presented a revised base case, which included:
the ERG's correction and alternative costs for adverse events
a cure state at 3 years instead of 2 (see section 3.5)
the dose intensity of venetoclax that reflects clinical practice (see section 3.8).This resulted in an updated base-case ICER of £26,760 per QALY gained for venetoclax plus azacitidine compared with azacitidine alone in the 20% to 30% blasts population, and £38,900 per QALY gained compared with low dose cytarabine in the over 30% blasts population. The company and ERG presented scenario analyses in which only a proportion of people who were in remission at 3 years were assumed to be cured. When the ERG included the confidential discount for gilteritinib subsequent treatment in its analyses, the ICERs decreased slightly. Because of the confidentiality of this discount, the exact ICERs cannot be reported here. The committee noted that the ICER remained below £50,000 per QALY gained when only 10% or less of the patients in remission at 3 years were considered cured. The committee understood that this proportion was considerably lower than the proportion that the clinical experts had considered plausible (80% to 90%). The committee concluded that all the plausible ICERs presented were below £50,000 per QALY gained.
## Venetoclax with azacitidine is recommended for routine use in the NHS
Because all of the plausible ICERs were within the range that NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life, the committee recommended venetoclax plus azacitidine as an option for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable. This includes those in the 20% to 30% blast group and the over 30% blast group.
# Equality and innovation
## There are no equality issues relevant to the recommendations
A committee member highlighted that venetoclax could provide an effective treatment option for older people who have not benefitted from other recent advances in treatment, and that anyone who cannot easily travel to a major hospital may particularly benefit from being able to take venetoclax at home. The committee considered these potential issues but noted that the recommendation would apply to all patients, regardless of age or location. It concluded that no equality issues relevant to the recommendations had been identified.
## The benefits of venetoclax are captured in the cost-effectiveness analysis
The company, professional organisations and clinical experts considered that venetoclax was innovative because it was a targeted therapy, was different to currently available therapies, led to increased overall survival and rates of complete and deep remissions, and decreased the need for blood transfusions. The committee agreed that these were important benefits of venetoclax, but concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY calculation.
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{'Recommendations': "Venetoclax with azacitidine is recommended, within its marketing authorisation, as an option for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable. It is recommended only if the company provides venetoclax according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nWhen intensive chemotherapy is unsuitable, treatment for untreated acute myeloid leukaemia is usually azacitidine or low dose cytarabine. The clinical trial evidence shows that people having venetoclax plus azacitidine live longer than people having azacitidine or low dose cytarabine alone.\n\nVenetoclax with azacitidine meets NICE's criteria for a life-extending treatment at the end of life. The cost-effectiveness results are uncertain because it is not clear how many people who have venetoclax plus azacitidine might be considered cured. However, the likely cost-effectiveness estimates are within the range that NICE normally considers an acceptable use of NHS resources. Therefore, venetoclax plus azacitidine is recommended.", 'Information about venetoclax': "# Marketing authorisation indication\n\nVenetoclax (Venclyxto, AbbVie) in combination with a hypomethylating agent is indicated for 'the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for venetoclax.\n\n# Price\n\nThe cost of venetoclax is £299.34 for 7×100\xa0mg tablets (excluding VAT; BNF online accessed September\xa02021). The cost of azacitidine is £220\xa0per 100‑mg vial (excluding VAT; BNF online accessed September\xa02021). The company has a commercial arrangement. This makes venetoclax available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe general population mortality adjustment should be removed from the transition to the progression/relapse health state in the model (issue\xa02, see ERG report, section\xa04.2.6).\n\nThe company's updated approach to modelling time to treatment discontinuation is acceptable (issue\xa03, see ERG report, section\xa04.2.6).\n\nIt is acceptable in this case for adverse event data in the model to be sourced from a separate study to the VIALE trials, because it is unlikely to have a big impact on the cost-effectiveness results (issue\xa04, see ERG report, section\xa04.2.7).\n\nIt is acceptable in this case for treatment-independent utility values in the model to be derived from pooled data from both VIALE‑A and VIALE‑C, because it is unlikely to have a big impact on the cost-effectiveness results (issue\xa04, see ERG report, section\xa04.2.7).\n\nSeven\xa0days' wastage for venetoclax should be included in the model to account for tablets that are prescribed but not used because of treatment discontinuation or death during a cycle (issue\xa06, see ERG report, section\xa04.2.8).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision making. It discussed issues\xa01, 5 and an additional issue identified at technical engagement, issue\xa07, which were outstanding after the technical engagement stage.\n\n# New treatment option\n\n## People with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option\n\nIntensive chemotherapy is unsuitable for about 40% of people with untreated acute myeloid leukaemia. This may be because of fitness status, age or presence of comorbidities. The patient expert explained that patients in this group feel that treatment options for them are very limited. They value increased survival as much as increased quality of life, and the possibility of long-term remission with venetoclax plus azacitidine is appealing. Clinical experts also stated that there is a significant unmet need for new treatments for this population because outcomes with currently available treatments are poor. Venetoclax is an oral treatment that can be taken at home, so the time patients need to be in hospital might be significantly reduced. Patients would also appreciate being able to manage side effects at home when possible. The committee concluded that people with acute myeloid leukaemia for whom intensive chemotherapy is unsuitable would welcome a new treatment option.\n\n# Comparators\n\n## Splitting the trial population by blast cell count is necessary to compare venetoclax plus azacitidine with the relevant comparators but increases uncertainty\n\nThe evidence for venetoclax came from a randomised controlled trial, VIALE‑A (n=431), which compared venetoclax plus azacitidine with azacitidine alone in people with untreated acute myeloid leukaemia who could not have intensive chemotherapy because of age or comorbidities. The clinical experts considered that the population in the trial would be generalisable to people who would be eligible for venetoclax plus azacitidine in England. In the NHS in England, when intensive chemotherapy is unsuitable, acute myeloid leukaemia is treated with either azacitidine or low dose cytarabine. NICE's technology appraisal guidance on azacitidine recommends azacitidine only for acute myeloid leukaemia with 20% to 30% bone marrow blasts (from here, blasts). In practice, this means that low dose cytarabine is used for acute myeloid leukaemia with over 30% blasts. Therefore, the company did a post hoc subgroup analysis to split the trial population by blast count. It used the data from the subgroup with 20% to 30% blasts to compare venetoclax plus azacitidine with azacitidine alone. Another randomised controlled trial, VIALE‑C (n=211), compared venetoclax and low dose cytarabine with low dose cytarabine alone in the same overall population as VIALE‑A. To compare venetoclax plus azacitidine with low dose cytarabine in the group with over 30% blasts, the company used the over 30% blasts subgroup data on venetoclax plus azacitidine from VIALE‑A, and data on low dose cytarabine from a subgroup with over 30% blasts from VIALE‑C. The committee concluded that it was necessary to use the subgroup data to compare venetoclax plus azacitidine with the relevant comparators in clinical practice in England, but that the subgroup analysis increased uncertainty in the results.\n\n# Clinical efficacy\n\n## Venetoclax plus azacitidine increases overall survival compared with azacitidine or low dose cytarabine alone\n\nThe post hoc subgroup analysis splitting the trial population by blast count showed that venetoclax plus azacitidine increased overall survival compared with azacitidine alone in the subgroup with 20% to 30% blasts, but the increase was not statistically significant. The company noted that the VIALE trials were not powered to identify clinical benefit in these subgroups. The company considers the exact results to be academic in confidence, so they cannot be reported here. The post hoc analysis comparing venetoclax plus azacitidine (from VIALE‑A) with low dose cytarabine (from VIALE‑C) in the group with over 30% blasts showed that venetoclax plus azacitidine increased overall survival compared with low dose cytarabine, and that this increase was statistically significant. The company considers the exact results to be academic in confidence so they cannot be reported here. The company also did a network meta-analysis and propensity score matching to compare results across the 2\xa0trials in the group with over 30% blasts and noted that the results were similar to those of the unadjusted comparison. The committee concluded that venetoclax plus azacitidine increases overall survival compared with azacitidine or low dose cytarabine alone.\n\n# Economic model\n\n## The company's economic model included a cure health state\n\nThe company presented a cohort-level state transition model to assess the cost effectiveness of venetoclax plus azacitidine. The model included 5\xa0health states: remission, non-remission, cure, progressive disease/relapse and death. In the company's original model, patients having venetoclax who were alive after 2\xa0years of being in the remission health state moved into the cure state. Patients having azacitidine alone could not transition to the cure state.\n\n## The evidence for including a cure state in the model is uncertain, but it is plausible that some people may be cured\n\nThe company stated that the VIALE‑A results showed that complete remission rates with venetoclax plus azacitidine were similar to those seen in patients over 60 receiving intensive chemotherapy, and that rates of sustained deep remission were higher with venetoclax plus azacitidine than with azacitidine alone. It argued that there was an established relationship between complete remission and long-term survival, and that it was therefore plausible to assume that some patients having venetoclax plus azacitidine could be considered cured. It cited clinical advice that the rate of relapse after 2\xa0years in remission is low and commented that there was a plateau in the Kaplan–Meier curve at 2\xa0years. The ERG noted that there was a lack of long-term data to validate a cure assumption because the maximum follow up in VIALE‑A was 2.56\xa0years. It highlighted that, historically, non-intensive treatments such as azacitidine and low dose cytarabine have not been considered curative in this population, and that the Kaplan–Meier curve was based on very few patients by 2\xa0years. The clinical experts stated that it was plausible that there could be a proportion of patients who are cured after having venetoclax, but that it was difficult to specify a time frame, and there was a lack of evidence to inform this. At technical engagement, a professional organisation highlighted a small study by Chyn Chua et al. comparing stopping venetoclax treatment while in remission, with continuing it until relapse. It considered that the results suggested that venetoclax could be stopped after 2\xa0years in remission without a negative impact on outcomes. However, the committee noted that in this study, a number of relapses occurred after 2\xa0years. At consultation, the authors of the study commented that most of the late relapses were associated with new molecular or cytogenetic abnormalities, suggesting they were not relapses of the original disease. The company highlighted that a cure assumption had been included in NICE's technology appraisal guidance on gilteritinib for treating relapsed or refractory acute myeloid leukaemia. However, the committee noted that this appraisal was in a different population and that although the committee had accepted a cure assumption applied to all patients alive at between 2 and 3\xa0years in the gilteritinib model, a substantial proportion of people in the trial had received a stem cell transplant. The committee also noted that the cure assumption in the gilteritinib model applied to both the gilteritinib and salvage chemotherapy arms, whereas in the venetoclax model it only applied to the venetoclax arm. The committee agreed that any cure state in the venetoclax model should have been applied to both arms. However, the ERG presented scenario analyses applying the cure state to the azacitidine and low dose cytarabine arms, and this only had a small impact on the cost-effectiveness results. At consultation, the company updated its base-case model so that people moved into the cure state after 3\xa0years of being in remission, instead of 2\xa0years. It also presented scenario analyses in which only a proportion of people in remission transitioned to the cure state. The rest remained in the remission state with a continuing disease-related risk of relapse and death. The ERG presented further scenario analyses with alternative proportions and noted that the cost-effectiveness results were not sensitive to the different proportions explored in these scenarios. The clinical experts estimated that 10%\xa0to 20% of people having venetoclax plus azacitidine may reach 3\xa0years without a relapse and that 80%\xa0to 90% of these people would then never have a relapse. They explained that around 30% of people in this population have acute myeloid leukaemia with an NPM1, IDH1 or IDH2 mutation, and that these patients may be more likely to be cured. At the first committee meeting, the committee noted that cure fractions estimated from a mixture cure model may have been helpful to provide some basis for validating the proportion of patients remaining in the remission health state over time. At consultation, the company presented the proportion of people remaining in remission at various time points, based on removing the cure state and applying mixture cure models to separate transitions (from remission to relapse and from remission to death) to validate the proportion of the overall cohort who were in remission at different time points. The committee noted that it would have preferred to see the cure fraction reported from a mixture cure model fitted to the overall population. The committee concluded that the evidence for including a cure state in the model was uncertain, but that it was plausible that some people could be considered cured.\n\n## Using the remission state utility value in the cure state does not affect the cost-effectiveness results\n\nIn the cure health state, patients were assumed to have the same utility value as that of the general population. The clinical experts stated that most people would return to the same level of quality of life after treatment as could be expected in the general population, but that a small number would not. The committee did not consider it plausible that patients in the cure state would experience the same level of quality of life as the general population. However, at consultation, the company stated that because of the age of patients in the model at the point of cure, the age-adjusted general population utility was always lower than the remission health state utility. Therefore, using the remission utility value in the cure state, capped by general population utility, had no effect on the cost-effectiveness results. The committee accepted that using the remission state utility value in the cure state did not affect the cost-effectiveness results.\n\n## The company's updated assumptions about the proportions of people having subsequent gilteritinib are acceptable\n\nIn the company's original model, 3% of people in the venetoclax plus azacitidine arm had gilteritinib after venetoclax plus azacitidine, and all others who had subsequent treatment had hydroxycarbamide. The ERG suggested this proportion should be higher, based on clinical advice. At technical engagement, clinical experts and professional groups agreed that around 10% of people may have FLT3‑mutation‑positive disease and be eligible for gilteritinib after venetoclax plus azacitidine, azacitidine alone or low dose cytarabine. The company cited clinical advice that suggested more people who had venetoclax with azacitidine would be able to have subsequent treatment with gilteritinib than people who had azacitidine alone, because it was more likely their disease would go into complete remission. The company updated its base case to include 5% of people having gilteritinib after venetoclax plus azacitidine, and 3% having gilteritinib after azacitidine or low dose cytarabine. It also presented a scenario analysis showing that increasing the proportions to 15% after venetoclax plus azacitidine, and 10% after azacitidine or low dose cytarabine, had a small impact on the cost-effectiveness results. The ERG's clinical expert considered that the company's updated base-case assumptions were plausible. The committee agreed that the company's updated base-case assumptions were acceptable to use in the model.\n\n## The company's updated modelling of dose intensity reflects clinical practice\n\nThe dose of venetoclax in the summary of product characteristics in VIALE‑A and in the company's model was 400\xa0mg daily, after treatment initiation. The company applied a dose intensity of 50% to venetoclax in its model, based on clinical advice that the amount of venetoclax received by patients in the VIALE‑A trial was higher than would be expected in clinical practice in England. At technical engagement, clinical experts stated that in clinical practice in England, almost all patients with acute myeloid leukaemia would have concomitant treatment with azoles such as posaconazole as antifungal prophylaxis. Azoles are strong CYP3A inhibitors, which affect the metabolism of venetoclax and increase its plasma level. Therefore, in line with the summary of product characteristics advice on managing potential venetoclax interactions with CYP3A inhibitors, the dose of venetoclax used in clinical practice would be much lower than in the trial, usually 100\xa0mg a day rather than 400\xa0mg. The clinical experts also stated that they would often only give venetoclax for 14\xa0days from the second cycle onwards, rather than 28\xa0days, to limit toxicity. The company highlighted the summary of product characteristics for venetoclax, which notes that in most cases, this should be considered once the person's disease is in remission. The committee agreed that the dose intensity of venetoclax in the NHS in England would likely be 25% of the full licensed dose for the first cycle, and 12.5% from cycle\xa02 onwards. In response to consultation, the company updated its model to use a dose intensity for venetoclax of 25% for the first cycle and 12.5% from cycle\xa02 onwards. It presented a pharmacokinetic study that showed that a 100\xa0mg dose of venetoclax given with a strong CYP3A inhibitor led to drug exposure between that of a 400\xa0mg dose and the safe maximum dose of 1,200\xa0mg per day. The company also presented a post hoc analysis of VIALE‑A data showing that complete remission rates were similar when an adjusted dose was given with a CYP3A inhibitor, compared with the licensed dose and no CYP3A inhibitor. The committee concluded that the company's updated modelling was appropriate and reflected clinical practice.\n\n# End of life\n\n## Venetoclax meets the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Median overall survival in the VIALE trials for people having azacitidine in the 20% to 30% blast count group and low dose cytarabine in the over 30% blast count group was under 24\xa0months. The company considers the exact figures to be academic in confidence and so they cannot be reported here. The mean undiscounted life years in the model were 1.83\xa0years for the azacitidine (20%\xa0to 30% blast count) arm and 0.84\xa0years for the low dose cytarabine (over 30% blast count) arm. The committee agreed that the short life expectancy criterion was met. The increases in median overall survival from the trials for venetoclax plus azacitidine compared with azacitidine alone in the 20% to 30% blast count group and compared with low dose cytarabine in the over 30% blast count group were over 3\xa0months. The company considers the exact figures to be academic in confidence so they cannot be reported here. The mean incremental undiscounted life years in the model were over 3\xa0months across all scenarios for venetoclax plus azacitidine compared with azacitidine alone (20%\xa0to 30% blast count) and for venetoclax plus azacitidine compared with low dose cytarabine (over 30% blast count). The committee agreed that the extension to life criterion was met. It therefore concluded that venetoclax plus azacitidine met the criteria to be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness results\n\n## All the plausible ICERs presented are below £50,000 per QALY gained\n\nAll analyses included the patient access scheme for venetoclax. After technical engagement, the company's base-case incremental cost-effectiveness ratio (ICER) was £24,824 per quality-adjusted life year (QALY) gained for venetoclax plus azacitidine compared with azacitidine alone in the 20%\xa0to 30% blasts population, and £41,481 per QALY gained compared with low dose cytarabine in the over 30% blasts population. This included a cure point at 2\xa0years. In its exploratory analyses, the ERG preferred to use alternative costs for adverse events in the model, to account for long-stay admissions. It also corrected an error in the cost of subsequent treatment. After consultation, the company presented a revised base case, which included:\n\nthe ERG's correction and alternative costs for adverse events\n\na cure state at 3\xa0years instead of 2 (see section\xa03.5)\n\nthe dose intensity of venetoclax that reflects clinical practice (see section\xa03.8).This resulted in an updated base-case ICER of £26,760 per QALY gained for venetoclax plus azacitidine compared with azacitidine alone in the 20%\xa0to 30% blasts population, and £38,900 per QALY gained compared with low dose cytarabine in the over 30% blasts population. The company and ERG presented scenario analyses in which only a proportion of people who were in remission at 3\xa0years were assumed to be cured. When the ERG included the confidential discount for gilteritinib subsequent treatment in its analyses, the ICERs decreased slightly. Because of the confidentiality of this discount, the exact ICERs cannot be reported here. The committee noted that the ICER remained below £50,000 per QALY gained when only 10% or less of the patients in remission at 3\xa0years were considered cured. The committee understood that this proportion was considerably lower than the proportion that the clinical experts had considered plausible (80%\xa0to 90%). The committee concluded that all the plausible ICERs presented were below £50,000 per QALY gained.\n\n## Venetoclax with azacitidine is recommended for routine use in the NHS\n\nBecause all of the plausible ICERs were within the range that NICE normally considers to be a cost-effective use of NHS resources for a life-extending treatment at the end of life, the committee recommended venetoclax plus azacitidine as an option for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable. This includes those in the 20% to 30% blast group and the over 30% blast group.\n\n# Equality and innovation\n\n## There are no equality issues relevant to the recommendations\n\nA committee member highlighted that venetoclax could provide an effective treatment option for older people who have not benefitted from other recent advances in treatment, and that anyone who cannot easily travel to a major hospital may particularly benefit from being able to take venetoclax at home. The committee considered these potential issues but noted that the recommendation would apply to all patients, regardless of age or location. It concluded that no equality issues relevant to the recommendations had been identified.\n\n## The benefits of venetoclax are captured in the cost-effectiveness analysis\n\nThe company, professional organisations and clinical experts considered that venetoclax was innovative because it was a targeted therapy, was different to currently available therapies, led to increased overall survival and rates of complete and deep remissions, and decreased the need for blood transfusions. The committee agreed that these were important benefits of venetoclax, but concluded that it had not been presented with evidence of any additional benefits that were not captured in the QALY calculation."}
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https://www.nice.org.uk/guidance/ta765
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Evidence-based recommendations on venetoclax (Venclyxto) with azacitidine for untreated acute myeloid leukaemia in adults when intensive chemotherapy is unsuitable.
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59ccfe6747f6f0b1cd2bcfae58f4fe1413fa1bc9
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nice
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Pembrolizumab for adjuvant treatment of completely resected stage 3 melanoma
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Pembrolizumab for adjuvant treatment of completely resected stage 3 melanoma
Evidence-based recommendations on pembrolizumab (Keytruda) for adjuvant treatment of completely resected stage 3 melanoma in adults.
# Recommendations
Pembrolizumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of completely resected stage 3 melanoma with lymph node involvement in adults. It is recommended only if the company provides pembrolizumab according to the commercial arrangement.
Why the committee made this recommendation
Until recently, standard care for people with completely resected melanoma was routine surveillance. Adjuvant treatments such as nivolumab are now available for some people.
Clinical evidence shows that adjuvant pembrolizumab increases how long people live without the cancer coming back compared with placebo. There is still not enough data to know how much pembrolizumab increases how long people live.
Because of this uncertainty the cost-effectiveness estimates vary. However, the most likely estimates are within what NICE considers an acceptable use of NHS resources. Therefore, pembrolizumab is recommended.# Information about pembrolizumab
# Marketing authorisation indication
Pembrolizumab (Keytruda, MSD) is indicated 'for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for pembrolizumab.
# Price
The list price is £2,630.00 per 100 mg/4 ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed November 2021). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Clinical pathway
## Pembrolizumab is a highly valued treatment option for people with melanoma
Melanoma often affects people at a younger age than some other cancers. It has a substantial effect on people and their families and carers. Tumour and associated lymph node resections are standard treatment for most people with stage 3 melanoma. Until recently, standard care for people with completely resected melanoma was routine surveillance. In 2018, NICE's technology appraisal guidance on dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma recommended it for use. In 2021, NICE's technology appraisal guidance on nivolumab for adjuvant treatment of completely resected melanoma recommended it for use. Nivolumab and pembrolizumab have the same mechanism of action because both are checkpoint inhibitors (PD‑1 inhibitors). However, pembrolizumab can be administered every 6 weeks, whereas nivolumab is administered every 4 weeks. Clinical experts stated that about 80% of people have adjuvant pembrolizumab and 20% have nivolumab. They noted that nivolumab has a wider licence, because it is also available for adjuvant treatment of completely resected metastatic melanoma (that is, stage 4 melanoma). However, because of its reduced administration schedule, many patients and NHS services prefer pembrolizumab. This is because it means less time having infusions, and travelling for treatment less frequently. In the previous appraisal of pembrolizumab, NICE recommended it for use within the Cancer Drugs Fund for the adjuvant treatment of stage 3 melanoma with lymph node involvement in adults who have had complete resection (NICE technology appraisal guidance 553, from now TA553). The aim of adjuvant treatment is to remove any residual microscopic disease after resection to reduce the risk of relapse and progression to metastatic disease, which is currently considered incurable. The clinical experts explained that treatments that can be given very early (in the adjuvant setting) are expected to reduce the number of people returning with metastatic disease. The committee heard from the patient expert that the availability of pembrolizumab through the Cancer Drugs Fund had been life changing for many people with melanoma. The committee concluded that pembrolizumab was a highly valued adjuvant treatment option for people with stage 3 melanoma.
# Clinical evidence
## Pembrolizumab improves recurrence-free survival and distant metastases-free survival compared with placebo, but overall survival data is immature
KEYNOTE‑054 is an ongoing multinational randomised double-blind trial. It compared adjuvant pembrolizumab with placebo in 1,019 adults who have had complete resection of stage 3 melanoma. The median age of people who had pembrolizumab was 53.9 years. Of the people with known BRAF status who had pembrolizumab, just over half had melanoma with mutations in the BRAF gene (244/478; 51%). In TA553, people in KEYNOTE‑054 were followed for a median duration of 16 months. A statistically significant improvement in recurrence-free survival was seen with pembrolizumab compared with placebo (hazard ratio 0.57, 95% confidence interval 0.43 to 0.74). Both distant metastases-free survival data and overall survival data were immature. Since TA553, people in KEYNOTE‑054 have been followed for a median duration of 45.5 months. A statistically significant improvement in recurrence-free survival was seen with pembrolizumab compared with placebo (HR 0.59, 95% CI 0.49 to 0.70). A statistically significant improvement in distant metastases-free survival was seen with pembrolizumab compared with placebo (HR 0.60, 95% CI 0.49 to 0.73). Overall survival data was still immature. Through the Cancer Drugs Fund, systemic anti-cancer therapy (SACT) data was collected from people having adjuvant pembrolizumab for resected stage 3 melanoma. Between 19 November 2018 and 18 November 2020, 1,324 people had adjuvant pembrolizumab, with a median age of 64 years. Most people (81%) had disease without mutations in the BRAF gene. Most people had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 (69%). Compared with KEYNOTE‑054, people were older, fewer had mutations in the BRAF gene and fewer had an ECOG score of 0. At the end of the data collection period, 47% of people were still having treatment. The estimate of median overall survival was not reached. The committee concluded that pembrolizumab improves recurrence-free survival and distant metastases-free survival compared with placebo, but overall survival data is still immature.
## It is likely that improvements in recurrence-free and distant metastases-free survival are associated with an overall survival benefit
The committee was aware that there were challenges in gathering and interpreting overall survival data for adjuvant therapies, such as pembrolizumab for melanoma. This is because people have no known disease at the time of treatment. Instead, treatment is used as a precaution to make sure there is no remaining microscopic disease, and to minimise the risk of recurrence (see section 3.1). This means that some people having adjuvant treatment would not have gone on to develop advanced disease. People may live for a long time because adjuvant treatment is given in the earlier stages of cancer. However, this means that collecting sufficient data may take a long time. So, it is difficult to know whether adjuvant treatment permanently cures disease or just delays progression. The committee noted that a key reason for recommending pembrolizumab within the Cancer Drugs Fund in TA553 was to get more mature overall survival data. However, data remained immature after exit from the Cancer Drugs Fund. This is because there were too few deaths to estimate accurately the average time that people survive when having pembrolizumab or placebo. In the absence of overall survival data, the committee considered whether recurrence-free or distant metastases-free survival could be used as a surrogate for overall survival. The clinical experts explained that if a treatment makes a clinically meaningful difference to distant metastases-free survival then it was likely that this would be reflected in overall survival. The committee agreed that this was biologically plausible. The patient and clinical experts also advised that, for people with melanoma, overall survival was not their sole focus. Length of time without disease recurrence was also very important. Therefore, recurrence-free and distant metastases-free survival are important outcomes for people regardless of their likely associated improvement in overall survival. The committee concluded that, based on its earlier conclusion that pembrolizumab improved recurrence-free survival and distant metastases-free survival compared with placebo, it was likely that pembrolizumab also improved overall survival benefit. However, given the immaturity of overall survival data, the level of this benefit is uncertain.
## Although the data on subsequent treatments is still immature, the data from the SACT cohort reflects clinical practice
A number of therapies are available if the cancer comes back after adjuvant pembrolizumab (see NICE's webpage on skin cancer). These include immunotherapies (nivolumab with ipilimumab, nivolumab monotherapy, pembrolizumab monotherapy and ipilimumab monotherapy), and targeted therapy for melanoma with mutations in the BRAF gene (encorafenib with binimetinib, dabrafenib with trametinib, dabrafenib monotherapy and vemurafenib monotherapy). According to the company, further data on subsequent treatments collected from KEYNOTE‑054 was incomplete with respect to combination regimens and so did not reflect UK clinical practice. The evidence from the Cancer Drugs Fund after use of adjuvant pembrolizumab is limited, and so far only 12% of people have had subsequent treatments. Most people had nivolumab with ipilimumab (54.2%), ipilimumab (19%), dabrafenib with trametinib (13.7%) and encorafenib with binimetinib (8.5%). Because the data is immature, it is based on cancer that relapsed early, so may not be representative of all completely resected stage 3 melanoma. The clinical experts stated that the immaturity of the data is a positive aspect, because it suggests that the number of people whose disease comes back after adjuvant pembrolizumab is low. The committee was aware that the choice of subsequent treatment will depend on many factors. Most people who can tolerate a combination therapy would be offered nivolumab with ipilimumab after both routine surveillance and adjuvant pembrolizumab. People who cannot tolerate a combination therapy may be offered monotherapy. The choice of immunotherapy is likely to depend on whether adjuvant pembrolizumab was given and, if it was, on the time since the last dose. People with melanoma with mutations in the BRAF gene may choose targeted therapies because they are less toxic and can be taken orally (immunotherapy is given by intravenous infusion). Clinicians agreed that the subsequent treatments seen in the SACT cohort are consistent with what would be expected in clinical practice. Because the trial data was incomplete and therefore deemed to not reflect clinical practice, they considered there was a greater degree of certainty with data from the Cancer Drugs Fund. The committee concluded that subsequent treatment data is still immature but that data from the Cancer Drugs Fund reflects clinical practice.
# Adverse events
## Although pembrolizumab is well tolerated, it is important to carefully assess the likely benefits and adverse events of treatment
The committee had previously noted in TA553 that for people taking immunotherapies such as pembrolizumab, a small proportion have irreversible side effects like type 1 diabetes. The committee further heard that, although 80% of people have no toxicity associated with pembrolizumab, and 10% have low impact events, around 5% to 10% have high toxicity. This is frequently in the liver and bowel and needs immune suppression. A further group of people, though extremely small, are at risk of extreme toxicity. This includes immune-mediated damage to the heart, or toxicity on the endocrine system associated with long-term effects. The clinical experts explained that toxicity associated with the endocrine system does not resolve. Also, for people who do experience toxicity, it can take a lot of immune suppression to get the immune system back under control. This is partially because of the long half-lives of pembrolizumab and nivolumab. For these reasons, the clinical experts noted that it was important for patients to weigh up the risks and benefits when considering adjuvant treatment. The experts also stated that people who experience toxicity may in some cases have better outcomes, because it is an indication that their immune system has been activated. The committee concluded that although pembrolizumab is well tolerated, a careful assessment of the likely benefits and adverse events of treatment is important.
# The company's economic model
## The company's model structure is acceptable for decision making
Overall survival data is a requisite input for a partitioned survival model. In the absence of this, the company presented a 4‑state transition model to estimate the cost effectiveness of pembrolizumab as an adjuvant treatment compared with routine surveillance. Groups of patients were able to move between the recurrence-free survival, loco-regional recurrence, distant metastases and death health states. The model used updated data on recurrence-free survival from KEYNOTE‑054 to inform model transitions from the recurrence-free survival health state. The model used the distant metastases-free survival data now available to inform transition from the recurrence-free and loco-regional recurrence health states. A network meta-analysis done by the company was used to inform transitions from distant metastases to death. The ERG was satisfied that the model structure was suitable for estimating the cost effectiveness of pembrolizumab compared with routine surveillance. The committee concluded that the model structure is acceptable.
# Survival modelling in the economic model
## Estimates of overall survival are highly uncertain despite the additional analyses the company provided
As in TA553, overall survival data from KEYNOTE‑054 is not yet available because the trial is still ongoing. Despite not being in the model as a health state, overall survival is an output of the company's model. The ERG raised concerns that the modelled overall survival outputs for both pembrolizumab (likely overestimated) and routine surveillance (likely underestimated) were unreliable. The company accepted that its estimates were associated with uncertainty. It therefore attempted to explore this uncertainty by comparing its modelled estimates of overall survival with other validation sources (see section 3.8 and section 3.9). It also explored the effect on cost-effectiveness results of using other combinations of parametric curves fitted to the data (see section 3.10).
## The company explored alternative data validation sources for overall survival for routine surveillance, but all are uncertain
Because of the uncertainty associated with the survival data in its model, the company used a number of sources to validate the data it had used. For its modelled overall survival outputs for routine surveillance, the company compared it with:
the placebo arm from the COMBI‑AD trial (a randomised controlled trial comparing adjuvant dabrafenib plus trametinib with matched placebos for resected stage 3 melanoma with a BRAF V600 mutation)
the composite curve produced by the ERG during TA553
the placebo arm from EORTC‑18071 (an RCT comparing adjuvant ipilimumab with placebo for completely resected high-risk stage 3 melanoma)
data from the American Joint Committee on Cancer's (AJCC) 8th edition of melanoma staging
data from the surveillance epidemiology and end results (SEER) database in the US
projections taken from TA553. The company preferred the composite curve produced by the ERG during TA553. The ERG noted that this was based on SEER data published in 2010. It advised that significant gains in overall survival have been achieved since then, after the introduction of immunotherapies and targeted therapies. The committee noted that the SEER database was based in the US, so it was not sure if data would be generalisable to the NHS. The ERG's preferred validation measure was AJCC. Clinical experts stated that there is concern that this data is overly optimistic because it comes from 10 large academic centres and is not population-based registry data. They noted that 3 major publications report worse outcomes for people with stage 3 melanoma than those reported by the AJCC. The committee concluded that the data validation sources for routine surveillance were uncertain, and it would take this uncertainty into account in its decision making.
## The company explored alternative data validation sources for overall survival for pembrolizumab, but all are uncertain
Because of the uncertainty associated with the survival data in its model, the company used a number of sources to validate the data it had used. For its modelled overall survival outputs for pembrolizumab, the company compared it with:
the nivolumab arm from CheckMate 238 (an RCT comparing adjuvant nivolumab with ipilimumab in resected stage 3B to 3C and stage 4 melanoma)
pembrolizumab data from the SACT dataset provided by Public Health England; this was the validation measure preferred by the ER
the ipilimumab arm from EORTC‑18071 (described in section 3.8)
projections taken from TA553
KEYNOTE‑053/SWOG‑S1404 (an RCT comparing adjuvant pembrolizumab with high-dose interferon in high-risk resected melanoma).The committee noted that the population in the SACT dataset (the ERG's preferred source) were older and fewer people had an ECOG score of 0. Also, fewer people had a BRAF mutation (which clinical experts reported generally indicates a higher probability of the cancer responding to treatment) compared with KEYNOTE‑054. There is uncertainty around the company's preferred validation measures, the nivolumab arm from CheckMate 238 and the pembrolizumab arm from KEYNOTE‑053/SWOG‑S1404. The committee was willing to accept that these showed an overall survival benefit for these treatments, but the extent of this benefit was uncertain. The committee concluded that the data validation sources for pembrolizumab were uncertain, and that it would take this uncertainty into account in its decision making.
## The company explored alternative extrapolation curves for overall survival, but all are uncertain
The company explored alternative parametric extrapolation curves by either improving survival for the routine surveillance arm, worsening survival in the pembrolizumab arm, or both simultaneously. However, both the ERG and the committee noted that these curves lacked a clear justification for their selection. The ERG stated that the alternative curves did not add value because the additional overall survival did not appear until about 10 years. Because KEYNOTE‑054 has yet to report data on overall survival, the ERG stated that the parametric curves should show a difference in overall survival between 0 and 5 years to be considered valid. Such a difference would then be consistent with the lack of overall survival data from KEYNOTE‑054. The company agreed the model was probably underestimating overall survival. But it was confident that the modelled overall survival output for its pembrolizumab arm was accurate, because it closely matched data provided from a trial in a similar population, KEYNOTE‑053 (see section 3.9). The ERG stated that if this were true (that is, if the model was overestimating deaths but the modelled estimated deaths in the pembrolizumab arm were accurate), then this overestimation of deaths must be solely driven by an overestimation of deaths in the routine surveillance arm. If true, this would bias the cost-effectiveness results in favour of pembrolizumab. The committee concluded that the extrapolation of overall survival was uncertain.
# Cost-effectiveness results
## The cost-effectiveness estimates are uncertain
The committee considered the revised cost-effectiveness estimates submitted by the company. These included the confidential patient access schemes for pembrolizumab but did not include the patient access schemes for subsequent treatments. The company presented a range of incremental cost-effectiveness ratios (ICERs) that explored different assumptions. These included fitting different parametric curves to the recurrence-free and distant metastases-free survival data from the trial (see section 3.5). It also presented several other scenarios with different time horizons, different sources for subsequent treatment market shares and different utilities. The company's deterministic base case resulted in an ICER of £9,357 per quality-adjusted life year (QALY) gained. Its probabilistic base case gave an ICER of £10,378 per QALY gained. The ICER that was considered the most conservative in the range presented by the company was the scenario that used more pessimistic projections for pembrolizumab overall survival and more optimistic projections for routine surveillance overall survival. This resulted in an ICER of £26,493 per QALY gained. Because of the uncertainty in overall survival, the ERG did not consider any of the company's ICERs to be plausible. However, the ERG did not do any additional analyses to quantify this uncertainty, stating that it was not possible for it to produce more reliable estimates than what the company had produced. The committee agreed that there was uncertainty around overall survival (see section 3.5). But it concluded that the highest plausible ICER, which could be considered the most conservative, was £26,493 per QALY gained. This did not include the discounts for subsequent treatments used in the model.
## The most likely estimate is within what NICE considers a cost-effective use of NHS resources
When the committee took into account all the confidential patient access schemes for subsequent treatments, all of the resulting ICERs were less than £30,000 per QALY gained. However, these were all associated with uncertainty. The committee would have preferred that the company and ERG had more robustly explored this uncertainty. However, any remaining uncertainty could be mitigated by the fact that nivolumab is recommended in NICE's technology appraisal guidance on nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease. Nivolumab has a similar mechanism of action to pembrolizumab and was found to be cost effective. Also, unlike nivolumab, pembrolizumab is administered every 6 weeks rather than every 4 weeks. This dosing schedule is preferable for many patients and healthcare services (see section 3.1). Because appointments are further apart, the committee found it likely that pembrolizumab would have reduced administration costs compared with nivolumab, therefore reducing pressure on the NHS. Taking everything into account, the committee concluded pembrolizumab was a cost-effective use of NHS resources.
# Conclusion
## Pembrolizumab is recommended for routine use
The committee concluded that the most plausible cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, pembrolizumab is recommended for the adjuvant treatment of completely resected stage 3 melanoma with lymph node involvement in adults.
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{'Recommendations': 'Pembrolizumab is recommended, within its marketing authorisation, as an option for the adjuvant treatment of completely resected stage\xa03 melanoma with lymph node involvement in adults. It is recommended only if the company provides pembrolizumab according to the commercial arrangement.\n\nWhy the committee made this recommendation\n\nUntil recently, standard care for people with completely resected melanoma was routine surveillance. Adjuvant treatments such as nivolumab are now available for some people.\n\nClinical evidence shows that adjuvant pembrolizumab increases how long people live without the cancer coming back compared with placebo. There is still not enough data to know how much pembrolizumab increases how long people live.\n\nBecause of this uncertainty the cost-effectiveness estimates vary. However, the most likely estimates are within what NICE considers an acceptable use of NHS resources. Therefore, pembrolizumab is recommended.', 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, MSD) is indicated 'for the adjuvant treatment of adults with Stage\xa0III melanoma and lymph node involvement who have undergone complete resection'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for pembrolizumab.\n\n# Price\n\nThe list price is £2,630.00 per 100\xa0mg/4\xa0ml concentrate for solution for infusion vial (excluding VAT; BNF online, accessed November\xa02021). The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical pathway\n\n## Pembrolizumab is a highly valued treatment option for people with melanoma\n\nMelanoma often affects people at a younger age than some other cancers. It has a substantial effect on people and their families and carers. Tumour and associated lymph node resections are standard treatment for most people with stage\xa03 melanoma. Until recently, standard care for people with completely resected melanoma was routine surveillance. In 2018, NICE's technology appraisal guidance on dabrafenib with trametinib for adjuvant treatment of resected BRAF V600 mutation-positive melanoma recommended it for use. In 2021, NICE's technology appraisal guidance on nivolumab for adjuvant treatment of completely resected melanoma recommended it for use. Nivolumab and pembrolizumab have the same mechanism of action because both are checkpoint inhibitors (PD‑1 inhibitors). However, pembrolizumab can be administered every 6\xa0weeks, whereas nivolumab is administered every 4\xa0weeks. Clinical experts stated that about 80% of people have adjuvant pembrolizumab and 20% have nivolumab. They noted that nivolumab has a wider licence, because it is also available for adjuvant treatment of completely resected metastatic melanoma (that is, stage\xa04 melanoma). However, because of its reduced administration schedule, many patients and NHS services prefer pembrolizumab. This is because it means less time having infusions, and travelling for treatment less frequently. In the previous appraisal of pembrolizumab, NICE recommended it for use within the Cancer Drugs Fund for the adjuvant treatment of stage\xa03 melanoma with lymph node involvement in adults who have had complete resection (NICE technology appraisal guidance 553, from now TA553). The aim of adjuvant treatment is to remove any residual microscopic disease after resection to reduce the risk of relapse and progression to metastatic disease, which is currently considered incurable. The clinical experts explained that treatments that can be given very early (in the adjuvant setting) are expected to reduce the number of people returning with metastatic disease. The committee heard from the patient expert that the availability of pembrolizumab through the Cancer Drugs Fund had been life changing for many people with melanoma. The committee concluded that pembrolizumab was a highly valued adjuvant treatment option for people with stage\xa03 melanoma.\n\n# Clinical evidence\n\n## Pembrolizumab improves recurrence-free survival and distant metastases-free survival compared with placebo, but overall survival data is immature\n\nKEYNOTE‑054 is an ongoing multinational randomised double-blind trial. It compared adjuvant pembrolizumab with placebo in 1,019\xa0adults who have had complete resection of stage\xa03 melanoma. The median age of people who had pembrolizumab was 53.9\xa0years. Of the people with known BRAF status who had pembrolizumab, just over half had melanoma with mutations in the BRAF gene (244/478; 51%). In TA553, people in KEYNOTE‑054 were followed for a median duration of 16\xa0months. A statistically significant improvement in recurrence-free survival was seen with pembrolizumab compared with placebo (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.43\xa0to\xa00.74). Both distant metastases-free survival data and overall survival data were immature. Since TA553, people in KEYNOTE‑054 have been followed for a median duration of 45.5\xa0months. A statistically significant improvement in recurrence-free survival was seen with pembrolizumab compared with placebo (HR 0.59, 95% CI 0.49\xa0to\xa00.70). A statistically significant improvement in distant metastases-free survival was seen with pembrolizumab compared with placebo (HR 0.60, 95% CI 0.49\xa0to\xa00.73). Overall survival data was still immature. Through the Cancer Drugs Fund, systemic anti-cancer therapy (SACT) data was collected from people having adjuvant pembrolizumab for resected stage\xa03 melanoma. Between 19\xa0November\xa02018 and 18\xa0November\xa02020, 1,324\xa0people had adjuvant pembrolizumab, with a median age of 64\xa0years. Most people (81%) had disease without mutations in the BRAF gene. Most people had an Eastern Cooperative Oncology Group (ECOG) performance score of 0 (69%). Compared with KEYNOTE‑054, people were older, fewer had mutations in the BRAF gene and fewer had an ECOG score of 0. At the end of the data collection period, 47% of people were still having treatment. The estimate of median overall survival was not reached. The committee concluded that pembrolizumab improves recurrence-free survival and distant metastases-free survival compared with placebo, but overall survival data is still immature.\n\n## It is likely that improvements in recurrence-free and distant metastases-free survival are associated with an overall survival benefit\n\nThe committee was aware that there were challenges in gathering and interpreting overall survival data for adjuvant therapies, such as pembrolizumab for melanoma. This is because people have no known disease at the time of treatment. Instead, treatment is used as a precaution to make sure there is no remaining microscopic disease, and to minimise the risk of recurrence (see section\xa03.1). This means that some people having adjuvant treatment would not have gone on to develop advanced disease. People may live for a long time because adjuvant treatment is given in the earlier stages of cancer. However, this means that collecting sufficient data may take a long time. So, it is difficult to know whether adjuvant treatment permanently cures disease or just delays progression. The committee noted that a key reason for recommending pembrolizumab within the Cancer Drugs Fund in TA553 was to get more mature overall survival data. However, data remained immature after exit from the Cancer Drugs Fund. This is because there were too few deaths to estimate accurately the average time that people survive when having pembrolizumab or placebo. In the absence of overall survival data, the committee considered whether recurrence-free or distant metastases-free survival could be used as a surrogate for overall survival. The clinical experts explained that if a treatment makes a clinically meaningful difference to distant metastases-free survival then it was likely that this would be reflected in overall survival. The committee agreed that this was biologically plausible. The patient and clinical experts also advised that, for people with melanoma, overall survival was not their sole focus. Length of time without disease recurrence was also very important. Therefore, recurrence-free and distant metastases-free survival are important outcomes for people regardless of their likely associated improvement in overall survival. The committee concluded that, based on its earlier conclusion that pembrolizumab improved recurrence-free survival and distant metastases-free survival compared with placebo, it was likely that pembrolizumab also improved overall survival benefit. However, given the immaturity of overall survival data, the level of this benefit is uncertain.\n\n## Although the data on subsequent treatments is still immature, the data from the SACT cohort reflects clinical practice\n\nA number of therapies are available if the cancer comes back after adjuvant pembrolizumab (see NICE's webpage on skin cancer). These include immunotherapies (nivolumab with ipilimumab, nivolumab monotherapy, pembrolizumab monotherapy and ipilimumab monotherapy), and targeted therapy for melanoma with mutations in the BRAF gene (encorafenib with binimetinib, dabrafenib with trametinib, dabrafenib monotherapy and vemurafenib monotherapy). According to the company, further data on subsequent treatments collected from KEYNOTE‑054 was incomplete with respect to combination regimens and so did not reflect UK clinical practice. The evidence from the Cancer Drugs Fund after use of adjuvant pembrolizumab is limited, and so far only 12% of people have had subsequent treatments. Most people had nivolumab with ipilimumab (54.2%), ipilimumab (19%), dabrafenib with trametinib (13.7%) and encorafenib with binimetinib (8.5%). Because the data is immature, it is based on cancer that relapsed early, so may not be representative of all completely resected stage\xa03 melanoma. The clinical experts stated that the immaturity of the data is a positive aspect, because it suggests that the number of people whose disease comes back after adjuvant pembrolizumab is low. The committee was aware that the choice of subsequent treatment will depend on many factors. Most people who can tolerate a combination therapy would be offered nivolumab with ipilimumab after both routine surveillance and adjuvant pembrolizumab. People who cannot tolerate a combination therapy may be offered monotherapy. The choice of immunotherapy is likely to depend on whether adjuvant pembrolizumab was given and, if it was, on the time since the last dose. People with melanoma with mutations in the BRAF gene may choose targeted therapies because they are less toxic and can be taken orally (immunotherapy is given by intravenous infusion). Clinicians agreed that the subsequent treatments seen in the SACT cohort are consistent with what would be expected in clinical practice. Because the trial data was incomplete and therefore deemed to not reflect clinical practice, they considered there was a greater degree of certainty with data from the Cancer Drugs Fund. The committee concluded that subsequent treatment data is still immature but that data from the Cancer Drugs Fund reflects clinical practice.\n\n# Adverse events\n\n## Although pembrolizumab is well tolerated, it is important to carefully assess the likely benefits and adverse events of treatment\n\nThe committee had previously noted in TA553 that for people taking immunotherapies such as pembrolizumab, a small proportion have irreversible side effects like type\xa01 diabetes. The committee further heard that, although 80% of people have no toxicity associated with pembrolizumab, and 10% have low impact events, around 5%\xa0to\xa010% have high toxicity. This is frequently in the liver and bowel and needs immune suppression. A further group of people, though extremely small, are at risk of extreme toxicity. This includes immune-mediated damage to the heart, or toxicity on the endocrine system associated with long-term effects. The clinical experts explained that toxicity associated with the endocrine system does not resolve. Also, for people who do experience toxicity, it can take a lot of immune suppression to get the immune system back under control. This is partially because of the long half-lives of pembrolizumab and nivolumab. For these reasons, the clinical experts noted that it was important for patients to weigh up the risks and benefits when considering adjuvant treatment. The experts also stated that people who experience toxicity may in some cases have better outcomes, because it is an indication that their immune system has been activated. The committee concluded that although pembrolizumab is well tolerated, a careful assessment of the likely benefits and adverse events of treatment is important.\n\n# The company's economic model\n\n## The company's model structure is acceptable for decision making\n\nOverall survival data is a requisite input for a partitioned survival model. In the absence of this, the company presented a 4‑state transition model to estimate the cost effectiveness of pembrolizumab as an adjuvant treatment compared with routine surveillance. Groups of patients were able to move between the recurrence-free survival, loco-regional recurrence, distant metastases and death health states. The model used updated data on recurrence-free survival from KEYNOTE‑054 to inform model transitions from the recurrence-free survival health state. The model used the distant metastases-free survival data now available to inform transition from the recurrence-free and loco-regional recurrence health states. A network meta-analysis done by the company was used to inform transitions from distant metastases to death. The ERG was satisfied that the model structure was suitable for estimating the cost effectiveness of pembrolizumab compared with routine surveillance. The committee concluded that the model structure is acceptable.\n\n# Survival modelling in the economic model\n\n## Estimates of overall survival are highly uncertain despite the additional analyses the company provided\n\nAs in TA553, overall survival data from KEYNOTE‑054 is not yet available because the trial is still ongoing. Despite not being in the model as a health state, overall survival is an output of the company's model. The ERG raised concerns that the modelled overall survival outputs for both pembrolizumab (likely overestimated) and routine surveillance (likely underestimated) were unreliable. The company accepted that its estimates were associated with uncertainty. It therefore attempted to explore this uncertainty by comparing its modelled estimates of overall survival with other validation sources (see section\xa03.8 and section\xa03.9). It also explored the effect on cost-effectiveness results of using other combinations of parametric curves fitted to the data (see section\xa03.10).\n\n## The company explored alternative data validation sources for overall survival for routine surveillance, but all are uncertain\n\nBecause of the uncertainty associated with the survival data in its model, the company used a number of sources to validate the data it had used. For its modelled overall survival outputs for routine surveillance, the company compared it with:\n\nthe placebo arm from the COMBI‑AD trial (a randomised controlled trial [RCT] comparing adjuvant dabrafenib plus trametinib with matched placebos for resected stage\xa03 melanoma with a BRAF V600 mutation)\n\nthe composite curve produced by the ERG during TA553\n\nthe placebo arm from EORTC‑18071 (an RCT comparing adjuvant ipilimumab with placebo for completely resected high-risk stage\xa03 melanoma)\n\ndata from the American Joint Committee on Cancer's (AJCC) 8th edition of melanoma staging\n\ndata from the surveillance epidemiology and end results (SEER) database in the US\n\nprojections taken from TA553. The company preferred the composite curve produced by the ERG during TA553. The ERG noted that this was based on SEER data published in 2010. It advised that significant gains in overall survival have been achieved since then, after the introduction of immunotherapies and targeted therapies. The committee noted that the SEER database was based in the US, so it was not sure if data would be generalisable to the NHS. The ERG's preferred validation measure was AJCC. Clinical experts stated that there is concern that this data is overly optimistic because it comes from 10\xa0large academic centres and is not population-based registry data. They noted that 3\xa0major publications report worse outcomes for people with stage\xa03 melanoma than those reported by the AJCC. The committee concluded that the data validation sources for routine surveillance were uncertain, and it would take this uncertainty into account in its decision making.\n\n## The company explored alternative data validation sources for overall survival for pembrolizumab, but all are uncertain\n\nBecause of the uncertainty associated with the survival data in its model, the company used a number of sources to validate the data it had used. For its modelled overall survival outputs for pembrolizumab, the company compared it with:\n\nthe nivolumab arm from CheckMate\xa0238 (an RCT comparing adjuvant nivolumab with ipilimumab in resected stage\xa03B\xa0to 3C and stage\xa04 melanoma)\n\npembrolizumab data from the SACT dataset provided by Public Health England; this was the validation measure preferred by the ER\n\nthe ipilimumab arm from EORTC‑18071 (described in section\xa03.8)\n\nprojections taken from TA553\n\nKEYNOTE‑053/SWOG‑S1404 (an RCT comparing adjuvant pembrolizumab with high-dose interferon in high-risk resected melanoma).The committee noted that the population in the SACT dataset (the ERG's preferred source) were older and fewer people had an ECOG score of 0. Also, fewer people had a BRAF mutation (which clinical experts reported generally indicates a higher probability of the cancer responding to treatment) compared with KEYNOTE‑054. There is uncertainty around the company's preferred validation measures, the nivolumab arm from CheckMate\xa0238 and the pembrolizumab arm from KEYNOTE‑053/SWOG‑S1404. The committee was willing to accept that these showed an overall survival benefit for these treatments, but the extent of this benefit was uncertain. The committee concluded that the data validation sources for pembrolizumab were uncertain, and that it would take this uncertainty into account in its decision making.\n\n## The company explored alternative extrapolation curves for overall survival, but all are uncertain\n\nThe company explored alternative parametric extrapolation curves by either improving survival for the routine surveillance arm, worsening survival in the pembrolizumab arm, or both simultaneously. However, both the ERG and the committee noted that these curves lacked a clear justification for their selection. The ERG stated that the alternative curves did not add value because the additional overall survival did not appear until about 10\xa0years. Because KEYNOTE‑054 has yet to report data on overall survival, the ERG stated that the parametric curves should show a difference in overall survival between 0 and 5\xa0years to be considered valid. Such a difference would then be consistent with the lack of overall survival data from KEYNOTE‑054. The company agreed the model was probably underestimating overall survival. But it was confident that the modelled overall survival output for its pembrolizumab arm was accurate, because it closely matched data provided from a trial in a similar population, KEYNOTE‑053 (see section\xa03.9). The ERG stated that if this were true (that is, if the model was overestimating deaths but the modelled estimated deaths in the pembrolizumab arm were accurate), then this overestimation of deaths must be solely driven by an overestimation of deaths in the routine surveillance arm. If true, this would bias the cost-effectiveness results in favour of pembrolizumab. The committee concluded that the extrapolation of overall survival was uncertain.\n\n# Cost-effectiveness results\n\n## The cost-effectiveness estimates are uncertain\n\nThe committee considered the revised cost-effectiveness estimates submitted by the company. These included the confidential patient access schemes for pembrolizumab but did not include the patient access schemes for subsequent treatments. The company presented a range of incremental cost-effectiveness ratios (ICERs) that explored different assumptions. These included fitting different parametric curves to the recurrence-free and distant metastases-free survival data from the trial (see section\xa03.5). It also presented several other scenarios with different time horizons, different sources for subsequent treatment market shares and different utilities. The company's deterministic base case resulted in an ICER of £9,357 per quality-adjusted life year (QALY) gained. Its probabilistic base case gave an ICER of £10,378 per QALY gained. The ICER that was considered the most conservative in the range presented by the company was the scenario that used more pessimistic projections for pembrolizumab overall survival and more optimistic projections for routine surveillance overall survival. This resulted in an ICER of £26,493 per QALY gained. Because of the uncertainty in overall survival, the ERG did not consider any of the company's ICERs to be plausible. However, the ERG did not do any additional analyses to quantify this uncertainty, stating that it was not possible for it to produce more reliable estimates than what the company had produced. The committee agreed that there was uncertainty around overall survival (see section\xa03.5). But it concluded that the highest plausible ICER, which could be considered the most conservative, was £26,493 per QALY gained. This did not include the discounts for subsequent treatments used in the model.\n\n## The most likely estimate is within what NICE considers a cost-effective use of NHS resources\n\nWhen the committee took into account all the confidential patient access schemes for subsequent treatments, all of the resulting ICERs were less than £30,000 per QALY gained. However, these were all associated with uncertainty. The committee would have preferred that the company and ERG had more robustly explored this uncertainty. However, any remaining uncertainty could be mitigated by the fact that nivolumab is recommended in NICE's technology appraisal guidance on nivolumab for adjuvant treatment of completely resected melanoma with lymph node involvement or metastatic disease. Nivolumab has a similar mechanism of action to pembrolizumab and was found to be cost effective. Also, unlike nivolumab, pembrolizumab is administered every 6\xa0weeks rather than every 4\xa0weeks. This dosing schedule is preferable for many patients and healthcare services (see section\xa03.1). Because appointments are further apart, the committee found it likely that pembrolizumab would have reduced administration costs compared with nivolumab, therefore reducing pressure on the NHS. Taking everything into account, the committee concluded pembrolizumab was a cost-effective use of NHS resources.\n\n# Conclusion\n\n## Pembrolizumab is recommended for routine use\n\nThe committee concluded that the most plausible cost-effectiveness estimates are within what NICE considers an acceptable use of NHS resources. Therefore, pembrolizumab is recommended for the adjuvant treatment of completely resected stage\xa03 melanoma with lymph node involvement in adults."}
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https://www.nice.org.uk/guidance/ta766
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Evidence-based recommendations on pembrolizumab (Keytruda) for adjuvant treatment of completely resected stage 3 melanoma in adults.
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b82994df3168d2d1ddcfc7bbe4f95ae8d3a84c20
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nice
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Ponesimod for treating relapsing–remitting multiple sclerosis
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Ponesimod for treating relapsing–remitting multiple sclerosis
Evidence-based recommendations on ponesimod (Ponvory) for treating relapsing–remitting multiple sclerosis in adults.
# Recommendations
Ponesimod is recommended for treating relapsing–remitting multiple sclerosis with active disease defined by clinical or imaging features in adults, only if the company provides ponesimod according to the commercial arrangement.
This recommendation is not intended to affect treatment with ponesimod that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Ponesimod is a disease-modifying treatment for multiple sclerosis. There are other disease-modifying treatments in routine clinical use.
Clinical trial evidence shows that people who have ponesimod have fewer relapses than people who have teriflunomide. Its effect on disability progression is not clear. Comparisons with other disease-modifying treatments are uncertain because of limitations in the clinical evidence.
The cost-effectiveness estimates are also uncertain, because of limitations in the clinical evidence and how long-term clinical benefit is predicted from short-term evidence. However, taking this uncertainty into account, the estimates are below what NICE normally considers an acceptable use of NHS resources. Therefore, ponesimod is recommended.# Information about ponesimod
# Marketing authorisation indication
Ponesimod (Ponvory, Janssen) is indicated for 'the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features'.
# Dosage in the marketing authorisation
The dosage schedule for ponesimod is available in the summary of product characteristics for ponesimod.
# Price
The list price for ponesimod is commercial in confidence so cannot be reported here. The company has a commercial arrangement. This makes ponesimod available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Janssen, a review of the submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## People would welcome new treatment options for relapsing multiple sclerosis
Multiple sclerosis is a chronic, lifelong disease with no cure, resulting in progressive, irreversible disability. It has many symptoms including pain, chronic fatigue, unsteady gait, muscle loss, speech problems, incontinence, visual disturbance and cognitive impairment. Most people have the relapsing–remitting form of the disease, characterised by periods of new or worsened symptoms. The patient experts highlighted that the disease is complex and unpredictable and impacts all aspects of life and can affect carers too. The disease has a higher prevalence in women. Because it is typically diagnosed when people are of child-bearing age, the patient experts highlighted it is important to consider treatments that can be used during pregnancy. The company noted that although ponesimod is not indicated for pregnant women, its short half-life could be helpful for pregnancy planning compared with drugs with longer half-lives. The patient experts also highlighted that people generally prefer oral treatments and that ponesimod is an oral treatment. The committee concluded that despite many available treatments, people would welcome new treatment options for relapsing multiple sclerosis.
# Treatment pathway, population and comparators
## Ponesimod is likely to be used as a first- or second-line treatment for relapsing–remitting multiple sclerosis
Ponesimod's marketing authorisation is for active disease defined by clinical or imaging features. The company explained that the ponesimod clinical trials included people with active disease defined as at least:
relapse within the last year or 2 relapses within the last 2 years, or
at least 1 T1 gadolinium‑enhancing lesion on brain MRI within the last 6 months.The company positioned ponesimod as a first- or second-line treatment for active relapsing–remitting multiple sclerosis, and considered ponesimod would not be used for secondary progressive multiple sclerosis. The company also provided evidence for the highly active subgroup as defined in the NHS treatment algorithm. This defines it as: people with an unchanged or increased relapse rate or ongoing severe relapses compared with the last year, despite having previous disease-modifying treatment. The clinical experts considered that the different forms of multiple sclerosis are part of a disease spectrum rather than having clearly defined aspects. However, they agreed with the company's positioning of ponesimod for these subgroups. The clinical experts agreed that ponesimod would be of value as a first-line treatment because:
there are no oral treatments routinely available as first-line treatment for people who have only had 1 relapse in the last 2 years
there are no treatments with ponesimod's mechanism of action routinely available for people who have only had 1 relapse in the last 2 years
it has a shorter half-life than other treatments.Having another first- and second-line treatment option would offer people more choice. The committee concluded that ponesimod was likely to be used as a first- or second-line treatment for people with active relapsing–remitting multiple sclerosis, and would not be used for secondary progressive multiple sclerosis.
## All first- and second-line treatments used for relapsing–remitting multiple sclerosis are appropriate comparators
For people with active relapsing–remitting multiple sclerosis, the company submission compared ponesimod with beta interferons, dimethyl fumarate, glatiramer acetate, teriflunomide, ocrelizumab and peginterferon beta‑1a. For people with highly active relapsing–remitting multiple sclerosis, the company submission compared ponesimod with alemtuzumab, cladribine, fingolimod and ocrelizumab. A comparison with ofatumumab and ozanimod for both groups was added at the clarification stage because they were being appraised at the time of the company submission; however, ozanimod was not recommended. The clinical experts considered it unlikely that ponesimod would be the most effective treatment, but patients and clinicians would choose a treatment based on the risks and benefits. The committee noted that the most effective treatments likely included monoclonal antibodies (alemtuzumab, ocrelizumab and ofatumumab), but that different treatment strategies are used depending on the person's preferences. The committee acknowledged that alemtuzumab is an induction therapy, and a safety review had restricted its use to highly active disease. But, because ponesimod is expected to be used for highly active disease, the committee concluded it should be considered as a relevant comparator for this subgroup. So, the committee concluded that all first- and second-line treatments for active relapsing–remitting multiple sclerosis were relevant comparators.
# Clinical evidence
## Ponesimod reduces relapses and fatigue-related symptoms, but its effects on disability progression are uncertain
The key clinical evidence for ponesimod came from 2 clinical trials in people with relapsing–remitting multiple sclerosis, and their long-term open-label extension studies:
AC‑058B201 (B201): a phase 2 placebo-controlled dose-finding trial and AC‑058B202, an open-label uncontrolled extension trial for people who completed B201
OPTIMUM: a phase 3 active-controlled (compared with teriflunomide) parallel trial with the licensed dose and OPTIMUM‑LT, an open-label uncontrolled extension trial in people who completed OPTIMUM.In OPTIMUM, the primary outcome was annualised relapse rate. Key secondary outcomes included change from baseline in fatigue-related symptoms, 3‑month and 6‑month confirmed disability accumulation and adverse events. In B201, the primary outcome was the cumulative number of new gadolinium-enhancing lesions from week 12 to 24. Key secondary outcomes included annualised relapse rate and the number of people with first confirmed relapsed disease from baseline to week 24. Both extension trials assessed long-term efficacy, safety and tolerability of ponesimod. OPTIMUM showed a statistically significant difference in annualised relapse rate and change in fatigue-related symptoms for ponesimod compared with teriflunomide. However, there was no significant difference in 3‑month and 6‑month confirmed disability accumulation. The committee considered the differences seen in 3- and 6‑month confirmed disability accumulation were uncertain and noted that this had a substantial effect on the cost-effectiveness results (see section 3.12).
## Baseline characteristics in the trials are broadly generalisable to people with relapsing–remitting multiple sclerosis in the NHS
The company used baseline characteristics from OPTIMUM in the economic model (see section 3.4). OPTIMUM included adults mostly from Europe. Inclusion criteria specified an Expanded Disability Status Scale (EDSS) score of between 0 and 5.5. People had been previously treated with interferon beta‑1a, interferon beta‑1b, glatiramer acetate, natalizumab or dimethyl fumarate, or had had no previous treatment. The trial excluded pregnant women or anyone with progressive multiple sclerosis. The clinical experts considered that the inclusion and exclusion criteria and the baseline characteristics in both trials were generalisable to people in the NHS with relapsing–remitting multiple sclerosis. The clinical experts added that people with milder disease (lower EDSS scores and fewer relapses) tend to be included in clinical trials. The committee concluded that the studies broadly aligned with other populations in clinical trials and were appropriate for decision making.
## Fatigue is an important outcome measure, but is not included in the economic model
The company measured fatigue symptoms using the Fatigue Symptoms and Impacts Questionnaire: Relapsing Multiple Sclerosis (FSIQ‑RMS). It considered that OPTIMUM was the first trial to use a validated disease-specific fatigue measure as a prespecified end point and to show that a disease-modifying treatment can stabilise fatigue symptoms. The patient experts highlighted fatigue as an important element of quality of life and that some people would switch to a treatment that was shown to act on fatigue. The clinical experts suggested that ponesimod may reduce inflammation, which can reduce fatigue. The committee agreed that fatigue symptoms are an important element of the disease and that the FSIQ‑RMS has potential to be an important disease outcome measure. However, fatigue was not explicitly included in the model and was instead captured through measuring health-related quality of life by EDSS score (see section 3.12). The committee also noted that because there was no evidence on fatigue symptoms from other clinical trials using the FSIQ‑RMS, ponesimod could not be compared with drugs other than teriflunomide. The committee concluded that fatigue is an important outcome measure that was not explicitly modelled in the cost-effectiveness analysis. It was uncertain what effect fatigue would have on cost-effectiveness results without seeing data on how well the comparator treatments reduce fatigue.
# Network meta-analysis
## The results from the company's network meta-analyses are highly uncertain
To estimate ponesimod's relative effectiveness compared with all relevant comparators (see section 3.3), the company submitted network meta-analyses for the whole relapsing–remitting population and for the highly active subgroup. These were completed for 4 outcome measures: annualised relapse rate; 3‑ and 6‑month confirmed disability accumulation; and treatment discontinuation. Because of differing inclusion criteria, the company included studies in which at least 80% of the trial population had relapsing–remitting multiple sclerosis according to OPTIMUM's criteria. The ERG considered the company's approach to the network meta-analyses to be generally appropriate. However, it highlighted the extreme heterogeneity of the trial designs, including large differences in how the placebo effect was reported across trials for all outcomes. The ERG noted that the company made no attempt to address this heterogeneity (for example, by using meta-regression on baseline event rates), and considered it could bias the treatment effect. It considered that the outcomes of the studies included were short term and were unlikely to capture meaningful changes in disease. The relative treatment effects also had wide credible intervals, suggesting a highly uncertain treatment effect. For confirmed disability accumulation, which had a substantial effect on the cost-effectiveness results, the credible intervals of relative treatment effect of ponesimod crossed 1 for all treatments. This implied uncertainty that ponesimod was better or worse than any other treatment. To reduce heterogeneity in study design, at technical engagement the ERG suggested pooling interferons (see section 3.10). The clinical experts stated that the results of the network meta-analyses generally reflected which treatments are considered more effective in the NHS. The committee concluded that the network meta-analyses have major limitations, and the results were highly uncertain.
## It is appropriate to use 6-month confirmed disability accumulation in the network meta-analyses
The company used 6‑month confirmed disability accumulation in its base case but considered the 3‑month confirmed disability accumulation to be more robust to produce a network. The ERG considered the 6‑month confirmed disability accumulation to be a more appropriate measure of progression and that this outweighed the additional data available for 3‑month confirmed disability accumulation. The clinical experts also noted the long-established committee preference across recent technology appraisals for 6‑month confirmed disability progression. The committee concluded that using outputs from the 6‑month confirmed disability accumulation was appropriate.
## The model provided an unexpected treatment effect for cladribine, based on 6-month confirmed disability accumulation
The committee noted that cladribine had a substantially higher treatment effect for 6‑month confirmed disability accumulation than other treatments in the network meta-analysis for the highly active subgroup (see section 3.7). It noted that this estimate had wide credible intervals, indicating a high level of uncertainty. The committee noted that because 6‑month confirmed disability accumulation had a substantial effect on the cost-effectiveness results (see section 3.12), this estimate also had a large impact on the cost-effectiveness estimate of cladribine. The clinical experts did not expect the substantially greater treatment effect for cladribine compared with other comparators in clinical practice, and anticipated cladribine's treatment effect to reflect the results from the full population analysis. In response to consultation, a stakeholder presented a published analysis that showed that cladribine has similar estimates of efficacy to higher efficacy monoclonal antibodies, when adjusting for baseline risk and considering different definitions of highly active disease. The committee considered that this could partially explain why cladribine seemed more effective in the network meta-analysis than in clinical practice, but also considered there could be some sampling error, indicated by the wide credible intervals.
## It is appropriate to consider the results from the interferon studies in a hierarchical analysis, but the company's version was implemented incorrectly
The ERG noted substantial heterogeneity in the company's network meta-analyses, in part explained by varying treatment effects from interferon studies. To overcome this, the company provided an updated network analysis that considered all interferons as interchangeable, pooling them into a single node of the network. The ERG considered this appropriate and incorporated it into its base case. The clinical experts agreed that interferons could be presented as a class because they are considered similar in terms of efficacy and are treated as interchangeable in clinical practice. The committee considered that it was potentially appropriate to consider the interferon trials using a class-based analysis. But it also requested a hierarchical class-based model, in which exchangeable effects are drawn from a class-level distribution rather than assuming a single, pooled treatment effect. The company provided this analysis in response to consultation and included it in its revised base case. The model excluded 2 trials that included interferon, ADVANCE and INCOMIN. The point estimates of the model reflected those from the previous models, but it had substantially larger credible intervals for all comparator treatments. The committee considered that excluding the interferon trials did not meet the aim of requesting a hierarchical model and would have preferred the model to include them. The committee considered that the model must have been implemented incorrectly to create such wide credibility intervals, including for comparators that were not linked to an interferon. However, it noted that these changes to the network structure would mostly affect uncertainty parameters in the probabilistic analysis. The committee concluded that the hierarchical model would have been most appropriate if it had been implemented correctly. But it expected the results to lie between the pooled analysis and the company's original analysis with separate interferons and it considered both in its decision making.
## All appropriate safety evidence for serious and rare adverse events with ponesimod has been considered
The company provided direct safety evidence from OPTIMUM and B201, including a long-term safety set which pooled evidence from everyone who had ponesimod during OPTIMUM and B201 and their long-term extension studies. The ERG noted that the safety data presented by the company was comparable to that of other disease-modifying treatments. But it noted potential for an elevated risk of serious adverse events characteristic of the class of sphingosine 1‑phosphate inhibitors. This would need confirming with long-term safety data from a large group. The clinical experts considered that the adverse event profile would likely resemble that of fingolimod, which has an acceptable safety profile. The ERG considered that adverse events had been appropriately included in the economic model. The committee considered that further data would be needed to fully establish ponesimod's safety profile but that all appropriate safety evidence had been incorporated in the economic model.
# Economic model
## The company's model aligns with previous models in the disease area but has limitations
The company's model structure was similar to model structures used in previous multiple sclerosis technology appraisals. It was a Markov transition model consisting of 20 health states (10 EDSS states for relapsing–remitting multiple sclerosis, 9 for secondary progressive multiple sclerosis, and death). The model used the British Columbia Multiple Sclerosis registry as a source of natural history data. Treatment effects for ponesimod and all comparators were from the company's network meta-analyses and were applied to adjust progression through each of the EDSS states using 6‑month confirmed disability accumulation. Relapses were modelled independently, also using annualised relapse rate ratios from the network meta-analyses. The committee noted that many assumptions in the model had been accepted in previous technology appraisals in multiple sclerosis, including:
modelling 1 line of treatment only with no treatment switching
incorporating a treatment waning effect of 25% reduction in efficacy from years 2 to 5 and a 50% reduction in efficacy from year 6 onward (specific to technologies with a similar effectiveness profile, for example NICE's technology appraisal guidance on peginterferon beta-1a and NICE's technology appraisal guidance on dimethyl fumarate)
relative risk of death being applied to each EDSS health state, taken from Pokorski (1997) which demonstrated that risk of death because of multiple sclerosis was primarily dependent on disability
incorporating patient utility values from published literature (Orme, 2007) rather than OPTIMUM.The clinical experts considered that some of these modelling assumptions may not accurately represent the natural history of multiple sclerosis or use the most up-to-date data. They added that differences in treatment efficacy are often driven by disease activity, the age of the person, the number of relapses and disability at baseline. The committee noted that previous appraisals had criticised the lack of treatment switching or sequencing and the fixed treatment waning effect as major limitations of similar models. It considered that these oversimplify what would happen in NHS clinical practice. However, it acknowledged that a model that can simulate treatment sequencing and variable treatment waning would be complex to construct and difficult to populate because of limited data. The committee considered that longer-term efficacy is difficult to establish and extrapolate from the short-term trials used in the network meta-analyses, the outputs of which have broad credible intervals. The committee concluded that the model structure and inputs broadly aligned with previous models in the disease area, but had limitations.
## The modelled output shows an unlikely number of people in high EDSS states
The committee noted that the modelled outputs from the company's model, including total quality-adjusted life year (QALY) gain, were inconsistent with those of other appraisals. The committee was unclear why this was the case if the inputs and structure were all broadly similar to those of previous appraisals. One of the main reasons for the differences between models was the conversion rate between relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis. The ERG noted that the London Ontario database was used to inform the conversion rates as reported in Mauskopf (2016), but these rates differed from those used in NICE's technology appraisal guidance on peginterferon. The ERG provided a scenario analysis that used the rates used in the peginterferon appraisal and noticed that the cost-effectiveness results were sensitive to this assumption, though total QALYs remained low. The clinical experts commented that it would be plausible to assume that, in an average disease course, people would be in a relapsing–remitting multiple sclerosis state 50% of the time and in the secondary progressive multiple sclerosis state for the other 50%. But they commented that some people will be in the relapsing–remitting state longer, particularly if their disease is treated early. The committee queried why the company analysis modelled that people would spend a greater amount of time in the secondary progressive multiple sclerosis state. Another important difference was the transition between EDSS states within secondary progressive multiple sclerosis, which were informed by the London Ontario database. The clinical experts stated that once the disease has progressed to secondary progressive multiple sclerosis, most people would remain in EDSS 6 or EDSS 7 states for a long period of time. The committee noted that a large proportion of people were in EDSS 8 and EDSS 9 for most of the model's time horizon and that both states had negative utility values. It considered that these results were unlikely and explained some of the differences in total QALY gain between appraisals. But it was unclear which input was driving these transitions, because the transitions between EDSS states within secondary progressive multiple sclerosis had been used in previous appraisals. The committee was aware that the effect of this issue was uncertain because it was applied to all the modelled treatments. But it did not see enough analysis to judge what would happen if more likely outputs were included. The committee concluded further sensitivity analysis was needed to explore unlikely numbers of people in high EDSS health states. In response to consultation, the company compared its model with the one in NICE's technology appraisal guidance on peginterferon. The ERG said that the outputs from both models were broadly in line. It added that if peginterferon inputs were used in the ponesimod model, both models produced similar secondary progressive multiple sclerosis time outputs with minimal difference between comparators. But the committee felt that similarity with other appraisals did not necessarily indicate external validity. It also considered that this did not account for differences with other models or compared with clinical validation of the outputs. The committee concluded that this model, as with other multiple sclerosis models, is limited in its ability to accurately reflect the course of the condition, but considered that this model did show the relative benefit of ponesimod compared with comparator treatments. The committee concluded that the model should have more accurately portrayed the disease course of multiple sclerosis instead of showing an implausible number of people in high EDSS states. However, the committee concluded that the model showed the relative benefit of ponesimod compared with other treatments enough for decision making in this instance.
## More appropriate mortality data may be available and should be used in future
The company initially used mortality data from Pokorski (1997) to model mortality within each EDSS health state, for both relapsing–remitting and secondary progressive multiple sclerosis. The company noted that this method has been used in several previous appraisals. The clinical experts considered that this mortality data was outdated, and that managing acute infection and nursing has fundamentally reduced mortality with multiple sclerosis. They noted that new standardised mortality rates by EDSS state for people with multiple sclerosis had been recently published. This updated data showed higher risk of death in the EDSS states 8 and 9. When these rates were used to model mortality, it interacted with the implausibly high number of people in these states (see section 3.13) to produce overall survival that was substantially lower than that in the published data. The committee considered this implausible. The ERG considered that the new mortality model calculated mortality from few deaths and that there may be more appropriate sources of mortality data. It noted that this could be explored in a systematic review of mortality data in multiple sclerosis. For the purposes of decision making, the committee considered both sources of mortality but noted their limitations. The committee concluded that in future appraisals in multiple sclerosis, it would like to see more appropriate sources of mortality data in a model with plausible distributions of people in EDSS states.
## An economic model that accounts for treatment sequencing is needed to capture use of siponimod for secondary progressive multiple sclerosis
The ERG noted that siponimod has recently been approved for secondary progressive multiple sclerosis and the economic model did not allow for any treatment effect to be modelled after progression. The company obtained expert opinion that estimated 25% of people who develop secondary progressive multiple sclerosis would choose to have siponimod. However, the company and ERG base case only used the costs of siponimod use in the economic analysis. The clinical experts agreed that 25% of people with secondary progressive multiple sclerosis using siponimod seemed reasonable, but there was currently no data on uptake to base this on. They also noted that it was unlikely that siponimod would be offered to people whose disease progressed after they had ponesimod, because they both belong to the class of sphingosine 1‑phosphate type 1 inhibitors. The clinical experts acknowledged there is no evidence for this and no studies exploring this assumption. The committee also questioned whether siponimod would be used by people with EDSS scores greater than 7, which was the health state in which all treatments were stopped in the company assumptions. The clinical experts considered siponimod would not be offered to people with an EDSS greater than 7. This was confirmed by the NHS commissioning expert who noted that siponimod treatment would be stopped if a person is in EDSS 7 or greater for more than 6 months. The committee noted that this would be a large proportion of people in the modelled analysis because of the unlikely number of people in high EDSS states (see section 3.13). The committee concluded that the model did not allow for treatment sequencing that would reflect clinical practice and that including the costs but not the treatment effect of siponimod was not fully consistent. However, it acknowledged that an economic model that can simulate treatment sequencing would be complex to construct and that minimal evidence for siponimod use would be available in current practice.
# Cost-effectiveness estimates
## The most likely cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources
NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratios (ICERs). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically about the:
results from the network meta-analyses (see section 3.7 and section 3.10)
limitations of the model structure (see section 3.12)
likeliness of the modelled output (see section 3.13)
updated evidence on mortality (see section 3.14).The committee considered both the population with active disease (at the point a person would receive their first treatment) and the subgroup with highly active disease (see section 3.2) separately. Taking into account the high level of uncertainty and potential benefits that were not captured in the model (see section 3.18), the cost-effectiveness estimates for ponesimod compared with other treatments for relapsing–remitting multiple sclerosis were below what NICE normally considers an acceptable use of NHS resources for the population with active disease. Because of confidential commercial arrangements for ponesimod and comparator treatments, the cost-effectiveness results cannot be reported here. For the subgroup with highly active disease, some cost-effectiveness results for ponesimod compared with cladribine and alemtuzumab were above what NICE normally considers an acceptable use of NHS resources. However, the committee considered that the results for the comparison with cladribine may have been based on an unadjusted treatment effect (see section 3.9). It also considered that alemtuzumab offers different value because of its potential for good efficacy but with a high rate of adverse effects, and therefore patient choice was an important consideration. The committee concluded that, overall, the cost-effectiveness results were acceptable and the most likely estimates were below what NICE considers an acceptable use of NHS resources.
# Other factors
## No equality issues have been identified
A patient expert questioned whether there is an equality issue about gender. The committee concluded that its recommendation applies equally to all genders, so this issue is not something that can be addressed in a technology appraisal. A patient expert submission highlighted concerns about disease-modifying treatment options during pregnancy. The committee noted that the summary of product characteristics states that ponesimod is contraindicated for pregnant women and women who can have children and are not using effective contraception. But it noted ponesimod's short half-life may be an important factor in choosing a treatment for people that will become pregnant. The committee also considered this could not be addressed in a technology appraisal.
## Some benefits of ponesimod may not be captured in the economic analysis
The committee noted that there are no treatment options with ponesimod's mechanism of action available for all people with relapsing–remitting multiple sclerosis. It also noted that the effects of fatigue may not have been fully captured in the analysis (see section 3.6). It also noted other benefits such as the oral administration, short half-life and reduced monitoring burden. The committee considered that these could lead to additional gains in health-related quality of life over those already included in the QALY calculations. The committee considered this in its discussions.
|
{'Recommendations': 'Ponesimod is recommended for treating relapsing–remitting multiple sclerosis with active disease defined by clinical or imaging features in adults, only if the company provides ponesimod according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with ponesimod that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPonesimod is a disease-modifying treatment for multiple sclerosis. There are other disease-modifying treatments in routine clinical use.\n\nClinical trial evidence shows that people who have ponesimod have fewer relapses than people who have teriflunomide. Its effect on disability progression is not clear. Comparisons with other disease-modifying treatments are uncertain because of limitations in the clinical evidence.\n\nThe cost-effectiveness estimates are also uncertain, because of limitations in the clinical evidence and how long-term clinical benefit is predicted from short-term evidence. However, taking this uncertainty into account, the estimates are below what NICE normally considers an acceptable use of NHS resources. Therefore, ponesimod is recommended.', 'Information about ponesimod': "# Marketing authorisation indication\n\nPonesimod (Ponvory, Janssen) is indicated for 'the treatment of adult patients with relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for ponesimod is available in the summary of product characteristics for ponesimod.\n\n# Price\n\nThe list price for ponesimod is commercial in confidence so cannot be reported here. The company has a commercial arrangement. This makes ponesimod available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen, a review of the submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## People would welcome new treatment options for relapsing multiple sclerosis\n\nMultiple sclerosis is a chronic, lifelong disease with no cure, resulting in progressive, irreversible disability. It has many symptoms including pain, chronic fatigue, unsteady gait, muscle loss, speech problems, incontinence, visual disturbance and cognitive impairment. Most people have the relapsing–remitting form of the disease, characterised by periods of new or worsened symptoms. The patient experts highlighted that the disease is complex and unpredictable and impacts all aspects of life and can affect carers too. The disease has a higher prevalence in women. Because it is typically diagnosed when people are of child-bearing age, the patient experts highlighted it is important to consider treatments that can be used during pregnancy. The company noted that although ponesimod is not indicated for pregnant women, its short half-life could be helpful for pregnancy planning compared with drugs with longer half-lives. The patient experts also highlighted that people generally prefer oral treatments and that ponesimod is an oral treatment. The committee concluded that despite many available treatments, people would welcome new treatment options for relapsing multiple sclerosis.\n\n# Treatment pathway, population and comparators\n\n## Ponesimod is likely to be used as a first- or second-line treatment for relapsing–remitting multiple sclerosis\n\nPonesimod's marketing authorisation is for active disease defined by clinical or imaging features. The company explained that the ponesimod clinical trials included people with active disease defined as at least:\n\nrelapse within the last year\xa0or 2\xa0relapses within the last 2\xa0years, or\n\nat least 1 T1\xa0gadolinium‑enhancing lesion on brain MRI within the last 6\xa0months.The company positioned ponesimod as a first- or second-line treatment for active relapsing–remitting multiple sclerosis, and considered ponesimod would not be used for secondary progressive multiple sclerosis. The company also provided evidence for the highly active subgroup as defined in the NHS treatment algorithm. This defines it as: people with an unchanged or increased relapse rate or ongoing severe relapses compared with the last year, despite having previous disease-modifying treatment. The clinical experts considered that the different forms of multiple sclerosis are part of a disease spectrum rather than having clearly defined aspects. However, they agreed with the company's positioning of ponesimod for these subgroups. The clinical experts agreed that ponesimod would be of value as a first-line treatment because:\n\nthere are no oral treatments routinely available as first-line treatment for people who have only had 1\xa0relapse in the last 2\xa0years\n\nthere are no treatments with ponesimod's mechanism of action routinely available for people who have only had 1\xa0relapse in the last 2\xa0years\n\nit has a shorter half-life than other treatments.Having another first- and second-line treatment option would offer people more choice. The committee concluded that ponesimod was likely to be used as a first- or second-line treatment for people with active relapsing–remitting multiple sclerosis, and would not be used for secondary progressive multiple sclerosis.\n\n## All first- and second-line treatments used for relapsing–remitting multiple sclerosis are appropriate comparators\n\nFor people with active relapsing–remitting multiple sclerosis, the company submission compared ponesimod with beta interferons, dimethyl fumarate, glatiramer acetate, teriflunomide, ocrelizumab and peginterferon beta‑1a. For people with highly active relapsing–remitting multiple sclerosis, the company submission compared ponesimod with alemtuzumab, cladribine, fingolimod and ocrelizumab. A comparison with ofatumumab and ozanimod for both groups was added at the clarification stage because they were being appraised at the time of the company submission; however, ozanimod was not recommended. The clinical experts considered it unlikely that ponesimod would be the most effective treatment, but patients and clinicians would choose a treatment based on the risks and benefits. The committee noted that the most effective treatments likely included monoclonal antibodies (alemtuzumab, ocrelizumab and ofatumumab), but that different treatment strategies are used depending on the person's preferences. The committee acknowledged that alemtuzumab is an induction therapy, and a safety review had restricted its use to highly active disease. But, because ponesimod is expected to be used for highly active disease, the committee concluded it should be considered as a relevant comparator for this subgroup. So, the committee concluded that all first- and second-line treatments for active relapsing–remitting multiple sclerosis were relevant comparators.\n\n# Clinical evidence\n\n## Ponesimod reduces relapses and fatigue-related symptoms, but its effects on disability progression are uncertain\n\nThe key clinical evidence for ponesimod came from 2\xa0clinical trials in people with relapsing–remitting multiple sclerosis, and their long-term open-label extension studies:\n\nAC‑058B201 (B201): a phase\xa02 placebo-controlled dose-finding trial and AC‑058B202, an open-label uncontrolled extension trial for people who completed B201\n\nOPTIMUM: a phase\xa03 active-controlled (compared with teriflunomide) parallel trial with the licensed dose and OPTIMUM‑LT, an open-label uncontrolled extension trial in people who completed OPTIMUM.In OPTIMUM, the primary outcome was annualised relapse rate. Key secondary outcomes included change from baseline in fatigue-related symptoms, 3‑month and 6‑month confirmed disability accumulation and adverse events. In B201, the primary outcome was the cumulative number of new gadolinium-enhancing lesions from week\xa012\xa0to 24. Key secondary outcomes included annualised relapse rate and the number of people with first confirmed relapsed disease from baseline to week\xa024. Both extension trials assessed long-term efficacy, safety and tolerability of ponesimod. OPTIMUM showed a statistically significant difference in annualised relapse rate and change in fatigue-related symptoms for ponesimod compared with teriflunomide. However, there was no significant difference in 3‑month and 6‑month confirmed disability accumulation. The committee considered the differences seen in 3- and 6‑month confirmed disability accumulation were uncertain and noted that this had a substantial effect on the cost-effectiveness results (see section\xa03.12).\n\n## Baseline characteristics in the trials are broadly generalisable to people with relapsing–remitting multiple sclerosis in the NHS\n\nThe company used baseline characteristics from OPTIMUM in the economic model (see section\xa03.4). OPTIMUM included adults mostly from Europe. Inclusion criteria specified an Expanded Disability Status Scale (EDSS) score of between 0 and 5.5. People had been previously treated with interferon beta‑1a, interferon beta‑1b, glatiramer acetate, natalizumab or dimethyl fumarate, or had had no previous treatment. The trial excluded pregnant women or anyone with progressive multiple sclerosis. The clinical experts considered that the inclusion and exclusion criteria and the baseline characteristics in both trials were generalisable to people in the NHS with relapsing–remitting multiple sclerosis. The clinical experts added that people with milder disease (lower EDSS scores and fewer relapses) tend to be included in clinical trials. The committee concluded that the studies broadly aligned with other populations in clinical trials and were appropriate for decision making.\n\n## Fatigue is an important outcome measure, but is not included in the economic model\n\nThe company measured fatigue symptoms using the Fatigue Symptoms and Impacts Questionnaire: Relapsing Multiple Sclerosis (FSIQ‑RMS). It considered that OPTIMUM was the first trial to use a validated disease-specific fatigue measure as a prespecified end point and to show that a disease-modifying treatment can stabilise fatigue symptoms. The patient experts highlighted fatigue as an important element of quality of life and that some people would switch to a treatment that was shown to act on fatigue. The clinical experts suggested that ponesimod may reduce inflammation, which can reduce fatigue. The committee agreed that fatigue symptoms are an important element of the disease and that the FSIQ‑RMS has potential to be an important disease outcome measure. However, fatigue was not explicitly included in the model and was instead captured through measuring health-related quality of life by EDSS score (see section\xa03.12). The committee also noted that because there was no evidence on fatigue symptoms from other clinical trials using the FSIQ‑RMS, ponesimod could not be compared with drugs other than teriflunomide. The committee concluded that fatigue is an important outcome measure that was not explicitly modelled in the cost-effectiveness analysis. It was uncertain what effect fatigue would have on cost-effectiveness results without seeing data on how well the comparator treatments reduce fatigue.\n\n# Network meta-analysis\n\n## The results from the company's network meta-analyses are highly uncertain\n\nTo estimate ponesimod's relative effectiveness compared with all relevant comparators (see section\xa03.3), the company submitted network meta-analyses for the whole relapsing–remitting population and for the highly active subgroup. These were completed for 4\xa0outcome measures: annualised relapse rate; 3‑ and 6‑month confirmed disability accumulation; and treatment discontinuation. Because of differing inclusion criteria, the company included studies in which at least 80% of the trial population had relapsing–remitting multiple sclerosis according to OPTIMUM's criteria. The ERG considered the company's approach to the network meta-analyses to be generally appropriate. However, it highlighted the extreme heterogeneity of the trial designs, including large differences in how the placebo effect was reported across trials for all outcomes. The ERG noted that the company made no attempt to address this heterogeneity (for example, by using meta-regression on baseline event rates), and considered it could bias the treatment effect. It considered that the outcomes of the studies included were short term and were unlikely to capture meaningful changes in disease. The relative treatment effects also had wide credible intervals, suggesting a highly uncertain treatment effect. For confirmed disability accumulation, which had a substantial effect on the cost-effectiveness results, the credible intervals of relative treatment effect of ponesimod crossed 1 for all treatments. This implied uncertainty that ponesimod was better or worse than any other treatment. To reduce heterogeneity in study design, at technical engagement the ERG suggested pooling interferons (see section\xa03.10). The clinical experts stated that the results of the network meta-analyses generally reflected which treatments are considered more effective in the NHS. The committee concluded that the network meta-analyses have major limitations, and the results were highly uncertain.\n\n## It is appropriate to use 6-month confirmed disability accumulation in the network meta-analyses\n\nThe company used 6‑month confirmed disability accumulation in its base case but considered the 3‑month confirmed disability accumulation to be more robust to produce a network. The ERG considered the 6‑month confirmed disability accumulation to be a more appropriate measure of progression and that this outweighed the additional data available for 3‑month confirmed disability accumulation. The clinical experts also noted the long-established committee preference across recent technology appraisals for 6‑month confirmed disability progression. The committee concluded that using outputs from the 6‑month confirmed disability accumulation was appropriate.\n\n## The model provided an unexpected treatment effect for cladribine, based on 6-month confirmed disability accumulation\n\nThe committee noted that cladribine had a substantially higher treatment effect for 6‑month confirmed disability accumulation than other treatments in the network meta-analysis for the highly active subgroup (see section\xa03.7). It noted that this estimate had wide credible intervals, indicating a high level of uncertainty. The committee noted that because 6‑month confirmed disability accumulation had a substantial effect on the cost-effectiveness results (see section\xa03.12), this estimate also had a large impact on the cost-effectiveness estimate of cladribine. The clinical experts did not expect the substantially greater treatment effect for cladribine compared with other comparators in clinical practice, and anticipated cladribine's treatment effect to reflect the results from the full population analysis. In response to consultation, a stakeholder presented a published analysis that showed that cladribine has similar estimates of efficacy to higher efficacy monoclonal antibodies, when adjusting for baseline risk and considering different definitions of highly active disease. The committee considered that this could partially explain why cladribine seemed more effective in the network meta-analysis than in clinical practice, but also considered there could be some sampling error, indicated by the wide credible intervals.\n\n## It is appropriate to consider the results from the interferon studies in a hierarchical analysis, but the company's version was implemented incorrectly\n\nThe ERG noted substantial heterogeneity in the company's network meta-analyses, in part explained by varying treatment effects from interferon studies. To overcome this, the company provided an updated network analysis that considered all interferons as interchangeable, pooling them into a single node of the network. The ERG considered this appropriate and incorporated it into its base case. The clinical experts agreed that interferons could be presented as a class because they are considered similar in terms of efficacy and are treated as interchangeable in clinical practice. The committee considered that it was potentially appropriate to consider the interferon trials using a class-based analysis. But it also requested a hierarchical class-based model, in which exchangeable effects are drawn from a class-level distribution rather than assuming a single, pooled treatment effect. The company provided this analysis in response to consultation and included it in its revised base case. The model excluded 2\xa0trials that included interferon, ADVANCE and INCOMIN. The point estimates of the model reflected those from the previous models, but it had substantially larger credible intervals for all comparator treatments. The committee considered that excluding the interferon trials did not meet the aim of requesting a hierarchical model and would have preferred the model to include them. The committee considered that the model must have been implemented incorrectly to create such wide credibility intervals, including for comparators that were not linked to an interferon. However, it noted that these changes to the network structure would mostly affect uncertainty parameters in the probabilistic analysis. The committee concluded that the hierarchical model would have been most appropriate if it had been implemented correctly. But it expected the results to lie between the pooled analysis and the company's original analysis with separate interferons and it considered both in its decision making.\n\n## All appropriate safety evidence for serious and rare adverse events with ponesimod has been considered\n\nThe company provided direct safety evidence from OPTIMUM and B201, including a long-term safety set which pooled evidence from everyone who had ponesimod during OPTIMUM and B201 and their long-term extension studies. The ERG noted that the safety data presented by the company was comparable to that of other disease-modifying treatments. But it noted potential for an elevated risk of serious adverse events characteristic of the class of sphingosine 1‑phosphate inhibitors. This would need confirming with long-term safety data from a large group. The clinical experts considered that the adverse event profile would likely resemble that of fingolimod, which has an acceptable safety profile. The ERG considered that adverse events had been appropriately included in the economic model. The committee considered that further data would be needed to fully establish ponesimod's safety profile but that all appropriate safety evidence had been incorporated in the economic model.\n\n# Economic model\n\n## The company's model aligns with previous models in the disease area but has limitations\n\nThe company's model structure was similar to model structures used in previous multiple sclerosis technology appraisals. It was a Markov transition model consisting of 20\xa0health states (10\xa0EDSS states for relapsing–remitting multiple sclerosis, 9\xa0for secondary progressive multiple sclerosis, and death). The model used the British Columbia Multiple Sclerosis registry as a source of natural history data. Treatment effects for ponesimod and all comparators were from the company's network meta-analyses and were applied to adjust progression through each of the EDSS states using 6‑month confirmed disability accumulation. Relapses were modelled independently, also using annualised relapse rate ratios from the network meta-analyses. The committee noted that many assumptions in the model had been accepted in previous technology appraisals in multiple sclerosis, including:\n\nmodelling 1\xa0line of treatment only with no treatment switching\n\nincorporating a treatment waning effect of 25% reduction in efficacy from years\xa02 to 5 and a 50% reduction in efficacy from year\xa06 onward (specific to technologies with a similar effectiveness profile, for example NICE's technology appraisal guidance on peginterferon beta-1a and NICE's technology appraisal guidance on dimethyl fumarate)\n\nrelative risk of death being applied to each EDSS health state, taken from Pokorski (1997) which demonstrated that risk of death because of multiple sclerosis was primarily dependent on disability\n\nincorporating patient utility values from published literature (Orme, 2007) rather than OPTIMUM.The clinical experts considered that some of these modelling assumptions may not accurately represent the natural history of multiple sclerosis or use the most up-to-date data. They added that differences in treatment efficacy are often driven by disease activity, the age of the person, the number of relapses and disability at baseline. The committee noted that previous appraisals had criticised the lack of treatment switching or sequencing and the fixed treatment waning effect as major limitations of similar models. It considered that these oversimplify what would happen in NHS clinical practice. However, it acknowledged that a model that can simulate treatment sequencing and variable treatment waning would be complex to construct and difficult to populate because of limited data. The committee considered that longer-term efficacy is difficult to establish and extrapolate from the short-term trials used in the network meta-analyses, the outputs of which have broad credible intervals. The committee concluded that the model structure and inputs broadly aligned with previous models in the disease area, but had limitations.\n\n## The modelled output shows an unlikely number of people in high EDSS states\n\nThe committee noted that the modelled outputs from the company's model, including total quality-adjusted life year (QALY) gain, were inconsistent with those of other appraisals. The committee was unclear why this was the case if the inputs and structure were all broadly similar to those of previous appraisals. One of the main reasons for the differences between models was the conversion rate between relapsing–remitting multiple sclerosis and secondary progressive multiple sclerosis. The ERG noted that the London Ontario database was used to inform the conversion rates as reported in Mauskopf (2016), but these rates differed from those used in NICE's technology appraisal guidance on peginterferon. The ERG provided a scenario analysis that used the rates used in the peginterferon appraisal and noticed that the cost-effectiveness results were sensitive to this assumption, though total QALYs remained low. The clinical experts commented that it would be plausible to assume that, in an average disease course, people would be in a relapsing–remitting multiple sclerosis state 50% of the time and in the secondary progressive multiple sclerosis state for the other 50%. But they commented that some people will be in the relapsing–remitting state longer, particularly if their disease is treated early. The committee queried why the company analysis modelled that people would spend a greater amount of time in the secondary progressive multiple sclerosis state. Another important difference was the transition between EDSS states within secondary progressive multiple sclerosis, which were informed by the London Ontario database. The clinical experts stated that once the disease has progressed to secondary progressive multiple sclerosis, most people would remain in EDSS\xa06 or EDSS\xa07 states for a long period of time. The committee noted that a large proportion of people were in EDSS\xa08 and EDSS\xa09 for most of the model's time horizon and that both states had negative utility values. It considered that these results were unlikely and explained some of the differences in total QALY gain between appraisals. But it was unclear which input was driving these transitions, because the transitions between EDSS states within secondary progressive multiple sclerosis had been used in previous appraisals. The committee was aware that the effect of this issue was uncertain because it was applied to all the modelled treatments. But it did not see enough analysis to judge what would happen if more likely outputs were included. The committee concluded further sensitivity analysis was needed to explore unlikely numbers of people in high EDSS health states. In response to consultation, the company compared its model with the one in NICE's technology appraisal guidance on peginterferon. The ERG said that the outputs from both models were broadly in line. It added that if peginterferon inputs were used in the ponesimod model, both models produced similar secondary progressive multiple sclerosis time outputs with minimal difference between comparators. But the committee felt that similarity with other appraisals did not necessarily indicate external validity. It also considered that this did not account for differences with other models or compared with clinical validation of the outputs. The committee concluded that this model, as with other multiple sclerosis models, is limited in its ability to accurately reflect the course of the condition, but considered that this model did show the relative benefit of ponesimod compared with comparator treatments. The committee concluded that the model should have more accurately portrayed the disease course of multiple sclerosis instead of showing an implausible number of people in high EDSS states. However, the committee concluded that the model showed the relative benefit of ponesimod compared with other treatments enough for decision making in this instance.\n\n## More appropriate mortality data may be available and should be used in future\n\nThe company initially used mortality data from Pokorski (1997) to model mortality within each EDSS health state, for both relapsing–remitting and secondary progressive multiple sclerosis. The company noted that this method has been used in several previous appraisals. The clinical experts considered that this mortality data was outdated, and that managing acute infection and nursing has fundamentally reduced mortality with multiple sclerosis. They noted that new standardised mortality rates by EDSS state for people with multiple sclerosis had been recently published. This updated data showed higher risk of death in the EDSS states\xa08\xa0and 9. When these rates were used to model mortality, it interacted with the implausibly high number of people in these states (see section\xa03.13) to produce overall survival that was substantially lower than that in the published data. The committee considered this implausible. The ERG considered that the new mortality model calculated mortality from few deaths and that there may be more appropriate sources of mortality data. It noted that this could be explored in a systematic review of mortality data in multiple sclerosis. For the purposes of decision making, the committee considered both sources of mortality but noted their limitations. The committee concluded that in future appraisals in multiple sclerosis, it would like to see more appropriate sources of mortality data in a model with plausible distributions of people in EDSS states.\n\n## An economic model that accounts for treatment sequencing is needed to capture use of siponimod for secondary progressive multiple sclerosis\n\nThe ERG noted that siponimod has recently been approved for secondary progressive multiple sclerosis and the economic model did not allow for any treatment effect to be modelled after progression. The company obtained expert opinion that estimated 25% of people who develop secondary progressive multiple sclerosis would choose to have siponimod. However, the company and ERG base case only used the costs of siponimod use in the economic analysis. The clinical experts agreed that 25% of people with secondary progressive multiple sclerosis using siponimod seemed reasonable, but there was currently no data on uptake to base this on. They also noted that it was unlikely that siponimod would be offered to people whose disease progressed after they had ponesimod, because they both belong to the class of sphingosine 1‑phosphate type\xa01 inhibitors. The clinical experts acknowledged there is no evidence for this and no studies exploring this assumption. The committee also questioned whether siponimod would be used by people with EDSS scores greater than 7, which was the health state in which all treatments were stopped in the company assumptions. The clinical experts considered siponimod would not be offered to people with an EDSS greater than 7. This was confirmed by the NHS commissioning expert who noted that siponimod treatment would be stopped if a person is in EDSS\xa07 or greater for more than 6\xa0months. The committee noted that this would be a large proportion of people in the modelled analysis because of the unlikely number of people in high EDSS states (see section\xa03.13). The committee concluded that the model did not allow for treatment sequencing that would reflect clinical practice and that including the costs but not the treatment effect of siponimod was not fully consistent. However, it acknowledged that an economic model that can simulate treatment sequencing would be complex to construct and that minimal evidence for siponimod use would be available in current practice.\n\n# Cost-effectiveness estimates\n\n## The most likely cost-effectiveness estimates are below what NICE normally considers an acceptable use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the incremental cost-effectiveness ratios (ICERs). The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically about the:\n\nresults from the network meta-analyses (see section\xa03.7 and section\xa03.10)\n\nlimitations of the model structure (see section\xa03.12)\n\nlikeliness of the modelled output (see section\xa03.13)\n\nupdated evidence on mortality (see section\xa03.14).The committee considered both the population with active disease (at the point a person would receive their first treatment) and the subgroup with highly active disease (see section\xa03.2) separately. Taking into account the high level of uncertainty and potential benefits that were not captured in the model (see section\xa03.18), the cost-effectiveness estimates for ponesimod compared with other treatments for relapsing–remitting multiple sclerosis were below what NICE normally considers an acceptable use of NHS resources for the population with active disease. Because of confidential commercial arrangements for ponesimod and comparator treatments, the cost-effectiveness results cannot be reported here. For the subgroup with highly active disease, some cost-effectiveness results for ponesimod compared with cladribine and alemtuzumab were above what NICE normally considers an acceptable use of NHS resources. However, the committee considered that the results for the comparison with cladribine may have been based on an unadjusted treatment effect (see section\xa03.9). It also considered that alemtuzumab offers different value because of its potential for good efficacy but with a high rate of adverse effects, and therefore patient choice was an important consideration. The committee concluded that, overall, the cost-effectiveness results were acceptable and the most likely estimates were below what NICE considers an acceptable use of NHS resources.\n\n# Other factors\n\n## No equality issues have been identified\n\nA patient expert questioned whether there is an equality issue about gender. The committee concluded that its recommendation applies equally to all genders, so this issue is not something that can be addressed in a technology appraisal. A patient expert submission highlighted concerns about disease-modifying treatment options during pregnancy. The committee noted that the summary of product characteristics states that ponesimod is contraindicated for pregnant women and women who can have children and are not using effective contraception. But it noted ponesimod's short half-life may be an important factor in choosing a treatment for people that will become pregnant. The committee also considered this could not be addressed in a technology appraisal.\n\n## Some benefits of ponesimod may not be captured in the economic analysis\n\nThe committee noted that there are no treatment options with ponesimod's mechanism of action available for all people with relapsing–remitting multiple sclerosis. It also noted that the effects of fatigue may not have been fully captured in the analysis (see section\xa03.6). It also noted other benefits such as the oral administration, short half-life and reduced monitoring burden. The committee considered that these could lead to additional gains in health-related quality of life over those already included in the QALY calculations. The committee considered this in its discussions."}
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https://www.nice.org.uk/guidance/ta767
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Evidence-based recommendations on ponesimod (Ponvory) for treating relapsing–remitting multiple sclerosis in adults.
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633326cc48fe2dea951b55f98a94618e1dfb441c
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nice
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Upadacitinib for treating active psoriatic arthritis after inadequate response to DMARDs
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Upadacitinib for treating active psoriatic arthritis after inadequate response to DMARDs
Evidence-based recommendations on upadacitinib (Rinvoq) for treating active psoriatic arthritis in adults.
# Recommendations
Upadacitinib, alone or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults whose disease has not responded well enough to disease-modifying antirheumatic drugs (DMARDs) or who cannot tolerate them. It is recommended only if they have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and:
they have had 2 conventional DMARDs and at least 1 biological DMARD or
TNF-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Upadacitinib is recommended only if the company provides it according to the commercial arrangement.
Assess the response to upadacitinib after 12 weeks of treatment. Only continue treatment if there is clear evidence of response. This is defined as an improvement in at least 2 of the 4 Psoriatic Arthritis Response Criteria (PsARC), 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria. If PsARC response does not justify continuing treatment but there is a Psoriasis Area and Severity Index (PASI) 75 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response.
Take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the PsARC and make any appropriate adjustments.
Take into account how skin colour could affect the PASI score and make any appropriate adjustments.
These recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with psoriatic arthritis that is not controlled well enough after 2 conventional DMARDs usually have biological DMARDs. Many of these are already recommended by NICE for treating psoriatic arthritis.
Clinical evidence shows that upadacitinib is more effective than placebo for treating active psoriatic arthritis and may be similarly as effective as adalimumab, another biological DMARD. But upadacitinib has not been directly compared with any other biological DMARD for this condition. The results of an indirect comparison are uncertain but suggest that upadacitinib is likely to work as well as other biological DMARDs.
The economic model showed that upadacitinib was not cost effective compared with some biological DMARDs for people who had not had a biological DMARD before. But it was cost effective for people who had had at least 1 biological DMARD or who could not have TNF-alpha inhibitors. So upadacitinib is recommended for these people.# Information about upadacitinib
# Marketing authorisation indication
Upadacitinib (Rinvoq, AbbVie) 'is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). Upadacitinib may be used as monotherapy or in combination with methotrexate'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics for upadacitinib.
# Price
The cost of 28 15-mg tablets of upadacitinib is £805.56 (excluding VAT; BNF online, accessed August 2021). The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that none of the issues were resolved during the technical engagement stage. It discussed issues 1 to 9, which were outstanding after the technical engagement stage.
# Clinical need
## Psoriatic arthritis substantially affects health-related quality of life
The patient and clinical experts explained that psoriatic arthritis is a lifelong condition that seriously affects people's quality of life. It can develop at a young age and affects all aspects of a person's life, including education, career, relationships and family life. The patient experts explained that symptoms such as fatigue, pain and associated comorbidities such as inflammatory bowel disorders, cardiovascular disease and diabetes, can have a substantial physical and psychological effect. The clinical and patient experts explained that people with psoriatic arthritis have symptoms ranging from mild, non-destructive disease to erosive and deforming arthritis with substantial effects on physical functioning. Symptoms can include swollen fingers and toes through to inflammation of larger joints such as elbows and knees, joints in the back, and tendonitis. Skin and nail psoriasis also affect quality of life. The committee concluded that psoriatic arthritis substantially affects health-related quality of life.
# Clinical management
## Clinicians and people with psoriatic arthritis would welcome an additional treatment option
The clinical experts explained that the main aim of treatment for active psoriatic arthritis is to control joint and connective tissue inflammation. This prevents joint damage progressing and the associated pain and disability. People will usually have treatment with non-steroidal anti-inflammatory drugs, corticosteroids and conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. In line with NICE's technology appraisal guidance on etanercept, infliximab and adalimumab, people are eligible for biological or small-molecule treatments if their disease is poorly controlled after 2 conventional DMARDs. Biological or small-molecule treatments include:
tumour necrosis factor alpha inhibitor (TNFi) treatments such as etanercept and adalimumab
interleukin (IL) inhibitor treatments such as secukinumab and ixekizumab (IL‑17A inhibitors) and ustekinumab (an IL‑12 and IL‑23 inhibitor)
tofacitinib
apremilast.The clinical experts explained that psoriatic arthritis is an unpredictable disease that can flare and change over time. Sometimes it responds to the first conventional DMARD, or to a second or third, or it may not respond at all. The clinical experts highlighted that because flares and periods of disease remission are common, the treatment pathway is not always the same. After conventional DMARDs, people will often switch among the different TNFi treatments, or to different IL modulators (ustekinumab, secukinumab and ixekizumab) or to tofacitinib. People with psoriatic arthritis would benefit from an additional treatment targeting a different inflammatory mediator if:
their disease has not responded (or has stopped responding) to conventional DMARDs and other biologicals or small molecules or
they need to stop their previous treatment because of side effects.Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor that preferentially inhibits signalling by JAK1 or JAK1/3. Its selectivity for JAK1, compared with other JAK subtypes, provides upadacitinib with a degree of disease specificity that differentiates it from tofacitinib, the only JAK inhibitor currently approved in the UK for people with psoriatic arthritis. The patient experts explained that psoriatic arthritis is a lifelong disease for which treatments are often effective for a limited time. They further explained that many people with psoriatic arthritis want autonomy over their own health and so prefer oral treatments compared with treatments given by injection in a clinical setting. The committee concluded that clinicians and people with psoriatic arthritis would welcome an additional treatment option.
# Clinical evidence
## Upadacitinib is clinically effective compared with placebo
The company submission identified 4 subpopulations and presented analyses for 3 of these:
people whose disease is not adequately controlled by 2 conventional DMARDs but who have not previously had a biological DMARD (subpopulation 2)
people whose disease is not adequately controlled by 2 conventional DMARDs or by at least 1 previous biological DMARD (subpopulation 3)
people whose disease is not adequately controlled by 2 previous conventional DMARDs and the TNFi class of biological DMARD is contraindicated or not tolerated (subpopulation 4).The efficacy and safety evidence for upadacitinib in psoriatic arthritis was based on the results of 2 pivotal trials, SELECT-PsA 1 and SELECT-PsA 2. SELECT-PsA 1, which provided evidence in support of upadacitinib in subpopulations 2 and 4, enrolled people who had not previously had treatment with biological DMARDs and randomised them to upadacitinib, adalimumab, or placebo. SELECT-PsA 2 provided evidence in support of the use of upadacitinib in subpopulation 3. It enrolled people who had previously been treated with biological DMARDs and randomised them to upadacitinib or placebo. The primary outcome of the trials was American College of Rheumatology (ACR) 20 response, which is a composite measure defined as an improvement of 20% in both the number of tender joints and the number of swollen joints, and a 20% improvement in 3 of the following 5 criteria: patient global assessment, physician global assessment, functional ability measure, visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein. A higher proportion of people achieved an ACR 20 response with upadacitinib compared with placebo at 12 weeks in both trials. Upadacitinib resulted in statistically significant and clinically relevant improvements when compared with placebo across a range of secondary outcomes. SELECT-PsA 1 demonstrated statistically significantly better efficacy for upadacitinib compared with placebo for the first 9 secondary ranked endpoints. SELECT-PsA 2 demonstrated statistically significantly better efficacy for upadacitinib compared with placebo in all the ranked endpoints measured. Upadacitinib met statistical significance for non-inferiority compared with adalimumab and the committee considered that this could mean that upadacitinib is similar to adalimumab. The committee concluded that upadacitinib was clinically effective compared with placebo across a range of clinically important outcomes.
# Network meta-analyses
## Network meta-analyses are appropriate because of a lack of head-to-head trials with upadacitinib
The SELECT-PsA 1 trial provides direct evidence of the efficacy of upadacitinib compared with adalimumab and upadacitinib compared with placebo (assumed to represent best supportive care). No direct evidence is available to allow comparison of upadacitinib with 8 out of the 9 comparators. The SELECT-PsA 2 trial provides direct evidence for a comparison of upadacitinib compared with placebo. No direct evidence is available to allow comparison of upadacitinib with 5 of the 6 comparators. Clinical advice to the ERG was that adalimumab is commonly the first biological DMARD prescribed after at least 2 conventional DMARDs. The ERG explained that the lack of direct clinical evidence for all other active comparators meant that the company did network meta-analyses (NMAs). In the company submission, the NMA results for those who have not previously had treatment with biological DMARDs (subpopulation 2) were also assumed to apply to people for whom TNFi treatments are contraindicated or not tolerated (subpopulation 4). But the ERG explained that the company presented no clinical evidence to suggest that the effectiveness of biological DMARDs for subpopulation 2 is the same as for subpopulation 4. The ERG also explained that there is no evidence from the NMAs to support the use of upadacitinib to treat the biological-experienced population who have received prior treatment with apremilast or tofacitinib. The committee noted that the company's approach was broadly similar to recent appraisals in the disease area, and concluded that the results from the NMAs should be taken into account for decision making.
## The results of the NMAs are uncertain
To evaluate upadacitinib compared with comparator treatments, the company did NMAs for all main outcomes, for:
people who have not had a biological DMARD (subpopulation 2)
people who have had a biological DMARD (subpopulation 3).The company NMAs for people who have not had a biological DMARD (subpopulation 2) generated indirect evidence to allow comparisons of the clinical effectiveness of upadacitinib compared with all the comparators. The ERG explained that there were several sources of heterogeneity between the studies included in the NMAs, such as disease duration, prior treatments, the extent of concomitant plaque psoriasis and disease activity. The NMAs showed that, overall, upadacitinib had broadly equivalent results compared with the current therapeutic options for people with psoriatic arthritis who have not had treatment with biological DMARDs. The ERG noted that the credible intervals around the observed effect point estimates were often wide, and it is therefore not possible to draw definitive conclusions about the relative efficacy of upadacitinib from the NMAs. The company NMAs for people who have had a biological DMARD (subpopulation 3) generated indirect evidence to allow comparisons of the clinical effectiveness of upadacitinib compared with all the comparators. The NMAs showed that, overall, upadacitinib had broadly equivalent results compared with the current therapeutic options for people with psoriatic arthritis who had had prior treatment with biological DMARDs. Upadacitinib also had the highest probability of achieving a Psoriatic Arthritis Response Criteria (PsARC) response compared with other therapeutic options. The ERG explained that it was not possible to account for between-trial heterogeneity because of the small number of trials in the biological-experienced network. The credible intervals around the observed effect point estimates were often wide, so it is not possible to draw definitive conclusions about the relative efficacy of upadacitinib from the company NMA results. Despite these limitations, the ERG considered that the company's approach was methodologically appropriate, and that there is no alternative approach that would reduce the uncertainty around the results. The company emphasised that extensive sensitivity analyses were used to explore the assumptions and methods used in both the biological-naive and biological-experienced NMAs, and this provides greater confidence in the results. The committee agreed with both the company and the ERG that these limitations are unresolvable, that the appropriate approaches have been used and that there are no alternative approaches to consider. The committee concluded that upadacitinib has similar effectiveness to other therapeutic options for treating people with psoriatic arthritis after conventional DMARDs, but that the results of the NMA are uncertain.
# Economic model
## The model does not reflect NHS clinical practice but is appropriate for decision making
The committee noted that the company's model was based on that used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for the treatment of psoriatic arthritis. Using a Markov structure to capture all costs and outcomes associated with upadacitinib and the comparators, the model included up to 2 lines of active treatment before best supportive care. The company assumed an assessment for response to treatment after 12 weeks for upadacitinib. The committee noted this was consistent with the approach taken in previous NICE technology appraisal models. The ERG confirmed that the model structure was consistent with previous models used in NICE technology appraisals for psoriatic arthritis. But, using a limited number of active treatment lines may not represent NHS clinical practice. The number of treatment options (including best supportive care) that are available for the biological-naive, biological-experienced and TNFi-contraindicated populations are 9, 5 and 5, respectively. The committee recalled that because of the range of treatments and because the disease is varied and unpredictable there is no standard treatment sequence in the NHS (see section 3.2). People will almost always start treatment with conventional DMARDs such as methotrexate, and then move onto biological DMARDs if their disease is not adequately controlled. But the exact sequence of treatments is determined by the course of the disease for each person. The company agreed with the ERG that these are inherent limitations in the economic model, but emphasised that this was a standard model accepted in previous technology appraisals for psoriatic arthritis. The committee agreed that the model is limited in how accurately it represents the number and sequence of treatments used in clinical practice. But, the committee noted that it was consistent with previous NICE technology appraisals for psoriatic arthritis. The committee concluded that the model structure does not reflect NHS clinical practice but is appropriate for decision making. The committee also concluded that technology appraisals in the future should take into account the number and sequence of treatments used in clinical practice.
## The company's model does not reflect the treatment sequence for the TNFi-contraindicated population
The ERG was aware that in NHS clinical practice, the TNFi-contraindicated population generally have more than 1 line of treatment, and best supportive care is generally not an appropriate first-line treatment option for this population. The cost-effectiveness results for the TNFi-contraindicated population should therefore be identical to the biological-naive population who had ustekinumab as a second-line treatment (after excluding TNFi treatments as first-line options). The ERG explored this as a scenario, but this did not alter the overall conclusions on the cost effectiveness of upadacitinib in the TNFi-contraindicated population. The company agreed that the scenario analysis done by the ERG was appropriate. The committee agreed with the company and ERG, and concluded that the model does not accurately reflect the treatment sequence for the TNFi-contraindicated population that would be seen in NHS clinical practice. The committee also concluded that the ERG's approach for modelling the treatment sequence for the TNFi-contraindicated population was more appropriate.
## The clinical-effectiveness data in the model is derived from different sources for HAQ-DI conditional on PsARC
The health assessment questionnaire-disability index (HAQ-DI) is the quality-of-life measure used in the company's economic model. The company's model cost-effectiveness results are driven by PsARC response and HAQ-DI reduction conditional on PsARC. Therefore, the strength of the clinical-effectiveness evidence for these outcomes is central to the credibility of the cost-effectiveness results. The ERG identified several limitations with the implementation of HAQ-DI in the company's economic model. First, results for HAQ-DI conditional on PsARC were not available from the company NMAs for several comparators, and so these were sourced from previous technology appraisals in psoriatic arthritis. For the biological-naive population, these were results for certolizumab pegol, ixekizumab, secukinumab, and tofacitinib. For the biological-experienced population, these were ixekizumab, secukinumab (300 mg only), and tofacitinib. While the ERG recognises that no other sources of HAQ-DI change conditional on PsARC response are available, it explained that using results from different sources without appropriate adjustments adds uncertainty to the company's cost-effectiveness results. The company agreed with the ERG that no alternative data sources or approaches were possible. It explained that while this introduces some uncertainty, this represents a pragmatic approach that enabled reasonable effectiveness estimates and incremental cost-effectiveness ratios (ICERs) to be generated for all comparators. It noted that the same approach was accepted by the committee in the recent NICE technology appraisal guidance on tofacitinib for treating active psoriatic arthritis after inadequate response to DMARDs. The committee concluded that the identified limitations in the NMAs are common to previous technology appraisals for psoriatic arthritis and cannot be resolved.
## HAQ-DI progression in the model is implemented in a similar way to recent appraisals for psoriatic arthritis
The ERG identified a discrepancy in how the company describes the modelling of HAQ-DI over time in its evidence submission, and the way in which it has been implemented in the company's economic model. The company stated that, in line with the model on which all recent technology appraisals for psoriatic arthritis have been based (see section 3.5), people whose disease responds to a first- or second-line biological DMARD have a HAQ-DI score that is constant until the treatment is stopped. At that point it increases (deterioration in function) instantly to their baseline score. HAQ-DI then increases in line with the natural history (the rate of increase for people who did not respond to treatment). But this does not align with how it has been implemented in the company's model. In the company's model, when a responder to a biological DMARD stops treatment, their HAQ-DI score increases instantly to a value between their baseline value and the HAQ-DI score for non-responders to a biological DMARD. Those who are classed as non-responders to a biological DMARD have a HAQ-DI score that has already been increasing in line with natural history since the start of the model. The HAQ-DI score then converges with the rate of increase for non-responders, rather than progressing in parallel to that rate. In part, this is because HAQ-DI increases slowly over time for everybody, whether or not they have psoriatic arthritis. But, it is also possible that a person whose psoriatic arthritis is responding to active treatment may still develop some joint damage. Or, that existing joint damage is getting worse because of use of that joint over time. In addition, HAQ-DI might also be expected to increase over time because of the presence of comorbidities. However, the clinical expert further explained that when active treatment is stopped, it would be expected that the HAQ-DI gradient should be better than natural history, rather than worse. The committee agreed that the model should rebound to baseline, as previous models in this area do. Following the first appraisal committee meeting, the company explained that they considered the implementation to be appropriate and consistent with Markov models used in previous technology appraisals for psoriatic arthritis. NICE sought informal advice from an assessment group who developed the original model and who were the ERG for recent technology appraisals for psoriatic arthritis (The Centre for Reviews and Dissemination and Centre for Health Economic Technology Assessment Group at the University of York). They and the ERG for this appraisal agreed that the company's approach was inconsistent with the most recent accepted approach used in the NICE technology appraisal guidance on guselkumab for treating active psoriatic arthritis after inadequate response to DMARDs (from now on referred to as TA711). NICE provided the company with a technical solution to resolve this issue in a similar way to the approach used in TA711 provided by CRD and CHE TAG at the University of York. The company implemented this solution and provided a revised model. The ERG for this appraisal confirmed that the company's revised model using the technical solution reflected the approach used in TA711. The committee noted that the company's revised model results had a negligible impact on the cost-effectiveness results. The committee concluded that HAQ-DI progression in the model is implemented in a similar way to recent appraisals for psoriatic arthritis and was acceptable for decision making.
## Increasing HAQ-DI conditional on PsARC while responding to treatment does not affect cost effectiveness
At submission, the company did not present a scenario in which the effect of HAQ-DI increases for people whose disease responds to a biological DMARD while having treatment. The ERG had suggested to the company that results from such a scenario would have been informative. The company responded that this situation was not clinically plausible. Clinical expert opinion to the company suggested that it was implausible because people experiencing disease progression at the natural history rate would quickly be swapped to an alternative treatment because of a lack of response. Clinical expert opinion provided at the technical engagement stage confirmed that increasing HAQ-DI in a person responding to treatment would be an unusual scenario, and usually related to a parallel comorbidity rather than to psoriatic arthritis disease progression. Following the first appraisal committee meeting, the company provided this scenario analysis. The ERG was satisfied that it did not meaningfully affect the cost-effectiveness results. The committee concluded that given the lack of effect on the results, this did not need be considered further.
## Results based on psoriasis severity are relevant
The company did not present evidence of clinical effectiveness by presence of concomitant psoriasis. The committee recalled that in previous psoriatic arthritis appraisals results were presented by psoriasis subgroup. But the company and ERG did present the cost-effectiveness results by presence of concomitant psoriasis (no psoriasis, mild to moderate, moderate to severe) by using a combination of body surface area and psoriasis area and severity index (PASI) scores. The ERG considered that this approach was appropriate. The committee concluded that results based on psoriasis severity were relevant for consideration.
# Cost-effectiveness estimates
## Cost-effectiveness results differ by subpopulation
Because upadacitinib and the comparators have commercial arrangements, the exact ICERs are confidential and cannot be reported here. The company provided cost-effectiveness results for each subpopulation and by psoriasis severity:
For people who have not had a biological DMARD: the fully incremental cost-effectiveness analysis showed that upadacitinib was dominated (that is, upadacitinib was more costly, with fewer benefits) in all psoriasis severity. In the pairwise analysis, the committee noted upadacitinib was dominated by either infliximab or etanercept, or infliximab alone. The pairwise ICER compared with adalimumab was also above £20,000 per QALY gained. However, compared with many other technologies, upadacitinib either dominated (that is, it is more effective and cheaper), had ICERs below £20,000 per QALY gained or had ICER's above £20,000 per QALY lost in the situation where there was a south-west quadrant ICER (that is, when upadacitinib was less effective than the comparator).
For people who have had a biological DMARD: the fully incremental cost-effectiveness results showed that the ICER for upadacitinib compared with best supportive care was less than £20,000 per QALY gained in all the psoriasis severity subgroups. In the pairwise analysis, upadacitinib was either dominant (that is, cheaper and more effective), or had an ICERs more £20,000 per QALY lost where there was a south-west quadrant ICER compared with all other active comparators.
For people for whom TNFi treatments are contraindicated: the fully incremental cost-effectiveness results (based on the ERG's scenario where ustekinumab is given as second-line treatment) showed that the ICER for upadacitinib compared with tofacitinib was less than £20,000 per QALY gained in people with no concomitant psoriasis or mild to moderate psoriasis. In people with moderate to severe psoriasis upadacitinib dominated (that is, it is cheaper and more effective) all the other active comparators. In the pairwise analysis, upadacitinib was either dominant (that is, cheaper and more effective) or had ICERs below £20,000 per QALY gained compared with all other active comparators.
# Conclusion
## Upadacitinib is not recommended for people who have not had a biological DMARD before
The committee was aware that clinicians and people with psoriatic arthritis would welcome an additional treatment option. It was aware there were already several treatment options available and recommended by NICE for each of subpopulations (see section 3.2). The committee therefore agreed that it was important to consider fully incremental analyses to assess value for money, as outlined in NICE's guide to the methods of technology appraisal 2013. The committee noted that for the people who have not had a biological DMARD, the fully incremental analysis showed that upadacitinib would not be the most cost-effective option when taking into account what it considered an acceptable ICER range representing value for money for the NHS. Pairwise analysis showed that upadacitinib might be cost effective against some but not all options currently available in the NHS. The committee considered that the pairwise analysis results had limited relevance in this appraisal because all the comparators were relevant and therefore the fully incremental analysis was the most appropriate use. The committee acknowledged that previous technology appraisals for psoriatic arthritis may have considered the differences in benefits and costs to be small. However, this is no longer the case because of the availability of biosimilars, and changes to confidential arrangements. The committee concluded that upadacitinib was not a cost-effective use of NHS resources for people who have not had a biological DMARD and so was not recommended in this subpopulation.
## Upadacitinib is recommended for people who have tried a biological DMARD or when TNFi treatments are contraindicated
The cost-effectiveness results for people who have had a biological DMARD or when TNFi treatments are contraindicated were within what NICE considers a cost-effective use of NHS resources. Therefore, it concluded that it could recommend upadacitinib, alone or with methotrexate, for treating active psoriatic arthritis in adults whose disease has not responded well enough to DMARDs or who cannot tolerate them, only if:
they have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints (otherwise known as active psoriatic arthritis)
if they have had 2 conventional DMARDs and at least 1 biological DMARD, or TNFi treatments are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).
# Other factors
## Clinicians should consider factors that may affect PsARC and PASI and make any clinical adjustments needed
The committee considered that the recommendation to stop treatment based on an inadequate PsARC response (in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for upadacitinib. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score and make the clinical adjustments they consider appropriate.
|
{'Recommendations': "Upadacitinib, alone or with methotrexate, is recommended as an option for treating active psoriatic arthritis in adults whose disease has not responded well enough to disease-modifying antirheumatic drugs (DMARDs) or who cannot tolerate them. It is recommended only if they have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints and:\n\nthey have had 2 conventional DMARDs and at least 1 biological DMARD or\n\nTNF-alpha inhibitors are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).Upadacitinib is recommended only if the company provides it according to the commercial arrangement.\n\nAssess the response to upadacitinib after 12 weeks of treatment. Only continue treatment if there is clear evidence of response. This is defined as an improvement in at least 2 of the 4 Psoriatic Arthritis Response Criteria (PsARC), 1 of which must be joint tenderness or swelling score, with no worsening in any of the 4 criteria. If PsARC response does not justify continuing treatment but there is a Psoriasis Area and Severity Index (PASI) 75 response, a dermatologist should decide whether continuing treatment is appropriate based on skin response.\n\nTake into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the PsARC and make any appropriate adjustments.\n\nTake into account how skin colour could affect the PASI score and make any appropriate adjustments.\n\nThese recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with psoriatic arthritis that is not controlled well enough after 2 conventional DMARDs usually have biological DMARDs. Many of these are already recommended by NICE for treating psoriatic arthritis.\n\nClinical evidence shows that upadacitinib is more effective than placebo for treating active psoriatic arthritis and may be similarly as effective as adalimumab, another biological DMARD. But upadacitinib has not been directly compared with any other biological DMARD for this condition. The results of an indirect comparison are uncertain but suggest that upadacitinib is likely to work as well as other biological DMARDs.\n\nThe economic model showed that upadacitinib was not cost effective compared with some biological DMARDs for people who had not had a biological DMARD before. But it was cost effective for people who had had at least 1 biological DMARD or who could not have TNF-alpha inhibitors. So upadacitinib is recommended for these people.", 'Information about upadacitinib': "# Marketing authorisation indication\n\nUpadacitinib (Rinvoq, AbbVie) 'is indicated for the treatment of active psoriatic arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs). Upadacitinib may be used as monotherapy or in combination with methotrexate'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics for upadacitinib.\n\n# Price\n\nThe cost of 28 15-mg tablets of upadacitinib is £805.56 (excluding VAT; BNF online, accessed August 2021). The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that none of the issues were resolved during the technical engagement stage. It discussed issues 1 to 9, which were outstanding after the technical engagement stage.\n\n# Clinical need\n\n## Psoriatic arthritis substantially affects health-related quality of life\n\nThe patient and clinical experts explained that psoriatic arthritis is a lifelong condition that seriously affects people's quality of life. It can develop at a young age and affects all aspects of a person's life, including education, career, relationships and family life. The patient experts explained that symptoms such as fatigue, pain and associated comorbidities such as inflammatory bowel disorders, cardiovascular disease and diabetes, can have a substantial physical and psychological effect. The clinical and patient experts explained that people with psoriatic arthritis have symptoms ranging from mild, non-destructive disease to erosive and deforming arthritis with substantial effects on physical functioning. Symptoms can include swollen fingers and toes through to inflammation of larger joints such as elbows and knees, joints in the back, and tendonitis. Skin and nail psoriasis also affect quality of life. The committee concluded that psoriatic arthritis substantially affects health-related quality of life.\n\n# Clinical management\n\n## Clinicians and people with psoriatic arthritis would welcome an additional treatment option\n\nThe clinical experts explained that the main aim of treatment for active psoriatic arthritis is to control joint and connective tissue inflammation. This prevents joint damage progressing and the associated pain and disability. People will usually have treatment with non-steroidal anti-inflammatory drugs, corticosteroids and conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate. In line with NICE's technology appraisal guidance on etanercept, infliximab and adalimumab, people are eligible for biological or small-molecule treatments if their disease is poorly controlled after 2\xa0conventional DMARDs. Biological or small-molecule treatments include:\n\ntumour necrosis factor alpha inhibitor (TNFi) treatments such as etanercept and adalimumab\n\ninterleukin (IL) inhibitor treatments such as secukinumab and ixekizumab (IL‑17A inhibitors) and ustekinumab (an IL‑12 and IL‑23 inhibitor)\n\ntofacitinib\n\napremilast.The clinical experts explained that psoriatic arthritis is an unpredictable disease that can flare and change over time. Sometimes it responds to the first conventional DMARD, or to a second or third, or it may not respond at all. The clinical experts highlighted that because flares and periods of disease remission are common, the treatment pathway is not always the same. After conventional DMARDs, people will often switch among the different TNFi treatments, or to different IL modulators (ustekinumab, secukinumab and ixekizumab) or to tofacitinib. People with psoriatic arthritis would benefit from an additional treatment targeting a different inflammatory mediator if:\n\ntheir disease has not responded (or has stopped responding) to conventional DMARDs and other biologicals or small molecules or\n\nthey need to stop their previous treatment because of side effects.Upadacitinib is a selective and reversible Janus kinase (JAK) inhibitor that preferentially inhibits signalling by JAK1 or JAK1/3. Its selectivity for JAK1, compared with other JAK subtypes, provides upadacitinib with a degree of disease specificity that differentiates it from tofacitinib, the only JAK inhibitor currently approved in the UK for people with psoriatic arthritis. The patient experts explained that psoriatic arthritis is a lifelong disease for which treatments are often effective for a limited time. They further explained that many people with psoriatic arthritis want autonomy over their own health and so prefer oral treatments compared with treatments given by injection in a clinical setting. The committee concluded that clinicians and people with psoriatic arthritis would welcome an additional treatment option.\n\n# Clinical evidence\n\n## Upadacitinib is clinically effective compared with placebo\n\nThe company submission identified 4 subpopulations and presented analyses for 3 of these:\n\npeople whose disease is not adequately controlled by 2\xa0conventional DMARDs but who have not previously had a biological DMARD (subpopulation 2)\n\npeople whose disease is not adequately controlled by 2\xa0conventional DMARDs or by at least 1\xa0previous biological DMARD (subpopulation 3)\n\npeople whose disease is not adequately controlled by 2\xa0previous conventional DMARDs and the TNFi class of biological DMARD is contraindicated or not tolerated (subpopulation 4).The efficacy and safety evidence for upadacitinib in psoriatic arthritis was based on the results of 2\xa0pivotal trials, SELECT-PsA\xa01 and SELECT-PsA\xa02. SELECT-PsA\xa01, which provided evidence in support of upadacitinib in subpopulations 2 and 4, enrolled people who had not previously had treatment with biological DMARDs and randomised them to upadacitinib, adalimumab, or placebo. SELECT-PsA\xa02 provided evidence in support of the use of upadacitinib in subpopulation 3. It enrolled people who had previously been treated with biological DMARDs and randomised them to upadacitinib or placebo. The primary outcome of the trials was American College of Rheumatology (ACR) 20 response, which is a composite measure defined as an improvement of 20% in both the number of tender joints and the number of swollen joints, and a 20% improvement in 3 of the following 5 criteria: patient global assessment, physician global assessment, functional ability measure, visual analogue pain scale, and erythrocyte sedimentation rate or C-reactive protein. A higher proportion of people achieved an ACR\xa020 response with upadacitinib compared with placebo at 12\xa0weeks in both trials. Upadacitinib resulted in statistically significant and clinically relevant improvements when compared with placebo across a range of secondary outcomes. SELECT-PsA\xa01 demonstrated statistically significantly better efficacy for upadacitinib compared with placebo for the first 9\xa0secondary ranked endpoints. SELECT-PsA\xa02 demonstrated statistically significantly better efficacy for upadacitinib compared with placebo in all the ranked endpoints measured. Upadacitinib met statistical significance for non-inferiority compared with adalimumab and the committee considered that this could mean that upadacitinib is similar to adalimumab. The committee concluded that upadacitinib was clinically effective compared with placebo across a range of clinically important outcomes.\n\n# Network meta-analyses\n\n## Network meta-analyses are appropriate because of a lack of head-to-head trials with upadacitinib\n\nThe SELECT-PsA\xa01 trial provides direct evidence of the efficacy of upadacitinib compared with adalimumab and upadacitinib compared with placebo (assumed to represent best supportive care). No direct evidence is available to allow comparison of upadacitinib with 8 out of the 9\xa0comparators. The SELECT-PsA\xa02 trial provides direct evidence for a comparison of upadacitinib compared with placebo. No direct evidence is available to allow comparison of upadacitinib with 5 of the 6\xa0comparators. Clinical advice to the ERG was that adalimumab is commonly the first biological DMARD prescribed after at least 2 conventional DMARDs. The ERG explained that the lack of direct clinical evidence for all other active comparators meant that the company did network meta-analyses (NMAs). In the company submission, the NMA results for those who have not previously had treatment with biological DMARDs (subpopulation 2) were also assumed to apply to people for whom TNFi treatments are contraindicated or not tolerated (subpopulation 4). But the ERG explained that the company presented no clinical evidence to suggest that the effectiveness of biological DMARDs for subpopulation 2 is the same as for subpopulation 4. The ERG also explained that there is no evidence from the NMAs to support the use of upadacitinib to treat the biological-experienced population who have received prior treatment with apremilast or tofacitinib. The committee noted that the company's approach was broadly similar to recent appraisals in the disease area, and concluded that the results from the NMAs should be taken into account for decision making.\n\n## The results of the NMAs are uncertain\n\nTo evaluate upadacitinib compared with comparator treatments, the company did NMAs for all main outcomes, for:\n\npeople who have not had a biological DMARD (subpopulation 2)\n\npeople who have had a biological DMARD (subpopulation 3).The company NMAs for people who have not had a biological DMARD (subpopulation 2) generated indirect evidence to allow comparisons of the clinical effectiveness of upadacitinib compared with all the comparators. The ERG explained that there were several sources of heterogeneity between the studies included in the NMAs, such as disease duration, prior treatments, the extent of concomitant plaque psoriasis and disease activity. The NMAs showed that, overall, upadacitinib had broadly equivalent results compared with the current therapeutic options for people with psoriatic arthritis who have not had treatment with biological DMARDs. The ERG noted that the credible intervals around the observed effect point estimates were often wide, and it is therefore not possible to draw definitive conclusions about the relative efficacy of upadacitinib from the NMAs. The company NMAs for people who have had a biological DMARD (subpopulation 3) generated indirect evidence to allow comparisons of the clinical effectiveness of upadacitinib compared with all the comparators. The NMAs showed that, overall, upadacitinib had broadly equivalent results compared with the current therapeutic options for people with psoriatic arthritis who had had prior treatment with biological DMARDs. Upadacitinib also had the highest probability of achieving a Psoriatic Arthritis Response Criteria (PsARC) response compared with other therapeutic options. The ERG explained that it was not possible to account for between-trial heterogeneity because of the small number of trials in the biological-experienced network. The credible intervals around the observed effect point estimates were often wide, so it is not possible to draw definitive conclusions about the relative efficacy of upadacitinib from the company NMA results. Despite these limitations, the ERG considered that the company's approach was methodologically appropriate, and that there is no alternative approach that would reduce the uncertainty around the results. The company emphasised that extensive sensitivity analyses were used to explore the assumptions and methods used in both the biological-naive and biological-experienced NMAs, and this provides greater confidence in the results. The committee agreed with both the company and the ERG that these limitations are unresolvable, that the appropriate approaches have been used and that there are no alternative approaches to consider. The committee concluded that upadacitinib has similar effectiveness to other therapeutic options for treating people with psoriatic arthritis after conventional DMARDs, but that the results of the NMA are uncertain.\n\n# Economic model\n\n## The model does not reflect NHS clinical practice but is appropriate for decision making\n\nThe committee noted that the company's model was based on that used in NICE's technology appraisal guidance on certolizumab pegol and secukinumab for the treatment of psoriatic arthritis. Using a Markov structure to capture all costs and outcomes associated with upadacitinib and the comparators, the model included up to 2\xa0lines of active treatment before best supportive care. The company assumed an assessment for response to treatment after 12\xa0weeks for upadacitinib. The committee noted this was consistent with the approach taken in previous NICE technology appraisal models. The ERG confirmed that the model structure was consistent with previous models used in NICE technology appraisals for psoriatic arthritis. But, using a limited number of active treatment lines may not represent NHS clinical practice. The number of treatment options (including best supportive care) that are available for the biological-naive, biological-experienced and TNFi-contraindicated populations are 9, 5 and 5, respectively. The committee recalled that because of the range of treatments and because the disease is varied and unpredictable there is no standard treatment sequence in the NHS (see section 3.2). People will almost always start treatment with conventional DMARDs such as methotrexate, and then move onto biological DMARDs if their disease is not adequately controlled. But the exact sequence of treatments is determined by the course of the disease for each person. The company agreed with the ERG that these are inherent limitations in the economic model, but emphasised that this was a standard model accepted in previous technology appraisals for psoriatic arthritis. The committee agreed that the model is limited in how accurately it represents the number and sequence of treatments used in clinical practice. But, the committee noted that it was consistent with previous NICE technology appraisals for psoriatic arthritis. The committee concluded that the model structure does not reflect NHS clinical practice but is appropriate for decision making. The committee also concluded that technology appraisals in the future should take into account the number and sequence of treatments used in clinical practice.\n\n## The company's model does not reflect the treatment sequence for the TNFi-contraindicated population\n\nThe ERG was aware that in NHS clinical practice, the TNFi-contraindicated population generally have more than 1\xa0line of treatment, and best supportive care is generally not an appropriate first-line treatment option for this population. The cost-effectiveness results for the TNFi-contraindicated population should therefore be identical to the biological-naive population who had ustekinumab as a second-line treatment (after excluding TNFi treatments as first-line options). The ERG explored this as a scenario, but this did not alter the overall conclusions on the cost effectiveness of upadacitinib in the TNFi-contraindicated population. The company agreed that the scenario analysis done by the ERG was appropriate. The committee agreed with the company and ERG, and concluded that the model does not accurately reflect the treatment sequence for the TNFi-contraindicated population that would be seen in NHS clinical practice. The committee also concluded that the ERG's approach for modelling the treatment sequence for the TNFi-contraindicated population was more appropriate.\n\n## The clinical-effectiveness data in the model is derived from different sources for HAQ-DI conditional on PsARC\n\nThe health assessment questionnaire-disability index (HAQ-DI) is the quality-of-life measure used in the company's economic model. The company's model cost-effectiveness results are driven by PsARC response and HAQ-DI reduction conditional on PsARC. Therefore, the strength of the clinical-effectiveness evidence for these outcomes is central to the credibility of the cost-effectiveness results. The ERG identified several limitations with the implementation of HAQ-DI in the company's economic model. First, results for HAQ-DI conditional on PsARC were not available from the company NMAs for several comparators, and so these were sourced from previous technology appraisals in psoriatic arthritis. For the biological-naive population, these were results for certolizumab pegol, ixekizumab, secukinumab, and tofacitinib. For the biological-experienced population, these were ixekizumab, secukinumab (300\xa0mg only), and tofacitinib. While the ERG recognises that no other sources of HAQ-DI change conditional on PsARC response are available, it explained that using results from different sources without appropriate adjustments adds uncertainty to the company's cost-effectiveness results. The company agreed with the ERG that no alternative data sources or approaches were possible. It explained that while this introduces some uncertainty, this represents a pragmatic approach that enabled reasonable effectiveness estimates and incremental cost-effectiveness ratios (ICERs) to be generated for all comparators. It noted that the same approach was accepted by the committee in the recent NICE technology appraisal guidance on tofacitinib for treating active psoriatic arthritis after inadequate response to DMARDs. The committee concluded that the identified limitations in the NMAs are common to previous technology appraisals for psoriatic arthritis and cannot be resolved.\n\n## HAQ-DI progression in the model is implemented in a similar way to recent appraisals for psoriatic arthritis\n\nThe ERG identified a discrepancy in how the company describes the modelling of HAQ-DI over time in its evidence submission, and the way in which it has been implemented in the company's economic model. The company stated that, in line with the model on which all recent technology appraisals for psoriatic arthritis have been based (see section 3.5), people whose disease responds to a first- or second-line biological DMARD have a HAQ-DI score that is constant until the treatment is stopped. At that point it increases (deterioration in function) instantly to their baseline score. HAQ-DI then increases in line with the natural history (the rate of increase for people who did not respond to treatment). But this does not align with how it has been implemented in the company's model. In the company's model, when a responder to a biological DMARD stops treatment, their HAQ-DI score increases instantly to a value between their baseline value and the HAQ-DI score for non-responders to a biological DMARD. Those who are classed as non-responders to a biological DMARD have a HAQ-DI score that has already been increasing in line with natural history since the start of the model. The HAQ-DI score then converges with the rate of increase for non-responders, rather than progressing in parallel to that rate. In part, this is because HAQ-DI increases slowly over time for everybody, whether or not they have psoriatic arthritis. But, it is also possible that a person whose psoriatic arthritis is responding to active treatment may still develop some joint damage. Or, that existing joint damage is getting worse because of use of that joint over time. In addition, HAQ-DI might also be expected to increase over time because of the presence of comorbidities. However, the clinical expert further explained that when active treatment is stopped, it would be expected that the HAQ-DI gradient should be better than natural history, rather than worse. The committee agreed that the model should rebound to baseline, as previous models in this area do. Following the first appraisal committee meeting, the company explained that they considered the implementation to be appropriate and consistent with Markov models used in previous technology appraisals for psoriatic arthritis. NICE sought informal advice from an assessment group who developed the original model and who were the ERG for recent technology appraisals for psoriatic arthritis (The Centre for Reviews and Dissemination [CRD] and Centre for Health Economic [CHE] Technology Assessment Group [TAG] at the University of York). They and the ERG for this appraisal agreed that the company's approach was inconsistent with the most recent accepted approach used in the NICE technology appraisal guidance on guselkumab for treating active psoriatic arthritis after inadequate response to DMARDs (from now on referred to as TA711). NICE provided the company with a technical solution to resolve this issue in a similar way to the approach used in TA711 provided by CRD and CHE TAG at the University of York. The company implemented this solution and provided a revised model. The ERG for this appraisal confirmed that the company's revised model using the technical solution reflected the approach used in TA711. The committee noted that the company's revised model results had a negligible impact on the cost-effectiveness results. The committee concluded that HAQ-DI progression in the model is implemented in a similar way to recent appraisals for psoriatic arthritis and was acceptable for decision making.\n\n## Increasing HAQ-DI conditional on PsARC while responding to treatment does not affect cost effectiveness\n\nAt submission, the company did not present a scenario in which the effect of HAQ-DI increases for people whose disease responds to a biological DMARD while having treatment. The ERG had suggested to the company that results from such a scenario would have been informative. The company responded that this situation was not clinically plausible. Clinical expert opinion to the company suggested that it was implausible because people experiencing disease progression at the natural history rate would quickly be swapped to an alternative treatment because of a lack of response. Clinical expert opinion provided at the technical engagement stage confirmed that increasing HAQ-DI in a person responding to treatment would be an unusual scenario, and usually related to a parallel comorbidity rather than to psoriatic arthritis disease progression. Following the first appraisal committee meeting, the company provided this scenario analysis. The ERG was satisfied that it did not meaningfully affect the cost-effectiveness results. The committee concluded that given the lack of effect on the results, this did not need be considered further.\n\n## Results based on psoriasis severity are relevant\n\nThe company did not present evidence of clinical effectiveness by presence of concomitant psoriasis. The committee recalled that in previous psoriatic arthritis appraisals results were presented by psoriasis subgroup. But the company and ERG did present the cost-effectiveness results by presence of concomitant psoriasis (no psoriasis, mild to moderate, moderate to severe) by using a combination of body surface area and psoriasis area and severity index (PASI) scores. The ERG considered that this approach was appropriate. The committee concluded that results based on psoriasis severity were relevant for consideration.\n\n# Cost-effectiveness estimates\n\n## Cost-effectiveness results differ by subpopulation\n\nBecause upadacitinib and the comparators have commercial arrangements, the exact ICERs are confidential and cannot be reported here. The company provided cost-effectiveness results for each subpopulation and by psoriasis severity:\n\nFor people who have not had a biological DMARD: the fully incremental cost-effectiveness analysis showed that upadacitinib was dominated (that is, upadacitinib was more costly, with fewer benefits) in all psoriasis severity. In the pairwise analysis, the committee noted upadacitinib was dominated by either infliximab or etanercept, or infliximab alone. The pairwise ICER compared with adalimumab was also above £20,000 per QALY gained. However, compared with many other technologies, upadacitinib either dominated (that is, it is more effective and cheaper), had ICERs below £20,000 per QALY gained or had ICER's above £20,000 per QALY lost in the situation where there was a south-west quadrant ICER (that is, when upadacitinib was less effective than the comparator).\n\nFor people who have had a biological DMARD: the fully incremental cost-effectiveness results showed that the ICER for upadacitinib compared with best supportive care was less than £20,000 per QALY gained in all the psoriasis severity subgroups. In the pairwise analysis, upadacitinib was either dominant (that is, cheaper and more effective), or had an ICERs more £20,000 per QALY lost where there was a south-west quadrant ICER compared with all other active comparators.\n\nFor people for whom TNFi treatments are contraindicated: the fully incremental cost-effectiveness results (based on the ERG's scenario where ustekinumab is given as second-line treatment) showed that the ICER for upadacitinib compared with tofacitinib was less than £20,000 per QALY gained in people with no concomitant psoriasis or mild to moderate psoriasis. In people with moderate to severe psoriasis upadacitinib dominated (that is, it is cheaper and more effective) all the other active comparators. In the pairwise analysis, upadacitinib was either dominant (that is, cheaper and more effective) or had ICERs below £20,000 per QALY gained compared with all other active comparators.\n\n# Conclusion\n\n## Upadacitinib is not recommended for people who have not had a biological DMARD before\n\nThe committee was aware that clinicians and people with psoriatic arthritis would welcome an additional treatment option. It was aware there were already several treatment options available and recommended by NICE for each of subpopulations (see section\xa03.2). The committee therefore agreed that it was important to consider fully incremental analyses to assess value for money, as outlined in NICE's guide to the methods of technology appraisal 2013. The committee noted that for the people who have not had a biological DMARD, the fully incremental analysis showed that upadacitinib would not be the most cost-effective option when taking into account what it considered an acceptable ICER range representing value for money for the NHS. Pairwise analysis showed that upadacitinib might be cost\xa0effective against some but not all options currently available in the NHS. The committee considered that the pairwise analysis results had limited relevance in this appraisal because all the comparators were relevant and therefore the fully incremental analysis was the most appropriate use. The committee acknowledged that previous technology appraisals for psoriatic arthritis may have considered the differences in benefits and costs to be small. However, this is no longer the case because of the availability of biosimilars, and changes to confidential arrangements. The committee concluded that upadacitinib was not a cost-effective use of NHS resources for people who have not had a biological DMARD and so was not recommended in this subpopulation.\n\n## Upadacitinib is recommended for people who have tried a biological DMARD or when TNFi treatments are contraindicated\n\nThe cost-effectiveness results for people who have had a biological DMARD or when TNFi treatments are contraindicated were within what NICE considers a cost-effective use of NHS resources. Therefore, it concluded that it could recommend upadacitinib, alone or with methotrexate, for treating active psoriatic arthritis in adults whose disease has not responded well enough to DMARDs or who cannot tolerate them, only if:\n\nthey have peripheral arthritis with 3 or more tender joints and 3 or more swollen joints (otherwise known as active psoriatic arthritis)\n\nif they have had 2 conventional DMARDs and at least 1 biological DMARD, or TNFi treatments are contraindicated but would otherwise be considered (as described in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis).\n\n# Other factors\n\n## Clinicians should consider factors that may affect PsARC and PASI and make any clinical adjustments needed\n\nThe committee considered that the recommendation to stop treatment based on an inadequate PsARC response (in NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for the treatment of psoriatic arthritis) was also appropriate for upadacitinib. It noted that some people may have physical, sensory or learning disabilities or communication difficulties that could affect their responses to the PsARC, and concluded that this should be taken into account when using the PsARC. The committee was also aware that the PASI might underestimate disease severity in people with darker skin. The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score and make the clinical adjustments they consider appropriate."}
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https://www.nice.org.uk/guidance/ta768
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Evidence-based recommendations on upadacitinib (Rinvoq) for treating active psoriatic arthritis in adults.
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fcd969c8e48053178644d0b5278b7a23f71619c4
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nice
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Stereotactic radiosurgery for trigeminal neuralgia
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Stereotactic radiosurgery for trigeminal neuralgia
Evidence-based recommendations on stereotactic radiosurgery for trigeminal neuralgia in adults. This involves focusing radiation on the trigeminal nerve to damage it, thereby relieving pain.
# Recommendations
Evidence on the safety and efficacy of stereotactic radiosurgery for trigeminal neuralgia is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
For auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Patient selection should be done by a multidisciplinary team experienced in managing trigeminal neuralgia.
The procedure should only be done in specialist centres.# The condition, current treatments and procedure
# The condition
Trigeminal neuralgia is a chronic pain condition that affects the trigeminal (fifth) cranial nerve, one of the most widely distributed nerves in the head. The pain occurs in areas supplied by the trigeminal nerve: the cheeks, jaw, teeth, gums, lips and around the eye or forehead. The typical form, type 1, causes sudden and severe facial pain, usually affecting 1 side of the face and lasting for a few seconds or minutes. It may be triggered by touch, talking, eating or brushing teeth. Atypical trigeminal neuralgia (type 2) is characterised by constant aching, burning, or stabbing pain of lower intensity than type 1. Some people have both types.
Trigeminal neuralgia can be idiopathic or may be caused by pressure on the trigeminal nerve from an artery or a vein (primary trigeminal neuralgia). It can also result from a medical condition such as a tumour, multiple sclerosis or injury (secondary trigeminal neuralgia).
# Current treatments
Medication is the first-line treatment for trigeminal neuralgia. Other treatment options are considered for people who experience severe pain despite medication, or who have side effects from medication.
Percutaneous treatments include glycerol injection, radiofrequency lesioning (applying short bursts of radiofrequency to the nerve through a needle), and balloon microcompression (inflating a balloon near the nerve). The aim is to damage the trigeminal nerve and stop the transmission of pain signals. Recurrence rates of trigeminal neuralgia after these procedures are typically high.
Microvascular decompression is a more invasive procedure involving opening the skull to relieve the pressure on the trigeminal nerve. This can provide longer lasting relief but carries a risk of potentially serious complications such as facial numbness, hearing loss, stroke and death.
# The procedure
Stereotactic radiosurgery for trigeminal neuralgia uses precisely focused multiple beams of ionising radiation aimed at the trigeminal nerve where it enters the brainstem, to deliver a high dose in a single treatment session. It does not require open surgery, needle insertion or general anaesthesia. The aim is to damage the trigeminal nerve and stop the transmission of pain signals as with other percutaneous techniques.
There are different systems available for stereotactic radiosurgery and details of the techniques vary. Imaging is used to accurately locate the target area for treatment. A variety of approaches such as an external frame or a thermoplastic mask can be used to hold the head in a fixed position while the treatment is delivered.
It can take a few weeks or months for the patient to notice any change after stereotactic radiosurgery.
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{'Recommendations': "Evidence on the safety and efficacy of stereotactic radiosurgery for trigeminal neuralgia is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nFor auditing the outcomes of this procedure, the main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nPatient selection should be done by a multidisciplinary team experienced in managing trigeminal neuralgia.\n\nThe procedure should only be done in specialist centres.", 'The condition, current treatments and procedure': '# The condition\n\nTrigeminal neuralgia is a chronic pain condition that affects the trigeminal (fifth) cranial nerve, one of the most widely distributed nerves in the head. The pain occurs in areas supplied by the trigeminal nerve: the cheeks, jaw, teeth, gums, lips and around the eye or forehead. The typical form, type\xa01, causes sudden and severe facial pain, usually affecting 1\xa0side of the face and lasting for a few seconds or minutes. It may be triggered by touch, talking, eating or brushing teeth. Atypical trigeminal neuralgia (type\xa02) is characterised by constant aching, burning, or stabbing pain of lower intensity than type\xa01. Some people have both types.\n\nTrigeminal neuralgia can be idiopathic or may be caused by pressure on the trigeminal nerve from an artery or a vein (primary trigeminal neuralgia). It can also result from a medical condition such as a tumour, multiple sclerosis or injury (secondary trigeminal neuralgia).\n\n# Current treatments\n\nMedication is the first-line treatment for trigeminal neuralgia. Other treatment options are considered for people who experience severe pain despite medication, or who have side effects from medication.\n\nPercutaneous treatments include glycerol injection, radiofrequency lesioning (applying short bursts of radiofrequency to the nerve through a needle), and balloon microcompression (inflating a balloon near the nerve). The aim is to damage the trigeminal nerve and stop the transmission of pain signals. Recurrence rates of trigeminal neuralgia after these procedures are typically high.\n\nMicrovascular decompression is a more invasive procedure involving opening the skull to relieve the pressure on the trigeminal nerve. This can provide longer lasting relief but carries a risk of potentially serious complications such as facial numbness, hearing loss, stroke and death.\n\n# The procedure\n\nStereotactic radiosurgery for trigeminal neuralgia uses precisely focused multiple beams of ionising radiation aimed at the trigeminal nerve where it enters the brainstem, to deliver a high dose in a single treatment session. It does not require open surgery, needle insertion or general anaesthesia. The aim is to damage the trigeminal nerve and stop the transmission of pain signals as with other percutaneous techniques.\n\nThere are different systems available for stereotactic radiosurgery and details of the techniques vary. Imaging is used to accurately locate the target area for treatment. A variety of approaches such as an external frame or a thermoplastic mask can be used to hold the head in a fixed position while the treatment is delivered.\n\nIt can take a few weeks or months for the patient to notice any change after stereotactic radiosurgery.'}
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https://www.nice.org.uk/guidance/ipg715
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Evidence-based recommendations on stereotactic radiosurgery for trigeminal neuralgia in adults. This involves focusing radiation on the trigeminal nerve to damage it, thereby relieving pain.
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5f9dc04e74cc2925f112aa52dd5fc5ae19ff0230
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nice
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Sedaconda ACD-S for sedation with volatile anaesthetics in intensive care
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Sedaconda ACD-S for sedation with volatile anaesthetics in intensive care
Evidence-based recommendations on Sedaconda ACD‑S for sedation with volatile anaesthetics in intensive care.
# Recommendations
Sedaconda anaesthetic conserving device‑S (Sedaconda ACD‑S) is recommended as a cost‑saving option for delivering inhaled sedation in an intensive care setting when the volatile anaesthetics isoflurane or sevoflurane are being considered.
Further research is recommended to identify any health conditions or groups of patients that would benefit more from inhaled sedation with Sedaconda ACD‑S than from standard care. Please see the section on further research for more details.
Why the committee made these recommendations
Sedaconda ACD‑S is used in intensive care settings when people need inhaled sedation. The evidence for Sedaconda ACD‑S includes people with a wide range of conditions. But there were not enough people for each condition in the studies to identify who would particularly benefit from inhaled sedation with Sedaconda ACD‑S. Although there is no published evidence for Sedaconda ACD‑S in children, the committee accepted that the results from the adult studies will be generalisable to children. So, further research is recommended to identify the groups that could benefit from using the technology.
Cost modelling shows that, over 30 days, Sedaconda ACD‑S is cost saving compared with intravenous propofol sedation by £3,833.76 per adult. In children, Sedaconda ACD‑S is also cost saving compared with intravenous midazolam sedation, by £2,837.41 per child. These savings are from reduced time on mechanical ventilation, which may shorten the length of time in intensive care for the patient. Sedaconda ACD‑S was cost saving when the length of time a person spent in intensive care after being taken off mechanical ventilation was reduced by only a few hours (when non‑ventilated days in intensive care was only a few hours, 2.5 to 5 hours).
Evidence suggests that time to people waking up from sedation is shorter with inhaled sedation (using Sedaconda ACD‑S) than with intravenous sedation, but that a reduction in time on mechanical ventilation is uncertain. It is also uncertain if using Sedaconda ACD‑S shortens a person's length of stay in intensive care. Because these are the key drivers of cost savings, the cost analysis results are also uncertain. Even with these uncertainties, Sedaconda ACD‑S is still cost saving in both children and adults and shows promise as an option for use in intensive care settings for sedation with volatile anaesthetics, when sedation with isoflurane or sevoflurane is being considered.
Volatile anaesthetic drugs are potent greenhouse gases. Sedaconda ACD‑S may be associated with a lower consumption of volatile drugs compared with other delivery and scavenging systems for volatile sedation.# The technology
# Technology
The Sedaconda anaesthetic conserving device‑S (Sedaconda ACD‑S; Sedana Medical) is a volatile anaesthetic delivery system to give isoflurane or sevoflurane to people who are mechanically ventilated, usually in an intensive care setting. The technology conserves inhaled anaesthetics within the delivery system and any waste gas is captured by a passive or active gas scavenging system.
Sedaconda ACD‑S is a single-use device (replaced every 24 hours or earlier when needed). The device can be inserted into either the breathing circuit of a ventilator between the endotracheal tube and Y piece, replacing the heat and moisture exchanger (standard placement) or in the inspiratory port of the ventilator (alternative placement). Liquid sedative is injected through the anaesthetic agent line, into a porous rod in the Sedaconda ACD‑S device where the sedative is vaporised. The vaporised sedative is then inhaled by the patient with the inspiration flow from the ventilator. With continued breathing, most of the sedative agent that has not been absorbed by the lungs is exhaled and adsorbed by an active carbon filter in the device. On further inhalation, the sedative is desorbed from the filter and transported back to the lungs, reducing the amount of sedative agent wasted. The Sedaconda ACD‑S device also contains a bacterial and viral filter and a gas analyser port. This port is used to measure the exhalated sedative concentration in minimal alveolar concentration, a relative measure of the level of anaesthesia; or end-tidal concentration. Side stream or mainstream gas monitors, which can measure concentrations of carbon dioxide and anaesthetic gases, must be used to continually monitor sedation. These will need to be purchased separately if not already available. Sedaconda ACD‑S is also recommended to be used with a gas scavenging system. This can be either by a passive system like the manufacturer's FlurAbsorb and FlurAbsorb‑S products, or by an active scavenging system. This is usually built into the hospital system to capture volatile anaesthetics in operating theatres.
Sedaconda ACD‑S can be used with most kinds of ventilator, except high-frequency ventilators. It was launched in the UK in 2017 and is a newer version of the Sedaconda ACD‑L device (available in the UK since 2005), which is now only available on request in the UK. Sedaconda ACD‑S has a lower dead space of 50 ml (compared with 100 ml in the original device) and works with tidal volumes as low as 90 ml. The lower dead space allows Sedaconda ACD‑S to be used on smaller adults or children who have smaller minute or tidal ventilation.
# Care pathway
Adults who need sedation in intensive care have sedation with intravenous sedatives and analgesics, primarily propofol or midazolam with alfentanil, fentanyl or morphine. Children in intensive care usually have sedation with intravenous midazolam and morphine or fentanyl.
Volatile anaesthetics are not licensed for sedation in intensive care units but are licensed for inducting and maintaining anaesthesia in operating theatres. However, clinical experts reported that sedation is a continuum to anaesthesia. The off‑label use of volatile anaesthetics in sedation is widely accepted and is not considered to be harmful. The choice of type of sedation and sedative agents to be used is made by trained clinicians.
The company has submitted a marketing authorisation request to the Medicines and Healthcare products Regulatory Agency for licensing isoflurane (Sedaconda) for inhaled sedation. Sedaconda isoflurane would be indicated for sedation of mechanically ventilated adults during intensive care and should only be administered by the medical device Sedaconda ACD‑S. The regulatory approval is currently under review.
Expert advice suggests the technology is being used in the NHS as an alternative to intravenous sedation in:
people who need mechanical ventilation and who are difficult to sedate (both adults and children)
people who have severe bronchospasms that need mechanical ventilation (both adults and children)
people who need mechanical ventilation after cardiac surgery and cardiac arrest
people in whom intravenous access is difficult or not possible.
# Innovative aspects
The innovative aspect is that Sedaconda ACD‑S allows conserved delivery of inhaled anaesthetic in an intensive care setting in both adults and children.
# Intended use
Sedaconda ACD‑S is intended to be used as an alternative to intravenous sedation for people who need sedation and are mechanically ventilated in intensive care. The Sedaconda ACD‑S has a tidal volume working range of 200 ml to 800 ml when used in standard placement. Small tidal volume (90 ml) can be achieved when Sedaconda ACD‑S is used in the alternative placement.
Sedaconda ACD‑S is for use by healthcare professionals, trained to use inhalational anaesthetic drugs and recognise and manage any adverse effects, in an intensive care setting. In the NHS this would likely be intensivists, intensive care nurses and other technical staff.
# Costs
Sedaconda ACD‑S is available for purchase as a pack of 6 for £2,646. This includes component materials for 6 patient set-ups and approximately 5 treatment days each (30 treatment days in total). The costs used in the economic modelling were:
Device cost: £660 per full course per patient (10.9 days' sedation)
Consumables (FlurAbsorb, syringes, new fill adapter, measure line, Nafion tubing, accessories kit): £347.22 per patient
Multi-gas analyser: £36.61
Total cost of isoflurane administration: £110.78 per patient.For more details, see the website for Sedaconda ACD-S.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The main clinical evidence comprises 21 studies
The EAC assessed 21 full text comparative studies. Twelve were randomised controlled trials, 2 cross-over studies, 5 retrospective studies, 1 prospective study, and 1 study collected data prospectively for the Sedaconda ACD‑S arm but used retrospective data for the intravenous arm. Fifteen abstracts identified were not included in the evidence review. The EAC focused on primary studies only and did not extract data from 1 meta-analysis to avoid duplication of data. There was no published evidence on using Sedaconda ACD‑S in children.
All included studies were peer‑reviewed, and none were done in the UK. The included studies covered 6 population groups:
people after cardiac surgery (8 studies, 798 people)
people after cardiac arrest having therapeutic temperature management (3 studies, 816 people)
people with acute respiratory distress syndrome (2 studies, 88 people)
people with various surgical indications (2 studies, 270 people)
people having head and neck surgery who need a tracheostomy (1 study, 29 people)
people with pulmonary disorders (1 study, 30 people)
people with over 12 hour (1 study, 40 people) and 24‑hour sedation needs (2 studies, 361 people).For full details of the clinical evidence, see section 3 of the assessment report in the supporting documentation on the NICE website.
## Clinical experts identified 3 particularly important clinical outcomes
The EAC, after consultation with clinical experts, identified 3 outcomes of particular clinical importance: time on mechanical ventilation, wake‑up time and sedation efficiency. Other outcomes reported across the 21 included studies were: intensive care and hospital length of stay; cognitive and neurological status; cardiac, renal and hepatic markers and blood gas results.
## Evidence shows that inhaled sedation using Sedaconda ACD-S leads to faster wake-up time and maintains adequate sedation, but time on mechanical ventilation is uncertain
Wake‑up time, usually reported as extubation time (the time from stopping the sedative infusion to taking out the endotracheal tube), was measured in 6 studies and found to be significantly shorter in the volatile sedation arms compared with the intravenous arms across all the heterogeneous populations. The EAC concluded that sedation given using Sedaconda ACD‑S offers benefit over intravenous sedation in terms of wake‑up time. This is likely attributed to using the volatile sedatives that Sedaconda ACD‑S allows to be used rather than the device itself.
Inhaled sedation using isoflurane delivered with Sedaconda ACD‑S was non-inferior to propofol in maintaining adequate sedation (time spent at the desired sedation depth) without rescue medications in a large randomised clinical trial (n=301; Meiser 2021).
Eleven publications reported time on mechanical ventilation. The difference in time on mechanical ventilation between the volatile arms and the intravenous arms was uncertain because only 3 studies reported statistically significant differences (matched analysis of Krannich , Rohm and Rohm ) and the rest of the studies found non‑significant differences in time on ventilation.
## There is uncertainty in the evidence on length of stay for inhaled sedation and intravenous sedation
All included studies were inconclusive about the measured outcomes for length of stay. The studies looked at different sedative drug combinations, and any differences between groups are likely to be because of these drug differences as well as the variables involved in patient treatment and could not be solely attributed to using the device.
## Evidence is inconclusive for other outcomes that benefit patients
Eight publications reported on cognitive and neurological outcomes, 9 studies reported on cardiac, renal and hepatic biochemical markers and 6 studies reported on patient blood gas results. Most of the studies were not statistically significant in lowering the incidence of delirium, lowering organ‑specific biomarkers and improving oxygenation compared with intravenous sedatives.
# Cost evidence
## The company's cost analysis model compares inhaled sedation using the Sedaconda ACD-S device with intravenous sedation
The company's cost model compared inhaled isoflurane with intravenous propofol. The cost model had a 30‑day time horizon and included adult patients needing mechanical ventilation for 24 hours or longer in intensive care. The clinical input parameters included the mean body weight of people having sedation in intensive care, the time on mechanical ventilation (mean, in days) and the length of stay in intensive care (mean, in days). The company also submitted a scenario analysis that compared inhaled isoflurane with intravenous midazolam. The EAC adapted this analysis to extrapolate the cost analysis in children. The EAC inputted an average body weight of 12 kg for a child but did not change the other clinical parameters. For full details of the cost evidence, see section 4 of the assessment report in the supporting documentation on the NICE website.
## Sedaconda ACD-S device remains cost saving in the EAC's updated model
The EAC agreed with the company's cost model overall. The EAC noted that the time on mechanical ventilation and the length of stay in intensive care were based on the results of a post-hoc analysis done in a subset of people (n=177) from the original randomised clinical trial (n=301; Meiser 2021). This subgroup consisted of people that did not have their sedation approach switched after the 48‑hour randomisation period. The EAC corrected some costs, added the cost of training for switching from intravenous to inhaled sedation and found that Sedaconda ACD‑S remained cost saving by £3,833.76 per adult.
## The company cost analysis results are robust but there is uncertainty around the clinical inputs that drive cost savings
Sensitivity analysis indicated that the cost analysis was robust to changes to drug doses, drug costs and to the addition of training costs with Sedaconda ACD‑S. The EAC threshold analysis showed that, if time on mechanical ventilation is the same for both methods of sedation, inhaled sedation using Sedaconda ACD‑S was cost saving compared with intravenous propofol when the duration of intensive care stay is reduced by 1.5 days. However, the length of stay in intensive care and time on mechanical ventilation were sourced from the post-hoc analysis in a subset of study patients from Meiser (2021). These outcomes were not the primary outcomes of the trial and they were not included in the publication.
## Exploratory analysis suggests that inhaled sedation with Sedaconda ACD-S is cost saving in children
The EAC used the cost analysis model comparing inhaled isoflurane with intravenous midazolam to explore the economic impact of using inhaled sedation in children. Clinical parameters were informed from Krannich (2017). The cost analysis estimated a cost saving of £2,837.41 per child. The clinical experts considered it reasonable to assume that children have a similar response to intervention to adults.# Committee discussion
# Clinical-effectiveness overview
## Sedaconda ACD-S is an efficient delivery system for using inhaled sedation in an intensive care setting without needing a scavenging system
Experts explained that Sedaconda ACD‑S allows delivery of inhaled sedation in an intensive care setting without the need for a gas scavenging system. The alternative would be to use an anaesthetic trolley or machine used for general anaesthesia with a gas scavenger, but the clinical experts said that intensive care units are not routinely equipped with scavenging systems. The experts also said that before Sedaconda ACD‑S was implemented, patients needing inhaled sedation with vaporisers had to be transferred to operating theatres where scavenging systems for volatile anaesthetics are built into the hospital system (that is, the exhaust port of the anaesthetic circuit or ventilators are connected to the operating theatre scavenging system). The committee concluded that Sedaconda ACD‑S is an efficient delivery system for inhaled sedation in an intensive care setting not equipped with scavenging systems.
## No published clinical evidence is available on using Sedaconda ACD-S in children
Although no clinical evidence in children was presented to the committee, a clinical expert said that Sedaconda ACD‑S has been used for 15 years in their paediatric intensive care and it is an effective way of delivering inhaled sedation. No major contraindications exist for using inhaled sedation in children, apart from malignant hyperthermia susceptibility. The EAC extrapolation of the efficacy of inhaled sedation from adults to children considered it reasonable to assume that children respond similarly to the intervention to adults. The committee accepted the assumption and concluded that Sedaconda ACD‑S is a useful option for allowing delivery of volatile sedation in children.
## Evidence shows that inhaled sedation using Sedaconda ACD-S is consistently associated with faster wake-up time
Six clinical studies (5 randomised controlled trials and 1 comparative non‑RCT) reported statistically significant differences in wake up between the intravenous sedation and the inhaled sedation using Sedaconda ACD‑S. The EAC reported that the extubation time is likely dependent on the type of sedative agent used rather than using the Sedaconda ACD‑S device itself. Nevertheless, the clinical experts agreed that using inhaled sedation delivered with Sedaconda ACD‑S leads to more predictable wake-up time in people having sedation for a long time and this is useful when patients need to be woken quickly to make clinical assessments.
## The evidence for replacing intravenous sedation with inhaled sedation delivered by Sedaconda ACD-S is uncertain because of heterogeneity
The 21 studies had heterogenous patient populations that included people after cardiac surgery (9 studies), people after cardiac arrest having therapeutic temperature management (3 studies), people with acute respiratory distress syndrome (2 studies), patients with various surgical indications (2 studies), people having head and neck surgery who need a tracheostomy (1 study), people with pulmonary disorders (1 study) and people with over 12 hour (1 study) and 24‑hour sedation needs (2 studies). The committee concluded that there was uncertainty about which specific patient population would have the most clinical benefit from using inhaled sedation. But, based on expert advice, it agreed that Sedaconda ACD‑S should be an available option for delivering inhaled sedation in intensive care settings when considered clinically appropriate.
## Length of stay in intensive care and the time on mechanical ventilation depend on the underlying condition
Clinical experts said that the length of stay in intensive care and the time on mechanical ventilation are outcomes that depend on a patient's underlying condition. The committee understood that this means it is particularly challenging to show evidence of benefit for length of stay in the context of a clinical study. However, clinical experts explained that using inhaled sedation can reduce the time on mechanical ventilation and shorten the time the patient stays in intensive care after extubation by some hours. The committee concluded that type of sedation used was likely to only have a small effect on the length of stay in intensive care or time on mechanical ventilation.
## Sedaconda ACD-S delivered inhaled sedation is useful for sparing intravenous agents during emergency situations
Clinical experts reported that during the SARS‑CoV‑2 pandemic, inhaled sedation using Sedaconda ACD‑S has been used to preserve intravenous sedative agents that could potentially be in limited supply. The committee concluded that Sedaconda ACD‑S is a useful option to spare intravenous sedative agents during unexpected emergency situations when a large number of people need mechanical ventilation such as in the recent SARS‑CoV‑2 pandemic.
# Side effects and adverse events
## Adverse events associated with using Sedaconda ACD-S are uncommon but inhaled sedation is contraindicated in some patients
The committee heard that there were no reported safety concerns around using the Sedaconda ACD‑S device. It understood that people in intensive care have highly complex needs and as such most adverse events will be because of the different medications used to achieve sedation, rather than using the Sedaconda ACD‑S device itself. The only adverse event linked to the device is blockage, which can also happen in heat and moisture exchangers at a similar rate. There are adverse events associated with using volatile anaesthetic drugs. Volatile anaesthetics are contraindicated in patients with malignant hyperthermia susceptibility. Clinical experts said that using volatile anaesthetics in pregnant women, especially in the first trimester, involves clinical judgement in the risk/benefit balance to the unborn fetus and risk to the woman. The committee concluded that using Sedaconda ACD‑S is safe.
There are other adverse events associated with using volatile anaesthesia listed in the BNF.
# Other patient benefits or issues
## Some evidence shows that inhaled sedation seems to be beneficial to patients
Clinical experts explained that there are benefits for patients when volatile sedatives are used, such as liver, lung and cardiac protection. The EAC reported better awareness quality (1 study) and lower incidence of delirium (1 study) in the Sedaconda ACD‑S group compared with the intravenous group.
## Clinical experts suggest Sedaconda ACD-S may be more beneficial in some patient subgroups
The clinical experts agreed that inhaled sedation is likely to be beneficial in the following subgroups:
people who are difficult to sedate
people with acute bronchospasm
people with acute respiratory distress syndrome
people having multiple sedative agents
people with overdose who need a fast wake up
people who need neurological assessment after cardiac arrest
-lder people at high risk of delirium
children with resistant status epilepticus
people with difficult intravenous access
people with hypoxia.
# NHS considerations overview
## Children and adults having sedation with inhaled volatiles using Sedaconda ACD-S can be transported for transfer within hospital
While uncommon, clinical experts said that patients can be transported for additional tests or procedures within hospitals using Sedaconda ACD‑S. If transport ventilators do not have a scavenging system built in, canisters containing activated carbon, such as FlurAbsorb, can be added to the transport trolley.
# Training
## Only healthcare professionals trained in inhaled anaesthetic drugs can use Sedaconda ACD-S
The clinical experts said that the company offers face-to-face training and 3 accredited e‑learning modules for intensive care nurses and intensivists. The clinical experts noted that the company training resources were highly effective.
# Environmental impact
## Sedaconda ACD-S may minimise the release of greenhouse gases
Volatile anaesthetic drugs are potent greenhouse gases. However, the company claims that the conservation of gases within Sedaconda ACD‑S and using scavenging systems can reduce the release of gases into the atmosphere. The company also claims that Sedaconda ACD‑S would be associated with a lower consumption of volatile sedatives compared with other delivery systems for volatile sedation. The committee was concerned about the environmental effect of increased use of anaesthetic gases and was unsure about the company claims on the efficacy of their scavenging systems. They noted that there was a lack of evidence comparing Sedaconda ACD‑S with other vaporisers used for delivering volatile sedation. Nevertheless, the committee concluded that there was potential that Sedaconda ACD‑S would minimise the release of greenhouse gases.
# Cost modelling overview
## Economic modelling is limited by the uncertainty in some clinical inputs and its relevance to the NHS clinical pathway
The committee accepted the EAC's changes to the company model, which showed that inhaled sedation delivered with Sedaconda ACD‑S was cost saving when compared with intravenous sedation. However, the committee agreed that the modelled clinical scenario comparing intravenous sedation with inhaled sedation using Sedaconda ACD‑S does not reflect the average UK duration of time on mechanical ventilation in intensive care, so has limited applicability (mean time on mechanical ventilation used in the model was 10.9 days whereas experts reported 5 days to 7 days in the UK). The committee also noted that the clinical evidence used to populate the model had substantial limitations, which affected the robustness of the model and the certainty of the results.
# Main cost drivers
## Because of the outcomes measured in the study, the cost savings are not certain
The committee concluded that the evidence about length of stay in intensive care and the time on mechanical ventilation reported in the post-hoc analysis from the Meiser (2021) trial was weak. Because these inputs were the key drivers that led Sedaconda ACD‑S to be cost saving, the conclusion of the economic modelling was uncertain. Despite these uncertainties, the committee noted that Sedaconda ACD‑S has a low threshold to be cost saving. The EAC's threshold analysis found that Sedaconda ACD‑S was cost saving when duration of non‑ventilated days in intensive care was only a few hours shorter than that of intravenous sedation (2.5 hours to 5 hours). The committee concluded that Sedaconda ACD‑S was likely to be the cost saving.
# Scenario analyses
## Sedaconda ACD-S remains cost saving in all analysed scenarios
The committee noted that Sedaconda ACD‑S remained cost saving in all scenario analyses presented. However, the robustness of the estimates of length of stay in intensive care and time on mechanical ventilation were uncertain. The committee concluded that the uncertainty in the clinical inputs could lead to inaccuracies in the cost savings calculated.
# Cost savings
## Sedaconda ACD-S is likely to be cost saving compared with intravenous sedation in both adults and children
The EAC reported that in modelling, Sedaconda ACD‑S is cost saving compared with intravenous sedation by £3,833.76 per adult patient and by £2,837.41 per child. The committee concluded that Sedaconda ACD‑S was likely to be cost saving compared with propofol or midazolam but recognised the limitations in the underpinning clinical evidence which made the size of the potential cost savings uncertain.
# Further research
## Further good quality research is needed to address uncertainties about the population for whom Sedaconda ACD-S is most appropriate
The committee recognised that Sedaconda ACD‑S is an efficient and safe way of delivering volatile anaesthetics in intensive care units. It noted that, although there is clear evidence that inhaled sedation using Sedaconda ACD‑S can lead to faster wake-up time, the evidence around the decrease in length of stay in intensive care and time on mechanical ventilation are more difficult to understand because of the complexity of the underlying conditions of people in the intensive care unit. The committee concluded that further research is needed to address uncertainties in the appropriate population where Sedaconda ACD‑S would be recommended for use compared with standard care.
|
{'Recommendations': "Sedaconda anaesthetic conserving device‑S (Sedaconda ACD‑S) is recommended as a cost‑saving option for delivering inhaled sedation in an intensive care setting when the volatile anaesthetics isoflurane or sevoflurane are being considered.\n\nFurther research is recommended to identify any health conditions or groups of patients that would benefit more from inhaled sedation with Sedaconda ACD‑S than from standard care. Please see the section on further research for more details.\n\nWhy the committee made these recommendations\n\nSedaconda ACD‑S is used in intensive care settings when people need inhaled sedation. The evidence for Sedaconda ACD‑S includes people with a wide range of conditions. But there were not enough people for each condition in the studies to identify who would particularly benefit from inhaled sedation with Sedaconda ACD‑S. Although there is no published evidence for Sedaconda ACD‑S in children, the committee accepted that the results from the adult studies will be generalisable to children. So, further research is recommended to identify the groups that could benefit from using the technology.\n\nCost modelling shows that, over 30\xa0days, Sedaconda ACD‑S is cost saving compared with intravenous propofol sedation by £3,833.76 per adult. In children, Sedaconda ACD‑S is also cost saving compared with intravenous midazolam sedation, by £2,837.41 per child. These savings are from reduced time on mechanical ventilation, which may shorten the length of time in intensive care for the patient. Sedaconda ACD‑S was cost saving when the length of time a person spent in intensive care after being taken off mechanical ventilation was reduced by only a few hours (when non‑ventilated days in intensive care was only a few hours, 2.5\xa0to 5\xa0hours).\n\nEvidence suggests that time to people waking up from sedation is shorter with inhaled sedation (using Sedaconda ACD‑S) than with intravenous sedation, but that a reduction in time on mechanical ventilation is uncertain. It is also uncertain if using Sedaconda ACD‑S shortens a person's length of stay in intensive care. Because these are the key drivers of cost savings, the cost analysis results are also uncertain. Even with these uncertainties, Sedaconda ACD‑S is still cost saving in both children and adults and shows promise as an option for use in intensive care settings for sedation with volatile anaesthetics, when sedation with isoflurane or sevoflurane is being considered.\n\nVolatile anaesthetic drugs are potent greenhouse gases. Sedaconda ACD‑S may be associated with a lower consumption of volatile drugs compared with other delivery and scavenging systems for volatile sedation.", 'The technology': "# Technology\n\nThe Sedaconda anaesthetic conserving device‑S (Sedaconda ACD‑S; Sedana Medical) is a volatile anaesthetic delivery system to give isoflurane or sevoflurane to people who are mechanically ventilated, usually in an intensive care setting. The technology conserves inhaled anaesthetics within the delivery system and any waste gas is captured by a passive or active gas scavenging system.\n\nSedaconda ACD‑S is a single-use device (replaced every 24\xa0hours or earlier when needed). The device can be inserted into either the breathing circuit of a ventilator between the endotracheal tube and Y\xa0piece, replacing the heat and moisture exchanger (standard placement) or in the inspiratory port of the ventilator (alternative placement). Liquid sedative is injected through the anaesthetic agent line, into a porous rod in the Sedaconda ACD‑S device where the sedative is vaporised. The vaporised sedative is then inhaled by the patient with the inspiration flow from the ventilator. With continued breathing, most of the sedative agent that has not been absorbed by the lungs is exhaled and adsorbed by an active carbon filter in the device. On further inhalation, the sedative is desorbed from the filter and transported back to the lungs, reducing the amount of sedative agent wasted. The Sedaconda ACD‑S device also contains a bacterial and viral filter and a gas analyser port. This port is used to measure the exhalated sedative concentration in minimal alveolar concentration, a relative measure of the level of anaesthesia; or end-tidal concentration. Side stream or mainstream gas monitors, which can measure concentrations of carbon dioxide and anaesthetic gases, must be used to continually monitor sedation. These will need to be purchased separately if not already available. Sedaconda ACD‑S is also recommended to be used with a gas scavenging system. This can be either by a passive system like the manufacturer's FlurAbsorb and FlurAbsorb‑S products, or by an active scavenging system. This is usually built into the hospital system to capture volatile anaesthetics in operating theatres.\n\nSedaconda ACD‑S can be used with most kinds of ventilator, except high-frequency ventilators. It was launched in the UK in 2017 and is a newer version of the Sedaconda ACD‑L device (available in the UK since 2005), which is now only available on request in the UK. Sedaconda ACD‑S has a lower dead space of 50\xa0ml (compared with 100\xa0ml in the original device) and works with tidal volumes as low as 90\xa0ml. The lower dead space allows Sedaconda ACD‑S to be used on smaller adults or children who have smaller minute or tidal ventilation.\n\n# Care pathway\n\nAdults who need sedation in intensive care have sedation with intravenous sedatives and analgesics, primarily propofol or midazolam with alfentanil, fentanyl or morphine. Children in intensive care usually have sedation with intravenous midazolam and morphine or fentanyl.\n\nVolatile anaesthetics are not licensed for sedation in intensive care units but are licensed for inducting and maintaining anaesthesia in operating theatres. However, clinical experts reported that sedation is a continuum to anaesthesia. The off‑label use of volatile anaesthetics in sedation is widely accepted and is not considered to be harmful. The choice of type of sedation and sedative agents to be used is made by trained clinicians.\n\nThe company has submitted a marketing authorisation request to the Medicines and Healthcare products Regulatory Agency for licensing isoflurane (Sedaconda) for inhaled sedation. Sedaconda isoflurane would be indicated for sedation of mechanically ventilated adults during intensive care and should only be administered by the medical device Sedaconda ACD‑S. The regulatory approval is currently under review.\n\nExpert advice suggests the technology is being used in the NHS as an alternative to intravenous sedation in:\n\npeople who need mechanical ventilation and who are difficult to sedate (both adults and children)\n\npeople who have severe bronchospasms that need mechanical ventilation (both adults and children)\n\npeople who need mechanical ventilation after cardiac surgery and cardiac arrest\n\npeople in whom intravenous access is difficult or not possible.\n\n# Innovative aspects\n\nThe innovative aspect is that Sedaconda ACD‑S allows conserved delivery of inhaled anaesthetic in an intensive care setting in both adults and children.\n\n# Intended use\n\nSedaconda ACD‑S is intended to be used as an alternative to intravenous sedation for people who need sedation and are mechanically ventilated in intensive care. The Sedaconda ACD‑S has a tidal volume working range of 200\xa0ml to 800\xa0ml when used in standard placement. Small tidal volume (90\xa0ml) can be achieved when Sedaconda ACD‑S is used in the alternative placement.\n\nSedaconda ACD‑S is for use by healthcare professionals, trained to use inhalational anaesthetic drugs and recognise and manage any adverse effects, in an intensive care setting. In the NHS this would likely be intensivists, intensive care nurses and other technical staff.\n\n# Costs\n\nSedaconda ACD‑S is available for purchase as a pack of 6 for £2,646. This includes component materials for 6 patient set-ups and approximately 5 treatment days each (30 treatment days in total). The costs used in the economic modelling were:\n\nDevice cost: £660 per full course per patient (10.9\xa0days' sedation)\n\nConsumables (FlurAbsorb, syringes, new fill adapter, measure line, Nafion tubing, accessories kit): £347.22 per patient\n\nMulti-gas analyser: £36.61\n\nTotal cost of isoflurane administration: £110.78 per patient.For more details, see the website for Sedaconda ACD-S.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 21\xa0studies\n\nThe EAC assessed 21\xa0full text comparative studies. Twelve were randomised controlled trials, 2\xa0cross-over studies, 5\xa0retrospective studies, 1\xa0prospective study, and 1\xa0study collected data prospectively for the Sedaconda ACD‑S arm but used retrospective data for the intravenous arm. Fifteen abstracts identified were not included in the evidence review. The EAC focused on primary studies only and did not extract data from 1\xa0meta-analysis to avoid duplication of data. There was no published evidence on using Sedaconda ACD‑S in children.\n\nAll included studies were peer‑reviewed, and none were done in the UK. The included studies covered 6\xa0population groups:\n\npeople after cardiac surgery (8\xa0studies, 798\xa0people)\n\npeople after cardiac arrest having therapeutic temperature management (3\xa0studies, 816\xa0people)\n\npeople with acute respiratory distress syndrome (2\xa0studies, 88\xa0people)\n\npeople with various surgical indications (2\xa0studies, 270\xa0people)\n\npeople having head and neck surgery who need a tracheostomy (1\xa0study, 29\xa0people)\n\npeople with pulmonary disorders (1\xa0study, 30\xa0people)\n\npeople with over 12\xa0hour (1\xa0study, 40\xa0people) and 24‑hour sedation needs (2\xa0studies, 361\xa0people).For full details of the clinical evidence, see section\xa03 of the assessment report in the supporting documentation on the NICE website.\n\n## Clinical experts identified 3 particularly important clinical outcomes\n\nThe EAC, after consultation with clinical experts, identified 3\xa0outcomes of particular clinical importance: time on mechanical ventilation, wake‑up time and sedation efficiency. Other outcomes reported across the 21\xa0included studies were: intensive care and hospital length of stay; cognitive and neurological status; cardiac, renal and hepatic markers and blood gas results.\n\n## Evidence shows that inhaled sedation using Sedaconda ACD-S leads to faster wake-up time and maintains adequate sedation, but time on mechanical ventilation is uncertain\n\nWake‑up time, usually reported as extubation time (the time from stopping the sedative infusion to taking out the endotracheal tube), was measured in 6\xa0studies and found to be significantly shorter in the volatile sedation arms compared with the intravenous arms across all the heterogeneous populations. The EAC concluded that sedation given using Sedaconda ACD‑S offers benefit over intravenous sedation in terms of wake‑up time. This is likely attributed to using the volatile sedatives that Sedaconda ACD‑S allows to be used rather than the device itself.\n\nInhaled sedation using isoflurane delivered with Sedaconda ACD‑S was non-inferior to propofol in maintaining adequate sedation (time spent at the desired sedation depth) without rescue medications in a large randomised clinical trial (n=301; Meiser\xa02021).\n\nEleven publications reported time on mechanical ventilation. The difference in time on mechanical ventilation between the volatile arms and the intravenous arms was uncertain because only 3\xa0studies reported statistically significant differences (matched analysis of Krannich , Rohm and Rohm ) and the rest of the studies found non‑significant differences in time on ventilation.\n\n## There is uncertainty in the evidence on length of stay for inhaled sedation and intravenous sedation\n\nAll included studies were inconclusive about the measured outcomes for length of stay. The studies looked at different sedative drug combinations, and any differences between groups are likely to be because of these drug differences as well as the variables involved in patient treatment and could not be solely attributed to using the device.\n\n## Evidence is inconclusive for other outcomes that benefit patients\n\nEight\xa0publications reported on cognitive and neurological outcomes, 9\xa0studies reported on cardiac, renal and hepatic biochemical markers and 6\xa0studies reported on patient blood gas results. Most of the studies were not statistically significant in lowering the incidence of delirium, lowering organ‑specific biomarkers and improving oxygenation compared with intravenous sedatives.\n\n# Cost evidence\n\n## The company's cost analysis model compares inhaled sedation using the Sedaconda ACD-S device with intravenous sedation\n\nThe company's cost model compared inhaled isoflurane with intravenous propofol. The cost model had a 30‑day time horizon and included adult patients needing mechanical ventilation for 24\xa0hours or longer in intensive care. The clinical input parameters included the mean body weight of people having sedation in intensive care, the time on mechanical ventilation (mean, in days) and the length of stay in intensive care (mean, in days). The company also submitted a scenario analysis that compared inhaled isoflurane with intravenous midazolam. The EAC adapted this analysis to extrapolate the cost analysis in children. The EAC inputted an average body weight of 12\xa0kg for a child but did not change the other clinical parameters. For full details of the cost evidence, see section\xa04 of the assessment report in the supporting documentation on the NICE website.\n\n## Sedaconda ACD-S device remains cost saving in the EAC's updated model\n\nThe EAC agreed with the company's cost model overall. The EAC noted that the time on mechanical ventilation and the length of stay in intensive care were based on the results of a post-hoc analysis done in a subset of people (n=177) from the original randomised clinical trial (n=301; Meiser 2021). This subgroup consisted of people that did not have their sedation approach switched after the 48‑hour randomisation period. The EAC corrected some costs, added the cost of training for switching from intravenous to inhaled sedation and found that Sedaconda ACD‑S remained cost saving by £3,833.76 per adult.\n\n## The company cost analysis results are robust but there is uncertainty around the clinical inputs that drive cost savings\n\nSensitivity analysis indicated that the cost analysis was robust to changes to drug doses, drug costs and to the addition of training costs with Sedaconda ACD‑S. The EAC threshold analysis showed that, if time on mechanical ventilation is the same for both methods of sedation, inhaled sedation using Sedaconda ACD‑S was cost saving compared with intravenous propofol when the duration of intensive care stay is reduced by 1.5\xa0days. However, the length of stay in intensive care and time on mechanical ventilation were sourced from the post-hoc analysis in a subset of study patients from Meiser\xa0(2021). These outcomes were not the primary outcomes of the trial and they were not included in the publication.\n\n## Exploratory analysis suggests that inhaled sedation with Sedaconda ACD-S is cost saving in children\n\nThe EAC used the cost analysis model comparing inhaled isoflurane with intravenous midazolam to explore the economic impact of using inhaled sedation in children. Clinical parameters were informed from Krannich\xa0(2017). The cost analysis estimated a cost saving of £2,837.41 per child. The clinical experts considered it reasonable to assume that children have a similar response to intervention to adults.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Sedaconda ACD-S is an efficient delivery system for using inhaled sedation in an intensive care setting without needing a scavenging system\n\nExperts explained that Sedaconda ACD‑S allows delivery of inhaled sedation in an intensive care setting without the need for a gas scavenging system. The alternative would be to use an anaesthetic trolley or machine used for general anaesthesia with a gas scavenger, but the clinical experts said that intensive care units are not routinely equipped with scavenging systems. The experts also said that before Sedaconda ACD‑S was implemented, patients needing inhaled sedation with vaporisers had to be transferred to operating theatres where scavenging systems for volatile anaesthetics are built into the hospital system (that is, the exhaust port of the anaesthetic circuit or ventilators are connected to the operating theatre scavenging system). The committee concluded that Sedaconda ACD‑S is an efficient delivery system for inhaled sedation in an intensive care setting not equipped with scavenging systems.\n\n## No published clinical evidence is available on using Sedaconda ACD-S in children\n\nAlthough no clinical evidence in children was presented to the committee, a clinical expert said that Sedaconda ACD‑S has been used for 15\xa0years in their paediatric intensive care and it is an effective way of delivering inhaled sedation. No major contraindications exist for using inhaled sedation in children, apart from malignant hyperthermia susceptibility. The EAC extrapolation of the efficacy of inhaled sedation from adults to children considered it reasonable to assume that children respond similarly to the intervention to adults. The committee accepted the assumption and concluded that Sedaconda ACD‑S is a useful option for allowing delivery of volatile sedation in children.\n\n## Evidence shows that inhaled sedation using Sedaconda ACD-S is consistently associated with faster wake-up time\n\nSix\xa0clinical studies (5\xa0randomised controlled trials [RCTs] and 1\xa0comparative non‑RCT) reported statistically significant differences in wake up between the intravenous sedation and the inhaled sedation using Sedaconda ACD‑S. The EAC reported that the extubation time is likely dependent on the type of sedative agent used rather than using the Sedaconda ACD‑S device itself. Nevertheless, the clinical experts agreed that using inhaled sedation delivered with Sedaconda ACD‑S leads to more predictable wake-up time in people having sedation for a long time and this is useful when patients need to be woken quickly to make clinical assessments.\n\n## The evidence for replacing intravenous sedation with inhaled sedation delivered by Sedaconda ACD-S is uncertain because of heterogeneity\n\nThe 21\xa0studies had heterogenous patient populations that included people after cardiac surgery (9\xa0studies), people after cardiac arrest having therapeutic temperature management (3\xa0studies), people with acute respiratory distress syndrome (2\xa0studies), patients with various surgical indications (2\xa0studies), people having head and neck surgery who need a tracheostomy (1\xa0study), people with pulmonary disorders (1\xa0study) and people with over 12\xa0hour (1\xa0study) and 24‑hour sedation needs (2\xa0studies). The committee concluded that there was uncertainty about which specific patient population would have the most clinical benefit from using inhaled sedation. But, based on expert advice, it agreed that Sedaconda ACD‑S should be an available option for delivering inhaled sedation in intensive care settings when considered clinically appropriate.\n\n## Length of stay in intensive care and the time on mechanical ventilation depend on the underlying condition\n\nClinical experts said that the length of stay in intensive care and the time on mechanical ventilation are outcomes that depend on a patient's underlying condition. The committee understood that this means it is particularly challenging to show evidence of benefit for length of stay in the context of a clinical study. However, clinical experts explained that using inhaled sedation can reduce the time on mechanical ventilation and shorten the time the patient stays in intensive care after extubation by some hours. The committee concluded that type of sedation used was likely to only have a small effect on the length of stay in intensive care or time on mechanical ventilation.\n\n## Sedaconda ACD-S delivered inhaled sedation is useful for sparing intravenous agents during emergency situations\n\nClinical experts reported that during the SARS‑CoV‑2 pandemic, inhaled sedation using Sedaconda ACD‑S has been used to preserve intravenous sedative agents that could potentially be in limited supply. The committee concluded that Sedaconda ACD‑S is a useful option to spare intravenous sedative agents during unexpected emergency situations when a large number of people need mechanical ventilation such as in the recent SARS‑CoV‑2 pandemic.\n\n# Side effects and adverse events\n\n## Adverse events associated with using Sedaconda ACD-S are uncommon but inhaled sedation is contraindicated in some patients\n\nThe committee heard that there were no reported safety concerns around using the Sedaconda ACD‑S device. It understood that people in intensive care have highly complex needs and as such most adverse events will be because of the different medications used to achieve sedation, rather than using the Sedaconda ACD‑S device itself. The only adverse event linked to the device is blockage, which can also happen in heat and moisture exchangers at a similar rate. There are adverse events associated with using volatile anaesthetic drugs. Volatile anaesthetics are contraindicated in patients with malignant hyperthermia susceptibility. Clinical experts said that using volatile anaesthetics in pregnant women, especially in the first trimester, involves clinical judgement in the risk/benefit balance to the unborn fetus and risk to the woman. The committee concluded that using Sedaconda ACD‑S is safe.\n\nThere are other adverse events associated with using volatile anaesthesia listed in the BNF.\n\n# Other patient benefits or issues\n\n## Some evidence shows that inhaled sedation seems to be beneficial to patients\n\nClinical experts explained that there are benefits for patients when volatile sedatives are used, such as liver, lung and cardiac protection. The EAC reported better awareness quality (1\xa0study) and lower incidence of delirium (1\xa0study) in the Sedaconda ACD‑S group compared with the intravenous group.\n\n## Clinical experts suggest Sedaconda ACD-S may be more beneficial in some patient subgroups\n\nThe clinical experts agreed that inhaled sedation is likely to be beneficial in the following subgroups:\n\npeople who are difficult to sedate\n\npeople with acute bronchospasm\n\npeople with acute respiratory distress syndrome\n\npeople having multiple sedative agents\n\npeople with overdose who need a fast wake up\n\npeople who need neurological assessment after cardiac arrest\n\nolder people at high risk of delirium\n\nchildren with resistant status epilepticus\n\npeople with difficult intravenous access\n\npeople with hypoxia.\n\n# NHS considerations overview\n\n## Children and adults having sedation with inhaled volatiles using Sedaconda ACD-S can be transported for transfer within hospital\n\nWhile uncommon, clinical experts said that patients can be transported for additional tests or procedures within hospitals using Sedaconda ACD‑S. If transport ventilators do not have a scavenging system built in, canisters containing activated carbon, such as FlurAbsorb, can be added to the transport trolley.\n\n# Training\n\n## Only healthcare professionals trained in inhaled anaesthetic drugs can use Sedaconda ACD-S\n\nThe clinical experts said that the company offers face-to-face training and 3\xa0accredited e‑learning modules for intensive care nurses and intensivists. The clinical experts noted that the company training resources were highly effective.\n\n# Environmental impact\n\n## Sedaconda ACD-S may minimise the release of greenhouse gases\n\nVolatile anaesthetic drugs are potent greenhouse gases. However, the company claims that the conservation of gases within Sedaconda ACD‑S and using scavenging systems can reduce the release of gases into the atmosphere. The company also claims that Sedaconda ACD‑S would be associated with a lower consumption of volatile sedatives compared with other delivery systems for volatile sedation. The committee was concerned about the environmental effect of increased use of anaesthetic gases and was unsure about the company claims on the efficacy of their scavenging systems. They noted that there was a lack of evidence comparing Sedaconda ACD‑S with other vaporisers used for delivering volatile sedation. Nevertheless, the committee concluded that there was potential that Sedaconda ACD‑S would minimise the release of greenhouse gases.\n\n# Cost modelling overview\n\n## Economic modelling is limited by the uncertainty in some clinical inputs and its relevance to the NHS clinical pathway\n\nThe committee accepted the EAC's changes to the company model, which showed that inhaled sedation delivered with Sedaconda ACD‑S was cost saving when compared with intravenous sedation. However, the committee agreed that the modelled clinical scenario comparing intravenous sedation with inhaled sedation using Sedaconda ACD‑S does not reflect the average UK duration of time on mechanical ventilation in intensive care, so has limited applicability (mean time on mechanical ventilation used in the model was 10.9\xa0days whereas experts reported 5\xa0days to 7\xa0days in the UK). The committee also noted that the clinical evidence used to populate the model had substantial limitations, which affected the robustness of the model and the certainty of the results.\n\n# Main cost drivers\n\n## Because of the outcomes measured in the study, the cost savings are not certain\n\nThe committee concluded that the evidence about length of stay in intensive care and the time on mechanical ventilation reported in the post-hoc analysis from the Meiser\xa0(2021) trial was weak. Because these inputs were the key drivers that led Sedaconda ACD‑S to be cost saving, the conclusion of the economic modelling was uncertain. Despite these uncertainties, the committee noted that Sedaconda ACD‑S has a low threshold to be cost saving. The EAC's threshold analysis found that Sedaconda ACD‑S was cost saving when duration of non‑ventilated days in intensive care was only a few hours shorter than that of intravenous sedation (2.5\xa0hours to 5\xa0hours). The committee concluded that Sedaconda ACD‑S was likely to be the cost saving.\n\n# Scenario analyses\n\n## Sedaconda ACD-S remains cost saving in all analysed scenarios\n\nThe committee noted that Sedaconda ACD‑S remained cost saving in all scenario analyses presented. However, the robustness of the estimates of length of stay in intensive care and time on mechanical ventilation were uncertain. The committee concluded that the uncertainty in the clinical inputs could lead to inaccuracies in the cost savings calculated.\n\n# Cost savings\n\n## Sedaconda ACD-S is likely to be cost saving compared with intravenous sedation in both adults and children\n\nThe EAC reported that in modelling, Sedaconda ACD‑S is cost saving compared with intravenous sedation by £3,833.76 per adult patient and by £2,837.41 per child. The committee concluded that Sedaconda ACD‑S was likely to be cost saving compared with propofol or midazolam but recognised the limitations in the underpinning clinical evidence which made the size of the potential cost savings uncertain.\n\n# Further research\n\n## Further good quality research is needed to address uncertainties about the population for whom Sedaconda ACD-S is most appropriate\n\nThe committee recognised that Sedaconda ACD‑S is an efficient and safe way of delivering volatile anaesthetics in intensive care units. It noted that, although there is clear evidence that inhaled sedation using Sedaconda ACD‑S can lead to faster wake-up time, the evidence around the decrease in length of stay in intensive care and time on mechanical ventilation are more difficult to understand because of the complexity of the underlying conditions of people in the intensive care unit. The committee concluded that further research is needed to address uncertainties in the appropriate population where Sedaconda ACD‑S would be recommended for use compared with standard care."}
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https://www.nice.org.uk/guidance/mtg65
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Evidence-based recommendations on Sedaconda ACD‑S for sedation with volatile anaesthetics in intensive care.
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bf4b638cc926882fdba4ad954ce9da32fa23fb5c
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nice
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Glaucoma: diagnosis and management
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Glaucoma: diagnosis and management
This guideline covers diagnosing and managing glaucoma in people aged 18 and over. It includes recommendations on testing and referral (case-finding) for chronic open-angle glaucoma and ocular hypertension and on effective diagnosis, treatment and reassessment to stop these conditions progressing.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Case-finding
The recommendations on case-finding are for primary eye care professionals before referral for diagnosis of chronic open angle glaucoma (COAG) and related conditions and are separate from a sight test.
Before referral for further investigation and diagnosis of COAG and related conditions, offer all of the following tests:
central visual field assessment using standard automated perimetry (full threshold or supra-threshold)
-ptic nerve assessment and fundus examination using stereoscopic slit lamp biomicroscopy (with pupil dilatation if necessary), and optical coherence tomography (OCT) or optic nerve head image if available
intraocular pressure (IOP) measurement using Goldmann‑type applanation tonometry
peripheral anterior chamber configuration and depth assessments using gonioscopy or, if not available or the person prefers, the van Herick test or OCT.
Do not base a decision to refer solely on IOP measurement using non-contact tonometry.
Do not refer people who have previously been discharged from hospital eye services after assessment for COAG and related conditions unless clinical circumstances have changed and a new referral is needed.
Before deciding to refer, consider repeating visual field assessment and IOP measurement on another occasion to confirm a visual field defect or IOP of 24 mmHg or more, unless clinical circumstances indicate urgent or emergency referral is needed.
Refer for further investigation and diagnosis of COAG and related conditions, after considering repeat measures as in recommendation 1.1.4, if:
there is optic nerve head damage on stereoscopic slit lamp biomicroscopy or
there is a visual field defect consistent with glaucoma or
IOP is 24 mmHg or more using Goldmann‑type applanation tonometry.
Provide results of all examinations and tests with the referral.
Advise people with IOP below 24 mmHg to continue regular visits to their primary eye care professional.
The following recommendations are for people planning and providing eye care services before referral.
People planning and providing eye care services should use a service model that includes Goldmann‑type applanation tonometry before referral for diagnosis of COAG and related conditions.
People planning eye care services should consider commissioning referral filtering services (for example, repeat measures, enhanced case-finding, or referral refinement) for COAG and related conditions.
# Diagnosis
To diagnose COAG and related conditions, offer all of the following tests:
visual field assessment using standard automated perimetry (central thresholding test), repeated if necessary to establish severity at diagnosis
-ptic nerve assessment and fundus examination using stereoscopic slit lamp biomicroscopy, with pupil dilatation
IOP measurement using Goldmann applanation tonometry (slit lamp mounted)
peripheral anterior chamber configuration and depth assessments using gonioscopy
central corneal thickness (CCT) measurement.
Adopt professional or Department of Health and Social Care guidance to reduce the risk of transmitting infective agents via contact tonometry or gonioscopy.See the Royal College of Ophthalmologists' ophthalmic services guidance and the Department of Health and Social Care's guidance on minimising transmission risk of CJD and vCJD in healthcare settings.
Use the van Herick peripheral anterior chamber depth assessment if clinical circumstances rule out gonioscopy (for example, when people with physical or learning disabilities are unable to participate in the examination).
Obtain an optic nerve head image at diagnosis for baseline documentation (for example, a stereoscopic optic nerve head image or OCT).
After referral, consider an early assessment appointment if there is clinical concern based on the information provided.
At the time of diagnosis of ocular hypertension (OHT), assess the risk of future visual impairment, taking into account risk factors such as:
level of IOP
CCT
family history
life expectancy.
# Standard practice for all assessments
Ensure that all of the following are available at each clinical episode to all healthcare professionals involved in a person's care:
records of all previous tests and images relevant to COAG and OHT assessment
records of past medical history that could affect medicine choice
current systemic and topical medication
glaucoma medication record
drug allergies and intolerances.
Use alternative methods of assessment if clinical circumstances rule out standard methods (for example, when people with physical or learning disabilities are unable to participate in the examination).
Ensure that all machines and measurement instruments are calibrated regularly according to the manufacturers' instructions.
# Treatment
Take into account any cognitive and physical impairments when making decisions about management and treatment.
Check that there are no relevant comorbidities or potential drug interactions before offering pharmacological treatment.
## Treatment for people with OHT
Do not offer treatment to people with OHT who are not at risk of visual impairment within their lifetime. Advise people to continue regular visits to their primary eye care professional, at clinically appropriate intervals.
Offer 360° selective laser trabeculoplasty (SLT) to people with newly diagnosed OHT with IOP of 24 mmHg or more (excluding cases associated with pigment dispersion syndrome) if they are at risk of visual impairment within their lifetime (see the recommendation on taking account of risk factors in the section on diagnosis). To help inform their decision, tell people:
that having 360° SLT can delay the need for eye drops and can reduce but does not remove the chance they will be needed at all
how long it may take for their IOP to improve after the procedure
about 360° SLT‑specific side effects and complications and how long they are likely to last
that a second 360° SLT procedure may be needed at a later date.
Consider a second 360° SLT for people with OHT if the effect of an initial successful SLT has subsequently reduced over time.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma .
Full details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.
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Offer a generic prostaglandin analogue (PGA) to people with OHT with IOP of 24 mmHg or more if they are at risk of visual impairment within their lifetime (see the recommendation on taking account of risk factors in the section on diagnosis) and:
they choose not to have 360° SLT or
° SLT is not suitable (for example, because they have pigment dispersion syndrome) or
they are waiting for 360° SLT and need an interim treatment or
they have had 360° SLT but need additional treatment to reduce their IOP sufficiently to prevent the risk of visual impairment.Demonstrate correct eye drop installation technique and observe the person using the correct technique when eye drops are first prescribed.
See the recommendations on when to reassess for advice on when the next appointment should take place to assess the impact of any new treatments started.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on generic PGAs for people with OHT or COAG .
Full details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.
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Offer another pharmacological treatment to people with an IOP of 24 mmHg or more who cannot tolerate their current treatment. The first choice should be an alternative generic PGA, and if this is not tolerated, offer a beta‑blocker. If neither of these options is tolerated, offer a non-generic PGA, carbonic anhydrase inhibitor, sympathomimetic, miotic or a combination of treatments.
Offer a medicine from another therapeutic class (beta-blocker, carbonic anhydrase inhibitor or sympathomimetic) to people with an IOP of 24 mmHg or more whose current treatment is not reducing IOP sufficiently to prevent the risk of progression to sight loss. Topical medicines from different therapeutic classes may be needed at the same time to control IOP.
Refer people to a consultant ophthalmologist to discuss other options if their IOP cannot be reduced sufficiently with 360° SLT or pharmacological treatment or both to prevent the risk of progression to sight loss.
Offer preservative-free eye drops to people who have an allergy to preservatives or people with clinically significant and symptomatic ocular surface disease, but only if they are at high risk of conversion to COAG.
## Treatment for people with suspected COAG
Do not offer treatment to people with suspected COAG and IOP less than 24 mmHg unless they are at risk of visual impairment within their lifetime. Advise people to continue regular visits to their primary eye care professional, at clinically appropriate intervals.
## Stopping treatment for people with OHT or suspected COAG
Discuss the benefits and risks of stopping treatment with people with OHT or suspected COAG who have both:
a low risk of developing visual impairment within their lifetime and
an acceptable IOP. If a person decides to stop treatment after this discussion, offer to assess their IOP in 1 month to 4 months with further reassessment if clinically indicated.
## Treatment for people with COAG
In January 2022 the use of mitomycin-C (MMC) in recommendations 1.4.13 and 1.4.20 to 1.4.22 was off label. See NICE's information on prescribing medicines.
Offer people with advanced COAG, glaucoma surgery with pharmacological augmentation (MMC) as indicated. Give them information on the risks and benefits of surgery.
Offer people who present with advanced COAG and who are listed for glaucoma surgery, interim treatment with a generic PGA.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma .
Full details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.
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Offer 360° SLT to people with newly diagnosed COAG (excluding cases associated with pigment dispersion syndrome). For people with advanced COAG see the section on treatment for people with advanced COAG and recommendation 1.4.24. To help inform their decision, tell people:
that having 360° SLT can delay the need for eye drops and can reduce but does not remove the chance they will be needed at all
how long it may take for their IOP to improve after the procedure
about 360° SLT‑specific side effects and complications and how long they are likely to last
that a second 360° SLT procedure may be needed at a later date.
Consider a second 360° SLT for people with COAG if the effect of an initial successful SLT has subsequently reduced over time.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma .
Full details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.
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Offer a generic PGA to people with COAG if:
they choose not to have 360° SLT or
° SLT is not suitable (for example because they have pigment dispersion syndrome) or
they are waiting for an 360° SLT and need an interim treatment or
they have previously had 360° SLT but need additional treatment to reduce their IOP sufficiently to prevent the risk of visual impairment.Demonstrate correct eye drop installation technique and observe the patient using the technique when eye drops are first prescribed.
See recommendations on when to reassess for advice on when the next appointment should take place to assess the impact of any new treatments started.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on generic PGAs for people with OHT or COAG .
Full details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.
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Encourage people to continue with the same pharmacological treatment unless:
their IOP cannot be reduced sufficiently to prevent the risk of progression to sight loss
there is progression of optic nerve head damage
there is progression of visual field defect
they cannot tolerate the medicine.
Ask about adherence to treatment and check the eye drop instillation technique in people with COAG whose IOP has not been reduced sufficiently to prevent the risk of progression to sight loss, despite pharmacological treatment with a generic PGA.
Offer 1 of the following to people with satisfactory adherence to treatment and eye drop instillation technique whose IOP has not been reduced sufficiently to prevent the risk of progression to sight loss:
a medicine from another therapeutic class (a beta-blocker, carbonic anhydrase inhibitor or sympathomimetic); topical medicines from different therapeutic classes may be needed at the same time to control IOP or
° SLT or
glaucoma surgery with pharmacological augmentation (MMC) as indicated.
Consider 360° SLT or glaucoma surgery with pharmacological augmentation (MMC) as indicated for people with COAG who are at risk of progressing to sight loss despite treatment with medicines from 2 therapeutic classes. Give them information on the risks and benefits of surgery.
Consider 1 of the following for people with COAG who cannot tolerate a pharmacological treatment:
a medicine from another therapeutic class (a beta-blocker, carbonic anhydrase inhibitor or sympathomimetic) or
preservative-free eye drops if there is evidence that the person is allergic to the preservative or has clinically significant and symptomatic ocular surface disease.After treatment with medicines from 2 therapeutic classes, consider 360° SLT or glaucoma surgery with pharmacological augmentation (MMC) as indicated.
Offer 1 of the following to people with COAG whose IOP has not been reduced sufficiently to prevent the risk of progression to sight loss after glaucoma surgery:
pharmacological treatment; topical medicines from different therapeutic classes may be needed at the same time to control IOP or
further glaucoma surgery or
° SLT or
cyclodiode laser treatment.
Offer 1 of the following to people with COAG (including advanced COAG) who prefer not to have glaucoma surgery or for whom glaucoma surgery is not suitable:
pharmacological treatment; topical medicines from different therapeutic classes may be needed at the same time to control IOP or
° SLT (for example in people with systemic comorbidities) or
cyclodiode laser treatment.
# Reassessment
## Reassessment tests
At each assessment, offer the following tests to people with COAG, people with suspected COAG and people with OHT:
Goldmann applanation tonometry (slit lamp mounted)
anterior segment slit lamp examination with van Herick peripheral anterior chamber depth assessment when clinically indicated.
When clinically indicated, repeat gonioscopy, for example, if a previous examination has been inconclusive or there is suspicion of a change in clinical status of the anterior chamber angle.
When clinically indicated, repeat visual field testing using standard automated perimetry (central thresholding test) for people with COAG and those with suspected visual field defects who are being investigated for possible COAG (see table 2 and table 3 for recommended reassessment intervals).
When clinically indicated, repeat visual field testing using either a central thresholding test or a supra-threshold test for people with OHT and those with suspected COAG whose visual fields have previously been documented by standard threshold automated perimetry (central thresholding test) as being normal (see table 1 and table 2 for recommended reassessment intervals).
When a visual field defect has previously been detected, use the same measurement strategy for each visual field assessment.
When clinically indicated, repeat assessment of the optic nerve head (for example, stereoscopic slit lamp biomicroscopy or imaging).
When a change in optic nerve head status is detected by stereoscopic slit lamp biomicroscopy, obtain a new optic nerve head image for the person's records to provide a fresh benchmark for future assessments.
When an adequate view of the optic nerve head and surrounding area is unavailable at reassessment, people should have their pupils dilated before stereoscopic slit lamp biomicroscopy or optic nerve head imaging is repeated.
## When to reassess
At each assessment, re-evaluate the risk of conversion to COAG and the risk of sight loss to set time to next assessment.
At each assessment, ask about general health and, if appropriate, factors affecting adherence to treatment, including cognitive impairment and any treatment side effects.
For people with treated OHT (baseline IOP of 24 mmHg or more) and a normal optic head and visual field at the most recent assessment:
use clinical judgement to assess control of IOP and the risk of conversion to COAG, and
reassess according to table 1.
Conversion from ocular hypertension to chronic open angle glaucoma
Control of intraocular pressure
Time to next assessment
Not detected or uncertain conversion
No
Review management plan and reassess between 1 month and 4 months
Uncertain conversion
Yes
Reassess between 6 months and 12 months
No conversion detected
Yes
Reassess between 18 months and 24 months
Conversion
No or yes
See recommendations on diagnosis and reassessment of chronic open angle glaucoma
Use clinical judgement to decide when the next appointment should take place within the recommended interval, including the need to assess the impact of any new treatments started.
Uncertain conversion includes having insufficient accurate information (perhaps because the person was unable to participate in the assessment).
For people with suspected COAG:
use clinical judgement to assess control of IOP and risk of conversion to COAG (optic nerve head damage and visual field defect), and
reassess according to table 2.
Conversion to chronic open angle glaucoma
Control of intraocular pressure
Time to next assessment
Not detected or uncertain conversion
No
Review management plan and reassess between 1 month and 4 months
Uncertain conversion
Yes
Reassess between 6 months and 12 months
No conversion detected
Yes
Reassess between 12 months and 18 months
Conversion
No or yes
See recommendations on diagnosis and reassessment of chronic open angle glaucoma
Use clinical judgement to decide when the next appointment should take place within the recommended interval, including the need to assess the impact of any new treatments started.
Uncertain conversion includes having insufficient accurate information (perhaps because the person was unable to participate in the assessment).
For people with COAG:
use clinical judgement to assess risk of COAG progression to sight loss, and
reassess according to table 3.
Progression of chronic open angle glaucoma
Control of intraocular pressure
Time to next assessment
Not detected
No
Review treatment plan and reassess between 1 month and 4 months
Uncertain progression or progression
No
Review treatment plan and reassess between 1 month and 2 months
No progression detected and low clinical risk
Yes
Reassess between 12 months and 18 months
No progression detected and high clinical risk
Yes
Reassess between 6 months and 12 months
Uncertain progression or progression
Yes
Review treatment plan and reassess between 2 months and 6 months
Use clinical judgement to decide when the next appointment should take place within the recommended interval, including the need to assess the impact of any new treatments started.
Uncertain conversion includes having insufficient accurate information (perhaps because the person was unable to participate in the assessment).
## Discharge back to primary care
Discharge people back to primary eye care services if:
they were referred for OHT but do not need treatment
they were referred for suspected COAG but this is no longer suspected. Advise people that they should continue with regular visits to their primary eye care professional, at clinically appropriate intervals.
Give a discharge summary to people who have been assessed and discharged to primary care. Send a copy to their GP and, with patient consent, copy the relevant information to the primary eye care professional nominated by the patient. Advise people to take their discharge summary with them when attending future sight tests.
# Organisation of care
Refer people to a consultant ophthalmologist for consideration of a definitive diagnosis and formulation of a management plan if:
they have suspected optic nerve damage or repeatable visual field defect, or both, or
SLT treatment is suitable (see recommendation 1.4.4 and recommendation 1.4.15 for people with newly diagnosed OHT and COAG).
Diagnosis of OHT and suspected COAG and formulation of a management plan should be made by a suitably trained healthcare professional with:
a specialist qualification and
relevant experience.
Be aware that holding an independent or non-medical prescribing qualification alone (without a specialist qualification relevant to the case complexity of glaucoma being managed) is insufficient for managing glaucoma and related conditions.
Healthcare professionals involved in the diagnosis of OHT and COAG suspect status, and preliminary identification of COAG, should be trained in case detection and referral refinement and be able to identify abnormalities based on relevant clinical tests and assessments. They should understand the principles of diagnosis of OHT and COAG and be able to perform and interpret all of the following:
medical and ocular history
differential diagnosis
Goldmann applanation tonometry (slit lamp mounted)
standard automated perimetry (central thresholding test)
central supra-threshold perimetry
stereoscopic slit lamp biomicroscopic examination of anterior segment
examination of the posterior segment using slit lamp binocular indirect ophthalmoscopy
gonioscopy
van Herick peripheral anterior chamber depth assessment
CCT measurement.
People with OHT, suspected COAG or COAG should have monitoring and treatment from a trained healthcare professional who has all of the following:
a specialist qualification
relevant experience
ability to detect a change in clinical status.
Healthcare professionals involved in monitoring and treating OHT, suspected COAG and established COAG should be trained to make management decisions on:
risk factors for conversion to COAG
coexisting pathology
risk of sight loss
monitoring and detecting a change in clinical status (for example, visual field changes and stereoscopic slit lamp biomicroscopic examination of anterior segment and posterior segment)
pharmacology of IOP‑lowering medicines
eligibility for 360° SLT
treatment changes for COAG, suspected COAG and OHT (with consideration given to relevant contraindications and interactions).
Healthcare professionals should discuss with the responsible consultant ophthalmologist the decision to offer 360° SLT and how it will be performed. Healthcare professionals undertaking 360° SLT should be given support by the responsible consultant ophthalmologist. Training should include:
the suitability of the procedure
laser safety and procedures
benefits and risks of 360° SLT, and how to discuss these with patients and their family members or carers (as appropriate)
patient consent.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisation of care .
Full details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.
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People with a confirmed diagnosis of OHT or suspected COAG and who have an established management plan may have monitoring (but not treatment) from a suitably trained healthcare professional with knowledge of OHT and COAG, relevant experience and the ability to detect a change in clinical status. The healthcare professional should be able to perform and interpret all of the following:
Goldmann applanation tonometry (slit lamp mounted)
standard automated perimetry (central thresholding test)
central supra-threshold perimetry (this visual field strategy may be used for monitoring OHT or suspected COAG when the visual field is normal)
stereoscopic slit lamp biomicroscopic examination of the anterior segment
van Herick peripheral anterior chamber depth assessment
examination of the posterior segment using slit lamp binocular indirect ophthalmoscopy.
Healthcare professionals who diagnose, treat or monitor independently of consultant ophthalmologist supervision should take full responsibility for the care they provide.
# Providing information
Ensure that people are offered the opportunity to discuss their diagnosis, referral, prognosis, treatment and discharge so they can take an active part in decision making (see NICE's guideline on shared decision making). Provide them with relevant information in an accessible format at initial and subsequent visits. This should include telling them:
about their specific condition (OHT, suspected COAG and COAG), its life-long implications and their prognosis for retention of sight
that COAG in the early stages and OHT and suspected COAG are symptomless
that most people having treatment for COAG will have good quality of life and not go blind
that once lost, sight cannot be recovered
the different types of treatment options, including mode of action, frequency and severity of side effects, and risks and benefits of treatment
that glaucoma can run in families and that family members may wish to be tested for the condition
the importance of their role in their own treatment – for example, the ongoing regular application of eye drops to preserve sight.
Ensure that people are given practical information and advice on:
how to apply eye drops, including technique (punctal occlusion and devices) and hygiene (storage)
the need for regular monitoring as specified by the healthcare professional
methods of investigation during assessment
how long each appointment is likely to take and whether the person will need any help to attend (for example, driving soon after pupil dilatation would be inadvisable)
how to contact the eye clinic liaison officer (ECLO) and what information and assistance they can provide
support organisations and support groups
compliance aids (such as dispensers) available from their GP or community pharmacist
Letter of Vision Impairment (LVI), Referral of Vision Impairment (RVI) and Certificate of Vision Impairment (CVI), registration
Driver and Vehicle Licensing Agency (DVLA) regulations.
# Terms used in this guideline
## COAG and related conditions
These include COAG, OHT and suspected COAG.
## Enhanced case-finding
Enhanced community case-finding services use slit lamp mounted Goldmann-type applanation tonometry, dilated slit lamp indirect biomicroscopy and other tests deemed necessary by the healthcare professional.
## MMC
Mitomycin‑C is an antimetabolite used during the initial stages of trabeculectomy to prevent excessive postoperative scarring and therefore reduce the risk of failure.
## Primary eye care professionals
These include optometrists, GPs with a special interest in ophthalmology and community orthoptists.
## Referral filtering
A general term for any type of accuracy checking before referral to hospital eye services. Referral filtering may take the form of 'repeat measures', 'enhanced case-finding', 'referral refinement', 'hospital-based triage' or 'administrative paper-based triage'.
## Referral refinement
A 2‑tier assessment in which initial evidence of abnormality found during case-finding or screening is validated by an enhanced assessment, which adds value beyond that achieved through a simple 'repeat measures' scheme. A referral refinement service performs tests to diagnose OHT and suspected COAG and interprets the results in the light of clinical findings. Specialist practitioners who deliver this service independently have the qualifications and experience set out in the recommendations on organisation of care. Practitioners providing a referral refinement service should be qualified to make a diagnosis of OHT and suspected glaucoma, and to carry out gonioscopy to exclude angle-closure glaucoma.
## Repeat measures
The repeated measurement of parameters related to the diagnosis of glaucoma. A simple repeat measures scheme may involve repeat measurement of IOP only. Other repeat measures schemes may also include repeated measurement of visual fields and other relevant ocular parameters when clinically necessary.
## Sight loss
Sight loss in glaucoma is visual damage that manifests as blind spots in the field of vision. Early on these are mostly asymptomatic with many people being unaware of a problem. Sight loss may progress to visual impairment and eventually become symptomatic.
## Sight test
A sight test determines whether or not a person has a sight defect, and if so, what is needed to correct, remedy or relieve it. An optometrist performing a sight test must conduct the examinations specified in the Sight Testing (Examination and Prescription) (No 2) Regulations 1989. These include an internal and external examination of the eyes and any other examinations needed to detect signs of injury, disease or abnormality in the eye or elsewhere.
## Visual impairment
A severe reduction in vision that cannot be corrected with standard glasses or contact lenses and reduces a person's ability to function in a visual environment.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Risk tools to identify risk of developing chronic open angle glaucoma and risk of sight loss
What is the predictive value of risk tools for identifying people in the community who are at increased risk of developing chronic open angle glaucoma (COAG) and identifying people with COAG who are at increased risk of sight loss?
## Long-term effectiveness of selective laser trabeculoplasty
What is the long-term effectiveness and cost effectiveness of selective laser trabeculoplasty as a first-line treatment compared with intraocular pressure-lowering eye drops in ocular hypertension or COAG in adults?
## An instrument to measure quality of life in people with glaucoma
What instrument should be used to measure health-related quality of life in people with glaucoma?
## Optical coherence tomography for glaucoma
What is the effectiveness and cost effectiveness of optical coherence tomography for diagnosing and monitoring glaucoma?
## Referral filtering
What is the effectiveness and cost effectiveness of the different models for glaucoma filtering (pathways from case-finding to assessment in secondary ophthalmic care) for detecting glaucoma and glaucoma-related conditions (ocular hypertension and suspected glaucoma)?
# Other recommendations for research
## Treatment for people with an intraocular pressure of 22 mmHg or 23 mmHg
What is the clinical and cost effectiveness of treating an intraocular pressure of 22 mmHg or 23 mmHg in people with normal optic discs and visual fields?
For a short explanation of why the committee made the recommendation for research, see the rationale section on selective laser trabeculoplasty for people with ocular hypertension and chronic open angle glaucoma .
Full details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma
Recommendations 1.4.4 and 1.4.5 and recommendations 1.4.15 and 1.4.16
## Why the committee made the recommendations
The committee agreed that the key outcome for adults with ocular hypertension (OHT) or chronic open angle glaucoma (COAG) was visual field progression that, in the long-term, could affect people's vision. Intraocular pressure (IOP) was considered to be a relevant surrogate outcome because lowering IOP can prevent the risk of optic nerve damage and sight loss. High-quality evidence showed that there is no meaningful difference between 360° selective laser trabeculoplasty (SLT) and eye drops in achieving a target IOP, health-related quality of life, risk of total adverse events, and treatment adherence. The evidence did show that that there were transient adverse events associated with SLT such as transient discomfort, blurred vision, photophobia and hyperaemia. It was also highlighted that there are rare complications associated with SLT. While rare events were not highlighted in the evidence, corneal failure is possible after SLT procedures. In people who have first-line treatment with eye drops compared with first-line 360° SLT, more people used eye drops and more people have more than 1 eye drop medication at 12 months.
The cost-effectiveness evidence showed that first-line treatment with 360° SLT was more effective and less costly compared with eye drops, with at least 90% probability of being the more cost-effective option. For costs, this result was driven by treatment involving 360° SLT costing less overall compared with eye drops alone. This is because the additional upfront costs of 360° SLT were outweighed by the accumulating costs of eye drops over time. For quality of life, 360° SLT resulted in a longer period without eye drops, or with fewer eye drops, and slightly slower estimated progression rates for glaucoma. Although no statistically significant direct benefit on quality of life was found in the trial, additional data on the natural history of glaucoma, which was incorporated into the cost-effectiveness analysis, suggests that quality of life was likely to be improved. The cost-effectiveness analysis included the costs and benefits of a second 360° SLT if the clinicians deemed it necessary. Even if 360° SLT was assumed to have the same clinical effectiveness as eye drops, it would still be a highly cost-effective treatment, because of the estimated reduction in overall costs.
Based on this evidence and their clinical experience, the committee recommended 360° SLT as first-line treatment for people with newly diagnosed OHT or newly diagnosed COAG. The recommendation excludes cases associated with pigment dispersion syndrome. This was because there was no evidence on the use of 360° SLT in people with pigment dispersion syndrome and the committee agreed that eye drop treatment is more suitable for those people. The recommendation lists information to give to people to help them make a decision on having SLT as first-line treatment, including telling them about 360° SLT‑specific side effects and complications and how long they are likely to last.
The committee noted that SLT may need to be repeated. This was included in the cost-effectiveness analyses (with approximately 15% of people in the SLT arm having a second procedure within the first year), which gave the committee more confidence in the result, as it reflected their expectations of how the treatment would be used in practice. The committee recommended that a second 360° SLT could be needed if the effect of an initial successful 360° SLT has subsequently reduced over time. This means that the IOP level has gone up and clinicians need to decide if there is risk of progression of COAG or conversion of OHT to COAG. The second 360° SLT should be given at the discretion of the responsible consultant ophthalmologist. This follows the procedure used in the main UK randomised trial (the LiGHT trial).
The committee further highlighted that in general, treatment to reduce IOP has to work for at least 6 months to be considered successful. However, this can also be based on clinician discretion.
The committee highlighted that there was a lack of long-term evidence on progression of glaucomatous visual field defect and progression of optic nerve head damage. The committee also highlighted that patients care more about vision outcomes than other outcomes such as IOP. A research recommendation was developed to cover this gap in the evidence on the long-term effectiveness of 360° SLT (with follow-up times of 3 years or more, 5 years and 10 years).
## Impact on other recommendations
The committee considered the impact of recommending 360° SLT on other recommendations in the guideline. Recommendations were amended as necessary, taking into account the original evidence for each recommendation and the committee's knowledge and experience.
## How the recommendations might affect practice
The recommendations are likely to result in a significant change in practice, because more people with newly diagnosed OHT or COAG could be offered 360° SLT as their first treatment. The committee also noted that larger centres may see more referrals, resulting in an increase in the number of clinics per week. The committee highlighted that, although the increase should not be significant, any increase means there will be a change to the organisation of care. Overall, this is not likely to have a substantial cost impact because evidence shows that first-line 360° SLT (including the purchase and maintenance of the SLT machine) was less costly than first-line use of eye drops. However, there will be changes in the types of costs incurred, with significant reductions in the cost of eye drop prescriptions but increases in costs for SLT devices and staffing.
Return to recommendations 1.4.4 and 1.4.5
Return to recommendations 1.4.15 and 1.4.16
# Generic PGAs for people with OHT or COAG
Recommendation 1.4.6 and recommendation 1.4.17
## Why the committee made the recommendations
The 2017 guideline recommended prostaglandin analogue (PGA) eye drops for OHT or COAG. The committee amended this to reflect the new 2022 recommendations on using 360° SLT. They agreed that people who prefer not to have 360° SLT or for whom it is not suitable should be offered generic PGA eye drops. This was because PGA eye drops were used for first-line treatment in the 2017 guideline and in the LiGHT trial.
The recommendations were also amended to highlight that eye drop installation technique should be demonstrated and that healthcare professionals should observe the person to confirm that their installation technique is correct. It is recommended that this be done when eye drops are first prescribed.
Return to recommendation 1.4.6
Return to recommendation 1.4.17
# Organisation of care
Recommendations 1.6.6 and 1.6.7
## Why the committee made the recommendations
The committee noted that the first-line use of 360° SLT to treat OHT or COAG might lead to a significant change in practice that requires different organisation of care and the establishment of a multidisciplinary team. The committee wanted to make clear that if 360° SLT is suitable for a person, that person should be referred to a consultant ophthalmologist. They also discussed the safety of the 360° SLT procedure and agreed that healthcare professionals should discuss with the responsible consultant ophthalmologist the decision to offer it and how it will be performed. This means that with support from a consultant ophthalmologist, healthcare professionals such as specialty doctors, associate specialists, specialist nurses, optometrists and allied health professionals can perform 360° SLT.
The committee also noted that healthcare professionals who provide 360° SLT should be given support and have relevant training on the suitability and safety of the procedure, including its benefits and risks. They should also be trained in discussing these points and patient consent with patients and their family members or carers. A similar approach was taken in the LiGHT trial, in which training was given to all treating surgeons before recruitment, and the chief investigator, who was a consultant ophthalmic surgeon, observed each surgeon perform at least 1 laser treatment. Based on these discussions, new recommendations were added to provide further clarification on organisation of care.
## How the recommendations might affect practice
The recommendations are likely to result in a significant change in practice because training and support will be needed for healthcare professionals performing the 360° SLT procedure.
Return to recommendations 1.6.6 and 1.6.7# Context
The scope of this NICE guideline on diagnosis and management of glaucoma was extended to cover referral in 2017. This included the most effective service models for referral filtering schemes (repeat measures, enhanced case-finding and referral refinement), the tests to be used for finding people with chronic open angle glaucoma (COAG), suspected COAG and ocular hypertension (OHT), and thresholds for onward referral. In 2017, the guidance was also updated on tests for diagnosis and reassessment, pharmacological treatments for lowering intraocular pressure (IOP) and preserving visual field, and reassessment intervals, which depend on prognosis.
The 2017 update provided an opportunity to re-evaluate the clinical effectiveness, cost effectiveness and indications for treating OHT. Knowledge of corneal thickness is no longer needed to decide whether to treat OHT and a single threshold of 24 mmHg is now recommended for both onward referral and treatment. Changes in the costs of pharmacological treatments, acknowledgement of short- and long-term variations in IOP and the uneven relationship between rising pressure and increased risk have allowed a simplification of the indications for OHT treatment.
Control of IOP remains critical to the therapeutic approach. Intensity of treatment and ongoing management are guided by disease severity and progression as shown by visual field change, morphological change in the optic disc, and the likelihood of progressive sight loss. Reassessment at each visit is emphasised, encouraging flexible clinical judgement about the frequency of visits and options for treatment, including stopping treatment when the perceived lifetime risk of developing visual impairment is low.
Since the update in 2017, there has been new evidence on the use of 360° selective laser trabeculoplasty as a first-line treatment for OHT and COAG. Therefore, recommendations on treatment for people with OHT or COAG were updated.
Sections of the guideline on accuracy of visual field tests, surgical interventions, and information, education and support needed for adherence to treatment have not been updated because no new evidence was found.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Case-finding\n\nThe recommendations on case-finding are for primary eye care professionals before referral for diagnosis of chronic open angle glaucoma (COAG) and related conditions and are separate from a sight test.\n\nBefore referral for further investigation and diagnosis of COAG and related conditions, offer all of the following tests:\n\ncentral visual field assessment using standard automated perimetry (full threshold or supra-threshold)\n\noptic nerve assessment and fundus examination using stereoscopic slit lamp biomicroscopy (with pupil dilatation if necessary), and optical coherence tomography (OCT) or optic nerve head image if available\n\nintraocular pressure (IOP) measurement using Goldmann‑type applanation tonometry\n\nperipheral anterior chamber configuration and depth assessments using gonioscopy or, if not available or the person prefers, the van Herick test or OCT. \n\nDo not base a decision to refer solely on IOP measurement using non-contact tonometry. \n\nDo not refer people who have previously been discharged from hospital eye services after assessment for COAG and related conditions unless clinical circumstances have changed and a new referral is needed. \n\nBefore deciding to refer, consider repeating visual field assessment and IOP measurement on another occasion to confirm a visual field defect or IOP of 24\xa0mmHg or more, unless clinical circumstances indicate urgent or emergency referral is needed. \n\nRefer for further investigation and diagnosis of COAG and related conditions, after considering repeat measures as in recommendation\xa01.1.4, if:\n\nthere is optic nerve head damage on stereoscopic slit lamp biomicroscopy or\n\nthere is a visual field defect consistent with glaucoma or\n\nIOP is 24\xa0mmHg or more using Goldmann‑type applanation tonometry. \n\nProvide results of all examinations and tests with the referral. \n\nAdvise people with IOP below 24\xa0mmHg to continue regular visits to their primary eye care professional. \n\nThe following recommendations are for people planning and providing eye care services before referral.\n\nPeople planning and providing eye care services should use a service model that includes Goldmann‑type applanation tonometry before referral for diagnosis of COAG and related conditions. \n\nPeople planning eye care services should consider commissioning referral filtering services (for example, repeat measures, enhanced case-finding, or referral refinement) for COAG and related conditions. \n\n# Diagnosis\n\nTo diagnose COAG and related conditions, offer all of the following tests:\n\nvisual field assessment using standard automated perimetry (central thresholding test), repeated if necessary to establish severity at diagnosis\n\noptic nerve assessment and fundus examination using stereoscopic slit lamp biomicroscopy, with pupil dilatation\n\nIOP measurement using Goldmann applanation tonometry (slit lamp mounted)\n\nperipheral anterior chamber configuration and depth assessments using gonioscopy\n\ncentral corneal thickness (CCT) measurement. \n\nAdopt professional or Department of Health and Social Care guidance to reduce the risk of transmitting infective agents via contact tonometry or gonioscopy.See the Royal College of Ophthalmologists' ophthalmic services guidance and the Department of Health and Social Care's guidance on minimising transmission risk of CJD and vCJD in healthcare settings. \n\nUse the van Herick peripheral anterior chamber depth assessment if clinical circumstances rule out gonioscopy (for example, when people with physical or learning disabilities are unable to participate in the examination). \n\nObtain an optic nerve head image at diagnosis for baseline documentation (for example, a stereoscopic optic nerve head image or OCT). [2009, amended 2017]\n\nAfter referral, consider an early assessment appointment if there is clinical concern based on the information provided. \n\nAt the time of diagnosis of ocular hypertension (OHT), assess the risk of future visual impairment, taking into account risk factors such as:\n\nlevel of IOP\n\nCCT\n\nfamily history\n\nlife expectancy. \n\n# Standard practice for all assessments\n\nEnsure that all of the following are available at each clinical episode to all healthcare professionals involved in a person's care:\n\nrecords of all previous tests and images relevant to COAG and OHT assessment\n\nrecords of past medical history that could affect medicine choice\n\ncurrent systemic and topical medication\n\nglaucoma medication record\n\ndrug allergies and intolerances. \n\nUse alternative methods of assessment if clinical circumstances rule out standard methods (for example, when people with physical or learning disabilities are unable to participate in the examination). \n\nEnsure that all machines and measurement instruments are calibrated regularly according to the manufacturers' instructions. \n\n# Treatment\n\nTake into account any cognitive and physical impairments when making decisions about management and treatment. \n\nCheck that there are no relevant comorbidities or potential drug interactions before offering pharmacological treatment. \n\n## Treatment for people with OHT\n\nDo not offer treatment to people with OHT who are not at risk of visual impairment within their lifetime. Advise people to continue regular visits to their primary eye care professional, at clinically appropriate intervals. \n\nOffer 360° selective laser trabeculoplasty (SLT) to people with newly diagnosed OHT with IOP of 24\xa0mmHg or more (excluding cases associated with pigment dispersion syndrome) if they are at risk of visual impairment within their lifetime (see the recommendation on taking account of risk factors in the section on diagnosis). To help inform their decision, tell people:\n\nthat having 360° SLT can delay the need for eye drops and can reduce but does not remove the chance they will be needed at all\n\nhow long it may take for their IOP to improve after the procedure\n\nabout 360° SLT‑specific side effects and complications and how long they are likely to last\n\nthat a second 360° SLT procedure may be needed at a later date. \n\nConsider a second 360° SLT for people with OHT if the effect of an initial successful SLT has subsequently reduced over time. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.\n\nLoading. Please wait.\n\nOffer a generic prostaglandin analogue (PGA) to people with OHT with IOP of 24\xa0mmHg or more if they are at risk of visual impairment within their lifetime (see the recommendation on taking account of risk factors in the section on diagnosis) and:\n\nthey choose not to have 360° SLT or\n\n° SLT is not suitable (for example, because they have pigment dispersion syndrome) or\n\nthey are waiting for 360° SLT and need an interim treatment or\n\nthey have had 360° SLT but need additional treatment to reduce their IOP sufficiently to prevent the risk of visual impairment.Demonstrate correct eye drop installation technique and observe the person using the correct technique when eye drops are first prescribed. \n\nSee the recommendations on when to reassess for advice on when the next appointment should take place to assess the impact of any new treatments started.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on generic PGAs for people with OHT or COAG\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.\n\nLoading. Please wait.\n\nOffer another pharmacological treatment to people with an IOP of 24\xa0mmHg or more who cannot tolerate their current treatment. The first choice should be an alternative generic PGA, and if this is not tolerated, offer a beta‑blocker. If neither of these options is tolerated, offer a non-generic PGA, carbonic anhydrase inhibitor, sympathomimetic, miotic or a combination of treatments. [2017, amended 2022]\n\nOffer a medicine from another therapeutic class (beta-blocker, carbonic anhydrase inhibitor or sympathomimetic) to people with an IOP of 24\xa0mmHg or more whose current treatment is not reducing IOP sufficiently to prevent the risk of progression to sight loss. Topical medicines from different therapeutic classes may be needed at the same time to control IOP. [2009, amended 2017]\n\nRefer people to a consultant ophthalmologist to discuss other options if their IOP cannot be reduced sufficiently with 360° SLT or pharmacological treatment or both to prevent the risk of progression to sight loss. [2009, amended 2022]\n\nOffer preservative-free eye drops to people who have an allergy to preservatives or people with clinically significant and symptomatic ocular surface disease, but only if they are at high risk of conversion to COAG. [2009, amended 2017]\n\n## Treatment for people with suspected COAG\n\nDo not offer treatment to people with suspected COAG and IOP less than 24\xa0mmHg unless they are at risk of visual impairment within their lifetime. Advise people to continue regular visits to their primary eye care professional, at clinically appropriate intervals. [2017, amended 2022]\n\n## Stopping treatment for people with OHT or suspected COAG\n\nDiscuss the benefits and risks of stopping treatment with people with OHT or suspected COAG who have both:\n\na low risk of developing visual impairment within their lifetime and\n\nan acceptable IOP. If a person decides to stop treatment after this discussion, offer to assess their IOP in 1\xa0month to 4\xa0months with further reassessment if clinically indicated. \n\n## Treatment for people with COAG\n\nIn January\xa02022 the use of mitomycin-C (MMC) in recommendations\xa01.4.13 and 1.4.20 to 1.4.22 was off label. See NICE's information on prescribing medicines.\n\nOffer people with advanced COAG, glaucoma surgery with pharmacological augmentation (MMC) as indicated. Give them information on the risks and benefits of surgery. [2009, amended 2022]\n\nOffer people who present with advanced COAG and who are listed for glaucoma surgery, interim treatment with a generic PGA. [2009, amended 2022]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.\n\nLoading. Please wait.\n\nOffer 360° SLT to people with newly diagnosed COAG (excluding cases associated with pigment dispersion syndrome). For people with advanced COAG see the section on treatment for people with advanced COAG and recommendation\xa01.4.24. To help inform their decision, tell people:\n\nthat having 360° SLT can delay the need for eye drops and can reduce but does not remove the chance they will be needed at all\n\nhow long it may take for their IOP to improve after the procedure\n\nabout 360° SLT‑specific side effects and complications and how long they are likely to last\n\nthat a second 360° SLT procedure may be needed at a later date. \n\nConsider a second 360° SLT for people with COAG if the effect of an initial successful SLT has subsequently reduced over time. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.\n\nLoading. Please wait.\n\nOffer a generic PGA to people with COAG if:\n\nthey choose not to have 360° SLT or\n\n° SLT is not suitable (for example because they have pigment dispersion syndrome) or\n\nthey are waiting for an 360° SLT and need an interim treatment or\n\nthey have previously had 360° SLT but need additional treatment to reduce their IOP sufficiently to prevent the risk of visual impairment.Demonstrate correct eye drop installation technique and observe the patient using the technique when eye drops are first prescribed. \n\nSee recommendations on when to reassess for advice on when the next appointment should take place to assess the impact of any new treatments started.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on generic PGAs for people with OHT or COAG\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.\n\nLoading. Please wait.\n\nEncourage people to continue with the same pharmacological treatment unless:\n\ntheir IOP cannot be reduced sufficiently to prevent the risk of progression to sight loss\n\nthere is progression of optic nerve head damage\n\nthere is progression of visual field defect\n\nthey cannot tolerate the medicine. \n\nAsk about adherence to treatment and check the eye drop instillation technique in people with COAG whose IOP has not been reduced sufficiently to prevent the risk of progression to sight loss, despite pharmacological treatment with a generic PGA. [2009, amended 2022]\n\nOffer 1 of the following to people with satisfactory adherence to treatment and eye drop instillation technique whose IOP has not been reduced sufficiently to prevent the risk of progression to sight loss:\n\na medicine from another therapeutic class (a beta-blocker, carbonic anhydrase inhibitor or sympathomimetic); topical medicines from different therapeutic classes may be needed at the same time to control IOP or\n\n° SLT or\n\nglaucoma surgery with pharmacological augmentation (MMC) as indicated. [2009, amended 2022]\n\nConsider 360° SLT or glaucoma surgery with pharmacological augmentation (MMC) as indicated for people with COAG who are at risk of progressing to sight loss despite treatment with medicines from 2\xa0therapeutic classes. Give them information on the risks and benefits of surgery. [2009, amended 2022]\n\nConsider 1 of the following for people with COAG who cannot tolerate a pharmacological treatment:\n\na medicine from another therapeutic class (a beta-blocker, carbonic anhydrase inhibitor or sympathomimetic) or\n\npreservative-free eye drops if there is evidence that the person is allergic to the preservative or has clinically significant and symptomatic ocular surface disease.After treatment with medicines from 2\xa0therapeutic classes, consider 360° SLT or glaucoma surgery with pharmacological augmentation (MMC) as indicated. [2009, amended 2022]\n\nOffer 1 of the following to people with COAG whose IOP has not been reduced sufficiently to prevent the risk of progression to sight loss after glaucoma surgery:\n\npharmacological treatment; topical medicines from different therapeutic classes may be needed at the same time to control IOP or\n\nfurther glaucoma surgery or\n\n° SLT or\n\ncyclodiode laser treatment. [2009, amended 2022]\n\nOffer 1 of the following to people with COAG (including advanced COAG) who prefer not to have glaucoma surgery or for whom glaucoma surgery is not suitable:\n\npharmacological treatment; topical medicines from different therapeutic classes may be needed at the same time to control IOP or\n\n° SLT (for example in people with systemic comorbidities) or\n\ncyclodiode laser treatment. [2009, amended 2022]\n\n# Reassessment\n\n## Reassessment tests\n\nAt each assessment, offer the following tests to people with COAG, people with suspected COAG and people with OHT:\n\nGoldmann applanation tonometry (slit lamp mounted)\n\nanterior segment slit lamp examination with van Herick peripheral anterior chamber depth assessment when clinically indicated. \n\nWhen clinically indicated, repeat gonioscopy, for example, if a previous examination has been inconclusive or there is suspicion of a change in clinical status of the anterior chamber angle. \n\nWhen clinically indicated, repeat visual field testing using standard automated perimetry (central thresholding test) for people with COAG and those with suspected visual field defects who are being investigated for possible COAG (see table\xa02 and table 3 for recommended reassessment intervals). [2009, amended 2017]\n\nWhen clinically indicated, repeat visual field testing using either a central thresholding test or a supra-threshold test for people with OHT and those with suspected COAG whose visual fields have previously been documented by standard threshold automated perimetry (central thresholding test) as being normal (see table\xa01 and table\xa02 for recommended reassessment intervals). [2009, amended 2017]\n\nWhen a visual field defect has previously been detected, use the same measurement strategy for each visual field assessment. \n\nWhen clinically indicated, repeat assessment of the optic nerve head (for example, stereoscopic slit lamp biomicroscopy or imaging). \n\nWhen a change in optic nerve head status is detected by stereoscopic slit lamp biomicroscopy, obtain a new optic nerve head image for the person's records to provide a fresh benchmark for future assessments. \n\nWhen an adequate view of the optic nerve head and surrounding area is unavailable at reassessment, people should have their pupils dilated before stereoscopic slit lamp biomicroscopy or optic nerve head imaging is repeated. \n\n## When to reassess\n\nAt each assessment, re-evaluate the risk of conversion to COAG and the risk of sight loss to set time to next assessment. \n\nAt each assessment, ask about general health and, if appropriate, factors affecting adherence to treatment, including cognitive impairment and any treatment side effects. \n\nFor people with treated OHT (baseline IOP of 24\xa0mmHg or more) and a normal optic head and visual field at the most recent assessment:\n\nuse clinical judgement to assess control of IOP and the risk of conversion to COAG, and\n\nreassess according to table\xa01. \n\nConversion from ocular hypertension to chronic open angle glaucoma\n\nControl of intraocular pressure\n\nTime to next assessment\n\nNot detected or uncertain conversion\n\nNo\n\nReview management plan and reassess between 1\xa0month and 4\xa0months\n\nUncertain conversion\n\nYes\n\nReassess between 6\xa0months and 12\xa0months\n\nNo conversion detected\n\nYes\n\nReassess between 18\xa0months and 24\xa0months\n\nConversion\n\nNo or yes\n\nSee recommendations on diagnosis and reassessment of chronic open angle glaucoma\n\nUse clinical judgement to decide when the next appointment should take place within the recommended interval, including the need to assess the impact of any new treatments started.\n\nUncertain conversion includes having insufficient accurate information (perhaps because the person was unable to participate in the assessment).\n\nFor people with suspected COAG:\n\nuse clinical judgement to assess control of IOP and risk of conversion to COAG (optic nerve head damage and visual field defect), and\n\nreassess according to table\xa02. \n\nConversion to chronic open angle glaucoma\n\nControl of intraocular pressure\n\nTime to next assessment\n\nNot detected or uncertain conversion\n\nNo\n\nReview management plan and reassess between 1\xa0month and 4\xa0months\n\nUncertain conversion\n\nYes\n\nReassess between 6\xa0months and 12\xa0months\n\nNo conversion detected\n\nYes\n\nReassess between 12\xa0months and 18\xa0months\n\nConversion\n\nNo or yes\n\nSee recommendations on diagnosis and reassessment of chronic open angle glaucoma\n\nUse clinical judgement to decide when the next appointment should take place within the recommended interval, including the need to assess the impact of any new treatments started.\n\nUncertain conversion includes having insufficient accurate information (perhaps because the person was unable to participate in the assessment).\n\nFor people with COAG:\n\nuse clinical judgement to assess risk of COAG progression to sight loss, and\n\nreassess according to table\xa03. \n\nProgression of chronic open angle glaucoma\n\nControl of intraocular pressure\n\nTime to next assessment\n\nNot detected\n\nNo\n\nReview treatment plan and reassess between 1\xa0month and 4\xa0months\n\nUncertain progression or progression\n\nNo\n\nReview treatment plan and reassess between 1\xa0month and 2\xa0months\n\nNo progression detected and low clinical risk\n\nYes\n\nReassess between 12\xa0months and 18\xa0months\n\nNo progression detected and high clinical risk\n\nYes\n\nReassess between 6\xa0months and 12\xa0months\n\nUncertain progression or progression\n\nYes\n\nReview treatment plan and reassess between 2\xa0months and 6\xa0months\n\nUse clinical judgement to decide when the next appointment should take place within the recommended interval, including the need to assess the impact of any new treatments started.\n\nUncertain conversion includes having insufficient accurate information (perhaps because the person was unable to participate in the assessment).\n\n## Discharge back to primary care\n\nDischarge people back to primary eye care services if:\n\nthey were referred for OHT but do not need treatment\n\nthey were referred for suspected COAG but this is no longer suspected. Advise people that they should continue with regular visits to their primary eye care professional, at clinically appropriate intervals. \n\nGive a discharge summary to people who have been assessed and discharged to primary care. Send a copy to their GP and, with patient consent, copy the relevant information to the primary eye care professional nominated by the patient. Advise people to take their discharge summary with them when attending future sight tests. \n\n# Organisation of care\n\nRefer people to a consultant ophthalmologist for consideration of a definitive diagnosis and formulation of a management plan if:\n\nthey have suspected optic nerve damage or repeatable visual field defect, or both, or\n\nSLT treatment is suitable (see recommendation\xa01.4.4 and recommendation\xa01.4.15 for people with newly diagnosed OHT and COAG). [2009, amended 2022]\n\nDiagnosis of OHT and suspected COAG and formulation of a management plan should be made by a suitably trained healthcare professional with:\n\na specialist qualification and\n\nrelevant experience. [2009, amended 2017]\n\nBe aware that holding an independent or non-medical prescribing qualification alone (without a specialist qualification relevant to the case complexity of glaucoma being managed) is insufficient for managing glaucoma and related conditions. \n\nHealthcare professionals involved in the diagnosis of OHT and COAG suspect status, and preliminary identification of COAG, should be trained in case detection and referral refinement and be able to identify abnormalities based on relevant clinical tests and assessments. They should understand the principles of diagnosis of OHT and COAG and be able to perform and interpret all of the following:\n\nmedical and ocular history\n\ndifferential diagnosis\n\nGoldmann applanation tonometry (slit lamp mounted)\n\nstandard automated perimetry (central thresholding test)\n\ncentral supra-threshold perimetry\n\nstereoscopic slit lamp biomicroscopic examination of anterior segment\n\nexamination of the posterior segment using slit lamp binocular indirect ophthalmoscopy\n\ngonioscopy\n\nvan Herick peripheral anterior chamber depth assessment\n\nCCT measurement. \n\nPeople with OHT, suspected COAG or COAG should have monitoring and treatment from a trained healthcare professional who has all of the following:\n\na specialist qualification\n\nrelevant experience\n\nability to detect a change in clinical status. [2009, amended 2017]\n\nHealthcare professionals involved in monitoring and treating OHT, suspected COAG and established COAG should be trained to make management decisions on:\n\nrisk factors for conversion to COAG\n\ncoexisting pathology\n\nrisk of sight loss\n\nmonitoring and detecting a change in clinical status (for example, visual field changes and stereoscopic slit lamp biomicroscopic examination of anterior segment and posterior segment)\n\npharmacology of IOP‑lowering medicines\n\neligibility for 360° SLT\n\ntreatment changes for COAG, suspected COAG and OHT (with consideration given to relevant contraindications and interactions). [2009, amended 2022]\n\nHealthcare professionals should discuss with the responsible consultant ophthalmologist the decision to offer 360° SLT and how it will be performed. Healthcare professionals undertaking 360° SLT should be given support by the responsible consultant ophthalmologist. Training should include:\n\nthe suitability of the procedure\n\nlaser safety and procedures\n\nbenefits and risks of 360° SLT, and how to discuss these with patients and their family members or carers (as appropriate)\n\npatient consent. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisation of care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.\n\nLoading. Please wait.\n\nPeople with a confirmed diagnosis of OHT or suspected COAG and who have an established management plan may have monitoring (but not treatment) from a suitably trained healthcare professional with knowledge of OHT and COAG, relevant experience and the ability to detect a change in clinical status. The healthcare professional should be able to perform and interpret all of the following:\n\nGoldmann applanation tonometry (slit lamp mounted)\n\nstandard automated perimetry (central thresholding test)\n\ncentral supra-threshold perimetry (this visual field strategy may be used for monitoring OHT or suspected COAG when the visual field is normal)\n\nstereoscopic slit lamp biomicroscopic examination of the anterior segment\n\nvan Herick peripheral anterior chamber depth assessment\n\nexamination of the posterior segment using slit lamp binocular indirect ophthalmoscopy. \n\nHealthcare professionals who diagnose, treat or monitor independently of consultant ophthalmologist supervision should take full responsibility for the care they provide. \n\n# Providing information\n\nEnsure that people are offered the opportunity to discuss their diagnosis, referral, prognosis, treatment and discharge so they can take an active part in decision making (see NICE's guideline on shared decision making). Provide them with relevant information in an accessible format at initial and subsequent visits. This should include telling them:\n\nabout their specific condition (OHT, suspected COAG and COAG), its life-long implications and their prognosis for retention of sight\n\nthat COAG in the early stages and OHT and suspected COAG are symptomless\n\nthat most people having treatment for COAG will have good quality of life and not go blind\n\nthat once lost, sight cannot be recovered\n\nthe different types of treatment options, including mode of action, frequency and severity of side effects, and risks and benefits of treatment\n\nthat glaucoma can run in families and that family members may wish to be tested for the condition\n\nthe importance of their role in their own treatment – for example, the ongoing regular application of eye drops to preserve sight. [2009, amended 2017]\n\nEnsure that people are given practical information and advice on:\n\nhow to apply eye drops, including technique (punctal occlusion and devices) and hygiene (storage)\n\nthe need for regular monitoring as specified by the healthcare professional\n\nmethods of investigation during assessment\n\nhow long each appointment is likely to take and whether the person will need any help to attend (for example, driving soon after pupil dilatation would be inadvisable)\n\nhow to contact the eye clinic liaison officer (ECLO) and what information and assistance they can provide\n\nsupport organisations and support groups\n\ncompliance aids (such as dispensers) available from their GP or community pharmacist\n\nLetter of Vision Impairment (LVI), Referral of Vision Impairment (RVI) and Certificate of Vision Impairment (CVI), registration\n\nDriver and Vehicle Licensing Agency (DVLA) regulations. [2009, amended 2017]\n\n# Terms used in this guideline\n\n## COAG and related conditions\n\nThese include COAG, OHT and suspected COAG.\n\n## Enhanced case-finding\n\nEnhanced community case-finding services use slit lamp mounted Goldmann-type applanation tonometry, dilated slit lamp indirect biomicroscopy and other tests deemed necessary by the healthcare professional.\n\n## MMC\n\nMitomycin‑C is an antimetabolite used during the initial stages of trabeculectomy to prevent excessive postoperative scarring and therefore reduce the risk of failure.\n\n## Primary eye care professionals\n\nThese include optometrists, GPs with a special interest in ophthalmology and community orthoptists.\n\n## Referral filtering\n\nA general term for any type of accuracy checking before referral to hospital eye services. Referral filtering may take the form of 'repeat measures', 'enhanced case-finding', 'referral refinement', 'hospital-based triage' or 'administrative paper-based triage'.\n\n## Referral refinement\n\nA 2‑tier assessment in which initial evidence of abnormality found during case-finding or screening is validated by an enhanced assessment, which adds value beyond that achieved through a simple 'repeat measures' scheme. A referral refinement service performs tests to diagnose OHT and suspected COAG and interprets the results in the light of clinical findings. Specialist practitioners who deliver this service independently have the qualifications and experience set out in the recommendations on organisation of care. Practitioners providing a referral refinement service should be qualified to make a diagnosis of OHT and suspected glaucoma, and to carry out gonioscopy to exclude angle-closure glaucoma.\n\n## Repeat measures\n\nThe repeated measurement of parameters related to the diagnosis of glaucoma. A simple repeat measures scheme may involve repeat measurement of IOP only. Other repeat measures schemes may also include repeated measurement of visual fields and other relevant ocular parameters when clinically necessary.\n\n## Sight loss\n\nSight loss in glaucoma is visual damage that manifests as blind spots in the field of vision. Early on these are mostly asymptomatic with many people being unaware of a problem. Sight loss may progress to visual impairment and eventually become symptomatic.\n\n## Sight test\n\nA sight test determines whether or not a person has a sight defect, and if so, what is needed to correct, remedy or relieve it. An optometrist performing a sight test must conduct the examinations specified in the Sight Testing (Examination and Prescription) (No\xa02) Regulations 1989. These include an internal and external examination of the eyes and any other examinations needed to detect signs of injury, disease or abnormality in the eye or elsewhere.\n\n## Visual impairment\n\nA severe reduction in vision that cannot be corrected with standard glasses or contact lenses and reduces a person's ability to function in a visual environment.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Risk tools to identify risk of developing chronic open angle glaucoma and risk of sight loss\n\nWhat is the predictive value of risk tools for identifying people in the community who are at increased risk of developing chronic open angle glaucoma (COAG) and identifying people with COAG who are at increased risk of sight loss?\n\n## Long-term effectiveness of selective laser trabeculoplasty\n\nWhat is the long-term effectiveness and cost effectiveness of selective laser trabeculoplasty as a first-line treatment compared with intraocular pressure-lowering eye drops in ocular hypertension or COAG in adults?\n\n## An instrument to measure quality of life in people with glaucoma\n\nWhat instrument should be used to measure health-related quality of life in people with glaucoma?\n\n## Optical coherence tomography for glaucoma\n\nWhat is the effectiveness and cost effectiveness of optical coherence tomography for diagnosing and monitoring glaucoma?\n\n## Referral filtering\n\nWhat is the effectiveness and cost effectiveness of the different models for glaucoma filtering (pathways from case-finding to assessment in secondary ophthalmic care) for detecting glaucoma and glaucoma-related conditions (ocular hypertension and suspected glaucoma)?\n\n# Other recommendations for research\n\n## Treatment for people with an intraocular pressure of 22\xa0mmHg or 23\xa0mmHg\n\nWhat is the clinical and cost effectiveness of treating an intraocular pressure of 22\xa0mmHg or 23\xa0mmHg in people with normal optic discs and visual fields?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on selective laser trabeculoplasty for people with ocular hypertension and chronic open angle glaucoma\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: selective laser trabeculoplasty in ocular hypertension or chronic open-angle glaucoma adult patients.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Selective laser trabeculoplasty for people with ocular hypertension or chronic open angle glaucoma\n\nRecommendations 1.4.4 and 1.4.5 and recommendations 1.4.15 and 1.4.16\n\n## Why the committee made the recommendations\n\nThe committee agreed that the key outcome for adults with ocular hypertension (OHT) or chronic open angle glaucoma (COAG) was visual field progression that, in the long-term, could affect people's vision. Intraocular pressure (IOP) was considered to be a relevant surrogate outcome because lowering IOP can prevent the risk of optic nerve damage and sight loss. High-quality evidence showed that there is no meaningful difference between 360° selective laser trabeculoplasty (SLT) and eye drops in achieving a target IOP, health-related quality of life, risk of total adverse events, and treatment adherence. The evidence did show that that there were transient adverse events associated with SLT such as transient discomfort, blurred vision, photophobia and hyperaemia. It was also highlighted that there are rare complications associated with SLT. While rare events were not highlighted in the evidence, corneal failure is possible after SLT procedures. In people who have first-line treatment with eye drops compared with first-line 360° SLT, more people used eye drops and more people have more than 1\xa0eye drop medication at 12\xa0months.\n\nThe cost-effectiveness evidence showed that first-line treatment with 360° SLT was more effective and less costly compared with eye drops, with at least 90% probability of being the more cost-effective option. For costs, this result was driven by treatment involving 360° SLT costing less overall compared with eye drops alone. This is because the additional upfront costs of 360° SLT were outweighed by the accumulating costs of eye drops over time. For quality of life, 360° SLT resulted in a longer period without eye drops, or with fewer eye drops, and slightly slower estimated progression rates for glaucoma. Although no statistically significant direct benefit on quality of life was found in the trial, additional data on the natural history of glaucoma, which was incorporated into the cost-effectiveness analysis, suggests that quality of life was likely to be improved. The cost-effectiveness analysis included the costs and benefits of a second 360° SLT if the clinicians deemed it necessary. Even if 360° SLT was assumed to have the same clinical effectiveness as eye drops, it would still be a highly cost-effective treatment, because of the estimated reduction in overall costs.\n\nBased on this evidence and their clinical experience, the committee recommended 360° SLT as first-line treatment for people with newly diagnosed OHT or newly diagnosed COAG. The recommendation excludes cases associated with pigment dispersion syndrome. This was because there was no evidence on the use of 360° SLT in people with pigment dispersion syndrome and the committee agreed that eye drop treatment is more suitable for those people. The recommendation lists information to give to people to help them make a decision on having SLT as first-line treatment, including telling them about 360° SLT‑specific side effects and complications and how long they are likely to last.\n\nThe committee noted that SLT may need to be repeated. This was included in the cost-effectiveness analyses (with approximately 15% of people in the SLT arm having a second procedure within the first year), which gave the committee more confidence in the result, as it reflected their expectations of how the treatment would be used in practice. The committee recommended that a second 360° SLT could be needed if the effect of an initial successful 360° SLT has subsequently reduced over time. This means that the IOP level has gone up and clinicians need to decide if there is risk of progression of COAG or conversion of OHT to COAG. The second 360° SLT should be given at the discretion of the responsible consultant ophthalmologist. This follows the procedure used in the main UK randomised trial (the LiGHT trial).\n\nThe committee further highlighted that in general, treatment to reduce IOP has to work for at least 6\xa0months to be considered successful. However, this can also be based on clinician discretion.\n\nThe committee highlighted that there was a lack of long-term evidence on progression of glaucomatous visual field defect and progression of optic nerve head damage. The committee also highlighted that patients care more about vision outcomes than other outcomes such as IOP. A research recommendation was developed to cover this gap in the evidence on the long-term effectiveness of 360° SLT (with follow-up times of 3\xa0years or more, 5\xa0years and 10\xa0years).\n\n## Impact on other recommendations\n\nThe committee considered the impact of recommending 360° SLT on other recommendations in the guideline. Recommendations were amended as necessary, taking into account the original evidence for each recommendation and the committee's knowledge and experience.\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to result in a significant change in practice, because more people with newly diagnosed OHT or COAG could be offered 360° SLT as their first treatment. The committee also noted that larger centres may see more referrals, resulting in an increase in the number of clinics per week. The committee highlighted that, although the increase should not be significant, any increase means there will be a change to the organisation of care. Overall, this is not likely to have a substantial cost impact because evidence shows that first-line 360° SLT (including the purchase and maintenance of the SLT machine) was less costly than first-line use of eye drops. However, there will be changes in the types of costs incurred, with significant reductions in the cost of eye drop prescriptions but increases in costs for SLT devices and staffing.\n\nReturn to recommendations\xa01.4.4 and 1.4.5\n\nReturn to recommendations\xa01.4.15 and 1.4.16\n\n# Generic PGAs for people with OHT or COAG\n\nRecommendation\xa01.4.6 and recommendation\xa01.4.17\n\n## Why the committee made the recommendations\n\nThe 2017 guideline recommended prostaglandin analogue (PGA) eye drops for OHT or COAG. The committee amended this to reflect the new 2022 recommendations on using 360° SLT. They agreed that people who prefer not to have 360° SLT or for whom it is not suitable should be offered generic PGA eye drops. This was because PGA eye drops were used for first-line treatment in the 2017 guideline and in the LiGHT trial.\n\nThe recommendations were also amended to highlight that eye drop installation technique should be demonstrated and that healthcare professionals should observe the person to confirm that their installation technique is correct. It is recommended that this be done when eye drops are first prescribed.\n\nReturn to recommendation\xa01.4.6\n\nReturn to recommendation\xa01.4.17\n\n# Organisation of care\n\nRecommendations\xa01.6.6 and 1.6.7\n\n## Why the committee made the recommendations\n\nThe committee noted that the first-line use of 360° SLT to treat OHT or COAG might lead to a significant change in practice that requires different organisation of care and the establishment of a multidisciplinary team. The committee wanted to make clear that if 360° SLT is suitable for a person, that person should be referred to a consultant ophthalmologist. They also discussed the safety of the 360° SLT procedure and agreed that healthcare professionals should discuss with the responsible consultant ophthalmologist the decision to offer it and how it will be performed. This means that with support from a consultant ophthalmologist, healthcare professionals such as specialty doctors, associate specialists, specialist nurses, optometrists and allied health professionals can perform 360° SLT.\n\nThe committee also noted that healthcare professionals who provide 360° SLT should be given support and have relevant training on the suitability and safety of the procedure, including its benefits and risks. They should also be trained in discussing these points and patient consent with patients and their family members or carers. A similar approach was taken in the LiGHT trial, in which training was given to all treating surgeons before recruitment, and the chief investigator, who was a consultant ophthalmic surgeon, observed each surgeon perform at least 1\xa0laser treatment. Based on these discussions, new recommendations were added to provide further clarification on organisation of care.\n\n## How the recommendations might affect practice\n\nThe recommendations are likely to result in a significant change in practice because training and support will be needed for healthcare professionals performing the 360° SLT procedure.\n\nReturn to recommendations\xa01.6.6 and 1.6.7", 'Context': 'The scope of this NICE guideline on diagnosis and management of glaucoma was extended to cover referral in 2017. This included the most effective service models for referral filtering schemes (repeat measures, enhanced case-finding and referral refinement), the tests to be used for finding people with chronic open angle glaucoma (COAG), suspected COAG and ocular hypertension (OHT), and thresholds for onward referral. In 2017, the guidance was also updated on tests for diagnosis and reassessment, pharmacological treatments for lowering intraocular pressure (IOP) and preserving visual field, and reassessment intervals, which depend on prognosis.\n\nThe 2017 update provided an opportunity to re-evaluate the clinical effectiveness, cost effectiveness and indications for treating OHT. Knowledge of corneal thickness is no longer needed to decide whether to treat OHT and a single threshold of 24\xa0mmHg is now recommended for both onward referral and treatment. Changes in the costs of pharmacological treatments, acknowledgement of short- and long-term variations in IOP and the uneven relationship between rising pressure and increased risk have allowed a simplification of the indications for OHT treatment.\n\nControl of IOP remains critical to the therapeutic approach. Intensity of treatment and ongoing management are guided by disease severity and progression as shown by visual field change, morphological change in the optic disc, and the likelihood of progressive sight loss. Reassessment at each visit is emphasised, encouraging flexible clinical judgement about the frequency of visits and options for treatment, including stopping treatment when the perceived lifetime risk of developing visual impairment is low.\n\nSince the update in 2017, there has been new evidence on the use of 360° selective laser trabeculoplasty as a first-line treatment for OHT and COAG. Therefore, recommendations on treatment for people with OHT or COAG were updated.\n\nSections of the guideline on accuracy of visual field tests, surgical interventions, and information, education and support needed for adherence to treatment have not been updated because no new evidence was found.'}
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https://www.nice.org.uk/guidance/ng81
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This guideline covers diagnosing and managing glaucoma in people aged 18 and over. It includes recommendations on testing and referral (case-finding) for chronic open-angle glaucoma and ocular hypertension and on effective diagnosis, treatment and reassessment to stop these conditions progressing.
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a569cc1adf2fb659b21e15cb7f96baa47bdf5fc7
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nice
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Sodium zirconium cyclosilicate for treating hyperkalaemia
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Sodium zirconium cyclosilicate for treating hyperkalaemia
Evidence-based recommendations on sodium zirconium cyclosilicate (Lokelma) for treating hyperkalaemia in adults.
# Recommendations
Sodium zirconium cyclosilicate is recommended as an option for treating hyperkalaemia in adults only if used:
in emergency care for acute life-threatening hyperkalaemia alongside standard care or
for people with persistent hyperkalaemia and chronic kidney disease stage 3b to 5 or heart failure, if they:
have a confirmed serum potassium level of at least 6.0 mmol/litre and
because of hyperkalaemia, are not taking an optimised dosage of renin-angiotensin-aldosterone system (RAAS) inhibitor and
are not on dialysis.
Stop sodium zirconium cyclosilicate if RAAS inhibitors are no longer suitable.
This recommendation is not intended to affect treatment with sodium zirconium cyclosilicate that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Sodium zirconium cyclosilicate is a treatment for people with high blood potassium levels (hyperkalaemia). It may benefit adults with chronic kidney disease or heart failure, either:
in emergency care for life-threatening hyperkalaemia or
for persistent hyperkalaemia that prevents people from having an optimised dose of RAAS inhibitors.
Treating acute life-threatening hyperkalaemia in emergency care is established clinical practice. Evidence from people with hyperkalaemia having treatment in outpatient care suggests that sodium zirconium cyclosilicate could be a useful addition to emergency care. Other potassium-lowering treatments are rarely used in this setting because they are poorly tolerated.
The cost-effectiveness estimates for sodium zirconium cyclosilicate suggest that it is a good use of NHS resources for treating acute life-threatening hyperkalaemia in emergency care. Therefore, it is recommended.
Clinical trials show that sodium zirconium cyclosilicate lowers serum potassium when used in outpatient care. But there is no clinical evidence that it extends life or improves quality of life. Sodium zirconium cyclosilicate may allow people to stay on RAAS inhibitors (drugs used to treat heart failure and kidney disease) for longer. Staying on these drugs may extend life and improve quality of life.
Considering the benefit from more people being able to stay on RAAS inhibitors, the cost-effectiveness estimates for sodium zirconium cyclosilicate suggest that it is a good use of NHS resources. Therefore, it is recommended for treating confirmed persistent hyperkalaemia when started in specialist care, for people who are not taking an optimised dose of RAAS inhibitors because of hyperkalaemia.# Information about sodium zirconium cyclosilicate
Marketing authorisation indication
Sodium zirconium cyclosilicate (Lokelma, AstraZeneca) has a marketing authorisation 'for the treatment of hyperkalaemia in adult patients'.
Dosage in the marketing authorisation
Correction phase:
The recommended starting dose of sodium zirconium cyclosilicate is 10 g, administered 3 times a day orally as a suspension in water. When normal serum potassium levels are reached, the maintenance regimen should be followed. If normal serum potassium levels are not reached after 72 hours of treatment, sodium zirconium cyclosilicate should be stopped.
Maintenance phase:
For people with normal serum potassium levels after the correction phase, the minimal effective dose of sodium zirconium cyclosilicate to prevent recurrence of hyperkalaemia should be established. A starting dose of 5 g once daily is recommended, with possible titration up to a maximum of 10 g once daily or down to 5 g once every other day as needed to maintain a normal serum potassium level.
Price
The list price of sodium zirconium cyclosilicate is £10.40 per 10-g sachet or £5.20 per 5-g sachet (company information, November 2021).
Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee (section 6) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treating hyperkalaemia
## Patients in the NHS with serum potassium levels above the normal range do not always need treatment to lower potassium
Hyperkalaemia is a high level of potassium in the blood. The European Resuscitation Council classifies hyperkalaemia as mild (serum potassium level of 5.5 mmol/litre to 5.9 mmol/litre), moderate (6.0 mmol/litre to 6.4 mmol/litre) or severe (6.5 mmol/litre and above). The company's clinical trials recruited people with serum (blood) potassium levels above 5.0 mmol/litre. The committee understood that serum potassium tests may incorrectly identify hyperkalaemia, and potassium levels often need to be confirmed. It concluded that any use of sodium zirconium cyclosilicate would be limited to confirmed hyperkalaemia. Hyperkalaemia occurs most commonly in people with chronic kidney disease (stages 4 and 5), and in heart failure. It can also occur after starting treatments for high blood pressure, chronic kidney disease, proteinuria and heart failure, which include potassium-sparing diuretics or renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and aldosterone receptor antagonists. Clinicians routinely monitor serum potassium in people with chronic kidney disease and in people having RAAS inhibitors. The clinical experts at the second committee meeting explained they would consider drug treatment for hyperkalaemia, if a well-tolerated treatment were available, mainly to optimise the use of RAAS inhibitors. They would consider drug treatment for:
people with chronic kidney disease and serum potassium levels above 6.0 mmol/litre and
some people with heart failure and serum potassium levels above 5.5 mmol/litre.The committee understood that many people have both heart failure and chronic kidney disease, so it may be appropriate to start drug treatment at the same serum potassium level for both diseases. The committee was not presented with evidence for a differential effect of sodium zirconium cyclosilicate between people with chronic kidney disease and heart failure (see section 3.10). Once the diagnosis of hyperkalaemia is confirmed, the decision to use a treatment that actively lowers serum potassium takes into account whether the hyperkalaemia is life threatening. This is based on whether the rise in serum potassium is acute and whether there are characteristic electrocardiogram (ECG) changes. The committee concluded that most of the people in the company's clinical trials, which recruited people with serum potassium levels above 5.0 mmol/litre, would not have treatment for hyperkalaemia in the NHS.
## Treating life-threatening acute hyperkalaemia and chronic hyperkalaemia is different
The need for, and type of, treatment for hyperkalaemia depends on its severity. Life-threatening acute hyperkalaemia needs emergency treatment in hospital. NICE-accredited clinical practice guidelines for treating acute hyperkalaemia from the UK Renal Association state that the risk of cardiac arrhythmias increases with serum potassium levels above 6.5 mmol/litre. Small rises in serum potassium above this can cause ECG changes. To lower the risk of cardiac arrest, clinicians use active potassium-lowering treatments, then identify and remove the cause of hyperkalaemia. The guidelines include the following treatments:
Calcium chloride or calcium gluconate intravenously to protect the heart if there is ECG evidence of hyperkalaemia.
Insulin and glucose intravenously to move potassium from the blood into cells.
Nebulised salbutamol as an adjunctive therapy to insulin and glucose for serum potassium levels of 6.5 mmol/litre and above to move potassium from the blood into cells.
After severe hyperkalaemia has resolved, potassium-binding agents may be offered for 3 or more days (namely, calcium resonium given orally) to remove potassium from the body.
Stopping or reducing RAAS inhibitors, which can increase serum potassium levels.The aim of treatment of chronic hyperkalaemia is to lower potassium levels to prevent acute life-threatening hyperkalaemia. Treatment includes:
Advising people with chronic kidney disease to avoid foods high in potassium.
Stopping or reducing RAAS inhibitors and potassium-sparing diuretics.
Avoiding non-steroidal anti-inflammatory drugs and trimethoprim.The clinical expert at the first committee meeting explained that people who have normal serum potassium levels after emergency treatment do not have long-term (maintenance) treatment with a potassium-lowering drug in current clinical practice. He also noted that calcium resonium is poorly tolerated by patients. The committee concluded that managing acute life-threatening hyperkalaemia differs from managing persistent but non-life-threatening hyperkalaemia, which justified the separate analyses for sodium zirconium cyclosilicate in these populations.
## People with chronic hyperkalaemia would welcome an alternative to stopping RAAS inhibitors
The company proposed that people with chronic hyperkalaemia who have sodium zirconium cyclosilicate would be less likely to stop RAAS inhibitors. Therefore, they would live longer and have a lower risk of worsening kidney disease or heart failure and death. However, it did not provide any clinical evidence for this (see section 3.10). NICE's guideline on chronic kidney disease: assessment and management states that RAAS inhibitors should not be routinely started in people with serum potassium levels of 5.0 mmol/litre and above, and should be stopped in people with levels of 6.0 mmol/litre and above. NICE's guideline on chronic heart failure in adults: diagnosis and management states that serum potassium levels should be monitored before and after starting a RAAS inhibitor or changing RAAS inhibitor dose, but does not specify the serum potassium levels at which RAAS inhibitors should be avoided or stopped. The committee and the clinical experts at the committee meetings agreed that RAAS inhibitors would be used in the NHS for many people with serum potassium levels 5.0 mmol/litre and above, and would be stopped when serum potassium levels are 6.0 mmol/litre and above. At levels of serum potassium below 6.0 mmol/litre, clinicians would likely recommend reducing, rather than stopping, the RAAS inhibitor. This is because the perceived benefits of being on treatment outweigh the risks of having a serum potassium level between 5.0 mmol/litre and 6.0 mmol/litre. The committee noted that some people stop RAAS inhibitors for reasons other than hyperkalaemia. It concluded that patients and clinicians are keen for new treatments that would allow them to continue RAAS inhibitors.
## The long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary
The clinical expert at the first committee meeting explained that the benefit, or potential harm, of being on RAAS inhibitor treatment depended on:
the underlying condition
the class of RAAS inhibitor (ACE inhibitors, ARBs, aldosterone receptor antagonists) and
-utcome (for example, cardiovascular disease, worsening of kidney disease, death).The British Society for Heart Failure's response to consultation and a clinical expert present at the second meeting noted that RAAS inhibitors benefit people with heart failure with reduced ejection fraction, but not people with preserved ejection fraction. The committee concluded that the harms and benefits of stopping RAAS inhibitors because of hyperkalaemia compared with standard care could be affected by the:
underlying condition
type of RAAS inhibitor
dose of RAAS inhibitor
number of RAAS inhibitors
reason for stopping a RAAS inhibitor.The committee also concluded that the long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary and that it would consider the balance of benefits and harms in its decision making.
## Sodium zirconium cyclosilicate is unlikely to replace a low-potassium diet
The patient experts noted that maintaining a low-potassium diet is challenging because so many foods contain potassium. The clinical experts explained that they consider the diet worth trying; NICE recommends it for people with chronic kidney disease, and it lowers serum potassium compared with an unrestricted diet. They added that a new treatment option would not replace dietary advice but complement it, and may mean that the diet need not be so strict. The committee concluded that sodium zirconium cyclosilicate is unlikely to replace a low-potassium diet.
# Company positioning of sodium zirconium cyclosilicate
## The company proposes sodium zirconium cyclosilicate for a population narrower than that covered by the marketing authorisation
The marketing authorisation indication for sodium zirconium cyclosilicate specifies 'treatment for hyperkalaemia'. It was based on the company's trials in which people with serum potassium levels above 5.0 mmol/litre were recruited and had treatment (see section 3.8). The company focused its submission on people with chronic kidney disease (stages 3b to 5, excluding those on dialysis) or heart failure (who may also have chronic kidney disease, including stage 3a). The committee noted that the population in the company's submission was narrower than that covered by the marketing authorisation because the marketing authorisation includes people with other conditions (see section 2). At the third committee meeting, the company proposed that people with confirmed serum potassium levels of 6.0 mmol/litre and above would have treatment. The committee recalled that:
starting treatment at the same serum potassium level for chronic kidney disease and heart failure may be appropriate (see section 3.1)
it had not seen evidence justifying different starting levels between chronic kidney disease and heart failure
mmol/litre was the same serum potassium level as that for stopping RAAS inhibitors (see section 3.3).Therefore, the committee concluded that it would appraise sodium zirconium cyclosilicate for the population and the starting serum potassium level, 6.0 mmol/litre, the company proposed, which was narrower than that covered by the marketing authorisation.
## The company proposes that sodium zirconium cyclosilicate will be used alongside standard care for acute hyperkalaemia and started in specialist care for chronic hyperkalaemia
The marketing authorisation for sodium zirconium cyclosilicate covers using it as a corrective treatment for lowering serum potassium levels followed by maintenance treatment (at a lower dose) for people whose serum potassium levels return to normal after corrective treatment. The maintenance dose aims to avoid repeat hyperkalaemia. The committee noted that the marketing authorisation does not specify whether sodium zirconium cyclosilicate should be used to treat life-threatening hyperkalaemia needing emergency treatment, or persistent hyperkalaemia in outpatient care. The company proposed that sodium zirconium cyclosilicate would be used:
In emergency care, as an alternative to calcium resonium and permanently stopping RAAS inhibitors, in people with high levels of serum potassium who need immediate hospital treatment. It explained that sodium zirconium cyclosilicate would complement rather than replace the use of insulin and glucose in patients with life-threatening hyperkalaemia.
As an alternative to stopping RAAS inhibitors to manage chronic hyperkalaemia and to prevent life-threatening hyperkalaemia, in people with hyperkalaemia identified through routine monitoring. It explained that sodium zirconium cyclosilicate would complement rather than replace a low-potassium diet and may allow such a diet to be less strict (see section 3.5). It also explained that sodium zirconium cyclosilicate would be started in specialist care rather than in general practice.The committee concluded that it would appraise sodium zirconium cyclosilicate in the settings the company proposed, and that the comparators were both calcium resonium and managing RAAS inhibitors after emergency treatment, and managing RAAS inhibitors for chronic hyperkalaemia.
# Clinical effectiveness
## Trial evidence does not show whether sodium zirconium cyclosilicate is more clinically effective than NHS standard care
The clinical effectiveness evidence for sodium zirconium cyclosilicate came from the ZS004 and ZS005 trials. The trials were done in outpatient care. They included people who had lower serum potassium levels than would be treated in the NHS. In its consultation response, the company presented results for 8 patients in ZS004 with serum potassium levels of 6.5 mmol/litre and above, arguing that these patients would have emergency treatment in the NHS. However, the committee noted that these patients also had treatment as outpatients, so did not reflect patients who would have treatment in emergency care in the NHS. Both trials had 2 phases. The first 'correction' phase was single arm (everyone had treatment to lower serum potassium; there was no control group) in patients with serum potassium levels of 5.1 mmol/litre and above. The committee recognised that some of the response may have been related to regression to the mean. In response to the first consultation, the company presented data from a third trial, ZS003, which included a placebo-control arm in the 2‑day correction phase. The second phase of all 3 trials measured how well sodium zirconium cyclosilicate maintained serum potassium levels in people whose serum potassium levels had responded in the correction phase and were between 3.5 mmol/litre and 5.0 mmol/litre. In ZS004, people whose serum potassium levels had responded were randomised to placebo or to continue sodium zirconium cyclosilicate for 28 days. In ZS005, all people whose serum potassium levels had responded had sodium zirconium cyclosilicate for 52 weeks. The committee appreciated that the primary outcome measure in all the trials was mean serum potassium level. The trials all showed that sodium zirconium cyclosilicate treatment reduced serum potassium level from baseline. The single-arm maintenance part of ZS005 measured changing use of RAAS inhibitors as an exploratory end point. However, the single-arm design of this trial meant that there were no data on whether sodium zirconium cyclosilicate, compared with standard care, allowed more patients to continue on RAAS inhibitors, a key potential benefit suggested by the company (see section 3.3). The committee concluded that the company had not provided any data comparing sodium zirconium cyclosilicate with current NHS treatments to correct hyperkalaemia and maintain normal serum potassium levels in outpatient care (that is, management of RAAS inhibitors). Without these data, it could not determine whether sodium zirconium cyclosilicate is more clinically effective than current standard care in the NHS for treating chronic hyperkalaemia.
## Sodium zirconium cyclosilicate could be beneficial in treating acute life-threatening hyperkalaemia
The committee noted that acute hyperkalaemia can be fatal and treating acute life-threatening hyperkalaemia in hospital is established clinical practice. It agreed that lowering potassium levels for patients needing emergency care was a life-saving intervention. The committee therefore concluded that randomised evidence was not needed to show that treating life-threatening hyperkalaemia in emergency care prolonged life. As such, the uncontrolled evidence showing that sodium zirconium cyclosilicate reduces serum potassium (see section 3.8) was sufficient for the committee to conclude that it could be useful for people with hyperkalaemia needing treatment in emergency care.
## There is no direct evidence that sodium zirconium cyclosilicate increases length or quality of life for people having treatment for chronic hyperkalaemia
The company did a post-hoc analysis of the subgroups of patients in ZS004 and ZS005 who had baseline serum potassium levels of 6.0 mmol/litre and above. This is the threshold at which RAAS inhibitors are likely to be stopped and at which the company proposed sodium zirconium cyclosilicate would be used (see section 3.6). Most patients having sodium zirconium cyclosilicate had a serum potassium value of between 4.0 mmol/litre and 6.0 mmol/litre after the correction phase. For most of these patients, their serum potassium remained within these levels during the maintenance phase. The company also provided data from ZS003, which showed that patients having sodium zirconium cyclosilicate had stable serum potassium levels during the 12‑day maintenance period compared with small increases for patients on placebo. The committee noted:
The placebo in ZS003 did not reflect NHS practice (for example stopping RAAS inhibitors).
In ZS003 patients with serum potassium levels of above 5.0 mmol/litre started treatment. Clinicians in the NHS would not typically offer treatment at this level (see section 3.1).
Symptoms of hyperkalaemia may be similar to symptoms of the underlying condition, for example, heart failure. So, treating hyperkalaemia may not result in a noticeable effect on symptoms.
ZS005 was the longest trial, with follow up of 52 weeks. The company provided no evidence for the effectiveness of sodium zirconium cyclosilicate beyond 52 weeks. In its updated base case, the company assumed that patients would have the drug indefinitely (see section 3.14), an assumption 1 clinical expert supported.
The company did not present any statistical tests for interaction by subgroup, so it was unknown whether patients with chronic kidney disease or heart failure derived greater benefit from sodium zirconium cyclosilicate.The committee was also aware that the company claimed that treatment with sodium zirconium cyclosilicate would prolong life and improve quality of life, but none of the trials showed this. The ERG and the consultation responses noted that the company could resolve this uncertainty with a clinical trial designed to report on outcomes such as mortality, disease progression and patterns of RAAS inhibitor use. The company indicated that it was not planning such a trial. The committee concluded that, although the trial results showed that continuing sodium zirconium cyclosilicate was associated with lower serum potassium than stopping the drug, there was no direct evidence that sodium zirconium cyclosilicate improves survival or quality of life over other treatments for people with chronic hyperkalaemia.
## Sodium zirconium cyclosilicate is associated with adverse effects
The company presented data showing that treatment with sodium zirconium cyclosilicate was associated with hypokalaemia, that is low serum potassium. Hypokalaemia, like hyperkalaemia, is associated with life-threatening arrhythmias. The company explained that treating hyperkalaemia at 6.0 mmol/litre and above was less likely to cause hypokalaemia than when treating it at lower levels. The committee concluded that sodium zirconium cyclosilicate is associated with adverse effects.
## Stopping RAAS inhibitors likely increases the risk of death, hospitalisation and disease progression
Data were not collected in ZS003, ZS004 and ZS005 on the effect of sodium zirconium cyclosilicate on long-term outcomes such as progression of chronic kidney disease or mortality. However, the company proposed in its model that people with hyperkalaemia who have sodium zirconium cyclosilicate live longer and have a better quality of life than people who do not. This was because treatment with sodium zirconium cyclosilicate would allow them to maintain or restart treatment with RAAS inhibitors. The committee noted that the company provided only exploratory data from a single-arm trial (ZS005) of sodium zirconium cyclosilicate. This showed that most people on RAAS inhibitors continued to have the same dose and some people not on them at the start of the trial had started them by the end of the trial follow up. The committee recalled that there was no evidence showing that RAAS inhibitor dosing was different for people having sodium zirconium cyclosilicate than for people who didn't (see section 3.8). Independent of this, based on targeted reviews for chronic kidney disease and heart failure, the company presented data from a network meta-analysis of randomised controlled trials and several observational studies. The company assumed that, because these studies showed that starting a RAAS inhibitor is associated with living longer, people who stop a RAAS inhibitor would have shortened lives. The company also presented evidence that RAAS inhibitors are associated with delayed disease progression, and therefore improved quality of life. The committee recognised that the company's evidence addressed the decision problem indirectly. It noted that the trials in the company's literature search compared starting RAAS inhibitors with not starting them, rather than the question relevant to this appraisal, that is, reducing or stopping RAAS inhibitors compared with continuing them. In addition, sodium zirconium cyclosilicate may allow more people to remain on RAAS inhibitors. However, the reason for some people having high potassium levels may be a worsening of the underlying disease, and it is unclear whether the clinical benefit seen in the trials would translate fully. For example, the committee understood from the clinical expert and consultation responses that the benefits of RAAS inhibitors were well established for certain people, but their benefits were uncertain for others, for example, people close to needing kidney dialysis. It concluded that, in the population being considered, stopping RAAS inhibitors would generally be associated with an increased risk of adverse outcomes and disease progression. The committee was not satisfied that the company had presented robust data on how sodium zirconium cyclosilicate alters dosing of RAAS inhibitors compared with standard care, or the extent to which such alterations improved length and quality of life. However, the committee was also aware of NICE guidance recommending stopping RAAS inhibitors at serum potassium levels of 6.0 mmol/litre and above (see section 3.3). It concluded that starting RAAS inhibitors prolongs life for many people, so stopping them for people who benefit from them would likely shorten life.
## There is insufficient evidence to prove that lowering serum potassium levels improves long-term outcomes
The company also proposed in its model that lowering serum potassium with sodium zirconium cyclosilicate causes people to live longer. It based this on a review of evidence on the association between serum potassium and adverse outcomes for people with chronic kidney disease or heart failure. This evidence, from observational cohort studies, showed that a higher risk of death, hospitalisation and major adverse cardiovascular events was associated with high, but also with lower than normal, serum potassium levels. Using these data, the company assumed that, because people with higher than normal serum potassium have a higher risk of death, sodium zirconium cyclosilicate prolongs life because it lowers serum potassium. The committee noted that the observational data did not guarantee an independent causal effect between high serum potassium levels and death. Importantly, even if it did, the committee noted that the observational data did not provide evidence that lowering serum potassium extends life. The committee was aware that these studies could adjust only for known, measured confounders. It also noted that the authors of a company-supported observational study used in the model cautioned against assuming a causal effect, and acknowledged the possibility of residual confounding. At the third committee meeting, the company agreed that these observational data did not prove causality. The committee agreed that a relationship between lowering serum potassium to a normal range and fewer adverse outcomes was biologically plausible in certain clinical situations. The company did not provide interventional randomised evidence that lowering serum potassium prolongs life in chronic hyperkalaemia. The committee was aware that any association between serum potassium levels and mortality may have been influenced by time-dependent confounding. Specifically, patients with hyperkalaemia may have stopped having RAAS inhibitors, increasing the risk of death. The committee concluded that there was insufficient evidence to prove that lowering serum potassium levels for people in outpatient care improves outcomes.
# Cost-effectiveness modelling
## A patient-level simulation model is appropriate
The company modelled the cost effectiveness of sodium zirconium cyclosilicate using a patient-level simulation model. The model generated a serum potassium trajectory for each patient over time. The proportion of patients who entered the model on RAAS inhibitors was based on ZS005 (36% of people with chronic kidney disease and 70% of people with heart failure). Thereafter, RAAS inhibitor use was determined by the patient's serum potassium trajectory (as below). The company chose to model sodium zirconium cyclosilicate as prolonging life in 2 ways: by level of serum potassium (in which treatment led to the full theoretical benefit seen in epidemiological studies) and by whether the patient was on a RAAS inhibitor (see section 3.12 and section 3.13). The company modelled 2 settings:
Emergency care: patients had sodium zirconium cyclosilicate after insulin−glucose for up to 28 days. The company chose 28 days based on the length of ZS004. The time horizon was 52 weeks.
Outpatient care: patients had sodium zirconium cyclosilicate for 28 days if it was the first episode of hyperkalaemia or for a lifetime, if otherwise. The committee understood the company chose a lifetime duration of treatment because clinical experts stated that treatment would continue as long as there was evidence of clinical benefit (see section 3.10).The clinical experts noted that they may offer people sodium zirconium cyclosilicate only for a few days in emergency care, rather than 28 days. The committee noted that the company's updated base case incorporated some, but not all, of its preferred assumptions, including:
starting treatment with sodium zirconium cyclosilicate at serum potassium values of 6.0 mmol/litre and above for both chronic kidney disease and heart failure
comparative data for standard care during the correction phase (from ZS003, see section 3.8)
modelling a reduction in serum potassium level when patients stop or reduce their dose of RAAS inhibitors
% of patients with a serum potassium level between 5.5 mmol/litre and 6.0 mmol/litre reduce their dose of RAAS inhibitors and 20% stop them
all patients with a serum potassium level above 6.0 mmol/litre stop RAAS inhibitors for 12 weeks, after which around 50% of people restart them.The committee concluded that a patient-simulation model was appropriate for decision making.
## The company's approach to modelling the association between RAAS inhibitor use and outcomes is appropriate, but the data are inadequate
The company modelled an association between use of RAAS inhibitors and the risks of mortality, hospitalisation and major adverse cardiovascular events. This was based on odds ratios from a network meta-analysis of clinical trials of starting RAAS inhibitors (Xie et al. 2016). The committee recalled and accepted evidence from the clinical and patient experts that maintaining RAAS inhibitor therapy is likely to be beneficial for certain patients (see section 3.12). It noted that the company did scenario analyses using alternative data sources and assuming that RAAS inhibitor use had no effect on outcomes. The committee did not see robust evidence of the effect of sodium zirconium cyclosilicate on RAAS inhibitor use. However, it was aware that clinicians are encouraged to stop RAAS inhibitor treatment in people with serum potassium levels of 6.0 mmol/litre and above. The committee concluded that the company's approach to modelling the association between RAAS inhibitor use and outcomes was appropriate.
## It is appropriate to consider the company's scenario removing the association between serum potassium levels and outcomes
In its base case, the company modelled an association between serum potassium levels and the risks of mortality, hospitalisation and major adverse cardiovascular events using observational studies. The committee recalled that the observational studies supporting this assumption did not establish that lowering serum potassium improved outcomes. Also, it was aware that the underlying causes of hyperkalaemia may have led to poor outcomes rather than the hyperkalaemia itself. Importantly, it had not been presented with evidence that lowering serum potassium in chronic hyperkalaemia prolongs life. The committee concluded that it was not appropriate to assume that lowering serum potassium prolongs life in people with chronic hyperkalaemia, based only on observational studies relating a surrogate end point to adverse outcomes. The committee also noted that any association between serum potassium level and mortality may have been partially captured in the model. This is because patients in the model with a lower serum potassium level are more likely to be having RAAS inhibitors, and therefore have a decreased risk of death (see section 3.15). The company provided additional scenario analyses reducing the strength of the association from the observational evidence or removing it entirely. The committee concluded that it was appropriate to use the scenario analysis removing the association between serum potassium and adverse outcomes in its decision making.
# Cost-effectiveness estimates
## Sodium zirconium cyclosilicate alongside standard care is recommended as an option for people who need emergency treatment of hyperkalaemia
The committee considered the cost-effectiveness results in emergency care. It recalled that it did not need randomised evidence to show that treating hyperkalaemia in emergency care prolonged life, and that such treatment was standard clinical practice (see section 3.9). The committee was aware that acute hyperkalaemia can be fatal. It agreed that sodium zirconium cyclosilicate reduced serum potassium levels quickly so was a suitable treatment option in emergency care after standard treatments including insulin and glucose (see section 3.2). It recalled that the company had positioned sodium zirconium cyclosilicate to be used alongside standard care for the treatment of life-threatening acute hyperkalaemia (see section 3.7). The committee noted that the drug was associated with lower costs and improved quality of life in both the company's and ERG's base cases and all scenario analyses. It recalled that there was some uncertainty about the results because there was limited clinical evidence of sodium zirconium cyclosilicate's use in emergency care (see section 3.8). Also, the gain in quality-adjusted life years (QALYs) was very small. It also recalled that the model used a short time horizon for this analysis so any long-term benefits of sodium zirconium cyclosilicate (such as enabling patients to restart RAAS inhibitors) may have been underestimated. The committee agreed that people with life-threatening hyperkalaemia would value the option of another treatment to lower serum potassium levels that was better tolerated than calcium resonium (see section 3.2). It therefore concluded that it could recommend sodium zirconium cyclosilicate alongside standard care as an option for people needing treatment for acute hyperkalaemia in emergency care.
## Sodium zirconium cyclosilicate is recommended as a treatment option for chronic hyperkalaemia
The committee then considered the cost-effectiveness results for chronic hyperkalaemia. The company's revised base-case incremental cost-effectiveness ratios (ICERs) were less than £20,000 per QALY gained compared with standard care for people with hyperkalaemia who have either chronic kidney disease or heart failure. The exact ICERs cannot be reported here because they are considered confidential by the company. The committee noted that the company's base case included an association between serum potassium levels and mortality, which the committee did not accept (see section 3.16). However, in the scenario removing this association, the ICERs were also below £20,000 per QALY gained. Therefore, the committee concluded that sodium zirconium cyclosilicate was a cost-effective use of NHS resources for treating chronic hyperkalaemia. The committee noted that, in this scenario, most of the benefits arise because more people are able to have RAAS inhibitors with sodium zirconium cyclosilicate. However, it recalled that some people do not benefit from RAAS inhibitors (see section 3.4), and so concluded that it would not be appropriate for these people to start sodium zirconium cyclosilicate. It further concluded that some people may have to stop RAAS inhibitors for reasons other than hyperkalaemia. The committee concluded that, in these situations, people should also stop having sodium zirconium cyclosilicate. It emphasised that uncertainties remained around the clinical benefit of sodium zirconium cyclosilicate and that these could be addressed by clinical trials (see section 5.1).
# Innovation
## The company did not show that sodium zirconium cyclosilicate is innovative
The company proposed several benefits of sodium zirconium cyclosilicate, including preventing the need to modify RAAS inhibitor treatment and avoiding a restrictive low-potassium diet, but did not show evidence of these benefits. The committee was aware that other gastrointestinal potassium binders exist, and, although these are not well tolerated, sodium zirconium cyclosilicate does not represent a step-change in treatment. The committee concluded that sodium zirconium cyclosilicate could not be considered innovative.# Recommendations for research
The committee noted that there was no clinical evidence showing that having sodium zirconium cyclosilicate improved length or quality of life or allowed patients to stay on optimal doses of renin-angiotensin-aldosterone system (RAAS) inhibitors. It therefore considered that it would be valuable to have studies comparing sodium zirconium cyclosilicate plus standard care with standard care alone in people with confirmed hyperkalaemia of 6.0 mmol/litre and above, and that these should investigate:
mortality
disease progression
patterns of RAAS inhibitor use
healthcare utilisation, and
health-related quality of life.
|
{'Recommendations': 'Sodium zirconium cyclosilicate is recommended as an option for treating hyperkalaemia in adults only if used:\n\nin emergency care for acute life-threatening hyperkalaemia alongside standard care or\n\nfor people with persistent hyperkalaemia and chronic kidney disease stage\xa03b\xa0to\xa05 or heart failure, if they:\n\n\n\nhave a confirmed serum potassium level of at least 6.0\xa0mmol/litre and\n\nbecause of hyperkalaemia, are not taking an optimised dosage of renin-angiotensin-aldosterone system (RAAS) inhibitor and\n\nare not on dialysis. [amended 2022]\n\n\n\nStop sodium zirconium cyclosilicate if RAAS inhibitors are no longer suitable. [amended 2022]\n\nThis recommendation is not intended to affect treatment with sodium zirconium cyclosilicate that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nSodium zirconium cyclosilicate is a treatment for people with high blood potassium levels (hyperkalaemia). It may benefit adults with chronic kidney disease or heart failure, either:\n\nin emergency care for life-threatening hyperkalaemia or\n\nfor persistent hyperkalaemia that prevents people from having an optimised dose of RAAS inhibitors.\n\nTreating acute life-threatening hyperkalaemia in emergency care is established clinical practice. Evidence from people with hyperkalaemia having treatment in outpatient care suggests that sodium zirconium cyclosilicate could be a useful addition to emergency care. Other potassium-lowering treatments are rarely used in this setting because they are poorly tolerated.\n\nThe cost-effectiveness estimates for sodium zirconium cyclosilicate suggest that it is a good use of NHS resources for treating acute life-threatening hyperkalaemia in emergency care. Therefore, it is recommended.\n\nClinical trials show that sodium zirconium cyclosilicate lowers serum potassium when used in outpatient care. But there is no clinical evidence that it extends life or improves quality of life. Sodium zirconium cyclosilicate may allow people to stay on RAAS inhibitors (drugs used to treat heart failure and kidney disease) for longer. Staying on these drugs may extend life and improve quality of life.\n\nConsidering the benefit from more people being able to stay on RAAS inhibitors, the cost-effectiveness estimates for sodium zirconium cyclosilicate suggest that it is a good use of NHS resources. Therefore, it is recommended for treating confirmed persistent hyperkalaemia when started in specialist care, for people who are not taking an optimised dose of RAAS inhibitors because of hyperkalaemia.', 'Information about sodium zirconium cyclosilicate': "Marketing authorisation indication\n\nSodium zirconium cyclosilicate (Lokelma, AstraZeneca) has a marketing authorisation 'for the treatment of hyperkalaemia in adult patients'.\n\nDosage in the marketing authorisation\n\nCorrection phase:\n\nThe recommended starting dose of sodium zirconium cyclosilicate is 10\xa0g, administered 3\xa0times a day orally as a suspension in water. When normal serum potassium levels are reached, the maintenance regimen should be followed. If normal serum potassium levels are not reached after 72\xa0hours of treatment, sodium zirconium cyclosilicate should be stopped.\n\nMaintenance phase:\n\nFor people with normal serum potassium levels after the correction phase, the minimal effective dose of sodium zirconium cyclosilicate to prevent recurrence of hyperkalaemia should be established. A starting dose of 5\xa0g once daily is recommended, with possible titration up to a maximum of 10\xa0g once daily or down to 5\xa0g once every other day as needed to maintain a normal serum potassium level.\n\nPrice\n\nThe list price of sodium zirconium cyclosilicate is £10.40 per 10-g sachet or £5.20 per 5-g sachet (company information, November 2021).\n\nCosts may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee (section\xa06) considered evidence submitted by AstraZeneca and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treating hyperkalaemia\n\n## Patients in the NHS with serum potassium levels above the normal range do not always need treatment to lower potassium\n\nHyperkalaemia is a high level of potassium in the blood. The European Resuscitation Council classifies hyperkalaemia as mild (serum potassium level of 5.5\xa0mmol/litre to 5.9\xa0mmol/litre), moderate (6.0\xa0mmol/litre to 6.4\xa0mmol/litre) or severe (6.5\xa0mmol/litre and above). The company's clinical trials recruited people with serum (blood) potassium levels above 5.0\xa0mmol/litre. The committee understood that serum potassium tests may incorrectly identify hyperkalaemia, and potassium levels often need to be confirmed. It concluded that any use of sodium zirconium cyclosilicate would be limited to confirmed hyperkalaemia. Hyperkalaemia occurs most commonly in people with chronic kidney disease (stages\xa04 and\xa05), and in heart failure. It can also occur after starting treatments for high blood pressure, chronic kidney disease, proteinuria and heart failure, which include potassium-sparing diuretics or renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors include angiotensin-converting enzyme (ACE) inhibitors, angiotensin\xa0II receptor blockers (ARBs) and aldosterone receptor antagonists. Clinicians routinely monitor serum potassium in people with chronic kidney disease and in people having RAAS inhibitors. The clinical experts at the second committee meeting explained they would consider drug treatment for hyperkalaemia, if a well-tolerated treatment were available, mainly to optimise the use of RAAS inhibitors. They would consider drug treatment for:\n\npeople with chronic kidney disease and serum potassium levels above 6.0\xa0mmol/litre and\n\nsome people with heart failure and serum potassium levels above 5.5\xa0mmol/litre.The committee understood that many people have both heart failure and chronic kidney disease, so it may be appropriate to start drug treatment at the same serum potassium level for both diseases. The committee was not presented with evidence for a differential effect of sodium zirconium cyclosilicate between people with chronic kidney disease and heart failure (see section\xa03.10). Once the diagnosis of hyperkalaemia is confirmed, the decision to use a treatment that actively lowers serum potassium takes into account whether the hyperkalaemia is life threatening. This is based on whether the rise in serum potassium is acute and whether there are characteristic electrocardiogram (ECG) changes. The committee concluded that most of the people in the company's clinical trials, which recruited people with serum potassium levels above 5.0\xa0mmol/litre, would not have treatment for hyperkalaemia in the NHS.\n\n## Treating life-threatening acute hyperkalaemia and chronic hyperkalaemia is different\n\nThe need for, and type of, treatment for hyperkalaemia depends on its severity. Life-threatening acute hyperkalaemia needs emergency treatment in hospital. NICE-accredited clinical practice guidelines for treating acute hyperkalaemia from the UK Renal Association state that the risk of cardiac arrhythmias increases with serum potassium levels above 6.5\xa0mmol/litre. Small rises in serum potassium above this can cause ECG changes. To lower the risk of cardiac arrest, clinicians use active potassium-lowering treatments, then identify and remove the cause of hyperkalaemia. The guidelines include the following treatments:\n\nCalcium chloride or calcium gluconate intravenously to protect the heart if there is ECG evidence of hyperkalaemia.\n\nInsulin and glucose intravenously to move potassium from the blood into cells.\n\nNebulised salbutamol as an adjunctive therapy to insulin and glucose for serum potassium levels of 6.5\xa0mmol/litre and above to move potassium from the blood into cells.\n\nAfter severe hyperkalaemia has resolved, potassium-binding agents may be offered for 3\xa0or more days (namely, calcium resonium given orally) to remove potassium from the body.\n\nStopping or reducing RAAS inhibitors, which can increase serum potassium levels.The aim of treatment of chronic hyperkalaemia is to lower potassium levels to prevent acute life-threatening hyperkalaemia. Treatment includes:\n\nAdvising people with chronic kidney disease to avoid foods high in potassium.\n\nStopping or reducing RAAS inhibitors and potassium-sparing diuretics.\n\nAvoiding non-steroidal anti-inflammatory drugs and trimethoprim.The clinical expert at the first committee meeting explained that people who have normal serum potassium levels after emergency treatment do not have long-term (maintenance) treatment with a potassium-lowering drug in current clinical practice. He also noted that calcium resonium is poorly tolerated by patients. The committee concluded that managing acute life-threatening hyperkalaemia differs from managing persistent but non-life-threatening hyperkalaemia, which justified the separate analyses for sodium zirconium cyclosilicate in these populations.\n\n## People with chronic hyperkalaemia would welcome an alternative to stopping RAAS inhibitors\n\nThe company proposed that people with chronic hyperkalaemia who have sodium zirconium cyclosilicate would be less likely to stop RAAS inhibitors. Therefore, they would live longer and have a lower risk of worsening kidney disease or heart failure and death. However, it did not provide any clinical evidence for this (see section\xa03.10). NICE's guideline on chronic kidney disease: assessment and management states that RAAS inhibitors should not be routinely started in people with serum potassium levels of 5.0\xa0mmol/litre and above, and should be stopped in people with levels of 6.0\xa0mmol/litre and above. NICE's guideline on chronic heart failure in adults: diagnosis and management states that serum potassium levels should be monitored before and after starting a RAAS inhibitor or changing RAAS inhibitor dose, but does not specify the serum potassium levels at which RAAS inhibitors should be avoided or stopped. The committee and the clinical experts at the committee meetings agreed that RAAS inhibitors would be used in the NHS for many people with serum potassium levels 5.0\xa0mmol/litre and above, and would be stopped when serum potassium levels are 6.0\xa0mmol/litre and above. At levels of serum potassium below 6.0\xa0mmol/litre, clinicians would likely recommend reducing, rather than stopping, the RAAS inhibitor. This is because the perceived benefits of being on treatment outweigh the risks of having a serum potassium level between 5.0\xa0mmol/litre and 6.0\xa0mmol/litre. The committee noted that some people stop RAAS inhibitors for reasons other than hyperkalaemia. It concluded that patients and clinicians are keen for new treatments that would allow them to continue RAAS inhibitors.\n\n## The long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary\n\nThe clinical expert at the first committee meeting explained that the benefit, or potential harm, of being on RAAS inhibitor treatment depended on:\n\nthe underlying condition\n\nthe class of RAAS inhibitor (ACE inhibitors, ARBs, aldosterone receptor antagonists) and\n\noutcome (for example, cardiovascular disease, worsening of kidney disease, death).The British Society for Heart Failure's response to consultation and a clinical expert present at the second meeting noted that RAAS inhibitors benefit people with heart failure with reduced ejection fraction, but not people with preserved ejection fraction. The committee concluded that the harms and benefits of stopping RAAS inhibitors because of hyperkalaemia compared with standard care could be affected by the:\n\nunderlying condition\n\ntype of RAAS inhibitor\n\ndose of RAAS inhibitor\n\nnumber of RAAS inhibitors\n\nreason for stopping a RAAS inhibitor.The committee also concluded that the long-term benefit of continuing RAAS inhibitors on quality of life and survival in people with hyperkalaemia may vary and that it would consider the balance of benefits and harms in its decision making.\n\n## Sodium zirconium cyclosilicate is unlikely to replace a low-potassium diet\n\nThe patient experts noted that maintaining a low-potassium diet is challenging because so many foods contain potassium. The clinical experts explained that they consider the diet worth trying; NICE recommends it for people with chronic kidney disease, and it lowers serum potassium compared with an unrestricted diet. They added that a new treatment option would not replace dietary advice but complement it, and may mean that the diet need not be so strict. The committee concluded that sodium zirconium cyclosilicate is unlikely to replace a low-potassium diet.\n\n# Company positioning of sodium zirconium cyclosilicate\n\n## The company proposes sodium zirconium cyclosilicate for a population narrower than that covered by the marketing authorisation\n\nThe marketing authorisation indication for sodium zirconium cyclosilicate specifies 'treatment for hyperkalaemia'. It was based on the company's trials in which people with serum potassium levels above 5.0\xa0mmol/litre were recruited and had treatment (see section\xa03.8). The company focused its submission on people with chronic kidney disease (stages\xa03b to\xa05, excluding those on dialysis) or heart failure (who may also have chronic kidney disease, including stage\xa03a). The committee noted that the population in the company's submission was narrower than that covered by the marketing authorisation because the marketing authorisation includes people with other conditions (see section\xa02). At the third committee meeting, the company proposed that people with confirmed serum potassium levels of 6.0\xa0mmol/litre and above would have treatment. The committee recalled that:\n\nstarting treatment at the same serum potassium level for chronic kidney disease and heart failure may be appropriate (see section\xa03.1)\n\nit had not seen evidence justifying different starting levels between chronic kidney disease and heart failure\n\nmmol/litre was the same serum potassium level as that for stopping RAAS inhibitors (see section\xa03.3).Therefore, the committee concluded that it would appraise sodium zirconium cyclosilicate for the population and the starting serum potassium level, 6.0\xa0mmol/litre, the company proposed, which was narrower than that covered by the marketing authorisation.\n\n## The company proposes that sodium zirconium cyclosilicate will be used alongside standard care for acute hyperkalaemia and started in specialist care for chronic hyperkalaemia\n\nThe marketing authorisation for sodium zirconium cyclosilicate covers using it as a corrective treatment for lowering serum potassium levels followed by maintenance treatment (at a lower dose) for people whose serum potassium levels return to normal after corrective treatment. The maintenance dose aims to avoid repeat hyperkalaemia. The committee noted that the marketing authorisation does not specify whether sodium zirconium cyclosilicate should be used to treat life-threatening hyperkalaemia needing emergency treatment, or persistent hyperkalaemia in outpatient care. The company proposed that sodium zirconium cyclosilicate would be used:\n\nIn emergency care, as an alternative to calcium resonium and permanently stopping RAAS inhibitors, in people with high levels of serum potassium who need immediate hospital treatment. It explained that sodium zirconium cyclosilicate would complement rather than replace the use of insulin and glucose in patients with life-threatening hyperkalaemia.\n\nAs an alternative to stopping RAAS inhibitors to manage chronic hyperkalaemia and to prevent life-threatening hyperkalaemia, in people with hyperkalaemia identified through routine monitoring. It explained that sodium zirconium cyclosilicate would complement rather than replace a low-potassium diet and may allow such a diet to be less strict (see section\xa03.5). It also explained that sodium zirconium cyclosilicate would be started in specialist care rather than in general practice.The committee concluded that it would appraise sodium zirconium cyclosilicate in the settings the company proposed, and that the comparators were both calcium resonium and managing RAAS inhibitors after emergency treatment, and managing RAAS inhibitors for chronic hyperkalaemia.\n\n# Clinical effectiveness\n\n## Trial evidence does not show whether sodium zirconium cyclosilicate is more clinically effective than NHS standard care\n\nThe clinical effectiveness evidence for sodium zirconium cyclosilicate came from the ZS004 and ZS005 trials. The trials were done in outpatient care. They included people who had lower serum potassium levels than would be treated in the NHS. In its consultation response, the company presented results for 8\xa0patients in ZS004 with serum potassium levels of 6.5\xa0mmol/litre and above, arguing that these patients would have emergency treatment in the NHS. However, the committee noted that these patients also had treatment as outpatients, so did not reflect patients who would have treatment in emergency care in the NHS. Both trials had 2\xa0phases. The first 'correction' phase was single arm (everyone had treatment to lower serum potassium; there was no control group) in patients with serum potassium levels of 5.1\xa0mmol/litre and above. The committee recognised that some of the response may have been related to regression to the mean. In response to the first consultation, the company presented data from a third trial, ZS003, which included a placebo-control arm in the 2‑day correction phase. The second phase of all 3\xa0trials measured how well sodium zirconium cyclosilicate maintained serum potassium levels in people whose serum potassium levels had responded in the correction phase and were between 3.5\xa0mmol/litre and 5.0\xa0mmol/litre. In ZS004, people whose serum potassium levels had responded were randomised to placebo or to continue sodium zirconium cyclosilicate for 28\xa0days. In ZS005, all people whose serum potassium levels had responded had sodium zirconium cyclosilicate for 52\xa0weeks. The committee appreciated that the primary outcome measure in all the trials was mean serum potassium level. The trials all showed that sodium zirconium cyclosilicate treatment reduced serum potassium level from baseline. The single-arm maintenance part of ZS005 measured changing use of RAAS inhibitors as an exploratory end point. However, the single-arm design of this trial meant that there were no data on whether sodium zirconium cyclosilicate, compared with standard care, allowed more patients to continue on RAAS inhibitors, a key potential benefit suggested by the company (see section\xa03.3). The committee concluded that the company had not provided any data comparing sodium zirconium cyclosilicate with current NHS treatments to correct hyperkalaemia and maintain normal serum potassium levels in outpatient care (that is, management of RAAS inhibitors). Without these data, it could not determine whether sodium zirconium cyclosilicate is more clinically effective than current standard care in the NHS for treating chronic hyperkalaemia.\n\n## Sodium zirconium cyclosilicate could be beneficial in treating acute life-threatening hyperkalaemia\n\nThe committee noted that acute hyperkalaemia can be fatal and treating acute life-threatening hyperkalaemia in hospital is established clinical practice. It agreed that lowering potassium levels for patients needing emergency care was a life-saving intervention. The committee therefore concluded that randomised evidence was not needed to show that treating life-threatening hyperkalaemia in emergency care prolonged life. As such, the uncontrolled evidence showing that sodium zirconium cyclosilicate reduces serum potassium (see section\xa03.8) was sufficient for the committee to conclude that it could be useful for people with hyperkalaemia needing treatment in emergency care.\n\n## There is no direct evidence that sodium zirconium cyclosilicate increases length or quality of life for people having treatment for chronic hyperkalaemia\n\nThe company did a post-hoc analysis of the subgroups of patients in ZS004 and ZS005 who had baseline serum potassium levels of 6.0\xa0mmol/litre and above. This is the threshold at which RAAS inhibitors are likely to be stopped and at which the company proposed sodium zirconium cyclosilicate would be used (see section\xa03.6). Most patients having sodium zirconium cyclosilicate had a serum potassium value of between 4.0\xa0mmol/litre and 6.0\xa0mmol/litre after the correction phase. For most of these patients, their serum potassium remained within these levels during the maintenance phase. The company also provided data from ZS003, which showed that patients having sodium zirconium cyclosilicate had stable serum potassium levels during the 12‑day maintenance period compared with small increases for patients on placebo. The committee noted:\n\nThe placebo in ZS003 did not reflect NHS practice (for example stopping RAAS inhibitors).\n\nIn ZS003 patients with serum potassium levels of above 5.0\xa0mmol/litre started treatment. Clinicians in the NHS would not typically offer treatment at this level (see section\xa03.1).\n\nSymptoms of hyperkalaemia may be similar to symptoms of the underlying condition, for example, heart failure. So, treating hyperkalaemia may not result in a noticeable effect on symptoms.\n\nZS005 was the longest trial, with follow up of 52\xa0weeks. The company provided no evidence for the effectiveness of sodium zirconium cyclosilicate beyond 52\xa0weeks. In its updated base case, the company assumed that patients would have the drug indefinitely (see section\xa03.14), an assumption 1\xa0clinical expert supported.\n\nThe company did not present any statistical tests for interaction by subgroup, so it was unknown whether patients with chronic kidney disease or heart failure derived greater benefit from sodium zirconium cyclosilicate.The committee was also aware that the company claimed that treatment with sodium zirconium cyclosilicate would prolong life and improve quality of life, but none of the trials showed this. The ERG and the consultation responses noted that the company could resolve this uncertainty with a clinical trial designed to report on outcomes such as mortality, disease progression and patterns of RAAS inhibitor use. The company indicated that it was not planning such a trial. The committee concluded that, although the trial results showed that continuing sodium zirconium cyclosilicate was associated with lower serum potassium than stopping the drug, there was no direct evidence that sodium zirconium cyclosilicate improves survival or quality of life over other treatments for people with chronic hyperkalaemia.\n\n## Sodium zirconium cyclosilicate is associated with adverse effects\n\nThe company presented data showing that treatment with sodium zirconium cyclosilicate was associated with hypokalaemia, that is low serum potassium. Hypokalaemia, like hyperkalaemia, is associated with life-threatening arrhythmias. The company explained that treating hyperkalaemia at 6.0\xa0mmol/litre and above was less likely to cause hypokalaemia than when treating it at lower levels. The committee concluded that sodium zirconium cyclosilicate is associated with adverse effects.\n\n## Stopping RAAS inhibitors likely increases the risk of death, hospitalisation and disease progression\n\nData were not collected in ZS003, ZS004 and ZS005 on the effect of sodium zirconium cyclosilicate on long-term outcomes such as progression of chronic kidney disease or mortality. However, the company proposed in its model that people with hyperkalaemia who have sodium zirconium cyclosilicate live longer and have a better quality of life than people who do not. This was because treatment with sodium zirconium cyclosilicate would allow them to maintain or restart treatment with RAAS inhibitors. The committee noted that the company provided only exploratory data from a single-arm trial (ZS005) of sodium zirconium cyclosilicate. This showed that most people on RAAS inhibitors continued to have the same dose and some people not on them at the start of the trial had started them by the end of the trial follow up. The committee recalled that there was no evidence showing that RAAS inhibitor dosing was different for people having sodium zirconium cyclosilicate than for people who didn't (see section\xa03.8). Independent of this, based on targeted reviews for chronic kidney disease and heart failure, the company presented data from a network meta-analysis of randomised controlled trials and several observational studies. The company assumed that, because these studies showed that starting a RAAS inhibitor is associated with living longer, people who stop a RAAS inhibitor would have shortened lives. The company also presented evidence that RAAS inhibitors are associated with delayed disease progression, and therefore improved quality of life. The committee recognised that the company's evidence addressed the decision problem indirectly. It noted that the trials in the company's literature search compared starting RAAS inhibitors with not starting them, rather than the question relevant to this appraisal, that is, reducing or stopping RAAS inhibitors compared with continuing them. In addition, sodium zirconium cyclosilicate may allow more people to remain on RAAS inhibitors. However, the reason for some people having high potassium levels may be a worsening of the underlying disease, and it is unclear whether the clinical benefit seen in the trials would translate fully. For example, the committee understood from the clinical expert and consultation responses that the benefits of RAAS inhibitors were well established for certain people, but their benefits were uncertain for others, for example, people close to needing kidney dialysis. It concluded that, in the population being considered, stopping RAAS inhibitors would generally be associated with an increased risk of adverse outcomes and disease progression. The committee was not satisfied that the company had presented robust data on how sodium zirconium cyclosilicate alters dosing of RAAS inhibitors compared with standard care, or the extent to which such alterations improved length and quality of life. However, the committee was also aware of NICE guidance recommending stopping RAAS inhibitors at serum potassium levels of 6.0\xa0mmol/litre and above (see section\xa03.3). It concluded that starting RAAS inhibitors prolongs life for many people, so stopping them for people who benefit from them would likely shorten life.\n\n## There is insufficient evidence to prove that lowering serum potassium levels improves long-term outcomes\n\nThe company also proposed in its model that lowering serum potassium with sodium zirconium cyclosilicate causes people to live longer. It based this on a review of evidence on the association between serum potassium and adverse outcomes for people with chronic kidney disease or heart failure. This evidence, from observational cohort studies, showed that a higher risk of death, hospitalisation and major adverse cardiovascular events was associated with high, but also with lower than normal, serum potassium levels. Using these data, the company assumed that, because people with higher than normal serum potassium have a higher risk of death, sodium zirconium cyclosilicate prolongs life because it lowers serum potassium. The committee noted that the observational data did not guarantee an independent causal effect between high serum potassium levels and death. Importantly, even if it did, the committee noted that the observational data did not provide evidence that lowering serum potassium extends life. The committee was aware that these studies could adjust only for known, measured confounders. It also noted that the authors of a company-supported observational study used in the model cautioned against assuming a causal effect, and acknowledged the possibility of residual confounding. At the third committee meeting, the company agreed that these observational data did not prove causality. The committee agreed that a relationship between lowering serum potassium to a normal range and fewer adverse outcomes was biologically plausible in certain clinical situations. The company did not provide interventional randomised evidence that lowering serum potassium prolongs life in chronic hyperkalaemia. The committee was aware that any association between serum potassium levels and mortality may have been influenced by time-dependent confounding. Specifically, patients with hyperkalaemia may have stopped having RAAS inhibitors, increasing the risk of death. The committee concluded that there was insufficient evidence to prove that lowering serum potassium levels for people in outpatient care improves outcomes.\n\n# Cost-effectiveness modelling\n\n## A patient-level simulation model is appropriate\n\nThe company modelled the cost effectiveness of sodium zirconium cyclosilicate using a patient-level simulation model. The model generated a serum potassium trajectory for each patient over time. The proportion of patients who entered the model on RAAS inhibitors was based on ZS005 (36% of people with chronic kidney disease and 70% of people with heart failure). Thereafter, RAAS inhibitor use was determined by the patient's serum potassium trajectory (as below). The company chose to model sodium zirconium cyclosilicate as prolonging life in 2\xa0ways: by level of serum potassium (in which treatment led to the full theoretical benefit seen in epidemiological studies) and by whether the patient was on a RAAS inhibitor (see section\xa03.12 and section\xa03.13). The company modelled 2\xa0settings:\n\nEmergency care: patients had sodium zirconium cyclosilicate after insulin−glucose for up to 28\xa0days. The company chose 28\xa0days based on the length of ZS004. The time horizon was 52\xa0weeks.\n\nOutpatient care: patients had sodium zirconium cyclosilicate for 28\xa0days if it was the first episode of hyperkalaemia or for a lifetime, if otherwise. The committee understood the company chose a lifetime duration of treatment because clinical experts stated that treatment would continue as long as there was evidence of clinical benefit (see section\xa03.10).The clinical experts noted that they may offer people sodium zirconium cyclosilicate only for a few days in emergency care, rather than 28\xa0days. The committee noted that the company's updated base case incorporated some, but not all, of its preferred assumptions, including:\n\nstarting treatment with sodium zirconium cyclosilicate at serum potassium values of 6.0\xa0mmol/litre and above for both chronic kidney disease and heart failure\n\ncomparative data for standard care during the correction phase (from ZS003, see section\xa03.8)\n\nmodelling a reduction in serum potassium level when patients stop or reduce their dose of RAAS inhibitors\n\n% of patients with a serum potassium level between 5.5\xa0mmol/litre and 6.0\xa0mmol/litre reduce their dose of RAAS inhibitors and 20% stop them\n\nall patients with a serum potassium level above 6.0\xa0mmol/litre stop RAAS inhibitors for 12\xa0weeks, after which around 50% of people restart them.The committee concluded that a patient-simulation model was appropriate for decision making.\n\n## The company's approach to modelling the association between RAAS inhibitor use and outcomes is appropriate, but the data are inadequate\n\nThe company modelled an association between use of RAAS inhibitors and the risks of mortality, hospitalisation and major adverse cardiovascular events. This was based on odds ratios from a network meta-analysis of clinical trials of starting RAAS inhibitors (Xie et al. 2016). The committee recalled and accepted evidence from the clinical and patient experts that maintaining RAAS inhibitor therapy is likely to be beneficial for certain patients (see section\xa03.12). It noted that the company did scenario analyses using alternative data sources and assuming that RAAS inhibitor use had no effect on outcomes. The committee did not see robust evidence of the effect of sodium zirconium cyclosilicate on RAAS inhibitor use. However, it was aware that clinicians are encouraged to stop RAAS inhibitor treatment in people with serum potassium levels of 6.0\xa0mmol/litre and above. The committee concluded that the company's approach to modelling the association between RAAS inhibitor use and outcomes was appropriate.\n\n## It is appropriate to consider the company's scenario removing the association between serum potassium levels and outcomes\n\nIn its base case, the company modelled an association between serum potassium levels and the risks of mortality, hospitalisation and major adverse cardiovascular events using observational studies. The committee recalled that the observational studies supporting this assumption did not establish that lowering serum potassium improved outcomes. Also, it was aware that the underlying causes of hyperkalaemia may have led to poor outcomes rather than the hyperkalaemia itself. Importantly, it had not been presented with evidence that lowering serum potassium in chronic hyperkalaemia prolongs life. The committee concluded that it was not appropriate to assume that lowering serum potassium prolongs life in people with chronic hyperkalaemia, based only on observational studies relating a surrogate end point to adverse outcomes. The committee also noted that any association between serum potassium level and mortality may have been partially captured in the model. This is because patients in the model with a lower serum potassium level are more likely to be having RAAS inhibitors, and therefore have a decreased risk of death (see section\xa03.15). The company provided additional scenario analyses reducing the strength of the association from the observational evidence or removing it entirely. The committee concluded that it was appropriate to use the scenario analysis removing the association between serum potassium and adverse outcomes in its decision making.\n\n# Cost-effectiveness estimates\n\n## Sodium zirconium cyclosilicate alongside standard care is recommended as an option for people who need emergency treatment of hyperkalaemia\n\nThe committee considered the cost-effectiveness results in emergency care. It recalled that it did not need randomised evidence to show that treating hyperkalaemia in emergency care prolonged life, and that such treatment was standard clinical practice (see section\xa03.9). The committee was aware that acute hyperkalaemia can be fatal. It agreed that sodium zirconium cyclosilicate reduced serum potassium levels quickly so was a suitable treatment option in emergency care after standard treatments including insulin and glucose (see section\xa03.2). It recalled that the company had positioned sodium zirconium cyclosilicate to be used alongside standard care for the treatment of life-threatening acute hyperkalaemia (see section\xa03.7). The committee noted that the drug was associated with lower costs and improved quality of life in both the company's and ERG's base cases and all scenario analyses. It recalled that there was some uncertainty about the results because there was limited clinical evidence of sodium zirconium cyclosilicate's use in emergency care (see section\xa03.8). Also, the gain in quality-adjusted life years (QALYs) was very small. It also recalled that the model used a short time horizon for this analysis so any long-term benefits of sodium zirconium cyclosilicate (such as enabling patients to restart RAAS inhibitors) may have been underestimated. The committee agreed that people with life-threatening hyperkalaemia would value the option of another treatment to lower serum potassium levels that was better tolerated than calcium resonium (see section\xa03.2). It therefore concluded that it could recommend sodium zirconium cyclosilicate alongside standard care as an option for people needing treatment for acute hyperkalaemia in emergency care.\n\n## Sodium zirconium cyclosilicate is recommended as a treatment option for chronic hyperkalaemia\n\nThe committee then considered the cost-effectiveness results for chronic hyperkalaemia. The company's revised base-case incremental cost-effectiveness ratios (ICERs) were less than £20,000 per QALY gained compared with standard care for people with hyperkalaemia who have either chronic kidney disease or heart failure. The exact ICERs cannot be reported here because they are considered confidential by the company. The committee noted that the company's base case included an association between serum potassium levels and mortality, which the committee did not accept (see section\xa03.16). However, in the scenario removing this association, the ICERs were also below £20,000 per QALY gained. Therefore, the committee concluded that sodium zirconium cyclosilicate was a cost-effective use of NHS resources for treating chronic hyperkalaemia. The committee noted that, in this scenario, most of the benefits arise because more people are able to have RAAS inhibitors with sodium zirconium cyclosilicate. However, it recalled that some people do not benefit from RAAS inhibitors (see section\xa03.4), and so concluded that it would not be appropriate for these people to start sodium zirconium cyclosilicate. It further concluded that some people may have to stop RAAS inhibitors for reasons other than hyperkalaemia. The committee concluded that, in these situations, people should also stop having sodium zirconium cyclosilicate. It emphasised that uncertainties remained around the clinical benefit of sodium zirconium cyclosilicate and that these could be addressed by clinical trials (see section\xa05.1).\n\n# Innovation\n\n## The company did not show that sodium zirconium cyclosilicate is innovative\n\nThe company proposed several benefits of sodium zirconium cyclosilicate, including preventing the need to modify RAAS inhibitor treatment and avoiding a restrictive low-potassium diet, but did not show evidence of these benefits. The committee was aware that other gastrointestinal potassium binders exist, and, although these are not well tolerated, sodium zirconium cyclosilicate does not represent a step-change in treatment. The committee concluded that sodium zirconium cyclosilicate could not be considered innovative.", 'Recommendations for research': 'The committee noted that there was no clinical evidence showing that having sodium zirconium cyclosilicate improved length or quality of life or allowed patients to stay on optimal doses of renin-angiotensin-aldosterone system (RAAS) inhibitors. It therefore considered that it would be valuable to have studies comparing sodium zirconium cyclosilicate plus standard care with standard care alone in people with confirmed hyperkalaemia of 6.0\xa0mmol/litre and above, and that these should investigate:\n\nmortality\n\ndisease progression\n\npatterns of RAAS inhibitor use\n\nhealthcare utilisation, and\n\nhealth-related quality of life.'}
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https://www.nice.org.uk/guidance/ta599
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Evidence-based recommendations on sodium zirconium cyclosilicate (Lokelma) for treating hyperkalaemia in adults.
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8907197896abea85ba10ffe3d4e6288326a498cd
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nice
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Osimertinib for adjuvant treatment of EGFR mutation-positive non-small-cell lung cancer after complete tumour resection
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Osimertinib for adjuvant treatment of EGFR mutation-positive non-small-cell lung cancer after complete tumour resection
Evidence-based recommendations on osimertinib (Tagrisso) for adjuvant treatment of EGFR mutation‑positive non‑small‑cell lung cancer in adults after complete tumour resection.
# Recommendations
Osimertinib is recommended for use within the Cancer Drugs Fund as adjuvant treatment after complete tumour resection in adults with stage 1b to 3a non‑small‑cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations. It is recommended only if:
-simertinib is stopped at 3 years, or earlier if there is disease recurrence or unacceptable toxicity and
the company provides osimertinib according to the managed access agreement.
This recommendation is not intended to affect treatment with osimertinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
There are currently no targeted adjuvant treatments (including those specific to EGFR mutations) available in England for NSCLC after complete tumour resection.
Current clinical trial evidence shows that compared with active monitoring, treatment with osimertinib reduces the risk of the disease coming back. It may also lower the risk of death. However, this evidence is uncertain because information from the trial was released early and the data is still immature.
Because of this, the cost‑effectiveness estimates for osimertinib are also uncertain. It has the potential to be cost effective, but more evidence is needed to address these uncertainties before it can be recommended for routine use.
Because more data is being collected that addresses these uncertainties, osimertinib is recommended for use in the Cancer Drugs Fund.# Information about osimertinib
# Marketing authorisation indication
Osimertinib (Tagrisso, AstraZeneca) is indicated for 'adjuvant treatment after complete tumour resection in adult patients with stage 1b to 3a non‑small‑cell lung cancer whose tumours have epidermal growth factor receptor exon 19 deletions or exon 21 (L858R) substitution mutations'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for thirty 80 mg tablets is £5,770 (BNF online, accessed July 2021).
The company has a commercial arrangement. This makes osimertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
# New treatment option
## Patients and their families would welcome new effective treatments that reduce the risk of recurrence
Surgical removal of tumours is the preferred treatment for many people with early‑stage non‑small‑cell lung cancer (NSCLC) because it is potentially a cure. But despite the curative intent of complete resection, the disease recurs within about 5 years of surgery in 45% of patients with stage 1b, 62% with stage 2, and 76% with stage 3 disease. In the UK, around 13% of people with stage 1b NSCLC and up to about 50% of people with stage 3a NSCLC have adjuvant chemotherapy after resection. Because it provides only a relatively small benefit in overall and disease‑free survival compared with no chemotherapy over 5 years, many people decline adjuvant therapy. The patient experts explained that people with fully resected stage 1b to 3a epidermal growth factor receptor (EGFR) mutation‑positive NSCLC would welcome new effective adjuvant treatments that reduce the risk of recurrence. They highlighted that people with EGFR mutation‑positive NSCLC tended to be younger than people with other types of NSCLC, so having a treatment option that delays or prevents recurrence or central nervous system (CNS) metastases is important. Being disease free allows people to spend more time working or with their families. Patient experts stated that osimertinib is also better tolerated than other tyrosine kinase inhibitors (TKIs). The committee concluded that patients and their families would welcome new, effective treatments that reduce the risk of recurrence.
# Treatment pathway
## Osimertinib is an oral treatment in a new place in the pathway
The only treatment currently available in England as adjuvant therapy for NSCLC (including for EGFR mutations) after complete resection is adjuvant chemotherapy, which provides a small benefit in overall survival. Treatment options for people with resectable EGFR mutation‑positive NSCLC are therefore only those that are generally available and are non‑targeted. The clinical and patient experts explained that osimertinib is well tolerated with manageable side effects. The patient experts explained that having an oral option would be welcomed because it would not require a visit to hospital. The committee acknowledged that positioning osimertinib as an adjuvant treatment may address an unmet need for people who have had a resection. It concluded that osimertinib is an oral treatment in a new place in the pathway.
## Retreatment with osimertinib would be offered to some people whose disease has progressed
The company assumed that everyone who develops distant metastases within 5 years of starting adjuvant osimertinib treatment would have pemetrexed plus cisplatin followed by docetaxel. It assumed that after this 5-year timepoint, 50% of people who develop distant metastases would have retreatment with osimertinib as first-line therapy (see NICE's technology appraisal guidance on osimertinib for untreated EGFR mutation-positive NSCLC) followed by pemetrexed plus cisplatin, with the remaining 50% having pemetrexed plus cisplatin followed by docetaxel. The ERG explained that in its base case, it had included atezolizumab, bevacizumab, carboplatin and paclitaxel as a second-line treatment in both groups and that it had excluded retreatment with osimertinib in the adjuvant osimertinib group. The clinical experts suggested that people are likely to have chemotherapy or atezolizumab, bevacizumab, carboplatin and paclitaxel if their disease progresses during treatment with osimertinib, while osimertinib would be offered to people whose disease progresses after adjuvant treatment with osimertinib. The Cancer Drugs Fund clinical lead agreed that if disease relapsed after treatment with osimertinib stopped, then retreatment would be commissioned in the NHS. They explained that this would depend on the time since finishing osimertinib and the onset of metastatic disease. If this time gap was short then there may not be much benefit, but they noted that the time gap would not need to be as long as that assumed by the company (at least 2 years, depending on when adjuvant osimertinib is taken). The Cancer Drugs Fund clinical lead also said that atezolizumab, bevacizumab, carboplatin and paclitaxel would be offered first-line if treatment with TKIs is inappropriate. The committee was concerned that the 50% split used in the company model is arbitrary. After consultation, the company provided additional sensitivity analyses where the proportion of people who had retreatment with osimertinib was varied between 40% to 60%. The committee noted that although the proportion of people having retreatment with osimertinib remained uncertain, it made no significant difference to the cost‑effectiveness estimates since the cure timepoint used in the company's model coincided with when retreatment is allowed. The committee concluded that retreatment with osimertinib would be offered to some people whose disease had progressed after having osimertinib as an adjuvant treatment.
# Clinical evidence
## The clinical evidence for osimertinib is from ADAURA, a phase 3, randomised, placebo-controlled trial
The clinical‑effectiveness evidence for osimertinib is based on the ADAURA randomised controlled trial. This is a phase 3 randomised, double‑blind, placebo-controlled, multicentre trial in adults with completely resected stage 1b to 3a NSCLC (stratified by tumour stage, race and EGFR status). ADAURA compared adjuvant osimertinib 80 mg (n=339) with placebo (n=343) over a follow‑up period of 12 and 24 weeks. Some people in both arms of the trial also had adjuvant chemotherapy. The planned treatment duration was 3 years. However, the trial results were released 2 years early after determination of overwhelming efficacy with osimertinib. In the overall trial population, treatment with osimertinib resulted in significantly longer disease‑free survival, with a lower risk of disease recurrence (hazard ratio: 0.20; 99.12% confidence intervals: 0.14 to 0.30; p<0.001). However, the disease‑free survival data is immature and there have been very few events from which to calculate overall survival.
## It is not certain to what extent a benefit in disease-free survival translates into a benefit in overall survival
Because results of the ADAURA trial have been released 2 years early, overall survival data is immature. The company explained that even though overall survival data from ADAURA is very immature, adjuvant osimertinib is expected to have a long‑term survival benefit. This is because of the size of the disease-free survival benefit, a significant reduction in CNS metastases, and a consistent overall survival benefit when it is used to treat metastatic disease. Both the ERG and clinical experts agreed that disease‑free survival is a clinically relevant end point. The clinical experts also emphasised the important benefits of a reduction in CNS metastases. However, the ERG explained that because of the immaturity of the overall survival data from ADAURA, the size of any potential overall survival benefit is uncertain. The committee acknowledged that uncertainty remains around the extent to which adjuvant osimertinib prevents disease recurrence compared with delaying disease recurrence. Very few patients had reached 3 years of treatment with osimertinib and data on recurrence after stopping treatment was not presented. Therefore, it is uncertain what will happen after stopping treatment. The committee was also aware of recent publications by Gyawali (2021) and Uprety (2021), which noted that other adjuvant TKIs showed disease‑free survival benefits that have not translated to an overall survival benefit. The committee was concerned that the experience with earlier generation TKIs such as erlotinib suggested that disease often recurred after stopping treatment. However, a clinical expert cautioned against placing too much weight on this because erlotinib does not have the same brain penetration as osimertinib. In response to consultation, the company stated that the comparison to earlier TKI data in the adjuvant setting was not appropriate. It noted that the benefits of osimertinib, particularly around reducing CNS metastases, were greater than with the earlier TKIs. However, the committee noted there is currently no evidence to show that after stopping treatment with osimertinib, the hazards, and therefore the hazard ratios, for disease‑free survival do not increase (as with the other TKIs). Therefore, the committee reiterated its concern over the immaturity of the disease‑free survival and overall survival data as well as the uncertainty around the extent to which disease‑free survival can accurately predict overall survival. The committee concluded that it was not certain to what extent a benefit in disease‑free survival translates into a benefit in overall survival.
# The company's economic model
## The company's model structure is acceptable for decision making, but more formal statistical modelling of cure may address some uncertainty
The company used a state transition, semi‑Markov model with 5 health states: disease free, loco-regional recurrence, first‑line treatment for distant metastases, second‑line treatment for distant metastases, and dead. In the company's model, retreatment with osimertinib for distant metastases is assumed for 50% of people, with the remaining 50% having pemetrexed plus cisplatin. The committee recalled that chemotherapy or atezolizumab, bevacizumab, carboplatin and paclitaxel would be offered to people whose disease had progressed during treatment with osimertinib. Retreatment with osimertinib would be offered to people whose disease had progressed after adjuvant treatment with osimertinib (see section 3.3). In its model, the company had also assumed that 100% of people in the active monitoring arm have osimertinib as their first treatment for metastatic disease (see section 3.10). The ERG explained that the company's model therefore did not reflect the expected treatment pathway. After consultation, the company did additional scenario analyses:
including proportions of 80% and 90% to represent people in the active monitoring arm having osimertinib as their first treatment for metastatic disease
varying the proportion of people who have retreatment with osimertinib (40%, 50% and 60%).The committee noted that these additional scenario analyses done by the company may address some concerns around the company's economic model not reflecting the treatment pathway. The company's model also included a structural cure assumption (see section 3.8). The ERG noted that the cure timepoint used in the company's model coincided with when retreatment is allowed, the latter meant that this has little impact on the incremental cost-effectiveness ratio (ICER). The proportion of people relapsing in the model is also uncertain. The company explained that this proportion varied between its clinical experts. The ERG noted that it would have preferred to have seen formal statistical modelling of cure (for example, using a mixture‑cure model). The company stated that it had attempted to fit the trial data to a mixture‑cure model, but the data was too immature and gave highly uncertain results. The committee concluded that the company's model structure is acceptable for decision making, but more formal statistical modelling of cure may address some uncertainty.
## Including a 3-year stopping rule is acceptable but the effect of stopping treatment at 3 years is uncertain
The company included a 3‑year treatment stopping rule in its model. This is based on the trial design of ADAURA, where the maximum possible treatment duration was 3 years. It is also stated in the summary of product characteristics that treatment for more than 3 years was not studied. The clinical experts said that adjuvant treatment could not be indefinite and that the 3‑year time period is appropriate. However, the patient experts said they would prefer to continue treatment beyond 3 years if the disease had not progressed. They explained that some people would find stopping treatment difficult because they would fear the disease coming back. The committee noted that in ADAURA, 12% of patients in the intervention arm and 10% in the active monitoring arm had reached 3 years of treatment. The committee concluded that a 3‑year treatment stopping rule, in line with the clinical and cost-effectiveness evidence, was acceptable but the impact of stopping treatment at 3 years is uncertain.
# Modelling survival and cure assumptions
## Other approaches to modelling overall survival may be plausible
The predicted overall survival gain is a function of all transitions included in the model (see section 3.6), most of which are informed by external data and the company's structural cure assumption (a reduction in risk by 95% for people without disease recurrence at 5 years in both arms). The company's choice of survival models was based on a visual inspection of the combined disease‑free survival and overall survival curves, with input from its clinical experts. In line with advice in the NICE Decision Support Unit Technical Support Document 14, the company applied the same parametric curves across both treatment arms. For the transition from disease free to loco‑regional recurrence, the company applied log‑normal curves, whereas generalised gamma curves were applied for the transition from disease free to distant metastatic NSCLC. The committee was aware that disease‑free survival was a key driver of the company's economic model. It was concerned that most of the disease‑free and overall survival benefits were gained during the extrapolated period, so the choice of extrapolation has a significant effect on the results. For the transition from disease free to distant metastases, the generalised gamma chosen by the company had the best statistical fit for the placebo arm. However, the log‑normal had the best fit for the osimertinib arm. The ERG explained that because of the cure assumption, the choice of extrapolation has little effect beyond the cure timepoint. So, in this situation it is appropriate to give more weight to the statistical fit to the observed data. The ERG did additional sensitivity analyses in which it applied alternative parametric survival models to represent the transition from disease free to distant metastatic NSCLC. These used a log‑normal distribution in:
both arms of the model
the treatment arm of the model only.In response to consultation, the company suggested that these analyses were inappropriate, because the curves cross. However, the ERG explained that this was not the case for disease‑free survival overall, when the cure assumption is factored in. The committee considered that the log‑normal distribution was as plausible as the generalised gamma. Usually, it is appropriate to use the same distribution for both arms. However, given the cure assumption and stopping of treatment with osimertinib, the committee considered that it was possible that there might be a different profile of hazards between the 2 arms. The committee concluded that other approaches to modelling overall survival may be plausible and it would consider these in its decision making.
## There is uncertainty about the company's cure assumptions
The company originally applied a 5‑year cure timepoint in its modelling based on information from its clinical experts. Clinical expert advice to the ERG was that, for the active monitoring arm of the model, a 5‑year cure timepoint may be appropriate, but a potential cure timepoint for the intervention arm is uncertain. The ERG did exploratory analyses to assess the effect of changing the timepoint at which the cure assumption is applied in the company's economic model. The ERG's optimistic analysis retained the company's original approach, whereas the pessimistic analysis applied a later timepoint for cure in the adjuvant osimertinib group of 8 years (5‑year cure timepoint in the active monitoring group plus the 3‑year osimertinib treatment period). In response to technical engagement, the company proposed a 6‑year cure timepoint, which was supported by its clinical experts. The committee was aware that the maximum follow‑up period in ADAURA was 4 years, so the company's cure assumption was uncertain. Very few patients had reached 3 years of treatment with osimertinib so it is also uncertain what will happen after stopping treatment. The committee was concerned that osimertinib may only delay rather than prevent recurrence. Taking into account that there was no data on people who have stopped osimertinib treatment, and the evidence from other TKIs used as adjuvant treatment (see section 3.5), the committee noted that the ERG's pessimistic analysis may also be plausible. After consultation, the company did a scenario analysis where the cure assumption was removed. The ERG explained that this analysis may not be meaningful because it applies parametric survival models, which do not explicitly allow for the potential of cure, to a population in whom cure is expected for a proportion of people. The committee concluded that there was significant uncertainty about the company's cure assumptions, and it would consider both of the ERG's approaches in its decision making.
## It is not appropriate to assume 100% of people in the active monitoring arm have osimertinib as their first treatment for metastatic disease
NICE recently recommended osimertinib for untreated EGFR mutation-positive NSCLC for metastatic disease. The company base case assumes that 100% of people in the active monitoring arm will have osimertinib as their first treatment for metastatic disease. The committee recognised that people in the ADAURA trial are being actively monitored and disease may be identified at an earlier stage of progression than in current practice. Therefore, more people could be fit enough to have treatment, so outcomes in advanced disease could be better than seen in the FLAURA (a randomised double blind, phase 3 controlled trial comparing osimertinib with erlotinib or gefitinib for the first-line treatment of EGFR mutation-positive advanced NSCLC) trial data. The ERG presented a scenario analysis using a different mix of TKIs. This was based on the latest TKI prescribing data as presented by the company. The committee considered that the proportion of people having osimertinib is likely to increase over time but may not reach 100%. After consultation, the company provided additional sensitivity analyses where 80% to 90% of people in the active monitoring arm had osimertinib as their first treatment for metastatic disease. It noted that the latest prescribing data shows this figure to be around 80%. The committee concluded that it was appropriate to base its decision making on the latest available prescribing data and that 80% was therefore appropriate to use in the analyses.
# Health-related quality of life
## The company's utility values are acceptable for decision making
The company included utility values based on EQ-5D-3L estimates from ADAURA, EQ‑5D‑3L estimates from FLAURA and published EQ‑5D‑3L estimates from the literature (Labbé et al. 2017). Disutilities associated with adverse events were based on published literature (Nafees et al. 2008, standard gamble) and on a previous appraisal of osimertinib used second line for metastatic disease (see NICE's guidance on osimertinib for EGFR T790M mutation-positive advanced NSCLC). The ERG was concerned that the utility values applied in the disease free, loco‑regional recurrence and distant metastatic NSCLC health states may be implausibly high compared with the general population. The ERG was also concerned that the model does not include health‑related quality of life decrements for late effects of adjuvant treatment or downstream adverse events. However, it suggested that although the utility values may have been overestimated, they did not necessarily favour osimertinib. The ERG explained that it did an additional sensitivity analysis using utility values from a study by Andreas et al. (2018). This had a limited effect on the cost-effectiveness estimates. The committee concluded that the company's utility values were acceptable for decision making.
# Cost-effectiveness estimate
## The most plausible ICERs for osimertinib are highly uncertain
Because of confidential discounts for subsequent therapies, the cost‑effectiveness results are commercial in confidence and cannot be reported here. However, the company's base case including all discounts was less than £20,000 per quality‑adjusted life year (QALY) gained. The ERG made several changes to the company's base case and presented 2 analyses. The first was based on a 5‑year cure point in both arms and produced a similar ICER to the company's base case. The second was based on an 8‑year cure point in the osimertinib arm and produced an ICER greater than £20,000 per QALY gained. At the second committee meeting, the committee considered several modelling assumptions plausible:
The ERG's optimistic base case, which included a cure point at 5 years for the osimertinib group and 5 years for the active monitoring group.
The ERG's pessimistic base case, which included a cure point at 8 years for the osimertinib group and 5 years for the active monitoring group.
Assuming 80% of people in the active monitoring arm have osimertinib as their first treatment for metastatic disease.
Alternative plausible modelling assumptions for the transition from the disease free to distant metastatic NSCLC health states using a log‑normal distribution in:
both arms of the model
the treatment arm of the model only.
Including retreatment with osimertinib after recurrence in the intervention arm of the model (using proportions of 40%, 50% and 60%).Combining any of these assumptions with the ERG's optimistic base case resulted in ICERs of below £20,000 per QALY gained. However, combining them with the ERG's pessimistic base case resulted in ICERs above £30,000 per QALY gained. Combining the ERG's pessimistic base case, 80% osimertinib treatment for first‑line distant metastases and the log‑normal extrapolation for the transition from the disease free to distant metastases in the treatment arm only increased the ICER substantially above £30,000 per QALY gained. Using these preferred assumptions, the committee considered that the most plausible ICERs for osimertinib were in the range of less than £20,000 per QALY gained to more than £30,000 per QALY gained. The committee concluded that the upper end of the most plausible ICER range may not be within the range usually considered a cost‑effective use of resources.
## Osimertinib is not recommended for routine use in the NHS
Because results from ADAURA were released 2 years early, the disease‑free survival and overall survival data for osimertinib is immature. After considering the uncertainty with the clinical evidence along with its preferred assumptions, the committee considered that the upper end of the most plausible ICER range may not be within the range usually considered a cost‑effective use of resources. The committee concluded it could not recommend osimertinib for the adjuvant treatment of stage 1b to 3a NSCLC after complete resection in adults whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations for routine use in the NHS.
## Osimertinib is recommended for use in the Cancer Drugs Fund
Having concluded that osimertinib could not be recommended for routine use, the committee then considered if it could be recommended for treating stage 1b to 3a NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee acknowledged that the disease-free survival and overall survival data from ADAURA was not mature and that further data collection may help address uncertainty. After consultation, the company stated that it would welcome a recommendation in the Cancer Drugs Fund if the committee recognised plausible uncertainties that would result in ICERs higher than what NICE normally considers a cost‑effective use of NHS resources. The committee was aware that, although a period of time in the Cancer Drugs Fund may not produce enough mature overall survival data for a robust mixture‑cure model, there would still be benefits:
the disease‑free survival data will be more mature
there will be a better understanding of the impact of the 3‑year stopping rule
more data will be available to estimate the extent of the cure proportion.The committee acknowledged that osimertinib has plausible potential to be cost effective. It understood that there is uncertainty around the cure time point, if osimertinib will prevent or only delay disease recurrence, the proportion of patients that would have retreatment with osimertinib, if the benefit in disease‑free survival will translate into a benefit in overall survival and if the log‑normal or generalised gamma distribution should be used to extrapolate the transition from disease free to distant metastases. If the cure time point was earlier than 8 years, then osimertinib may represent a cost‑effective use of NHS resources, depending on the trajectory of disease-free survival. The Cancer Drugs Fund clinical lead indicated that they would welcome collecting data on osimertinib through the Cancer Drugs Fund. The committee concluded that osimertinib could be recommended for use in the Cancer Drugs Fund. It noted that when the guidance is reviewed, the company should consider using formal statistical modelling of cure (for example a mixture‑cure model) if the data allows (see section 3.6).
# Innovation
## Osimertinib is recognised as an innovative therapy in the adjuvant setting
The company said that osimertinib is innovative because there has been little innovation in adjuvant treatment for stage 1b to 3a EGFR mutation-positive NSCLC, aside from adjuvant chemotherapy, in 20 years. Osimertinib has been reviewed as part of Project Orbis because it is considered an innovative adjuvant treatment. In response to consultation, the company stated that not all additional benefits associated with osimertinib had been captured in the economic analysis. In particular, the company highlighted the effect osimertinib has on reducing CNS metastases. It stated that a utility decrement had not been applied in the modelling for people whose quality of life had declined because of CNS metastases. It therefore suggested that the ICERs were a conservative estimate. The ERG stated that it did not accept that any relevant aspects of the value of adjuvant osimertinib had clearly been omitted from the company's economic analyses. The committee recognised osimertinib as an innovative therapy in the adjuvant setting but concluded that it did not consider there were any additional benefits associated with osimertinib that had not been captured in the economic analysis.
# Equality
## EGFR mutation-positive NSCLC is more common in women and people with a Chinese family background
The clinical experts explained that EGFR mutation‑positive NSCLC tends to be more common in women and people with a Chinese family background. The committee noted that the issue of different disease prevalence cannot be addressed in a technology appraisal.
# Other factors
## Less common EGFR mutations were not considered
The only EGFR mutations considered within the scope of this appraisal are EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. This is in line with osimertinib's current marketing authorisation. The Cancer Drugs Fund clinical lead explained that if NICE recommends osimertinib for these mutations, NHS England would consider commissioning adjuvant osimertinib treatment for other less common EGFR mutations. The committee noted that NICE can only appraise a medicine within its marketing authorisation and welcomed the comments from the Cancer Drugs Fund clinical lead.
## The end of life criteria are not met
The company did not make a case for osimertinib meeting NICE's end of life criteria. NICE's advice about life‑extending treatments for people with a short life expectancy did not apply.
# Conclusion
The committee recognises that osimertinib is a promising new treatment option. However, there is not enough clinical- and cost‑effectiveness evidence to recommend it for routine use in the NHS. Therefore osimertinib is recommended for use in the Cancer Drugs Fund as an adjuvant treatment of stage 1b to 3a NSCLC after complete tumour resection, in adults whose tumours have EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. The committee recognised that the ADAURA trial used the Union for International Cancer Control (UICC) TNM 7th edition lung cancer staging criteria and that this evidence underpinned the marketing authorisation. It was aware that these criteria had been recently updated and that the 8th edition is also now used in NHS clinical practice. It understood from the Cancer Drugs Fund clinical lead that the population as per 7th edition (stages 1b to 3a – as specified in the marketing authorisation) corresponds to stages 1b to N2 only stage 3b in the 8th edition. It also understood that the Cancer Drugs Fund would ensure patient access in accordance with this translation from the 7th to the 8th edition lung cancer staging criteria.
|
{'Recommendations': 'Osimertinib is recommended for use within the Cancer Drugs Fund as adjuvant treatment after complete tumour resection in adults with stage\xa01b to\xa03a non‑small‑cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor (EGFR) exon\xa019 deletions or exon\xa021 (L858R) substitution mutations. It is recommended only if:\n\nosimertinib is stopped at 3\xa0years, or earlier if there is disease recurrence or unacceptable toxicity and\n\nthe company provides osimertinib according to the managed access agreement.\n\nThis recommendation is not intended to affect treatment with osimertinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nThere are currently no targeted adjuvant treatments (including those specific to EGFR mutations) available in England for NSCLC after complete tumour resection.\n\nCurrent clinical trial evidence shows that compared with active monitoring, treatment with osimertinib reduces the risk of the disease coming back. It may also lower the risk of death. However, this evidence is uncertain because information from the trial was released early and the data is still immature.\n\nBecause of this, the cost‑effectiveness estimates for osimertinib are also uncertain. It has the potential to be cost effective, but more evidence is needed to address these uncertainties before it can be recommended for routine use.\n\nBecause more data is being collected that addresses these uncertainties, osimertinib is recommended for use in the Cancer Drugs Fund.', 'Information about osimertinib': "# Marketing authorisation indication\n\nOsimertinib (Tagrisso, AstraZeneca) is indicated for 'adjuvant treatment after complete tumour resection in adult patients with stage\xa01b to\xa03a non‑small‑cell lung cancer whose tumours have epidermal growth factor receptor exon\xa019 deletions or exon\xa021 (L858R) substitution mutations'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for thirty 80\xa0mg tablets is £5,770 (BNF online, accessed July\xa02021).\n\nThe company has a commercial arrangement. This makes osimertinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AstraZeneca, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## Patients and their families would welcome new effective treatments that reduce the risk of recurrence\n\nSurgical removal of tumours is the preferred treatment for many people with early‑stage non‑small‑cell lung cancer (NSCLC) because it is potentially a cure. But despite the curative intent of complete resection, the disease recurs within about 5\xa0years of surgery in 45% of patients with stage\xa01b, 62% with stage\xa02, and 76% with stage\xa03 disease. In the UK, around 13% of people with stage\xa01b NSCLC and up to about 50% of people with stage\xa03a NSCLC have adjuvant chemotherapy after resection. Because it provides only a relatively small benefit in overall and disease‑free survival compared with no chemotherapy over 5\xa0years, many people decline adjuvant therapy. The patient experts explained that people with fully resected stage\xa01b to\xa03a epidermal growth factor receptor (EGFR) mutation‑positive NSCLC would welcome new effective adjuvant treatments that reduce the risk of recurrence. They highlighted that people with EGFR mutation‑positive NSCLC tended to be younger than people with other types of NSCLC, so having a treatment option that delays or prevents recurrence or central nervous system (CNS) metastases is important. Being disease free allows people to spend more time working or with their families. Patient experts stated that osimertinib is also better tolerated than other tyrosine kinase inhibitors (TKIs). The committee concluded that patients and their families would welcome new, effective treatments that reduce the risk of recurrence.\n\n# Treatment pathway\n\n## Osimertinib is an oral treatment in a new place in the pathway\n\nThe only treatment currently available in England as adjuvant therapy for NSCLC (including for EGFR mutations) after complete resection is adjuvant chemotherapy, which provides a small benefit in overall survival. Treatment options for people with resectable EGFR mutation‑positive NSCLC are therefore only those that are generally available and are non‑targeted. The clinical and patient experts explained that osimertinib is well tolerated with manageable side effects. The patient experts explained that having an oral option would be welcomed because it would not require a visit to hospital. The committee acknowledged that positioning osimertinib as an adjuvant treatment may address an unmet need for people who have had a resection. It concluded that osimertinib is an oral treatment in a new place in the pathway.\n\n## Retreatment with osimertinib would be offered to some people whose disease has progressed\n\nThe company assumed that everyone who develops distant metastases within 5\xa0years of starting adjuvant osimertinib treatment would have pemetrexed plus cisplatin followed by docetaxel. It assumed that after this 5-year timepoint, 50% of people who develop distant metastases would have retreatment with osimertinib as first-line therapy (see NICE's technology appraisal guidance on osimertinib for untreated EGFR mutation-positive NSCLC) followed by pemetrexed plus cisplatin, with the remaining 50% having pemetrexed plus cisplatin followed by docetaxel. The ERG explained that in its base case, it had included atezolizumab, bevacizumab, carboplatin and paclitaxel as a second-line treatment in both groups and that it had excluded retreatment with osimertinib in the adjuvant osimertinib group. The clinical experts suggested that people are likely to have chemotherapy or atezolizumab, bevacizumab, carboplatin and paclitaxel if their disease progresses during treatment with osimertinib, while osimertinib would be offered to people whose disease progresses after adjuvant treatment with osimertinib. The Cancer Drugs Fund clinical lead agreed that if disease relapsed after treatment with osimertinib stopped, then retreatment would be commissioned in the NHS. They explained that this would depend on the time since finishing osimertinib and the onset of metastatic disease. If this time gap was short then there may not be much benefit, but they noted that the time gap would not need to be as long as that assumed by the company (at least 2\xa0years, depending on when adjuvant osimertinib is taken). The Cancer Drugs Fund clinical lead also said that atezolizumab, bevacizumab, carboplatin and paclitaxel would be offered first-line if treatment with TKIs is inappropriate. The committee was concerned that the 50% split used in the company model is arbitrary. After consultation, the company provided additional sensitivity analyses where the proportion of people who had retreatment with osimertinib was varied between 40% to 60%. The committee noted that although the proportion of people having retreatment with osimertinib remained uncertain, it made no significant difference to the cost‑effectiveness estimates since the cure timepoint used in the company's model coincided with when retreatment is allowed. The committee concluded that retreatment with osimertinib would be offered to some people whose disease had progressed after having osimertinib as an adjuvant treatment.\n\n# Clinical evidence\n\n## The clinical evidence for osimertinib is from ADAURA, a phase\xa03, randomised, placebo-controlled trial\n\nThe clinical‑effectiveness evidence for osimertinib is based on the ADAURA randomised controlled trial. This is a phase\xa03 randomised, double‑blind, placebo-controlled, multicentre trial in adults with completely resected stage\xa01b to\xa03a NSCLC (stratified by tumour stage, race [Asian versus non‑Asian] and EGFR [exon\xa019 deletions or L858R] status). ADAURA compared adjuvant osimertinib 80\xa0mg (n=339) with placebo (n=343) over a follow‑up period of 12\xa0and 24\xa0weeks. Some people in both arms of the trial also had adjuvant chemotherapy. The planned treatment duration was 3\xa0years. However, the trial results were released 2\xa0years early after determination of overwhelming efficacy with osimertinib. In the overall trial population, treatment with osimertinib resulted in significantly longer disease‑free survival, with a lower risk of disease recurrence (hazard ratio: 0.20; 99.12% confidence intervals: 0.14 to 0.30; p<0.001). However, the disease‑free survival data is immature and there have been very few events from which to calculate overall survival.\n\n## It is not certain to what extent a benefit in disease-free survival translates into a benefit in overall survival\n\nBecause results of the ADAURA trial have been released 2\xa0years early, overall survival data is immature. The company explained that even though overall survival data from ADAURA is very immature, adjuvant osimertinib is expected to have a long‑term survival benefit. This is because of the size of the disease-free survival benefit, a significant reduction in CNS metastases, and a consistent overall survival benefit when it is used to treat metastatic disease. Both the ERG and clinical experts agreed that disease‑free survival is a clinically relevant end point. The clinical experts also emphasised the important benefits of a reduction in CNS metastases. However, the ERG explained that because of the immaturity of the overall survival data from ADAURA, the size of any potential overall survival benefit is uncertain. The committee acknowledged that uncertainty remains around the extent to which adjuvant osimertinib prevents disease recurrence compared with delaying disease recurrence. Very few patients had reached 3\xa0years of treatment with osimertinib and data on recurrence after stopping treatment was not presented. Therefore, it is uncertain what will happen after stopping treatment. The committee was also aware of recent publications by Gyawali (2021) and Uprety (2021), which noted that other adjuvant TKIs showed disease‑free survival benefits that have not translated to an overall survival benefit. The committee was concerned that the experience with earlier generation TKIs such as erlotinib suggested that disease often recurred after stopping treatment. However, a clinical expert cautioned against placing too much weight on this because erlotinib does not have the same brain penetration as osimertinib. In response to consultation, the company stated that the comparison to earlier TKI data in the adjuvant setting was not appropriate. It noted that the benefits of osimertinib, particularly around reducing CNS metastases, were greater than with the earlier TKIs. However, the committee noted there is currently no evidence to show that after stopping treatment with osimertinib, the hazards, and therefore the hazard ratios, for disease‑free survival do not increase (as with the other TKIs). Therefore, the committee reiterated its concern over the immaturity of the disease‑free survival and overall survival data as well as the uncertainty around the extent to which disease‑free survival can accurately predict overall survival. The committee concluded that it was not certain to what extent a benefit in disease‑free survival translates into a benefit in overall survival.\n\n# The company's economic model\n\n## The company's model structure is acceptable for decision making, but more formal statistical modelling of cure may address some uncertainty\n\nThe company used a state transition, semi‑Markov model with 5 health states: disease free, loco-regional recurrence, first‑line treatment for distant metastases, second‑line treatment for distant metastases, and dead. In the company's model, retreatment with osimertinib for distant metastases is assumed for 50% of people, with the remaining 50% having pemetrexed plus cisplatin. The committee recalled that chemotherapy or atezolizumab, bevacizumab, carboplatin and paclitaxel would be offered to people whose disease had progressed during treatment with osimertinib. Retreatment with osimertinib would be offered to people whose disease had progressed after adjuvant treatment with osimertinib (see section\xa03.3). In its model, the company had also assumed that 100% of people in the active monitoring arm have osimertinib as their first treatment for metastatic disease (see section\xa03.10). The ERG explained that the company's model therefore did not reflect the expected treatment pathway. After consultation, the company did additional scenario analyses:\n\nincluding proportions of 80% and 90% to represent people in the active monitoring arm having osimertinib as their first treatment for metastatic disease\n\nvarying the proportion of people who have retreatment with osimertinib (40%, 50% and 60%).The committee noted that these additional scenario analyses done by the company may address some concerns around the company's economic model not reflecting the treatment pathway. The company's model also included a structural cure assumption (see section\xa03.8). The ERG noted that the cure timepoint used in the company's model coincided with when retreatment is allowed, the latter meant that this has little impact on the incremental cost-effectiveness ratio (ICER). The proportion of people relapsing in the model is also uncertain. The company explained that this proportion varied between its clinical experts. The ERG noted that it would have preferred to have seen formal statistical modelling of cure (for example, using a mixture‑cure model). The company stated that it had attempted to fit the trial data to a mixture‑cure model, but the data was too immature and gave highly uncertain results. The committee concluded that the company's model structure is acceptable for decision making, but more formal statistical modelling of cure may address some uncertainty.\n\n## Including a 3-year stopping rule is acceptable but the effect of stopping treatment at 3\xa0years is uncertain\n\nThe company included a 3‑year treatment stopping rule in its model. This is based on the trial design of ADAURA, where the maximum possible treatment duration was 3\xa0years. It is also stated in the summary of product characteristics that treatment for more than 3\xa0years was not studied. The clinical experts said that adjuvant treatment could not be indefinite and that the 3‑year time period is appropriate. However, the patient experts said they would prefer to continue treatment beyond 3\xa0years if the disease had not progressed. They explained that some people would find stopping treatment difficult because they would fear the disease coming back. The committee noted that in ADAURA, 12% of patients in the intervention arm and 10% in the active monitoring arm had reached 3\xa0years of treatment. The committee concluded that a 3‑year treatment stopping rule, in line with the clinical and cost-effectiveness evidence, was acceptable but the impact of stopping treatment at 3\xa0years is uncertain.\n\n# Modelling survival and cure assumptions\n\n## Other approaches to modelling overall survival may be plausible\n\nThe predicted overall survival gain is a function of all transitions included in the model (see section\xa03.6), most of which are informed by external data and the company's structural cure assumption (a reduction in risk by 95% for people without disease recurrence at 5\xa0years in both arms). The company's choice of survival models was based on a visual inspection of the combined disease‑free survival and overall survival curves, with input from its clinical experts. In line with advice in the NICE Decision Support Unit Technical Support Document 14, the company applied the same parametric curves across both treatment arms. For the transition from disease free to loco‑regional recurrence, the company applied log‑normal curves, whereas generalised gamma curves were applied for the transition from disease free to distant metastatic NSCLC. The committee was aware that disease‑free survival was a key driver of the company's economic model. It was concerned that most of the disease‑free and overall survival benefits were gained during the extrapolated period, so the choice of extrapolation has a significant effect on the results. For the transition from disease free to distant metastases, the generalised gamma chosen by the company had the best statistical fit for the placebo arm. However, the log‑normal had the best fit for the osimertinib arm. The ERG explained that because of the cure assumption, the choice of extrapolation has little effect beyond the cure timepoint. So, in this situation it is appropriate to give more weight to the statistical fit to the observed data. The ERG did additional sensitivity analyses in which it applied alternative parametric survival models to represent the transition from disease free to distant metastatic NSCLC. These used a log‑normal distribution in:\n\nboth arms of the model\n\nthe treatment arm of the model only.In response to consultation, the company suggested that these analyses were inappropriate, because the curves cross. However, the ERG explained that this was not the case for disease‑free survival overall, when the cure assumption is factored in. The committee considered that the log‑normal distribution was as plausible as the generalised gamma. Usually, it is appropriate to use the same distribution for both arms. However, given the cure assumption and stopping of treatment with osimertinib, the committee considered that it was possible that there might be a different profile of hazards between the 2\xa0arms. The committee concluded that other approaches to modelling overall survival may be plausible and it would consider these in its decision making.\n\n## There is uncertainty about the company's cure assumptions\n\nThe company originally applied a 5‑year cure timepoint in its modelling based on information from its clinical experts. Clinical expert advice to the ERG was that, for the active monitoring arm of the model, a 5‑year cure timepoint may be appropriate, but a potential cure timepoint for the intervention arm is uncertain. The ERG did exploratory analyses to assess the effect of changing the timepoint at which the cure assumption is applied in the company's economic model. The ERG's optimistic analysis retained the company's original approach, whereas the pessimistic analysis applied a later timepoint for cure in the adjuvant osimertinib group of 8\xa0years (5‑year cure timepoint\xa0in the active monitoring group plus the 3‑year osimertinib treatment period). In response to technical engagement, the company proposed a 6‑year cure timepoint, which was supported by its clinical experts. The committee was aware that the maximum follow‑up period in ADAURA was 4\xa0years, so the company's cure assumption was uncertain. Very few patients had reached 3\xa0years of treatment with osimertinib so it is also uncertain what will happen after stopping treatment. The committee was concerned that osimertinib may only delay rather than prevent recurrence. Taking into account that there was no data on people who have stopped osimertinib treatment, and the evidence from other TKIs used as adjuvant treatment (see section\xa03.5), the committee noted that the ERG's pessimistic analysis may also be plausible. After consultation, the company did a scenario analysis where the cure assumption was removed. The ERG explained that this analysis may not be meaningful because it applies parametric survival models, which do not explicitly allow for the potential of cure, to a population in whom cure is expected for a proportion of people. The committee concluded that there was significant uncertainty about the company's cure assumptions, and it would consider both of the ERG's approaches in its decision making.\n\n## It is not appropriate to assume 100% of people in the active monitoring arm have osimertinib as their first treatment for metastatic disease\n\nNICE recently recommended osimertinib for untreated EGFR mutation-positive NSCLC for metastatic disease. The company base case assumes that 100% of people in the active monitoring arm will have osimertinib as their first treatment for metastatic disease. The committee recognised that people in the ADAURA trial are being actively monitored and disease may be identified at an earlier stage of progression than in current practice. Therefore, more people could be fit enough to have treatment, so outcomes in advanced disease could be better than seen in the FLAURA (a randomised double blind, phase 3 controlled trial comparing osimertinib with erlotinib or gefitinib for the first-line treatment of EGFR mutation-positive advanced NSCLC) trial data. The ERG presented a scenario analysis using a different mix of TKIs. This was based on the latest TKI prescribing data as presented by the company. The committee considered that the proportion of people having osimertinib is likely to increase over time but may not reach 100%. After consultation, the company provided additional sensitivity analyses where 80% to 90% of people in the active monitoring arm had osimertinib as their first treatment for metastatic disease. It noted that the latest prescribing data shows this figure to be around 80%. The committee concluded that it was appropriate to base its decision making on the latest available prescribing data and that 80% was therefore appropriate to use in the analyses.\n\n# Health-related quality of life\n\n## The company's utility values are acceptable for decision making\n\nThe company included utility values based on EQ-5D-3L estimates from ADAURA, EQ‑5D‑3L estimates from FLAURA and published EQ‑5D‑3L estimates from the literature (Labbé et al. 2017). Disutilities associated with adverse events were based on published literature (Nafees et al. 2008, standard gamble) and on a previous appraisal of osimertinib used second line for metastatic disease (see NICE's guidance on osimertinib for EGFR T790M mutation-positive advanced NSCLC). The ERG was concerned that the utility values applied in the disease free, loco‑regional recurrence and distant metastatic NSCLC health states may be implausibly high compared with the general population. The ERG was also concerned that the model does not include health‑related quality of life decrements for late effects of adjuvant treatment or downstream adverse events. However, it suggested that although the utility values may have been overestimated, they did not necessarily favour osimertinib. The ERG explained that it did an additional sensitivity analysis using utility values from a study by Andreas et al. (2018). This had a limited effect on the cost-effectiveness estimates. The committee concluded that the company's utility values were acceptable for decision making.\n\n# Cost-effectiveness estimate\n\n## The most plausible ICERs for osimertinib are highly uncertain\n\nBecause of confidential discounts for subsequent therapies, the cost‑effectiveness results are commercial in confidence and cannot be reported here. However, the company's base case including all discounts was less than £20,000 per quality‑adjusted life year (QALY) gained. The ERG made several changes to the company's base case and presented 2\xa0analyses. The first was based on a 5‑year cure point in both arms and produced a similar ICER to the company's base case. The second was based on an 8‑year cure point in the osimertinib arm and produced an ICER greater than £20,000 per QALY gained. At the second committee meeting, the committee considered several modelling assumptions plausible:\n\nThe ERG's optimistic base case, which included a cure point at 5\xa0years for the osimertinib group and 5\xa0years for the active monitoring group.\n\nThe ERG's pessimistic base case, which included a cure point at 8\xa0years for the osimertinib group and 5\xa0years for the active monitoring group.\n\nAssuming 80% of people in the active monitoring arm have osimertinib as their first treatment for metastatic disease.\n\nAlternative plausible modelling assumptions for the transition from the disease free to distant metastatic NSCLC health states using a log‑normal distribution in:\n\n\n\nboth arms of the model\n\nthe treatment arm of the model only.\n\n\n\nIncluding retreatment with osimertinib after recurrence in the intervention arm of the model (using proportions of 40%, 50% and 60%).Combining any of these assumptions with the ERG's optimistic base case resulted in ICERs of below £20,000 per QALY gained. However, combining them with the ERG's pessimistic base case resulted in ICERs above £30,000 per QALY gained. Combining the ERG's pessimistic base case, 80% osimertinib treatment for first‑line distant metastases and the log‑normal extrapolation for the transition from the disease free to distant metastases in the treatment arm only increased the ICER substantially above £30,000 per QALY gained. Using these preferred assumptions, the committee considered that the most plausible ICERs for osimertinib were in the range of less than £20,000 per QALY gained to more than £30,000 per QALY gained. The committee concluded that the upper end of the most plausible ICER range may not be within the range usually considered a cost‑effective use of resources.\n\n## Osimertinib is not recommended for routine use in the NHS\n\nBecause results from ADAURA were released 2\xa0years early, the disease‑free survival and overall survival data for osimertinib is immature. After considering the uncertainty with the clinical evidence along with its preferred assumptions, the committee considered that the upper end of the most plausible ICER range may not be within the range usually considered a cost‑effective use of resources. The committee concluded it could not recommend osimertinib for the adjuvant treatment of stage\xa01b to\xa03a NSCLC after complete resection in adults whose tumours have EGFR exon\xa019 deletions or exon\xa021 (L858R) substitution mutations for routine use in the NHS.\n\n## Osimertinib is recommended for use in the Cancer Drugs Fund\n\nHaving concluded that osimertinib could not be recommended for routine use, the committee then considered if it could be recommended for treating stage\xa01b to\xa03a NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee acknowledged that the disease-free survival and overall survival data from ADAURA was not mature and that further data collection may help address uncertainty. After consultation, the company stated that it would welcome a recommendation in the Cancer Drugs Fund if the committee recognised plausible uncertainties that would result in ICERs higher than what NICE normally considers a cost‑effective use of NHS resources. The committee was aware that, although a period of time in the Cancer Drugs Fund may not produce enough mature overall survival data for a robust mixture‑cure model, there would still be benefits:\n\nthe disease‑free survival data will be more mature\n\nthere will be a better understanding of the impact of the 3‑year stopping rule\n\nmore data will be available to estimate the extent of the cure proportion.The committee acknowledged that osimertinib has plausible potential to be cost effective. It understood that there is uncertainty around the cure time point, if osimertinib will prevent or only delay disease recurrence, the proportion of patients that would have retreatment with osimertinib, if the benefit in disease‑free survival will translate into a benefit in overall survival and if the log‑normal or generalised gamma distribution should be used to extrapolate the transition from disease free to distant metastases. If the cure time point was earlier than 8\xa0years, then osimertinib may represent a cost‑effective use of NHS resources, depending on the trajectory of disease-free survival. The Cancer Drugs Fund clinical lead indicated that they would welcome collecting data on osimertinib through the Cancer Drugs Fund. The committee concluded that osimertinib could be recommended for use in the Cancer Drugs Fund. It noted that when the guidance is reviewed, the company should consider using formal statistical modelling of cure (for example a mixture‑cure model) if the data allows (see section\xa03.6).\n\n# Innovation\n\n## Osimertinib is recognised as an innovative therapy in the adjuvant setting\n\nThe company said that osimertinib is innovative because there has been little innovation in adjuvant treatment for stage\xa01b to\xa03a EGFR mutation-positive NSCLC, aside from adjuvant chemotherapy, in 20\xa0years. Osimertinib has been reviewed as part of Project Orbis because it is considered an innovative adjuvant treatment. In response to consultation, the company stated that not all additional benefits associated with osimertinib had been captured in the economic analysis. In particular, the company highlighted the effect osimertinib has on reducing CNS metastases. It stated that a utility decrement had not been applied in the modelling for people whose quality of life had declined because of CNS metastases. It therefore suggested that the ICERs were a conservative estimate. The ERG stated that it did not accept that any relevant aspects of the value of adjuvant osimertinib had clearly been omitted from the company's economic analyses. The committee recognised osimertinib as an innovative therapy in the adjuvant setting but concluded that it did not consider there were any additional benefits associated with osimertinib that had not been captured in the economic analysis.\n\n# Equality\n\n## EGFR mutation-positive NSCLC is more common in women and people with a Chinese family background\n\nThe clinical experts explained that EGFR mutation‑positive NSCLC tends to be more common in women and people with a Chinese family background. The committee noted that the issue of different disease prevalence cannot be addressed in a technology appraisal.\n\n# Other factors\n\n## Less common EGFR mutations were not considered\n\nThe only EGFR mutations considered within the scope of this appraisal are EGFR exon\xa019 deletions or exon\xa021 (L858R) substitution mutations. This is in line with osimertinib's current marketing authorisation. The Cancer Drugs Fund clinical lead explained that if NICE recommends osimertinib for these mutations, NHS England would consider commissioning adjuvant osimertinib treatment for other less common EGFR mutations. The committee noted that NICE can only appraise a medicine within its marketing authorisation and welcomed the comments from the Cancer Drugs Fund clinical lead.\n\n## The end of life criteria are not met\n\nThe company did not make a case for osimertinib meeting NICE's end of life criteria. NICE's advice about life‑extending treatments for people with a short life expectancy did not apply.\n\n# Conclusion\n\nThe committee recognises that osimertinib is a promising new treatment option. However, there is not enough clinical- and cost‑effectiveness evidence to recommend it for routine use in the NHS. Therefore osimertinib is recommended for use in the Cancer Drugs Fund as an adjuvant treatment of stage\xa01b to\xa03a NSCLC after complete tumour resection, in adults whose tumours have EGFR exon\xa019 deletions or exon\xa021 (L858R) substitution mutations. The committee recognised that the ADAURA trial used the Union for International Cancer Control (UICC) TNM 7th edition lung cancer staging criteria and that this evidence underpinned the marketing authorisation. It was aware that these criteria had been recently updated and that the 8th edition is also now used in NHS clinical practice. It understood from the Cancer Drugs Fund clinical lead that the population as per 7th edition (stages\xa01b to\xa03a – as specified in the marketing authorisation) corresponds to stages\xa01b to\xa0N2 only stage\xa03b in the 8th edition. It also understood that the Cancer Drugs Fund would ensure patient access in accordance with this translation from the 7th to the 8th edition lung cancer staging criteria."}
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https://www.nice.org.uk/guidance/ta761
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Evidence-based recommendations on osimertinib (Tagrisso) for adjuvant treatment of EGFR mutation‑positive non‑small‑cell lung cancer in adults after complete tumour resection.
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d83fee855b5ee3df64814fb7c3ba94bf823cb498
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nice
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Rehabilitation after traumatic injury
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Rehabilitation after traumatic injury
This guideline covers complex rehabilitation needs after traumatic injury, including assessment and goal setting, rehabilitation plans and programmes, physical, psychological and cognitive rehabilitation, rehabilitation for specific injuries, coordination of rehabilitation in hospital, at discharge and in the community, and commissioning and organising rehabilitation services.
# Context
Traumatic injury is a significant cause of early death and morbidity – particularly in the working population. Major trauma is the biggest cause of death in children and adults under the age of 40.
This guideline defines traumatic injury as any injury that requires admission to hospital at the time of injury. This could include musculoskeletal injuries, visceral injuries, nerve injuries, soft tissue damage, spinal injury, limb reconstruction and limb loss. Minor injuries can also lead to a hospital admission.
This guideline does not cover the management of traumatic brain injury, except in relation to early screening for onward referral and the coordination of services for people with multiple injuries, one of which may be traumatic brain injury. The specialist assessment and delivery of rehabilitation services for traumatic brain injury will be covered in a new NICE guideline on rehabilitation for chronic neurological disorders including traumatic brain injury.
In England, 45,000 people are affected by very severe or major trauma every year. A further 500,000 people (included in the population for this guideline) experience less severe trauma, and a proportion of those will need hospital admission because of pre-existing conditions, disability, frailty, or because the functional impact of injuries and environmental factors means that they will not be able to manage in their own home.
Trauma affects all age groups, but there are 2 peaks: younger age and older age. People may have different rehabilitation needs that reflect different functional expectations and priorities. Trauma can negatively affect quality of life, both physically and mentally. It can lead to problems with mobility, pain, breathing, swallowing, eating, drinking, toileting, cognitive function, speech, language and communication, sensory problems, and can lead to depression, anxiety and other psychological difficulties. These issues can similarly have a social and financial impact on the person, as well as on their family and carers. The impact of these problems may be influenced by pre-existing conditions.
After a traumatic injury, people need rehabilitation assessment and interventions that take account of any pre-existing conditions and focus on helping them regain optimum function and independence as quickly as possible.
This guideline focuses on people with complex rehabilitation needs after a traumatic injury. The defined population in this guideline has not been based on the severity of the injury (sometimes measured using an injury severity score) but on the complexity of the rehabilitation need, taking into account existing conditions and circumstances that will impact rehabilitation. Complex needs cover multiple needs, and will involve coordinated multidisciplinary input from at least 2 allied health professional disciplines, which may include rehabilitation medicine, and could also include:
vocational or educational social support for the person to return to their previous functional level, including return to work, school or college
emotional, psychological and psychosocial support
equipment or adaptations
-ngoing recovery from injury that may change the person's rehabilitation needs (for example, restrictions of weight-bearing, cast immobilisation in fracture clinic)
further surgery and readmissions to hospital.
Currently, people who meet 'major trauma' criteria should have a rehabilitation assessment and prescription carried out during the hospital admission. Further assessments are performed over time to capture changing needs. For people who do not meet major trauma criteria (currently those with an injury severity score of less than 9), the pathway for rehabilitation is less clear.
There are limitations in access to the appropriate rehabilitation services for people after trauma, which may be related to geography, age, injury type or rehabilitation need. There is significant variation in practice, with no national network of services.
Improvement in survival rates resulting from the introduction of major trauma networks in 2012 has led to an increased need for rehabilitation.
Military experience has shown better outcomes with improved rehabilitation, where early and intensive rehabilitation has been shown to improve function, pain, quality of life and mental health outcomes. It can also improve outcomes for carers of those affected by traumatic injury.
Costs of treatment after a traumatic injury are high in the acute phase, and there are also long-term care costs to the NHS through ongoing treatment. Social care costs may be high for people who need ongoing care and support in the community. There are wider costs to the community if people are unable to return to work or education. Rehabilitation may be able to reduce these costs through improving overall function. Interventions may improve outcomes at a number of stages.
There are several NICE guidelines about the assessment, treatment and management of specific injuries for adults and children. There is guidance about service delivery, assessment and management of major trauma, and rehabilitation after critical illness and stroke. There are also guidelines about the transition between hospital and home, from children's to adults' services, and about home care services.# How to use this guideline
All the recommendations apply to all people with complex rehabilitation needs after a traumatic injury, regardless of age or the nature of the injury, unless:
the recommendation specifically states that it is for adults only, or children and young people only or
the recommendation or section of the guideline specifically states that it is for people with a particular injury.
The following sections provide a pathway from assessment through to goal setting, agreeing and coordinating the delivery of a rehabilitation plan and programmes of therapy, and coordinating and organising rehabilitation at and following discharge:
Initial assessment and early interventions for people with complex rehabilitation needs
Multidisciplinary team rehabilitation needs assessment
Setting rehabilitation goals
Developing a rehabilitation plan and making referrals
Rehabilitation programmes of therapies and treatments
Principles for sharing information and involving family and carers
Coordination of rehabilitation care in hospital:
From admission to hospital
When transferring between services and settings
Coordination of rehabilitation care at discharge
Supporting access and participation in education, work and community (adjustment and goal settings)
Commissioning and organisation of rehabilitation services
The rehabilitation therapies and interventions included in the following sections apply to ALL people with complex rehabilitation needs after a traumatic injury:
Physical rehabilitation
Cognitive rehabilitation
Psychological rehabilitation
The following injury-specific sections should be read in conjunction with the sections on physical rehabilitation, cognitive rehabilitation and psychological rehabilitation:
Rehabilitation after limb reconstruction, limb loss or amputation
Rehabilitation after spinal cord injury
Rehabilitation after nerve injury
Rehabilitation after chest injury# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Initial assessment and early interventions for people with complex rehabilitation needs
Be aware that the severity of a person's traumatic injury does not necessarily correlate with the complexity of their rehabilitation needs, so assess the impact of the injury using a person-centred, individualised and holistic approach at all stages of their care pathway.
After a traumatic injury, assess the person's rehabilitation needs as an integral part of their care pathway from admission. This may include:
discussing findings from early rehabilitation assessments with the person, and their family members or carers (as appropriate)
helping the person, and their family members or carers (as appropriate), to think about preferred rehabilitation goals to inform shared decision making about medical or surgical options
involving rehabilitation specialists (ideally including a consultant in rehabilitation) alongside acute care teams to discuss the implications for rehabilitation depending on different medical and surgical options.
All practitioners involved in the person's care should provide immediate psychological and emotional support for people who are mentally distressed and/or cognitively impaired after a traumatic injury. Request additional support and/or advice from psychology services as needed.
After a traumatic injury:
Avoid delays in acute treatment so that rehabilitation can start as soon as possible, for example, to maintain movement.
Start rehabilitation when the person is ready and able to engage and participate (see also recommendation 1.2.5). For people who lack capacity to engage in making decisions about their rehabilitation, follow the NICE guideline on decision making and mental capacity.
Provide access to rehabilitation therapies:
before surgery, to maintain respiratory function and functional abilities (if surgery is delayed) and
as soon as possible after surgery (starting ideally no later than the following day).
As soon as possible after the traumatic injury, assess how the person's physical impairments might affect their ability to engage in activities of daily living. Involve occupational therapy for:
input and advice on therapies and referral for aids and
equipment and adaptations.
As soon as possible after a traumatic injury, start to assess whether the person has new or existing cognitive, hearing, visual or communication impairments or emotional difficulties that might affect their ability to engage in rehabilitation and in activities of daily living. Involve occupational therapy, psychology and speech and language therapy as appropriate.
Use equipment as appropriate to encourage movement (for example, walking aids and transfer devices) and to protect the injury (for example, splints or orthotics).
Ask about the person's diet and nutrition, including their weight, eating habits and any use of health supplements such as vitamins and minerals or high-calorie drinks.
Ensure that the initial assessment checks to see if the person can swallow safely. Also see recommendation 1.11.51 and the NICE guideline on nutrition support for adults.
Assess the person's risk of malnutrition using, for example, the Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP) score in children and young people under 16 years and, for example, the Malnutrition Universal Screening Tool (MUST) score for adults (see the section on screening for malnutrition and the risk of malnutrition in hospital and the community in the NICE guideline on nutrition support for adults).
Monitor the person's nutritional intake and weight throughout their hospital stay, provide nutrition support in line with the NICE guideline on nutrition support for adults, and refer for a specialist dietitian review if needed.
Complete a safeguarding assessment for children, young people and vulnerable adults after a traumatic injury, taking into account any known or suspected non-accidental injury. (Also see the NICE guidelines on child abuse and neglect and child maltreatment, and the Care Act 2014.)
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on initial assessment and early interventions for people with complex rehabilitation needs .
Full details of the evidence and the committee's discussion are in:
evidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury
evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury
evidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury
evidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury
evidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury.
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# Multidisciplinary team rehabilitation needs assessment
The multidisciplinary team should complete a personalised and holistic rehabilitation needs assessment in partnership with the person and their family members or carers (as appropriate), which should include:
physical functioning (see the section on assessing physical functioning)
cognitive functioning (see the section on assessing cognitive functioning)
psychological functioning (see the section on assessing psychological functioning).
In addition to the holistic rehabilitation needs assessment in recommendation 1.2.1, the multidisciplinary team should complete specialist assessments for the following injuries:
for limb injuries, see the section on rehabilitation after limb reconstruction, limb loss or amputation
for nerve injuries, see the section on rehabilitation after nerve injury
for spinal injuries, see the section on rehabilitation after spinal cord injury
for chest injuries, see the section on rehabilitation after chest injury.
Always think about the mechanism of injury and whether the person may have had a head injury. Be aware that the symptoms of traumatic brain injury can be subtle and regular screening may be necessary. If there are clinical symptoms, refer the person for a specialist assessment with healthcare professionals with expertise in traumatic brain injury rehabilitation. See also the NICE guideline on head injury.
The multidisciplinary team involved in assessing people's rehabilitation needs in hospital should consist of healthcare professionals and practitioners with expertise in rehabilitation after traumatic injury. Depending on the nature of the injury, the setting for assessment and treatment, the age of the person and other pre-existing health or care issues, the multidisciplinary team could involve:
surgeons, rehabilitation medicine specialists, intensive care specialists, elderly care specialists and/or paediatricians (as appropriate)
allied health professionals such as occupational therapists, physiotherapists, dietitians, orthotists and speech and language therapists
practitioner psychologists
specialist nurses
play therapists
pharmacists
a trauma coordinator and/or rehabilitation coordinator
when planning discharge:
a social worker
a discharge coordinator.
The multidisciplinary team should assess the person's rehabilitation needs as soon as possible after the traumatic injury, when measures are being taken to optimise their ability to engage in the assessment process. These measures include:
pain management
resolution of infections
resolution of acute confusion or delirium
consideration of psychological wellbeing
making available hearing aids, glasses, dentures and other orthodontic appliances
access to communication aids (if needed)
access to interpreters (for example, for people who do not speak English)
having in place drug or alcohol dependence withdrawal management
restarting long-term medications to maintain physical and mental health; see also the NICE guideline on medicines optimisation.
Be aware that traumatic injury may affect sexual function. Discuss this with people at assessment and review, and seek specialist advice about sexual function, fertility issues and psychological support.
If a person lacks mental capacity, carry out a rehabilitation needs assessment based on the principles of best interests decision making, as set out in the NICE guideline on decision making and mental capacity.
As part of the rehabilitation needs assessment, the multidisciplinary team should ask about the person's pre-injury activities, for example:
the person's background, personal history, relationships, work, education, meaningful activities, spiritual and religious practices, and hobbies and interests
usual activities of daily living, including mobility and other physical activity
motivational factors such as the person's lifestyle, previous ability, future aspirations, priorities and core values.
The multidisciplinary team should allow adequate time to:
liaise with the clinical team managing any pre-existing, long-term conditions that may affect rehabilitation
complete the rehabilitation needs assessment, which should include a detailed and accurate analysis of the person's injuries, impairments, goals and likely rehabilitation needs and
discuss the findings together, to reduce the need to repeat questions and to improve the efficiency of the assessment process.
When discussing rehabilitation needs with people, and their family members or carers (as appropriate):
be sensitive about the timing because pain, confusion, fatigue and trauma can make it more difficult for people to absorb and retain information
give people sufficient time to process information about their injuries and rehabilitation options, to help them adjust after the traumatic injury and engage more readily in the rehabilitation therapy
if people ask for information about the likely long-term prognosis, recognise that this may be difficult to predict and should only be discussed with the person after multidisciplinary team review.
Use validated tools (for example, the rehabilitation complexity scale , patient categorisation tool , complex needs checklist or post-ICU presentation screen ), in the rehabilitation needs assessment to determine the need for early referral to specialist rehabilitation units.
Regularly reassess (using clinical assessment and validated tools) whether referral for specialised rehabilitation is still needed and what other referrals may now be needed.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multidisciplinary team rehabilitation needs assessment .
Full details of the evidence and the committee's discussion are in:
evidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury
evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury
evidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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## Assessing physical functioning
As part of the rehabilitation needs assessment after a traumatic injury, the multidisciplinary team should assess the person's pre-injury and current physical functioning, which should include:
assessing pain management to enable physical rehabilitation activities to begin
a comprehensive neuromusculoskeletal assessment to identify physical impairments such as nerve injury, muscle imbalance and proprioception problems
assessing upper and lower limb function and the impact of the injury on the person's ability to move and use walking aids (if needed)
assessing and recording the range of movement for each joint affected
asking about any problems with balance or dizziness and other vestibular symptoms (either pre-existing or new), and considering assessment for benign paroxysmal positional vertigo (BPPV) and for head injury
if the traumatic injury has been caused by a fall, asking about previous falls and considering a falls risk assessment in line with the section on multifactorial risk assessment in the NICE guideline on falls
assessing pre-existing or newly acquired vision or hearing problems
assessing whether there are any new difficulties with communication, speech and language
assessing ability to do transfers, for example, to move from lying to sitting, and sitting to standing
assessing trunk control and core stability (if relevant)
assessing ability to move and level of aerobic fitness and/or exercise tolerance
assessing skin care, wound care and pressure area management
for children and young people, asking about previous developmental attainment and functioning.
Refer the person for a specialist assessment if the multidisciplinary team does not have appropriate skills or expertise to perform the assessment needed. Examples are:
to determine when and how splints and orthoses should be used, taking into account that people with complex traumatic injuries may need bespoke splints or orthoses
if they have external fixation for lower limb fractures
if they have sensory loss or nerve injury (see the section on rehabilitation after nerve injury).
Assess the person for factors that may affect their ability to engage in rehabilitation. These may include balance and coordination issues (neurovestibular disorders), and newly acquired vision or hearing loss. Refer for specialist assessment and management as needed. Also see the section on sudden or rapid onset of hearing loss in the NICE guideline on hearing loss in adults.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing physical functioning .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Assessing cognitive functioning
Please note this guideline does not cover assessment or specific rehabilitation interventions for people with traumatic brain injuries. See recommendation 1.2.3 in the section on multidisciplinary team rehabilitation needs assessment.
Be aware that even if there has been no brain injury, problems with cognitive functioning are common after a traumatic injury because of the psychological shock and trauma.
As part of the rehabilitation needs assessment after a traumatic injury, the multidisciplinary team should ask about any cognitive problems, for example:
confusion
disorientation
slowed thinking and/or slowed processing of information
withdrawal
memory problems
agitation
communication, speech or language changes (for example, withdrawal or selective mutism).
If a person has problems with cognitive functioning after a traumatic injury, investigate for other causes such as:
pre-existing cognitive impairment or dementia (see the NICE guideline on dementia)
delirium (for example, alcohol or drug misuse, drug toxicity or opiate-related confusion, infection or sepsis, or hypoxia; see the NICE guideline on delirium)
behavioural problems or learning disabilities (see the NICE guideline on challenging behaviour and learning disabilities)
traumatic brain injury (this may not show up on scans immediately and further investigations will be needed if it is suspected; see also recommendation 1.2.3).
If a person has problems with cognitive functioning after a traumatic injury and the potential causes in recommendation 1.2.18 have been ruled out, assess the person's:
-rientation to time, place, person and situation
ability to follow simple instructions
ability to recall information and communicate it correctly after a short period of time.
If the assessment in recommendation 1.2.19 confirms difficulties with cognitive functioning, refer the person to an occupational therapist, practitioner psychologist (ideally a neuropsychologist) or a speech and language therapist (as appropriate) for a specialist cognitive assessment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing cognitive functioning .
Full details of the evidence and the committee's discussion are in evidence review B.2: cognitive interventions for people with complex rehabilitation needs after traumatic injury.
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## Assessing psychological functioning
As part of the rehabilitation needs assessment after a traumatic injury, the multidisciplinary team should ask about psychological and psychosocial risk factors, for example:
past or present mental health problems, such as anxiety or depression
past or present mental illness or psychiatric treatment
history of traumatic brain injury
history of self-harm or suicide attempts
any experience of domestic violence or abuse
any safeguarding concerns (if the person is a child or a vulnerable adult)
excessive alcohol consumption or recreational drug use
the circumstances of the injury, for example, self-harm or a violent crime
social factors that mean the person may need additional support, for example, if the person is socially isolated, homeless, a refugee or recent migrant, if they have difficulty reading or speaking English, or if they have learning disabilities or other needs.
As part of the rehabilitation needs assessment after a traumatic injury, look for indicators of psychological problems (including lack of engagement with rehabilitation) beyond that of an acute stress response (see recommendation 1.13.1). Take into account any psychological and psychosocial risk factors (see recommendation 1.2.21) and, if needed, refer the person for a psychological assessment with a practitioner psychologist (with relevant expertise in physical trauma and rehabilitation) or a member of the liaison psychiatry team to inform their rehabilitation plan and goals.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing psychological functioning .
Full details of the evidence and the committee's discussion are in evidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury.
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# Setting rehabilitation goals
Also see the section on supporting access and participation in education, work and community (adjustment and goal setting).
Agree short-term and long-term rehabilitation goals with the person and their family members or carers (as appropriate), and review them regularly based on:
what is most important to the person and what they most value
activities that are meaningful for the person and relate to what is important
a strengths-based approach, which builds on positive function and ability
the person's home circumstances
the person's aspirations about returning to work or education, and their preferred timeframe
developing the knowledge, skills and confidence to manage their own health and wellbeing
an understanding that there may be setbacks as well as gains, so goals should be flexible.
When setting long-term rehabilitation goals, agree small steps so that progress can be monitored in a way that is meaningful and motivational for the person.
Members of the multidisciplinary team involved in setting rehabilitation goals should be skilled and competent in:
helping people identify goals that are right for them
understanding how the psychological impact of trauma can affect goal setting and rehabilitation planning.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on setting rehabilitation goals .
Full details of the evidence and the committee's discussion are in evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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# Developing a rehabilitation plan and making referrals
Use the rehabilitation needs assessment (see the section on multidisciplinary team rehabilitation needs assessment) and the person's rehabilitation goals (see the section on setting rehabilitation goals) to develop a rehabilitation plan for the person (this may be in the form of a rehabilitation prescription). The rehabilitation plan should include:
information about the person's injuries
the person's short-term and long-term rehabilitation goals (see the section on setting rehabilitation goals)
information about the person's needs and preferences
a suggested rehabilitation programme of therapies and treatments (see the section on rehabilitation programmes of therapies and treatments)
how the rehabilitation programme of therapies and treatments will be delivered
information and sources of further information about returning to vocational or leisure activities
information about associated risks, responsibilities, and possible legal issues about returning to driving and sources of specific advice (for example, the DVLA )
information about referrals or sources of further information
any follow-up arrangements (especially when transferring to home or community settings)
who the rehabilitation plan should be shared with (with the person's consent) and details about any information that the person wants to remain confidential
details of a rehabilitation coordinator or key worker, and the lead healthcare professional involved in the person's care.
The rehabilitation plan should be:
a tailored and personalised journey towards the person's agreed goals, focusing on what is important to them
developed with the person, and their family members or carers (as appropriate)
based on advice and input from all members of the multidisciplinary team
written in clear English
a single document or file
shared with the person, their families and carers (as appropriate), the person's GP, and healthcare professionals involved in their ongoing care
regularly updated in partnership with the person to reflect their progress, goals, ongoing needs and key contact information, particularly at key points of transition in care.
Where it is not possible or appropriate for the person to have access to all of the information in a rehabilitation plan, ensure that important components of the plan are included in a summarised patient-held document that is regularly updated with progress, appointment times and contact details.
If there are aspects of the rehabilitation plan that the multidisciplinary team cannot implement, the rehabilitation coordinator or another senior member of the multidisciplinary team should make appropriate referrals without delay, including referrals to specialised rehabilitation services.
Manage the care of adults with fragility fractures of the femur within a specialist pathway involving orthogeriatricians. Also see the NICE guideline on hip fracture.
If an older person with a traumatic injury is on a care pathway that does not routinely involve geriatrician support, consider referral to an orthogeriatrician, a surgical liaison or a perioperative physician (as appropriate).
For adults with a fragility fracture, assess bone health and refer as necessary, for example, to a specialist bone health clinic or outpatient service. Also see the NICE guideline on osteoporosis.
If a traumatic injury has been caused by a fall, ask the person about previous falls, and consider a falls risk assessment and a referral to a community falls service (as appropriate). Also see the section on multifactorial risk assessment in the NICE guideline on falls.
Assess all adults over 65 who have a traumatic injury for their risk of falls in line with the recommendations on multifactorial risk assessment in the NICE guideline on falls.
Provide information about, or refer people to, services that may help prevent future injury, such as falls prevention, safeguarding services, domestic abuse services, violence prevention programmes, and condition-specific support organisations.
For people admitted to hospital with violent injuries related to suspected criminal activity, consider a violence prevention programme and follow-up as part of their rehabilitation plans. This could include psychological support (for example, counselling), substance abuse rehabilitation, employment or education training, group sessions, family development, liaison with the police, social worker involvement, and rehousing, when needed.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on developing a rehabilitation plan and making referrals .
Full details of the evidence and the committee's discussion are in:
evidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury
evidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury
evidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community.
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# Rehabilitation programmes of therapies and treatments
## General principles for rehabilitation programmes
Rehabilitation programmes of therapies and treatments should:
form part of the person's rehabilitation plan, and be tailored to their individual needs (see the section on developing a rehabilitation plan and making referrals)
focus on outcomes (for example, return to work, school or leisure activities) and be based on the person's short-term and long-term rehabilitation goals (see the section on setting rehabilitation goals)
include educational material to help people understand the nature of their injuries, to promote self-care and to prepare them for any long-term or intensive periods of rehabilitation (for example, sleep, pacing activities and pain management)
include (as appropriate) physical, cognitive and psychological therapies and treatments such as physiotherapy, exercise, occupational therapy, psychology and orthotics, as well as injury-specific therapies and treatments; see the sections on:
physical rehabilitation
cognitive rehabilitation
psychological rehabilitation
rehabilitation after limb reconstruction, limb loss or amputation
rehabilitation after spinal cord injury
rehabilitation after nerve injury
rehabilitation after chest injury
include access to specialist services to address complex issues such as fertility and endocrine concerns
include (as appropriate) a combination of group and individual sessions as well as the development of a self-management rehabilitation programme (see the section on supporting access and participation in education, work and community )
include and document regular progress reviews and a final assessment to review outcomes, update the rehabilitation plan and detail any ongoing rehabilitation needs for onward referrals to GP, outpatient and/or community services
include post-programme follow-up, in person or virtually.
Tailor the start time, frequency, intensity and duration of the rehabilitation programme to have the most beneficial effect on the person's recovery (for example, a short period of intensive rehabilitation at an important time point might be better than weekly sessions over a long period).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on general principles for rehabilitation programmes .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Intensive rehabilitation programmes
In the post-acute period, consider an intensive (for example, 3 weeks) inpatient or outpatient (including residential) rehabilitation programme for adults, young people and children with complex injuries and rehabilitation needs if such an intervention is likely to have a significant impact on change in function (for example, it could result in return to work or education and living independently).
When providing intensive rehabilitation programmes:
-ffer education and learning materials (see the section on guided self-managed rehabilitation) to prepare people for intensive rehabilitation, for example, 1 week of remote learning followed by a (for example, 3‑week) residential or outpatient programme
answer questions, such as those relating to the person's injuries and rehabilitation
consider delivering rehabilitation therapies with regular breaks (for example, only during weekdays to allow for rest periods at weekends and time to review progress)
communicate any changes to the rehabilitation plan with the local team following the intensive period of rehabilitation.
Start an intensive rehabilitation programme at the appropriate time for the person, taking into account:
that the timing and nature of rehabilitation therapies and treatments will depend on issues such as bone and soft tissue healing, weight-bearing, and removal of weight-bearing restrictions
the person's psychological and emotional wellbeing, levels of adjustment and engagement with the rehabilitation process.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intensive rehabilitation programmes .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Guided self-managed rehabilitation
Consider guided self-managed rehabilitation to allow the person to engage in rehabilitation in their own time and by their own schedule, working with rehabilitation healthcare professionals and practitioners, with regular reviews to check on progress, provide ongoing reassurance and answer queries.
As part of a self-management rehabilitation programme, consider providing a tailored package of online education and learning materials for people after a traumatic injury, which could include information on:
movement and physical activity
energy conservation and pacing
sleep
activities of daily living
work, social activities and hobbies
nutrition and diet
pain management and medicines
wound healing
mental health
local and national sources of information
peer support services, including local and national groups. For people who cannot access the internet, explore alternative ways to provide these materials.
If people are following a self-management rehabilitation programme, consider arranging follow-up appointments and regular reviews with rehabilitation healthcare professionals and practitioners to check on self-managed progress, provide ongoing reassurance and answer new queries.
For children, young people and vulnerable adults, offer additional support to develop and deliver a self-management programme that takes into account their communication needs, their own views and priorities and (for children) their developmental stage.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on guided self-managed rehabilitation .
Full details of the evidence and the committee's discussion are in:
evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury
evidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury
evidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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## Monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments
Monitor the person's progress after starting rehabilitation. Use tools such as patient-reported outcome measures (PROMs) and clinician-reported outcome measures (CROMs) for adults; parent- and child-reported measures for children and young people; and consider using tools that involve family members and carers. Additional specific clinical assessments may be used as appropriate.
Encourage people to record information about their injuries, treatments and rehabilitation therapy options (for example, using a diary as part of their rehabilitation plan) to assist discussions and shared decision making.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments .
Full details of the evidence and the committee's discussion are in:
evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community.
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# Principles for sharing information and involving family and carers
Involve people, and their families and carers (as appropriate), in assessments, in planning their coordination of care and in making decisions at all stages of the rehabilitation process. This should include discussing medical or surgical treatment options, discussing findings from assessments, setting goals, discussing potential discharge destinations and examining the different rehabilitation options after discharge.
Encourage and support children and young people to be actively involved in decision making about their rehabilitation to the best of their ability.
Be aware that encouragement from family members, carers, friends and healthcare professionals can all have a positive effect on a person's rehabilitation after a traumatic injury, so involve the person's family members, carers and friends (as appropriate) as much as possible throughout the person's rehabilitation journey.
In discussions and when giving information to people, and their family members or carers (as appropriate), use clear language, and tailor the timing, content and delivery of information to the needs and preferences of the person. Information should be:
specific to the person's injuries
-ffered in face-to-face (in person or remotely by video link) discussions, and in a suitable format, for example, digital, printed, braille or Easy Read
-ffered throughout the person's care
personalised and sensitive
supportive and respectful
evidence-based and consistent between healthcare professionals.For more guidance on communication, providing information (including different formats and languages) and shared decision making, see the NICE guidelines on patient experience in adult NHS services, babies, children and young people's experience of healthcare, decision making and mental capacity and shared decision making.
Be aware that if a person has severe and complex rehabilitation needs after a traumatic injury, if they have had a brain injury or if they have problems with cognitive functioning after a traumatic injury, information giving may need to be enhanced and reinforced by:
repeating information on several occasions
providing information in a suitable format (for example, Easy Read)
giving information in the presence of family members or carers (as appropriate).
Be aware that people who lack mental capacity may be legally entitled to professional advocacy (see the Mental Capacity Act 2005), as may people who have care and support needs (see the Care Act 2014). Also see the NICE guideline on decision making and mental capacity.
Advise carers about their right to a carer's assessment, an assessment for replacement care, and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles for sharing information and involving family and carers .
Full details of the evidence and the committee's discussion are:
evidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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# Coordination of rehabilitation care in hospital
## From admission to hospital
Where possible, provide continuity of staff throughout the person's rehabilitation pathway.
Assign a named rehabilitation coordinator or key worker to oversee the person's care as soon as possible and within 72 hours of admission. Ensure that the person knows who their rehabilitation coordinator or key worker is, how they will coordinate care, and how they can be contacted.
The trauma team should agree the core members of the rehabilitation multidisciplinary team who will establish an injury management plan and start developing a rehabilitation plan and goals. See recommendation 1.2.4 for details of the multidisciplinary team after hospital admission.
A member of the rehabilitation multidisciplinary team should discuss the person's rehabilitation at daily trauma meetings or ward rounds.
Where assessment identifies the need for specialist rehabilitation (see the section on multidisciplinary team rehabilitation needs assessment), complete the referral to specialist rehabilitation units as soon as possible.
Use a unique identifier, preferably the NHS number if this is known, when exchanging clinical information about the person's assessment, rehabilitation plan, onward referral, transition between services, discharge to community services, and all aspects of their care pathway.
## When transferring between services and settings
Make follow-up appointments with acute teams (if needed) for people moving from an acute unit to rehabilitation services, and ensure that the person is informed before they are transferred.
When people transfer between service providers or settings (for example, wards, hospitals and inpatient rehabilitation facilities), share information (with the person's consent) by providing a detailed verbal and written or online handover (for example, the rehabilitation plan and the person's progress against it) and let the person know this has been done. Ensure information is promptly communicated:
to those coordinating and delivering rehabilitation in the new setting or service
to the person, and family members and carers (as appropriate)
to any other service providers involved in the person's care and support.
The detailed handover and report should include oral and online or printed information about:
all of the person's injuries
different treatment options and their benefits and risks
the person's current rehabilitation plan and goals
the person's cultural, language and communication needs
psychological approaches to managing pain and fatigue, if relevant
beneficial activities, and activities to avoid
how to manage activities of daily living, including self-care and re-engaging with everyday life
plans for returning to work or school, housing and benefits, and driving, if relevant
how to recognise possible problems or complications, and what to do
local support groups, opportunities to access peer support, online forums and national charities, and how to get in touch with them
services that provide independent legal, financial, employment and welfare advice
advice for the family or carers about:
what to expect and how to support the person at home
the impact of the traumatic injury on family members and carers, and how they can get support.
When people transfer between service providers or settings, discuss with them:
their expected recovery pathway
what might happen if recovery is slower than expected
the emotional impact of living with possible long-term symptoms and treatments.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on coordination of rehabilitation care in hospital .
Full details of the evidence and the committee's discussion are in:
evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury
evidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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# Coordination of rehabilitation care at discharge
## Discharge planning and a multidisciplinary approach
Consider early, multidisciplinary discharge planning to ensure appropriate and smooth discharge and transition to outpatient and community services.
Reassess the person's needs and review the rehabilitation plan before discharge to ensure that their needs are addressed alongside any long-term, existing health conditions or disabilities.
Be aware that family members and carers can play a key role in the smooth transition to outpatient and community services. If the person consents and their family members or carers agree, actively involve them in the transition process.
Give people information and support at the earliest opportunity if they need to apply for funded equipment for use after discharge from hospital (for example, wheelchairs) because applications can take time to process and may delay the person's discharge.
For children and young people, arrange a meeting between the school or education setting, 1 or more members of the multidisciplinary team, and their parents or carers, to inform the education provider about the changes to the environment and education plan that the child or young person may need to meet their education and support needs. This should take into account transport needs.
Advise people that further help with funding for equipment, assistive technology, environmental adaptations and other forms of support with rehabilitation might be available for their home, education and workplace settings (for example, through local authorities, the education, health and care plan, Access to Work grants, voluntary sector grants and the Department for Work and Pensions).
Give people, and their family members or carers (as appropriate), information about services that provide independent legal, financial, employment and welfare advice (for example, Citizens Advice).
If a person has significant ongoing and complex medical and therapy needs, offer a gradual and incremental return into the community, for example, transfer to a local hospital, a stepdown bed or a pre-discharge visit to home, to reduce the distress of the sudden loss of support as an inpatient.
Ensure that ongoing advice about pain management, including a plan to reduce analgesia, is discussed with the person and passed onto the person's GP or another lead clinician. See also the NICE guideline on medicines optimisation.
Where possible, arrange joint inpatient and community team home visits with the person before discharge, especially for people with significant ongoing needs.
If there are any concerns about how the person will manage at home after they are discharged, consider overnight or weekend visits home before discharge, depending on their needs, preferences and home circumstances.
When arranging overnight or weekend visits home, involve the person in discussing the possible risks and how to manage them, especially if they live alone.
## Planning for rehabilitation and other support following discharge
If a person is likely to have continuing health and social care needs after discharge to home:
inform relevant healthcare professionals, social care practitioners and education practitioners (as appropriate)
establish the person's eligibility for funded social care support, including for families and carers
use the NHS continuing healthcare checklist, to establish the person's eligibility for a full continuing healthcare assessment before discharge
for children and young people, establish their eligibility for emergency education funding for short-term support at school and for funded support through an education, health and social care plan (if appropriate). Also see the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.
Offer a multidisciplinary approach to meet the person's rehabilitation and social care needs that is coordinated, consistent and as integrated as possible, to support the person, and their family or carer (as appropriate), through transfer from inpatient to outpatient rehabilitation services.
Document in the rehabilitation plan and handover report how rehabilitation after discharge will be delivered (see recommendations 1.7.7 to 1.7.9 for what should be included). When transferring the person to outpatient and community settings (including home), also include:
whether ongoing support and follow-up after discharge is needed, for example, community rehabilitation, referrals and review appointments
when community rehabilitation appointments will be likely to take place.
For people who will have significant ongoing needs after discharge:
arrange a pre-discharge planning meeting with community practitioners who will be involved in the person's rehabilitation, care and support (for example, therapists, social workers and care coordinators)
encourage pre-discharge visits by community practitioners to meet the person, and their family or carer (as appropriate)
consider organising a joint 'handover' appointment between the inpatient multidisciplinary team and community practitioners at the point of discharge.
Liaise with community teams (such as community and voluntary sector providers, physiotherapists and occupational therapists, education support, and special educational needs coordinators in schools and nurseries for children and young people) to agree a staged return to the workplace or education. (See also the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.)
When planning discharge, address potential barriers that may prevent the person accessing rehabilitation in the community. For example, ensure that they can travel to and access the location of treatments, and ensure that the timing and length of appointments will be manageable for them.
If a person cannot travel to rehabilitation appointments, offer telephone or video consultations, or rehabilitation in the person's home.
Consider arranging telephone or video consultations or rehabilitation in the person's home, rather than in a clinic or hospital setting (for example, if the person needs help to learn to live independently in their own home).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on coordination of rehabilitation care at discharge .
Full details of the evidence and the committee's discussion are in:
evidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury
evidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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## A single point of contact, key contact and key worker after discharge
At discharge from hospital, provide people and their family or carers (as appropriate) with a single point of contact at the hospital for information, help and advice for a limited time period (for example, 3 months).
If people need ongoing rehabilitation and other health and social care support after discharge, the inpatient multidisciplinary team and community practitioners should agree who will be the key contact after discharge when contact with the hospital is no longer appropriate (see recommendation 1.8.23). This person may be a GP, rehabilitation physician, special educational needs coordinator, allied health professional, family support worker, social worker, case manager, disability paediatrician or speciality-specific coordinator, for example, a neuro navigator.
If people have complex or long-term conditions or social care needs, consider appointing a key worker as a direct source of advice, support and signposting. This should be a healthcare or social care professional with knowledge and expertise about inpatient or community-based rehabilitation and support, including education or training support for children and young people.
For young people who are transitioning between children's and adults' services, see recommendations about the role of the named worker in the NICE guideline on transition from children's to adults' services for young people using health or social care services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on a single point of contact, key contact and key worker after discharge .
Full details of the evidence and the committee's discussion are in:
evidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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# Supporting access and participation in education, work and community (adjustment and goal setting)
Also see the section on setting rehabilitation goals.
Help and support the person to adjust after a traumatic injury by asking them and their family members or carers (as appropriate) about:
their life, hobbies, occupation, usual activities, and personal and family history, and finding out what is important to them
their views and feelings about their injuries and rehabilitation options
the support they think they will need by asking about their views and feelings
allowing time for adjustment and considering this before starting any new rehabilitation therapies or interventions.
Support the person to achieve realistic rehabilitation goals for life skills, work-related training or education (see the section on setting rehabilitation goals). Support should be tailored to the person's needs and may include:
providing equipment and adaptations (for example, wheelchairs and seating)
increasing independence in activities of daily living (for example, personal care, dressing and bathing, housework, shopping, food preparation, eating and drinking, managing money, how to access carers' and disability benefits and grants, driving or using public transport)
work-related training (for example, careers advice and retraining)
advice from job centres (for example, disability employment advisers and access to work scheme)
access to adult education settings
access to education for children and young people (for example, special educational needs and disabilities adjustments in school, or new school placements).
Revisit rehabilitation goals with the person at regular intervals and align them with ongoing emotional and psychological adjustment.
Give people information about opportunities for engaging in daily meaningful activity (for example, hobbies, social activities or voluntary work) while they are in the process of a staged return to work.
Adapt rehabilitation activities to promote social interaction and participation in the person's normal activities of daily living consistent with the person's lifestyle and preferences.
Provide information for the person's employer or education provider about:
the person's rehabilitation needs and
how they can make adjustments to support the person's rehabilitation goals, for example, a staged or part-time return to work or education, and/or amended duties.
See the section on workplace culture and policies in the NICE guideline on workplace health: long-term sickness absence and capability to work for recommendations about vocational support and returning to work.
Provide information for early years settings or schools about the child or young person's rehabilitation needs, and the adjustments needed to enable their return to education and sports, for example, a staged return.
Give children and young people, and their families and carers (as appropriate), information about educational support and return to school.
For young people who are starting to access support from adult rehabilitation services, see the NICE guideline on transition from children's to adults' services for young people using health or social care services.
Community practitioners should offer emotional and psychological support to adults and their families and carers to help with lifestyle adjustments and the effects of the traumatic injury (for example, prolonged hospitalisations), and support their gradual return to work, education, social roles and leisure activities.
The team around the child should offer emotional and psychological support to children, young people and their families and carers to help with lifestyle adjustments and the effects of the traumatic injury (for example, prolonged hospitalisations), and support their gradual return to education, play, social and leisure activities.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting access and participation in education, work and community (adjustment and goal setting) .
Full details of the evidence and the committee's discussion are in:
evidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury
evidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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# Commissioning and organisation of rehabilitation services
## Commissioning
When planning, commissioning and coordinating the delivery of rehabilitation and related services (for example, social care and the voluntary sector), commissioners and providers should design services with whole care pathways in mind, from acute treatment and inpatient rehabilitation through to community provision, including specialised and non-specialised elements.
Ensure collaboration between commissioners from different commissioning bodies to ensure seamless provision, for example, to include specialist community, vocational and educational rehabilitation provision for people after a traumatic injury, including those transferring between children's and adults' services.
Ensure that it is clear locally who has overall designated commissioning responsibility for rehabilitation services.
Commissioners and providers should ensure that rehabilitation services for people after a traumatic injury:
meet the needs of people of all ages and at all stages of rehabilitation
are developed and co‑designed in collaboration with the people who use rehabilitation services and the healthcare professionals who work within them
are outcome-focused and relevant for the people who use them.
Consider commissioning intensive (for example, 3‑week) residential or outpatient rehabilitation programmes for people of all ages in addition to existing rehabilitation pathways, for example, as a tertiary service for trauma rehabilitation within the trauma network.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on commissioning .
Full details of the evidence and the committee's discussion are in:
evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury
evidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury.
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## Organisation
Establish care networks (for example, trauma networks) and clear guidance on coordination and communication between rehabilitation settings and services to meet the needs of the local population across different aspects of rehabilitation service commissioning.
Rehabilitation units should maintain an online directory of care pathways, rehabilitation facilities and voluntary sector services (including recreational facilities) so that practitioners have access to up-to-date information and contact details to pass on to people with complex rehabilitation needs.
If community treatments and services remain uncertain at the point of discharge, give people and their families and carers (as appropriate) information about rehabilitation community and social services available in their local area and from national support networks, and how they can access these.
Offer networking opportunities between different rehabilitation, social care and related services to enhance inter-service awareness and working relationships.
Consider technology-enabled follow-up, support and rehabilitation sessions if people request more local, accessible therapy or if rehabilitation practitioners are not available in their area, for example, in rural areas.
Consider group rehabilitation sessions to allow people to interact with peers, share experiences and to provide valuable support.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisation .
Full details of the evidence and the committee's discussion are in:
evidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community.
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## Rehabilitation skills, knowledge and expertise in the workforce
Ensure that staff working with people with complex rehabilitation needs have specialist skills, knowledge and expertise in the person's injuries, the complexity of their rehabilitation needs and goals, and the stages of their recovery journey.
Ensure that hospital staff have access to supervision and training to develop their specialist knowledge in the management and rehabilitation of traumatic injuries.
Ensure that community rehabilitation practitioners have access to training expertise, advice or peer support from specialist services, especially where specific rehabilitation interventions or services are not widely available. For example, healthcare professionals such as speech and language therapists, practitioner psychologists and consultants with specialist knowledge of specific injuries and complex rehabilitation could work together with general rehabilitation staff working in community-based rehabilitation services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation skills, knowledge and expertise in the workforce .
Full details of the evidence and the committee's discussion are in:
evidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury
evidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.
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# Physical rehabilitation
## Physical rehabilitation – early interventions and principles
Provide personalised exercises as soon as possible after a traumatic injury to maintain and improve muscle function, strength and range of movement.
Proactively support people in managing their pain, and ensure that they have adequate analgesia so that rehabilitation can go ahead.
Choose a pain scale appropriate for the person, taking into account a range of factors such as their developmental age, cognitive ability, any communication difficulties and their first language.
If needed, provide aids, splints or orthotics to maintain range of movement or protect the injury (for example, an ankle-foot orthosis, knee brace or spinal orthosis).
Use clinical judgement and expertise to determine the frequency and dose of the prescribed exercises because this is vital to the success of the interventions, and will differ depending on the individual needs and goals.
Before starting weight-bearing exercises, be aware of the effects of low blood pressure (for example, postural hypotension or vasovagal syncope ) and monitor the person for hypotensive symptoms when starting therapy.
Minimise adverse effects of low blood pressure and loss of postural reflexes by:
-ptimising the person's bed position and using strategies such as thromboembolic stockings
ensuring adequate hydration
carrying out a medication review
using abdominal binders and tilt tables.
Be aware that traumatic injury that requires intubation, or causes facial trauma, oedema or loss of dentition may lead to a voice disorder, decreased speech intelligibility and/or swallowing difficulties. Consider early referral to appropriate professionals as needed; this may include maxillofacial specialists, dental services, ear, nose and throat services, or speech and language therapy.
Promote independence with activities of daily living, in particular personal activities of daily living, and consider referral to occupational therapy if needed.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical rehabilitation – early interventions and principles .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Early weight-bearing
The surgical team should define and document the person's weight-bearing status at the earliest opportunity after a traumatic injury, and inform the rehabilitation multidisciplinary team, explaining the reasons for restricted weight-bearing, what limits should be put in place and for how long.
Start a programme of weight-bearing exercises, including exercises through play for children and young people, as soon as possible after a traumatic injury to encourage mobility and maintain postural reflexes, muscle mass, strength and function.
For people with lower limb injuries, start a programme of targeted weight-bearing exercises, including exercises through play for children and young people, to improve range of movement of the affected joint(s), improve muscle activation, and improve strength and balance. Aim to progress the person's function with weight-bearing tasks such as mobility, ability to move from sitting to standing, and ability to lateral step.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on early weight-bearing .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Aerobic and strengthening exercises
As soon as possible after a traumatic injury, start a tailored exercise programme to help with reconditioning, fitness, strengthening, balance, proprioception and vestibular function, irrespective of the person's age, stage of rehabilitation or combination of injuries. The exercise programme:
could be self-directed and/or delivered as one-to-one sessions or in a group
should include resistance training, core strengthening exercises and general aerobic fitness
should include task-specific balance training if needed
should be incorporated into the usual play activities for children
should be tailored to the person's needs and goals (for example, the frequency of the sessions and the exercises involved).
Consider a continued programme of aerobic exercise when agreeing a rehabilitation plan and at appropriate points along the rehabilitation pathway.
For people with limited lower limb mobility or immobility after a traumatic injury, consider a programme of upper body aerobic training or seated exercises.
Tailor the aerobic exercise programme to the person's interests to help with personal commitment and adherence, and depending on the nature of their traumatic injuries.
Do not withhold aerobic exercise programmes from older people after a traumatic injury.
After discharge from hospital after a traumatic injury, offer people a home exercise programme that includes aerobic and strengthening exercises, and review their progress at outpatient clinics or key worker appointments.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on aerobic and strengthening exercises .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Gait training and re-education
For people who are unable to weight-bear (because of clinical restrictions or pre-existing conditions), start an exercise programme as soon as possible after the traumatic injury to reduce the impact of non-weight-bearing and to optimise the transition to gait training when possible.
As soon as possible after a traumatic injury and once weight-bearing can begin, start a gait re-education programme that:
aims to restore gait patterns
includes passive stretches and range of movement exercises
reduces the impact of non-weight-bearing on joints and muscles.
For people who need a non-weight-bearing period after a traumatic injury:
assess muscle weakness and joint range of movement as soon as possible after the non-weight-bearing period ends and
start an exercise programme aimed at muscle strengthening and gait progression.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on gait training and re-education .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Manual therapies and maintaining joint range of movement
Provide a programme of passive, active assisted or active range of movement exercises for all affected joints.
Consider a programme of targeted stretching techniques in addition to the standard range of movement exercise programme in recommendation 1.11.22.
If the person is unable to engage in range of movement exercises independently, consider using controlled motion devices to help with range of movement at the knee and ankle joints.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on manual therapies and maintaining joint range of movement .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Splinting and orthotics
Regularly review the use of splints (as part of donning and doffing ), cautiously increasing the length of time the splint is in use to ensure that it is still appropriate and that there are not complications such as nerve injury or pressure sores.
Ensure that the person, and their families and carers (as appropriate), know how to put on and take off their orthoses and splints, when to wear them and when to seek advice.
For people with lower limb fractures or nerve injuries, consider an orthosis (for example, a dorsi-wedge in a moon boot or an ankle-foot orthosis) if there is a risk of loss of ankle range of movement.
For people with external fixation for lower limb fractures, carry out specialised splinting to maintain ankle range of movement.
Monitor the pressure effects on skin by orthoses or splints, particularly in people with reduced cutaneous sensation and/or recent skin graft or flaps. Seek advice from tissue viability services and/or plastic surgery specialists as needed.
Be aware that spinal orthoses, such as cervical collars and thoraco-lumbar spinal orthoses, may be poorly tolerated by some people, particularly older people or those with delirium, cognitive impairment or dementia.
If spinal orthoses are causing problems (such as pain, pressure sores, or swallowing or breathing difficulties) or are significantly affecting the person's ability to engage with rehabilitation, inform the relevant surgical team.
If splints or braces are used to immobilise and protect joints, avoid positions that may result in loss of function or complications in the future.
For people with upper limb injuries that affect range of movement in their hands and fingers, offer bespoke (thermoplastic) splints as early as clinically possible to maintain range of movement. Refer people with complex hand injuries to a hand therapy specialist, as appropriate.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on splinting and orthotics .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Management of swelling and oedema, and scars
Discuss with people what swelling to expect after a traumatic injury. Explain how to monitor swelling on a daily basis, and advise them about signs or symptoms that they should seek medical advice for.
Consider alternative medical causes for unexpected swelling such as deep vein thrombosis, and investigate as necessary.
Start a programme of circulation exercises and elevate the person's affected limb to prevent and reduce swelling after a traumatic injury, for example, by using elevating leg rests for wheelchairs.
Consider providing compression bandaging under specialist supervision, for example, from a specialist in hand therapy.
Help the person desensitise themselves to their injury by encouraging them to:
look at the affected area
gently touch the affected area
move their affected limb.
For children and young people, keep their hospital bed as a 'safe' space, and carry out potentially painful scar management techniques such as massage, or other painful treatments, away from their bed if possible.
Reassure people that unpleasant sensations (for example, pain and itchiness) in the area of wounds or skin injuries are normal after a traumatic injury, and may change as recovery progresses.
Discuss and give people information about scar management such as keeping the wound out of direct sunlight for 1 year, and using recommended emollients.
Provide a massage programme for scar tissue after healing, to desensitise the affected area and increase tissue mobility.
Consider referral for specialist treatments for people with problematic scars such as hypertrophy or contracture across joints.
If the person's injuries and scars have had a significant psychological impact on them, consider referral to psychology services and/or signpost to appropriate support groups. See also the section on assessing psychological functioning and the section on psychological rehabilitation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of swelling and oedema, and scars .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Nutritional supplementation
Monitor the person's intake of adequate food and drink to maintain weight, taking into account the effects of post-surgical anorexia, pain medications, constipation and nausea, and the increased calorific needs of healing.
Regularly and proactively review the person's nutritional needs and the dietary plan for effective rehabilitation. See recommendations in the NICE guideline on nutrition support for adults.
Following assessment by a dietitian specialising in trauma care, consider supplementation of dietary protein for people who are frail, have gastrointestinal health issues or have multiple injuries.
Involve specialist dietitians when considering dietary protein requirements for people with severe kidney impairment.
For people with a fragility fracture, measure vitamin D levels and consider a supplement. Also see the recommendations in the NICE guideline on osteoporosis: assessing the risk of fragility fracture and the NICE guideline on vitamin D: supplement use in specific population groups.
For people with burns in combination with other traumatic injuries, regularly monitor their weight and involve a dietitian with experience of burns, for example, if the person's weight fluctuates or they are at risk of losing muscle mass and strength.
If there are concerns about safe swallowing and risk of aspiration (see recommendation 1.1.10), keep the person nil by mouth and carry out a swallowing assessment by an appropriately trained healthcare professional as soon as possible. If immediate assessment is not available, maintain hydration and nutrition by non-oral means. Also see the NICE guideline on nutrition support for adults.
Involve a dietitian and nutrition team for treatments to maintain nutritional supply, for example, a nasogastric tube, percutaneous endoscopic gastrostomy (PEG), radiologically inserted percutaneous gastrostomy (RIG) or parenteral nutrition (PN).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on nutritional supplementation .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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# Cognitive rehabilitation
Please note this guideline does not cover assessment or specific rehabilitation interventions for people with traumatic brain injuries. See recommendation 1.2.3 in the section on multidisciplinary team rehabilitation needs assessment.
Reassure people that most trauma-related problems with cognitive functioning are temporary.
Adapt rehabilitation therapy to the person's current cognitive function and emotional needs, taking into account any problems with motor development and skills, and any coexisting neurodevelopmental conditions.
If problems with cognitive functioning persist, get worse or recur, carry out further assessments to understand the cause.
If a person has problems with cognitive functioning after a traumatic injury, provide information:
using clear language
with the timing, content and delivery tailored to the person's needs and preferences
in a suitable format (for example, Easy Read)
with written plans to aid recall
that uses pictures, symbols and objects of reference
with calendar or diary prompts for sessions or appointments.
Share information with family members or carers (as appropriate) so they can help the person understand the key messages and aid recall.
For children and young people:
ask parents and carers if there are any pre-injury cognitive issues, for example, any known special educational needs
liaise with their education provider if information about their pre-injury cognitive performance is needed
inform education providers and teachers, including those in the hospital setting, about the child or young person's needs and any problems with cognitive functioning.
Be aware that after a traumatic injury, people may present with fluctuations in mental capacity, and that this may affect decision making. See the NICE guideline on decision making and mental capacity.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on cognitive rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review B.2: cognitive interventions for people with complex rehabilitation needs after traumatic injury.
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# Psychological rehabilitation
Reassure people that short-term psychological problems in the form of an acute stress response are common after a traumatic injury. Symptoms can last for 4 to 6 weeks and may include:
disturbed sleep
intrusive thoughts and memories
nightmares
bedwetting in children
flashbacks
low mood
anxiety.
Be aware that:
there is an ongoing risk of low mood in people after a traumatic injury
psychological problems and mental distress commonly accompany ongoing emotional and psychological adjustments, for example, as a result of life-changing injuries
psychological problems and mental distress can recur or deteriorate when a person is discharged home or transferred to another setting
anxiety, depression and post-traumatic stress disorder (PTSD) can occur or recur at any time after a traumatic injury.
Discuss psychological support with the person, and their family members or carers (as appropriate), and offer psychological and emotional support that is tailored to their rehabilitation goals, needs and preferences as part of an overall rehabilitation treatment programme.
If the person's rehabilitation is adversely affected by their psychological problems (for example, if the person is struggling to engage with the rehabilitation process), refer them urgently to psychology services for psychological assessment and treatment, ideally to a practitioner psychologist with appropriate expertise with physical trauma and rehabilitation.
Ask about thoughts of self-harm and suicide regularly, as part of psychological assessment, and particularly at key milestones such as hospital discharge and changes of setting.
The multidisciplinary team should regularly check for signs and symptoms of anxiety, depression and PTSD when reviewing the person's progress against rehabilitation goals and plans.
Treat PTSD, anxiety, and depression in adults, children and young people as part of an overall coordinated rehabilitation treatment package, and in line with the NICE guidelines on:
post-traumatic stress disorder
social anxiety disorder
generalised anxiety disorder and panic disorder in adults
depression in adults
depression in adults with a chronic physical health problem
depression in children and young people
service user experience in adult mental health.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury.
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# Rehabilitation after limb reconstruction, limb loss or amputation
This section covers specific rehabilitation for people after limb reconstruction, limb loss or amputation. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to spinal cord injury, nerve injury or chest injury.
## Rehabilitation after limb-threatening injury – early assessment, decision making and support
Discuss limb reconstruction and/or amputation with the person, and their family members or carers (as appropriate), when making decisions about treatment pathways and assessing rehabilitation options. Recognise that, for some people who have had a complex limb-threatening injury, amputation may be the option that best delivers the person's most important rehabilitation goals.
Members of a specialist multidisciplinary team (for example, a limb reconstruction team or prosthetics team) alongside the trauma rehabilitation team should discuss the implications of the following, as part of assessing rehabilitation needs, as soon as possible with the person, and their family members or carers (as appropriate):
rehabilitation pathways
pain management
recovery timescales
long-term expectations
impact on daily life, for example, work, hobbies, activities, education and play.
When amputation is being considered and if time permits before surgery, a member or members of the specialist multidisciplinary team with expertise in prosthetic prescription and rehabilitation should carry out a pre-amputation rehabilitation assessment and consultation.
Offer psychological support before limb reconstruction or amputation (see the section on psychological support).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after limb-threatening injury – early assessment, decision making and support .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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## Rehabilitation after limb reconstruction
After limb reconstruction, start rehabilitation therapy as early as possible (ideally the day after surgery) to maintain range of movement. This may include:
splinting
exercise
pain management
swelling and oedema management
hand therapy
mobility
positioning.
Avoid early rapid irreversible loss of range of movement after limb reconstruction by ensuring that the person carries out range of movement exercises for the affected joint and other joints to optimise recovery and avoid contractures.
Continue psychological and emotional support after limb reconstruction (see the section on psychological support).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after limb reconstruction .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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## Rehabilitation after limb loss or amputation
After limb loss or amputation, refer the person to the amputee and prosthetic rehabilitation service as soon as possible if the referral was not made before the surgery.
After limb loss or amputation, start rehabilitation therapy as early as possible and ideally the day after surgery. This may include:
pain management (see the section on pain management)
residual limb oedema and shaping (see the section on residual limb oedema and shaping)
range of movement and strengthening exercises (see the section on range of movement and strengthening)
functional independence, including play for children (see the section on functional independence)
psychological support (see the section on psychological support).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after limb loss or amputation .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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Plan analgesia with the person before surgery, and ensure that their pain is managed after surgery so that they can effectively participate in rehabilitation therapies.
Manage the different types of pain that can develop, for example, phantom limb pain, neurogenic pain, psychogenic pain, myogenic pain and complex regional pain, and refer the person to a specialist pain team if needed.
Consider visualisation interventions such as graded motor imagery or mirror therapy to manage phantom limb pain in people who have had an amputation or limb loss after trauma.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain management after limb loss or amputation .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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Manage residual limb oedema using elevation and compression therapy to reduce swelling and improve shaping in preparation for prosthetics fitting.
For people with a below-knee amputation, keep the limb elevated using a residual limb (stump) board when using a wheelchair.
Avoid residual limb swelling when using walking aids, for example, by using crutches or a frame with the limb in a dependent position.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on residual limb oedema and shaping after limb loss or amputation .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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Maintain and improve range of movement and strength after limb loss or amputation (particularly in hip flexors, hip abductors and knee flexors) by starting rehabilitation therapy that includes:
exercise
mobility, including early walking aids (for example, amputee-specific early walking aids) after surgery when the wound has settled
positioning.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on range of movement and strengthening after limb loss or amputation .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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Do not wait for prosthetics to be fitted before starting rehabilitation after limb loss or amputation.
Ensure that wheelchairs:
are provided as early as possible
include appropriate accessories (for example, anti-tippers and residual limb boards)
are adjusted to accommodate the changes in the person's weight distribution after limb loss or amputation.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on functional independence after limb loss or amputation .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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## Psychological support after limb loss, amputation or limb reconstruction
Continue psychological support and ensure that the multidisciplinary team has access to a practitioner psychologist with appropriate expertise in physical trauma and rehabilitation, ideally with experience of working with people with limb loss, amputation or limb reconstruction.
For children, consider play or play therapy when offering psychological and emotional support.
For children and young people, the team around the child should actively monitor for any emerging emotional difficulties as the child or young person grows and develops (for example, moving schools, puberty and emotional relationships).
Take into account the long-term psychological impact of change in body image as a result of injury for all people and the psychological impact for children and young people as they grow.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological support after limb loss, amputation or limb reconstruction .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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## Continuing rehabilitation after limb reconstruction, limb loss or amputation and after discharge
When completing a rehabilitation plan (see the section on developing a rehabilitation plan and making referrals) for people after limb reconstruction, limb loss or amputation, ensure that the following are always included in the person's rehabilitation programme:
exercise and mobility
psychological and emotional support
referral and signposting to support groups
pin-site review (for limb reconstruction)
frame adjustment (for limb reconstruction)
prosthetics team review, if relevant.
The specialist multidisciplinary team should offer psychological and emotional support to enable the person to adjust to their altered body image, manage pain and cope with the possibility that they may need further procedures. Psychological and emotional support should involve:
listening carefully and validating feelings
supporting reflection and reasoning around realistic goals and care
supporting planning
-ffering feedback about progress towards goals.
Carry out reviews of the rehabilitation plan (for example, equipment, home environment, clothing and footwear needs) at key points, for example:
at discharge
when an external-fixation frame is removed
when weight-bearing status changes
when prosthetics are changed
when the person starts to go outside
when the person starts to return to education, work or community activities
if the person is readmitted because of complications.(Also see the section on monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments.)
For children and young people, monitor the impact of growth on the residual limb and prosthetic fitting, and refer without delay for specialist assessment when there are changes.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on continuing rehabilitation after limb reconstruction, limb loss or amputation and after discharge .
Full details of the evidence and the committee's discussion are in evidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.
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# Rehabilitation after spinal cord injury
This section covers specific rehabilitation for people after spinal cord injury. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to limb injury, nerve injury or chest injury.
These recommendations focus on the rehabilitation and supportive needs of people with spinal cord injury (after initial acute assessment) who are not currently in a regional specialist spinal cord injury centre. See also the NICE guideline on spinal injury: assessment and initial management.
## Rehabilitation after spinal cord injury – referral, assessment and general principles
For people with a spinal cord injury:
ensure that ongoing contact with the regional specialist spinal cord injury centre is made in line with the recommendations on communication with tertiary services in the NICE guideline on spinal injury and
refer using the national spinal injuries database within 24 hours of the diagnosis.
Seek advice from the regional specialist spinal cord injury centre outreach team throughout the person's inpatient stay and at discharge to support their rehabilitation.
A healthcare professional with appropriate clinical skills should complete an assessment using an American Spinal Injury Association (ASIA) chart as soon as possible after a spinal cord injury, and repeat this as clinically indicated.
Be aware that spinal cord injury may affect areas of physical function including bowel, bladder and sexual function, and seek specialist advice as appropriate (see also recommendation 1.2.6 in the multidisciplinary team rehabilitation needs assessment section).
Refer children and young people with a spinal cord injury:
to specialist play services to support their emotional and physical development and wellbeing
to education services to support their ongoing educational development.
For children and young people, monitor growth and nutrition throughout the rehabilitation process.
When discharge planning for children and young people after a spinal cord injury, ensure that meetings take place early and involve the child or young person, and their parents and carers (as appropriate), together with the local education authority, specialist play services and multidisciplinary teams involved in their care.
After hospital discharge, consider ongoing contact between the rehabilitation team and the person, and their family members and carers (as appropriate), with education and a structured review of progress in rehabilitation as part of outpatient follow-up. This could be offered by telephone or video link.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after spinal cord injury – referral, assessment and general principles .
Full details of the evidence and the committee's discussion are in evidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.
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## Bladder and bowel function
Assess and manage bladder function after a spinal cord injury as follows:
protect upper renal function at all times by maintaining safe bladder emptying (inserting a urinary catheter if necessary), and ensuring that people understand and use bladder management techniques as a key part of their rehabilitation (see also the monitoring and surveillance section in the NICE guideline on urinary incontinence in neurological disease)
identify acute kidney injury in line with the NICE guideline on acute kidney injury
identify renal tract stones (see also the NICE guideline on urinary incontinence in neurological disease).
Regularly assess and manage bowel function after a spinal cord injury as follows:
assess anal tone and sensation
start and review a bowel management plan that includes laxatives, enemas, suppositories and manual evacuation, depending on the level and severity of the spinal injury.
Keep the person nil by mouth until their bowel function has been assessed because of the risk of neurogenic bowel stasis and aspiration pneumonia. Avoid unnecessary delays to assessing bowel function to avoid prolonged periods of nil by mouth.
For younger children, ask their parents and carers (as appropriate), about their pre-injury continence skills, and take their age and ability into account when assessing and managing bladder and bowel function.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bladder and bowel function .
Full details of the evidence and the committee's discussion are in evidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.
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## Respiratory function, swallowing and speech
Keep the person nil by mouth until their risk of aspiration has been assessed (see recommendation 1.11.51).
Be aware that people with cervical spine injuries and those managed on flat bed rest, are particularly at risk of swallowing and speech difficulties and should be assessed early for risk of aspiration.
Assess and manage respiratory function (taking into account age and ability when assessing children and young people) as follows:
use spirometry to measure vital capacity in line with the NICE guideline on spinal injury
consider prophylactic respiratory support with, for example, active cycle of breathing techniques, incentive spirometry, intermittent positive pressure breathing (IPPB) or non-invasive ventilation (NIV), to maintain forced vital capacity (FVC) and prevent chest complications
consider use of cough-assist techniques or devices.
Consider critical care management for people with a high-level spinal injury.
Assess voice quality and refer to a speech and language therapist and/or ear, nose and throat specialist as needed.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on respiratory function, swallowing and speech .
Full details of the evidence and the committee's discussion are in evidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.
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## Preventing complications
Assess skin and pressure care after a spinal cord injury as follows:
start a 24‑hour positioning and turning programme and use a pressure mattress if appropriate (ensuring that the spinal column has been assessed as mechanically stable) or indicated and
give information about skin protection for people with sensory deficits.
Be aware of the risk of autonomic dysreflexia, and treat it as a medical emergency.
Be aware that most people who have had a spinal cord injury will develop orthostatic hypotension, which can affect their participation in rehabilitation. Consider interventions to optimise blood pressure, for example, medication review, graduated positioning, abdominal binders and compression stockings.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing complications .
Full details of the evidence and the committee's discussion are in evidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.
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## Maintaining mobility and movement
For people with a spinal cord injury who are using a spinal orthosis (for example, cervical collar or thoraco-lumbar spinal orthosis), regularly assess them for complications such as pain, pressure sores, swallowing or breathing difficulties (particularly in older people or those with dementia or delirium).
If spinal orthoses are causing side effects or are significantly affecting the person's engagement with rehabilitation, inform the relevant surgical team.
Maintain joint range of motion after a spinal cord injury and consider early use of splints and orthoses.
Seek specialist advice about hand splints for people with a higher level cervical spinal injury to maintain tenodesis grasp and release ability where indicated; for example, do not splint into wrist extension if there is C6 involvement.
Consider interventions (for example, progressive sitting, tilt table) to increase mobility and aid early sitting as soon as possible after a spinal cord injury.
Consider additional techniques and specialised equipment (for example, functional electrical stimulation, gait orthoses, bodyweight-supported gait training and robotic devices) to promote mobility, upper limb function and independent walking.
Assess people's needs and refer them to specialist services without delay if assistive technology, such as environmental control systems, is needed.
For adults, treat spasticity to prevent losing range of joint movement and avoid contractures.
For adults, consider oral medications to treat spasticity or botulinum toxin type A targeted muscle injections, depending on the clinical circumstances. In January 2022, botulinum toxin type A was an off-label use for some of the available brands. See individual summaries of product characteristics and NICE's information on prescribing medicines.
Stop oral medications and targeted muscle injections for spasticity if there is no benefit at the maximum tolerated dose. (Explain to the person that special precautions may be needed when stopping certain medicines.)
If spasticity is causing significant impairments in mobility, posture or function, and initial treatments are unsuccessful, refer the person to a multidisciplinary team experienced in the management of spasticity for assessment and treatment planning.
For children and young people, assess spasticity and follow the recommendations in the NICE guideline on spasticity in under 19s.
Be aware that pre-pubertal children have a high risk of early or late onset kyphoscoliosis, so monitor their spinal shape and curvature at regular intervals and refer early for specialist assessment if needed.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on maintaining mobility and movement .
Full details of the evidence and the committee's discussion are in:
evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury
evidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.
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## Low mood and psychological support
Be aware that there is significant risk of low mood and psychological trauma for people with spinal injury, and that this may have an impact on rehabilitation.
Consider psychological support after spinal cord injury, and ensure that the multidisciplinary team has access to a practitioner psychologist with appropriate expertise in physical trauma and rehabilitation, ideally with experience of working with people with spinal cord injury.
For children and young people, the team around the child should actively monitor for any emerging emotional difficulties as the child or young person grows and develops (for example, moving schools, puberty and emotional relationships).
Take into account the long-term psychological impact of change in body image as a result of injury for all people and for children and young people as they grow.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on low mood and psychological support .
Full details of the evidence and the committee's discussion are in evidence review C.2: specific programmes and packages in nerve injury for people with complex rehabilitation needs after traumatic injury.
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# Rehabilitation after nerve injury
This section covers specific rehabilitation for people after nerve injury. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to limb injury, spinal cord injury or chest injury.
## Rehabilitation after nerve injury – general principles
Be aware that nerve injuries may be hidden, particularly if the person:
has multiple injuries
has a cognitive impairment or a learning disability
has a head injury
is in critical care (adults) or paediatric intensive care (children and young people)
has a pre-existing neurological condition or injury
has a complex fracture.
If nerve injury is suspected, assess the peripheral nerves of the affected limb to identify the involved nerve and functional deficit. The surgical team should decide whether early surgical intervention is necessary (see also the section on assessing physical functioning).
Be aware of the risk to tissue viability if there is sensory or motor loss secondary to peripheral nerve injury.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after nerve injury – general principles .
Full details of the evidence and the committee's discussion are in evidence review C.2: specific programmes and packages in nerve injury for people with complex rehabilitation needs after traumatic injury.
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## Therapies and referral
After nerve injury, start rehabilitation therapy to maintain range of movement and regain function. This may include:
splinting
exercise (passive and active range of movement)
play therapy (for children)
pain management
sensory interventions (including mirror therapy, electrical stimulation and hand therapy)
hydrotherapy (where available)
functional or vocational therapy.
Regularly assess for signs of nerve recovery and review the programme of therapy as needed.
Consider nerve conduction or a specialist opinion to help determine prognosis and guide future therapy and management if early surgical intervention was not needed and:
there are no signs of nerve recovery 6 weeks after the injury or
if recovery is not as expected.
For people who have a poor prognosis for recovery after rehabilitation therapy and nerve conduction studies, consider referral to a specialist peripheral nerve injury service, for example, for surgery.
Be aware that people recovering from nerve injury may experience low mood, anxiety and lack of motivation because recovery may be a lengthy and ambiguous process (for example, because of uncertainty about the long-term prognosis).
Consider psychological support after nerve injury, and ensure that the multidisciplinary team has access to a practitioner psychologist with appropriate expertise in physical trauma and rehabilitation, ideally with experience of working with people with nerve injury.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on therapies and referral .
Full details of the evidence and the committee's discussion are in evidence review C.2: specific programmes and packages in nerve injury for people with complex rehabilitation needs after traumatic injury.
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# Rehabilitation after chest injury
This section covers specific rehabilitation for people after chest injury. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to limb injury, spinal cord injury or nerve injury.
Start rehabilitation after chest injury as soon as possible to optimise respiratory function and prevent deconditioning.
Assess pain regularly and provide adequate analgesia to allow people to be able to breathe deeply, cough, start moving around early and participate in rehabilitation activities.
If oral or intravenous analgesia is inadequate to enable people to breathe deeply, cough or start engaging in rehabilitation, consider early neuraxial (for example, epidural catheter) or regional (for example, paravertebral, erector spinae plane or serratus anterior blocks) analgesia delivered by an appropriately qualified healthcare professional.
Encourage people with chest trauma to start moving around as soon as it is safe to do so, to optimise respiratory function and prevent deconditioning.
Offer a range of rehabilitation therapies to prevent atelectasis and promote deep breathing and secretion clearance. Therapies may include:
supported cough to brace chest wall
active cycle breathing technique
incentive spirometry
portable intermittent positive pressure breathing (IPPB) devices.
Be aware that stiffness of the upper limbs is a common complication of chest and rib injury on the affected side.
The multidisciplinary team should discuss the risks and benefits of the use of spinal orthoses in people with a combination of spine injury and rib fracture.
Prevent stiffness of the upper limbs with range of movement exercises and advice about maintaining function. Encourage children to play to maintain their range of movement.
Give people information about what they can do to help themselves return to their normal activities of daily life (for example, how to increase their exercise tolerance), and how to seek help if they are worried about problems such as:
pain
shortness of breath
fatigue
cough.
Assess adults presenting with rib fractures for their risk of fragility fracture in line with NICE's guideline on osteoporosis.
If people have complex chest injuries that affect communication and swallowing skills, consider referral to speech and language therapy.
Consider assessing children and young people with rib fractures for bone density disorder and for the possibility of non-accidental injury (see recommendation 1.1.13 on safeguarding).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after chest injury .
Full details of the evidence and the committee's discussion are in evidence review C.4: specific programmes and packages in chest injury for people with complex rehabilitation needs after traumatic injury.
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# Terms used in this guideline
## Complex rehabilitation needs
Complex rehabilitation needs cover multiple needs due to traumatic injury or injuries (polytrauma), and will involve coordinated multidisciplinary input from 2 or more allied health professional disciplines.
## Controlled motion device
A device that gently flexes and extends the knee joint (usually after surgery) to allow the joint to bend without the person needing to exert any effort. Sometimes called a continuous passive motion machine.
## Key worker
A key worker is a named member of clinical staff (for example, a senior nurse, physiotherapist or occupational therapist) assigned at each stage of the care pathway who coordinates the person's rehabilitation and care; this may continue post-discharge. They act as a single point of contact for the person and their family and carers, and will support liaison with other services, such as social care. The person who fulfils this role may be different along the pathway, for example, following hospital discharge. This role may also be performed by case managers or case coordinators, who would coordinate care as well as liaise with insurers and legal teams, particularly following discharge.
For major trauma, the role of key worker is defined further in recommendation 1.6.3 in the NICE guideline on major trauma: service delivery.
## Neurovestibular disorders
Dizziness or problems with balance caused by damage to parts of the inner ear and/or the brain that process the sensory information involved with controlling balance and eye movements.
## Orthostatic hypotension
Low blood pressure on changing position from lying to sitting, and sitting to standing.
## Practitioner psychologists
The definition of practitioner psychologists is based on the Health and Care Professions Council (HCPC) registration criteria and standards of proficiency.
## Pre-amputation rehabilitation assessment and consultation
This follows the principles of the initial rehabilitation assessment in the section on assessment and early interventions for people with complex rehabilitation needs, and also takes into account implications for rehabilitation such as recovery timescales, quality of life and goal setting for different surgical options that may include amputation of all or part of the limb, or reconstructive surgery of the limb. Decisions about surgical interventions would affect the kind of rehabilitation interventions and therapies the person would need, the timescales involved and their personal goals.
## Rehabilitation coordinator
Rehabilitation coordinators are rehabilitation specialists, for example, allied health professionals such as physiotherapists, occupational therapists, speech and language therapists, or clinicians who play an active role in the multidisciplinary team. They are usually responsible for decisions about rehabilitation treatment options at the beginning of the pathway and for the implementation of the pathway, including referral or transfer to other services. They are usually part of the team that delivers the rehabilitation care, and the lead contact for the person receiving care.
## Rehabilitation plan
This may be in the form of a rehabilitation prescription. It may also come in different versions such as the rehabilitation passport, which is a patient-held document, and may be a simplified version of the plan. It is carried with the person and also communicated between rehabilitation teams and updated accordingly and used to document information about injuries and rehabilitation treatments in an accessible format.
## Single point of contact
A single point of hospital contact following discharge may be a key worker, trauma coordinator or a rehabilitation coordinator, or it may simply be a link to a unit, team or person that formed part of the person's rehabilitation care while in hospital. The point of contact may not be able to offer advice directly but can seek information and input from others if this is needed for a defined period post-discharge.
## Specialised rehabilitation services
Specialised elements of care pathways would include options for people with complex rehabilitation needs, for example, level 1, level 2a and level 2b units within a local area.
## Strengths-based approach
Strengths-based (or asset-based) approaches focus on the person's strengths (including personal strengths, and social and community networks) and not on their deficits. Strengths-based practice is holistic and multidisciplinary, and works with the individual person to promote their wellbeing.
## Team around the child
A group of professionals who work with an individual child or young person with a disability or complex needs who come together to share information and agree a plan – along with parents and carers – to meet the child's needs. The emphasis should be on the needs of the child and the aim is to provide joined-up support.
## Trauma coordinator
This person would work closely with the multidisciplinary team to coordinate the patient pathway between relevant specialties involved in the treatment, including acute surgical and medical teams and rehabilitation, from admission to discharge, particularly for people with highly complex traumatic injuries and rehabilitation needs. They offer clinical advice and sometimes this role is performed by a nurse and is sometimes called a nurse coordinator. This role may also include the responsibilities of a key worker, liaising with family and carers, especially in the early stages of the pathway.
## Traumatic injury
This includes multiple, major and severe injuries, sometimes referred to as polytrauma, and any musculoskeletal, visceral, nerve, soft tissue, spinal or limb injury that requires admission to hospital at the time of injury.
## Vocational therapy
Focuses on the rehabilitation interventions needed to help people with long-term health conditions or disabilities return to or stay in work, education or training. This may involve adapting working conditions, job roles or retraining.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Effectiveness of intensive rehabilitation in adults
What is the effectiveness and cost effectiveness of intensive rehabilitation programmes in adults with complex rehabilitation needs after a traumatic injury?
For a short explanation of why the committee made the recommendation for research, see the rationale section on intensive rehabilitation programmes .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Effectiveness of intensive rehabilitation in children and young people
What is the effectiveness and cost effectiveness of intensive rehabilitation programmes in children and young people with complex rehabilitation needs after a traumatic injury?
For a short explanation of why the committee made the recommendation for research, see the rationale section on intensive rehabilitation programmes .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Thoracic lumbar sacral orthoses in older people
What are the benefits and harms of using thoracic lumbar sacral orthoses in older people with thoraco-lumbar vertebral fractures?
For a short explanation of why the committee made the recommendation for research, see the rationale section on splinting and orthotics .
Full details of the evidence and the committee's discussion are in evidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.
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## Self-management materials
What is the effectiveness and cost effectiveness of rehabilitation programmes combined with self-management materials, compared with rehabilitation programmes alone, in people with complex rehabilitation needs after a traumatic injury?
For a short explanation of why the committee made the recommendation for research, see the rationale section on guided self-managed rehabilitation .
Full details of the evidence and the committee's discussion are in evidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury.
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## Length of bed rest after spinal cord injury
What is the effectiveness and cost effectiveness of short-term bed rest compared with long-term bed rest on functional outcomes in people with complex rehabilitation needs after traumatic injury that involves the spinal column or spinal cord injury?
For a short explanation of why the committee made the recommendation for research, see the rationale section on maintaining mobility and movement .
Full details of the evidence and the committee's discussion are in evidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect services.
# Initial assessment and early interventions for people with complex rehabilitation needs
Recommendations 1.1.1 to 1.1.13
## Why the committee made the recommendations
Rehabilitation can be a long journey, and people will need different interventions and will aim for different endpoints. Because of this, the committee agreed that healthcare professionals should think about each person's individual rehabilitation needs and what is important to them, and take into account their personal strengths, lifestyle and goals, rather than being primarily driven by the nature of the injury.
Psychological and emotional support is important immediately after the injury, to help the person come to terms with their experience and engage with rehabilitation assessment, early interventions and goal-setting discussions.
There was evidence that avoiding delays in acute treatment can improve the effectiveness of early rehabilitation interventions. In the committee's view, early assessments and interventions are also important so that healthcare professionals have up-to-date information and can plan and start rehabilitation promptly. Nutritional assessment (including swallowing safety) is an important factor (particularly in soft tissue healing) but is often overlooked.
The person's longer-term rehabilitation goals should be taken into account when discussing treatment options because these can affect decisions made about the timing and nature of rehabilitation. For example, if a person has upper and lower limb injuries, they might not have surgical treatment of their upper limb injuries because they want to use crutches to help with weight-bearing during rehabilitation for their lower limb injuries.
## How the recommendations might affect practice
The recommendations will not involve a major change in practice and are consistent with existing NICE guidelines. Healthcare professionals might need to spend more time assessing how traumatic injuries affect all aspects of a person's life, and explaining the implications of different medical and surgical treatments on rehabilitation. Spending time on initial assessment and early treatment immediately after a traumatic injury will lead to a better tailored rehabilitation plan and goals, which will save time later on. Generally, all professionals involved in the person's care following a traumatic injury will already be equipped to provide psychological and emotional support.
Return to recommendations
# Multidisciplinary team rehabilitation needs assessment
Recommendations 1.2.1 to 1.2.12
## Why the committee made the recommendations
There was no evidence in this area, so the committee made recommendations based on their knowledge and experience. They agreed that a comprehensive approach to needs assessment is vital to meet all aspects of the person's care needs, including personal history, usual activities and potential motivations. They also highlighted injuries or conditions that may need to be assessed by specialists who are better equipped to meet complex care needs.
The committee specified the healthcare professionals who should be members of the multidisciplinary team. These members of the multidisciplinary team do not necessarily have to be available all the time, but should be able to contribute when needed.
The committee suggested ways to help people engage in the assessment process because people can have problems with engagement after a traumatic injury. The timing of the needs assessment is also an important aspect of this, because pain, fatigue and confusion can make it difficult for people to understand what is happening. They may need more time than normal to process information and adjust after the trauma. This is particularly important for people with cognitive impairment or brain injuries.
The committee agreed that time was needed for members of the multidisciplinary team to work with clinical teams to fully understand the person's rehabilitation needs and in particular consider the impact of pre-existing conditions so that this could inform a tailored rehabilitation programme. The committee were keen to highlight the importance of validated outcome tools and checklists because these can help identify people who need to be referred to a specialist service early, which can prevent delays in rehabilitation.
## How the recommendations might affect services
It is standard practice to have multidisciplinary teams conduct needs assessments. Staff might need additional training on how to use assessment tools, and some extra time might be needed as a result of the recommendations. However, this will be offset by the benefits of appropriate and timely care, increased care coordination, and better outcomes. Overall, the recommendations reinforce current practice and are in line with other guidance.
Return to recommendations
# Assessing physical functioning
Recommendations 1.2.13 to 1.2.15
## Why the committee made the recommendations
The committee discussed the importance of assessing physical functioning as part of the rehabilitation needs assessment after a traumatic injury. There was no evidence in this area so the committee agreed, based on their knowledge and experience, that the assessment should include both pre-injury and current levels of physical functioning to inform rehabilitation goals. Referrals to specialists may be needed as part of this. The person's current level of physical functioning will serve as a baseline for initial rehabilitation needs and to monitor changes.
## How the recommendations might affect services
The recommendations are not expected to have a large resource impact or be difficult to implement, although extra time might be needed to complete the comprehensive assessment. There may also be more referrals to specialist services. However, the involvement of specialist services at the assessment stage will identify needs earlier and reduce unmet care needs.
Return to recommendations
# Assessing cognitive functioning
Recommendations 1.2.16 to 1.2.20
## Why the committee made the recommendations
There was no evidence in this area. However, the committee believed that recommendations are needed because problems with cognitive functioning are common after a traumatic injury (even without brain injury). The committee also highlighted some of the cognitive problems the multidisciplinary team should consider as part of the rehabilitation needs assessment, because these may not show up on scans immediately.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice may need to be amended. Some extra time might be needed to complete the comprehensive assessment. There may also be more referrals to specialist services. However, the involvement of specialist services at the assessment stage will identify needs earlier and reduce unmet care needs.
Return to recommendations
# Assessing psychological functioning
Recommendations 1.2.21 and 1.2.22
## Why the committee made the recommendations
There was no evidence in this area, so the committee made recommendations based on their knowledge and experience. They recommended asking about past risk factors to help inform future rehabilitation goals, and current risk factors to help form a baseline for initial rehabilitation needs and monitor changes.
Some people may need additional support because they react to trauma in different ways, have different barriers to rehabilitation, and may have different responses to psychological and psychosocial interventions. Because of this, the committee recommended referral to a practitioner psychologist with trauma and rehabilitation experience when needed.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended. Some extra time might be needed to complete the comprehensive assessment, and there might also be more referrals to specialist services. However, the involvement of specialist services at the assessment stage will identify needs earlier and reduce unmet care needs.
Return to recommendations
# Setting rehabilitation goals
Recommendations 1.3.1 to 1.3.3
## Why the committee made the recommendations
Based on qualitative evidence, the committee highlighted the need to agree patient-focused short- and long-term goals with people. They also recommended that these goals are reviewed regularly, to ensure a flexible approach that takes people's concerns into account.
Agreeing small steps as part of long-term rehabilitation goals ensures that efforts are consistently made towards achieving these goals.
The committee highlighted skills and competencies needed by the multidisciplinary team, to ensure that staff have the right training.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended. Some additional professional time might be needed to explore psychological and psychosocial risk factors.
Return to recommendations
# Developing a rehabilitation plan and making referrals
Recommendations 1.4.1 to 1.4.11
## Why the committee made the recommendations
There was convincing qualitative evidence on patient education, communication between settings, and follow-up. Combining this with their own knowledge and experience, the committee recommended several key components of a successful and comprehensive rehabilitation plan. This should be a single document that can be shared between people undergoing rehabilitation, families or carers, and healthcare professionals. It should be an evolving document, detailing a person's rehabilitation journey and any changes in goals and needs. The committee reflected that it is not always possible or appropriate for people to have access to all of a rehabilitation plan, and therefore recommended that a separate patient-held document be provided if this is the case.
The committee agreed that preventing recurrence of traumatic injury should form an essential component of the rehabilitation plan. Prevention is covered in several other NICE guidelines, so the committee made recommendations that supplement and refer to these guidelines.
There was strong qualitative evidence from both healthcare professionals and people undergoing rehabilitation that reducing delays leads to better coordination of care and rehabilitation outcomes. Based on this, the committee made a recommendation on referrals for parts of the plan that the multidisciplinary team cannot implement themselves. The committee also used their experience to recommend that older people have access to orthogeriatricians, surgical support or perioperative physicians. This is important because the needs of older people with traumatic injuries are complex, and it will prevent delays further on in rehabilitation.
Limited evidence showed that violence intervention programmes might reduce hospital admissions. There was also convincing economic evidence that such programmes represent value for money. The committee agreed that the effectiveness evidence combined with economic evidence was sufficient to support a recommendation on violence reduction interventions.
## How the recommendations might affect services
Practitioners should already be producing these rehabilitation plans, but some extra time might be needed to ensure they fulfil the expectations set out in these recommendations. However, this will be offset by reducing problems with the suitability of the plan further down the line, because the more it is tailored for the person, the more effective it will be at helping the person achieve their goals. The recommendations outline good practice points and should make practice more consistent. Having a clear rehabilitation plan will make the whole process more efficient and potentially reduce the amount of extra support people need (for example, asking the team for more information because they do not understand the rehabilitation plan).
Currently, violence reduction interventions are mainly funded by the voluntary sector, so the recommendation on these may represent a change in practice. However, any cost increase will be offset by a potential reduction in future NHS and personal social service costs (for example, readmissions as a result of violent crime).
Return to recommendations
# General principles for rehabilitation programmes
Recommendations 1.5.1 and 1.5.2
## Why the committee made the recommendations
Evidence showed that rehabilitation programmes should be tailored to a person's needs and rehabilitation goals to maximise their effectiveness. There is no 'one-size-fits-all' programme. Instead, they should be multidisciplinary and developed in conjunction with healthcare professionals and people undergoing rehabilitation, to ensure they are relevant to a person's everyday life. The committee used their knowledge and experience to recommend the content of rehabilitation programmes. There was also evidence on education materials, showing that they can help people learn about their trauma and rehabilitation in their own time, increasing their engagement in the process.
## How the recommendations might affect services
The recommendations reinforce current practice and should not be difficult to implement. Education materials on rehabilitation already exist in healthcare settings, but they might need to be changed into a suitable format for people undergoing rehabilitation.
Return to recommendations
# Intensive rehabilitation programmes
Recommendations 1.5.3 to 1.5.5
## Why the committee made the recommendations
There was no evidence on what to include in an intensive rehabilitation programme. Based on their own experience and expert testimony, the committee made a recommendation on general good practice principles.
There was also no evidence relating to the timing or intensity of rehabilitation. The committee were aware, based on their own experience and expert testimony, that delivering rehabilitation at the right time and providing short blocks of intensive rehabilitation might improve patient outcomes, leading to a quicker recovery and return to work. They gave the example of a 3‑week residential rehabilitation programme because economic modelling indicated that this type of programme could be cost effective. However, the committee agreed that an intensive rehabilitation programme would be appropriate only for the most severe injuries and complex needs, when a significant impact on rehabilitation outcomes is likely. Such an approach to rehabilitation may also reduce the health and social care costs associated with longer-term care and rehabilitation.
The expert witness supported the use of education materials before intensive rehabilitation starts, to prepare people for the programme.
The committee made research recommendations on the effectiveness of intensive rehabilitation in adults and the effectiveness of intensive rehabilitation in children and young people.
## How the recommendations might affect services
The recommendations are in line with current practice and should have little impact on resources. Intensive rehabilitation is already available for some people (for example, people who have lost a limb). Because rehabilitation services are already being carried out, intensive rehabilitation could be delivered through service redesign and repurposing of existing funds and resources rather than introducing them as completely new resources. Intensive rehabilitation would potentially represent value for money as per the economic model. Also, only a small group of people with the most severe injuries would be eligible for an intensive rehabilitation programme.
On education, existing materials for guided self-management rehabilitation could be used for intensive rehabilitation. This has the potential to reduce the amount of extra support people need, freeing up professionals for other work.
Return to recommendations
# Guided self-managed rehabilitation
Recommendations 1.5.6 to 1.5.9
## Why the committee made the recommendations
Evidence showed that self-management programmes are appreciated because they give people the flexibility to perform exercises at times most suitable for them. The committee used their experience and knowledge to recommend several possible components of a self-management programme.
Guided self-management rehabilitation was identified in the qualitative literature, as well as expert witness testimony and committee experience, but not in the quantitative literature. The committee made a research recommendation on self-management rehabilitation interventions to better inform future guideline development.
## How the recommendations might affect services
Guided self-managed rehabilitation is not provided consistently across the country. In areas where it is not currently provided, extra professional time might be needed for planning, particularly for children, young people and vulnerable adults. There may also be costs from adopting self-managed rehabilitation programmes to different settings.
For trusts that do not like sharing their content using external content-sharing services, there may be costs from hosting programme content on their own server. However, much of the content could be standardised for most people using guided self-managed rehabilitation, so the costs for creating the plans would be mostly one‑off. These programmes could be developed at a national level, reducing costs to individual services.
Guided self-managed rehabilitation programmes have the potential to reduce the amount of extra support people need, freeing up professionals for other work.
Return to recommendations
# Monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments
Recommendations 1.5.10 and 1.5.11
## Why the committee made the recommendations
In the committee's experience, rehabilitation plans and goals can only be helpful to people if progress is monitored consistently and accurately. There are many tools that can be used for this; the choice depends on the person's rehabilitation goals and the type of trauma. Because of this variation, the committee did not recommend specific measurement tools.
For some people, family members and carers will need to be involved in monitoring progress (for example, for young children or vulnerable adults). The paediatric professionals on the committee recommended using a measurement tool that includes both children- and parent-reported measures for this population. Another way to monitor progress is to use the person's own views. There was some evidence that supported asking people to record information to assist discussions and shared decision making while describing subjective measurements that are hard to quantify (for example, their motivation to continue rehabilitation).
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended. Some additional professional time may be needed to complete tools to monitor progress (for example, patient-reported outcome measures ).
Return to recommendations
# Principles for sharing information and involving family and carers
Recommendations 1.6.1 to 1.6.7
## Why the committee made the recommendations
One theme that appeared throughout the evidence was the importance of giving clear and consistent verbal and written information to people undergoing rehabilitation. Evidence showed that this communication should be tailored to a person's injury, needs and goals. If information was too general, people felt poorly prepared and less supported by healthcare staff and services.
People should be given sufficient time to process information in order for them to adjust after trauma and explore their rehabilitation options thoroughly. This is particularly important for people with cognitive impairment or brain injuries, and they may need professionals to repeat information to them.
Along with good evidence, the committee used their knowledge and experience to highlight the central role that families, carers and friends can have in encouraging and supporting people through rehabilitation.
## How the recommendations might affect services
The recommendations reinforce current practice and are in line with current guidance and legislation. Some extra time might be needed to consistently involve people and their families and carers in planning. Services might need to develop multiple templates for different communication formats. However, this will be offset by the benefits of people understanding their options, increased engagement and potentially better outcomes.
Return to recommendations
# Coordination of rehabilitation care in hospital
Recommendations 1.7.1 to 1.7.10
## Why the committee made the recommendations
The committee agreed with the evidence that multidisciplinary teams should be formed early. Evidence showed that delays in rehabilitation can cause poorer outcomes. In order to reduce this, the committee recommended that referrals to specialist rehabilitation services be made as soon as possible. Similarly, the committee recommended follow-up appointments with acute teams when people move to rehabilitation units to further reduce delays.
There was conflicting evidence on how people feel about receiving information from many different specialists. This may be confusing to people, and specialists may have difficulty prioritising different clinical perspectives. The committee believed that named rehabilitation coordinators or key workers are needed to help reduce this confusion. These should be assigned within 72 hours of admission because this is the time limit for starting a trauma prescription for major trauma patients.
There was evidence that providing continuity of staff enhances coordination by building trust and rapport between healthcare staff and the people they are caring for. However, the committee were aware that this is not always possible.
There was good evidence about the importance of prompt and consistent communication when transferring people between inpatient settings. Using their experience and knowledge, the committee agreed recommendations to improve communication between settings, including the use of unique identifiers.
Evidence showed that coordination is improved when a person is educated in their rehabilitation, because they are more engaged. The evidence also showed that coordination is improved when family members and carers receive this information, because they frequently act as a support network for people undergoing rehabilitation. The committee understood the important role that families and friends can fulfil, but were aware of the potential safeguarding concerns around this issue. Therefore, they recommended that this information is only provided to additional people if appropriate, and only with a person's consent.
The committee agreed that families and carers be advised about the support that is available to them at a time that can be confusing and distressing.
## How the recommendations might affect services
Multidisciplinary teams are a standard way of working. Having a named rehabilitation coordinator might lead to an increased workload for the coordinator, but this can be limited by daily conversations within the team and delegating responsibilities. Key workers are already routinely assigned to people with complex health and social care needs.
There may be more referrals as a result of involving specialist rehabilitation services earlier in the trauma pathway, but this will ensure timely care with a reduction in disability and will support optimal physical, cognitive and emotional recovery for patients. Most services have established processes and templates for handover. Where this is not the case, services will have to spend time creating them. Additionally, technology might need to be updated to ensure systems are compatible with those used by other services.
Return to recommendations
# Coordination of rehabilitation care at discharge
Recommendations 1.8.1 to 1.8.20
## Why the committee made the recommendations
Discharge home from inpatient settings is often a time of great stress and apprehension for people with a traumatic injury because they are facing a large reduction in monitoring and support from healthcare staff. The recommendations emphasise the importance of making sure that plans are in place, eventualities are covered and people have all the information they need.
There was evidence that early planning for discharge is needed to take into account the person's needs and preferences, contact relevant services to arrange necessary adjustments, and allow enough time to reassess the rehabilitation plan before discharge. For children and young people returning to education, a meeting between healthcare professionals, education staff and parents or carers should be arranged to discuss new education and support needs. This also gives time to address any potential barriers the person might face in using community rehabilitation services.
There was good evidence on the importance of providing adequate information to people and their families or carers before discharge. This should not be limited to immediate medical information, but should be as comprehensive as possible. The committee used the evidence and their own knowledge and experience to identify information that should be provided. Evidence also showed that including family members and carers in discharge planning can lead to a smoother transition back into the community. The committee agreed that it is important to include family and carers, but they should only be involved if all parties consent.
There was good evidence, supported by the committee's knowledge and experience, that people who have help with organising their access to rehabilitation services are more likely to use them. In the committee's experience, complex funding is a barrier to receiving equipment that a person may need once discharged. Similarly, there are many different services that a person may need to work with after a traumatic injury (for example, legal services and welfare advice). In order to prevent delays in discharge, information on these organisations should also be provided as soon as possible, to avoid delays in the application process.
There was evidence that people can find a gradual return home helpful, beginning with overnight or weekend visits home before final discharge. This allows people to adjust to being in their home with their new needs, identifying areas that might need further rehabilitation and multidisciplinary team input before permanently going home. The committee acknowledged that this is not appropriate for everyone, but should be discussed as part of discharge planning. Home visits were also identified as being good practice to highlight any potential risks and allow people to have a fully informed discussion about what would benefit them.
The need for flexibility in rehabilitation appointments after discharge was a key theme in the evidence, because people face certain barriers to access (for example, time constraints, or travel to and from rehabilitation appointments). The committee agreed that arranging rehabilitation sessions at home rather than in a clinic or hospital can help, by decreasing travel and waiting times. Based on the evidence and their experience, the committee also recommended alternative consultation formats (for example, phone or video), to increase the flexibility of rehabilitation appointments.
## How the recommendations might affect services
Additional time might be needed to compile information and discuss it with people and their support networks. However, by giving comprehensive information before discharge, there will be a decreased need to contact healthcare professionals with rehabilitation questions, and potentially reduced visits and readmissions to inpatient services.
Additional professional time might be needed to cover early discharge planning, checking access to community rehabilitation services, liaising with education providers and organising home visits. The recommendations imply more coordination between inpatient teams and other health and social care services, which will take more time. However, this additional time spent will result in patients feeling more supported, increasing their confidence in services and improving outcomes. There is a potential resource impact from staggering discharge through overnight or weekend visits home. However, this would only be needed in exceptional cases.
Telephone or video consultations may result in a greater uptake of some services, because people may find remote attendance easier. However, services would have planned to provide in-person consultations for these people anyway, so there should be no overall resource impact.
Return to recommendations
# A single point of contact, key contact and key worker after discharge
Recommendations 1.8.21 to 1.8.24
## Why the committee made the recommendations
There was good evidence that people benefit from having a single point of contact after discharge from hospital (for example, a discharge coordinator, a phone line or an email contact). Having a team or a professional as a single point of contact can build rapport and trust, increasing the person's confidence in accessing outpatient and community rehabilitation services. It also reduces communication delays or duplication. This contact can also provide injury-specific information and information about local rehabilitation services, help people organise their rehabilitation, and advocate for them. This should be provided for a limited time after discharge in order to provide a secure and safe transition of care. The committee gave an example of 3 months, which was designed to encompass the transition period while still providing a stimulus to ensure healthcare is properly transferred to the appropriate setting.
Based on both the evidence and their own experience, the committee recommended appointing a key contact or key worker for people with continued or complex health and social care needs after discharge. Because of the increased level of support these people might need, a one-to-one relationship will increase trust and rapport, which will benefit patients and healthcare professionals.
## How the recommendations might affect practice
Multiple healthcare professionals within the team have access to the relevant patient information and could therefore act as a point of contact, and so this would not need additional resources. Having a single point of contact may reduce the workload of case managers that are routinely assigned to people with complex healthcare and social care needs.
Key worker roles would be filled by existing healthcare or social care professionals. However, there may be more pressure on their time.
Return to recommendations
# Supporting access and participation in education, work and community after discharge (adjustment and goal setting)
Recommendations 1.9.1 to 1.9.12
## Why the committee made the recommendations
There was evidence showing that people appreciate psychological and emotional support to adjust to social roles (for example, parenting or other family roles, relationships, intimacy), access meaningful activities for day-to-day living, and return to work, education and training. This is in line with the committee's own knowledge and experience. In the committee's experience, it is difficult to predict the outcome of rehabilitation, and making realistic goals is essential (for example, some people will not be able to return to the same type of work and will need retraining). The committee agreed that it is beneficial for people to continue with their normal activities and hobbies as part of their rehabilitation therapy. Even if adjustments are needed, this improves participation in social activities, counteracts the social isolation people may feel after traumatic injury, and makes rehabilitation goals more tangible. And the longer a person is not undertaking their everyday activities, the more difficult it is for them to return to the same level as before their injury.
There was good evidence on the importance of providing adequate information to people and their families before discharge. Evidence also showed that people often rely on family, carers and friends to help them navigate the multiple appointments and services needed during rehabilitation.
## How the recommendations might affect services
More time might be needed to develop a rapport with people, to find out what goals are most important to them and to tailor support needs to them. Additional time may also be needed in order to provide information to employers or education providers.
All team members involved in the care of an individual provide emotional and psychological support, so this would not be an additional cost.
Return to recommendations
# Commissioning
Recommendations 1.10.1 to 1.10.5
## Why the committee made the recommendations
The qualitative and quantitative evidence identified aspects of planning, commissioning and coordinating that were important to the successful delivery of rehabilitation services. The committee agreed that rehabilitation services should collaborate and use joined-up commissioning approaches to provide a whole pathway rehabilitation. Based on their knowledge and experience, and limited qualitative evidence, the committee identified general principles that commissioners and providers should consider when planning, commissioning and coordinating rehabilitation services. Because these services will have different commissioners, collaboration and good communication will be needed.
There was no evidence on intensity of rehabilitation, so the committee took expert witness testimony on this. They expanded on the points raised by the expert witness to recommend providing an intensive rehabilitation programme. The committee recommended commissioning this as a tertiary service because it would only be appropriate for some people. This way, the service would be best designed to meet the needs of their local population.
Based on the qualitative evidence and their experience, the committee agreed that it is essential for an identified commissioner to have overall responsibility for local rehabilitation services, to avoid confusion and subsequent commissioning and budget errors.
## How the recommendations might affect services
The recommendations are in line with current practice and should have little impact on resources. Where practice differs, there may be some resource implications, because services will need to set up frameworks for more collaborative and integrated commissioning. Intensive rehabilitation is already commissioned for some patient groups (for example, people who have lost a limb).
Return to recommendations
# Organisation
Recommendations 1.10.6 to 1.10.11
## Why the committee made the recommendations
There was qualitative evidence showing that establishing care networks and pathways between different settings encourages conversation, allows services to share advice and support each other, and can help identify gaps in local provision.
There was qualitative evidence on the usefulness of an electronic directory of care pathways, rehabilitation facilities and voluntary sector services. Some trauma units already have these in place, but directories are often out of date or incomplete. Accessing this information is also often difficult.
There was qualitative evidence showing the importance of community and social services for overall rehabilitation and recovery. Non-medical rehabilitative services are wide-ranging and can include social care, housing, home adaptation, transport, and sports and recreational facilities. The committee made a recommendation to make sure that people and their families or carers know these other services exist.
There was qualitative evidence showing that continuity of care increases when various professionals involved are aware of other areas of rehabilitation and can network with each other. There was also qualitative evidence on the importance of professionals in generalised medical settings having access to networking opportunities. This allows greater familiarity between professionals and improves cooperation.
There was qualitative evidence showing that technology and telehealth can be suitable methods of improving flexibility and availability of specialist appointments. This can be particularly useful in rural areas, because qualitative evidence showed that these areas are underserved by specialist rehabilitation services. However, not everyone has the equipment needed for remote consultations, so they cannot completely replace face-to-face consultations.
There was qualitative evidence showing that socialising and interacting with peers can promote rehabilitation uptake and counteract isolation. In the committee's experience, group rehabilitation sessions are a good way for people to get peer support. This was supported by expert witness testimony. However, peer support might not be suitable for everyone (for example, some people may feel discouraged if they are not progressing at the same rate as others).
## How the recommendations might affect services
More resources may be needed to establish care networks and pathways. However, there are already examples of this in the NHS. Some trauma units already have electronic directories of care pathways, rehabilitation facilities and voluntary sector services. Services may need to do more to keep these up-to-date.
Most professionals already have opportunities for networking. However, practice may need to change for some services where this is not the case (for example, in rural areas).
Telehealth is becoming more common and does not need any specialist equipment.
Group rehabilitation sessions may represent a change in practice for some services.
Return to recommendations
# Rehabilitation skills, knowledge and expertise in the workforce
Recommendations 1.10.12 to 1.10.14
## Why the committee made the recommendations
The evidence identified a disparity in access to specialist rehabilitation services, depending on location (for example, rural areas are underserved) and individual needs (for example, if a person is not able to leave their home). A lack of rehabilitation knowledge within non-specialist healthcare services adversely impacts a person's trust in their rehabilitation services. The committee agreed that training is needed to address this. Community rehabilitation practitioners in general healthcare services should also have access to specialist rehabilitation support. This would not need to be full time, and could be provided remotely. Peer support and networking opportunities are also recommended. These will improve communication between professionals in different areas of healthcare and improve coordination for people undergoing rehabilitation.
## How the recommendations might affect services
Specialist rehabilitation professionals might need to spend more time providing peer support to general services. This could be done in low-cost ways, for example, virtual meetings. If non-specialist healthcare professionals are better supported, people's needs are more likely to be met locally and there will be less pressure on specialist services. Time and resources might be needed to provide more training for non-specialists. However, this will also reduce demand on specialist services.
Return to recommendations
# Physical rehabilitation – early interventions and principles
Recommendations 1.11.1 to 1.11.9
## Why the committee made the recommendations
There was conflicting evidence on the frequency and intensity of prescribed exercises because of the wide range of possible exercises, wide range of trauma and wide range of populations covered by the evidence. The committee agreed, based on their knowledge and experience, that healthcare professionals should set the frequency and intensity of rehabilitation exercises depending on the person's rehabilitation goals, but that these should be started as soon as possible. Analgesia may be needed to allow people to participate in rehabilitation. The committee also highlighted the importance of minimising the effects of low blood pressure when undergoing physical rehabilitation. This risk is increased because the person would need to change positions to perform certain rehabilitation exercises. Independence in performing everyday tasks should be encouraged, to prevent loss of these skills.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended. There may be more referrals to occupational therapy as a result of encouraging independence with activities of daily living. However, occupational therapists are already available in these settings, and this should not have a significant resource impact or be difficult to implement.
Return to recommendations
# Early weight-bearing
Recommendations 1.11.10 to 1.11.12
## Why the committee made the recommendations
The committee agreed with the evidence and current practice that weight-bearing exercises should be started as soon as possible. In their experience, this is important to encourage mobility and maintain postural reflexes, muscle mass, strength and function.
Decisions about weight-bearing should be led by the surgical team because it will be affected by any potential surgeries. However, bed rest can be harmful to muscle function, skin integrity, postural reflexes and respiratory function (especially in older people), and should be avoided as far as possible for most people with traumatic injury. The surgical team should communicate when a person is able to weight-bear as early as possible to keep bed rest to a minimum and so that weight-bearing can start without delay.
Lower limb injuries will affect a person's mobility, which affects their ability to participate in weight-bearing rehabilitation exercises to a greater extent than upper limb injuries, so the committee recommended a targeted weight-bearing programme. This programme should aim to progress the person's function with weight-bearing tasks such as mobility, ability to move from sitting to standing, and ability to lateral step (which is particularly important for people to maintain independence after discharge).
## How the recommendations might affect services
The recommendations reflect current practice and are not expected to need additional resources to implement. Some additional time might be needed for communication between medical and surgical teams.
Return to recommendations
# Aerobic and strengthening interventions
Recommendations 1.11.13 to 1.11.18
## Why the committee made the recommendations
There was evidence showing the importance of aerobic and strengthening exercises in rehabilitation after traumatic injury. These exercises lead to better rehabilitation outcomes in several different trauma populations. The committee supplemented this evidence with their own knowledge and experience to recommend several aspects that healthcare professionals should consider when designing aerobic and strengthening rehabilitation programmes. The recommendations cover general components rather than specific exercises because the evidence did not clearly show which exercises were best, and because the recommendations need to be applicable to a wide range of traumatic injuries. The committee also recommended tailoring aerobic and strengthening exercises to each person's interests, to make the exercises more enjoyable and to encourage people to take part.
The committee agreed that the exercise programme should begin as early as possible to limit the loss of muscle tone and physical fitness. Evidence showed that upper body aerobic training can improve rehabilitation outcomes in people with lower limb injuries. The committee discussed how for older people, fitness and strengthening programmes can help to optimise respiratory function, increase endurance when doing rehabilitation exercises, and improve mobility.
Finally, the committee stressed that these exercise rehabilitation programmes should be continued after people are discharged home, to ensure that their physical strength and fitness does not stagnate or decrease. Regular reviews should be carried out during rehabilitation appointments in order to gauge whether the programme components are still appropriate for people's rehabilitation needs, and to change them if not.
## How the recommendations might affect services
The recommendations are not expected to have a significant resource impact or be difficult to implement. However, extra time may be needed to tailor exercise programmes to each person's preferences.
Currently, some physiotherapists do not offer aerobic exercise programmes to older people who are frail. For these physiotherapists, there will be a change in practice and there may be a greater uptake of aerobic exercise in older people. Older people would already be working with a physiotherapist, so this will only change the type of exercise used and there will be no additional costs for services.
Return to recommendations
# Gait training and re-education
Recommendations 1.11.19 to 1.11.21
## Why the committee made the recommendations
Although there was evidence to show that gait re-education did not improve rehabilitation outcomes, the committee disagreed with these findings. In their knowledge and experience, gait re-education is a very effective rehabilitation tool, particularly for muscle strengthening. In people who are not mobile, gait re-education can still be introduced early but should be focused on reducing the impact of non-weight-bearing. This will maintain the current level of functioning and mobility, so people are ready to undertake weight-bearing gait re-education as soon as possible.
## How the recommendations might affect services
At some hospitals, physiotherapists do not get patients into their physiotherapy unit until they can weight-bear fully. These physiotherapists will need to change their practice. Overall, the recommendations are not expected to have a significant resource impact or be challenging to implement.
Return to recommendations
# Manual therapies and maintaining joint range of movement
Recommendations 1.11.22 to 1.11.24
## Why the committee made the recommendations
There are a variety of range of movement exercises that can be used for rehabilitation, with different levels of assistance depending on ability. Controlled motion devices should be considered if people are not able to perform exercises independently. The committee agreed that range of movement is particularly important during rehabilitation. Targeted stretching is a good method of preventing loss of movement, particularly after exercises, when muscles tighten as a response to activation.
## How the recommendations might affect services
The committee were aware of the potential resource impact of recommending specific controlled motion devices to assist range of motion. Generally, these devices are rarely used (and mostly only in hospitals to help with knee injury). However, once acquired, these devices can be used by multiple people. Overall, the recommendations are not expected to have a large resource impact or be difficult to implement.
Return to recommendations
# Splinting and orthotics
Recommendations 1.11.25 to 1.11.33
## Why the committee made the recommendations
Evidence showed a benefit from orthoses in rehabilitation after trauma. No evidence was found on splinting. The committee combined the available evidence with their experience and knowledge to recommend several specialised splints and orthoses, and to warn about positions known to cause complications and loss of function later on in recovery.
Because of their complexity, the committee recommended bespoke splints for people with hand injuries, as well as referral to a hand therapy specialist. 'Off-the-rack' splints can be ill-fitting and cause lost range of movement in the hands and fingers.
Regular review of splints is recommended because splinting can have adverse effects if not monitored carefully (for example, pressure sores). This risk is increased in people with reduced skin sensation and recent skin graft or flaps, so splints and orthoses may be contraindicated and specialist advice may be needed. People (and families and carers, if appropriate) should receive education on how to wear splints or orthoses to limit adverse effects and when to seek professional advice.
Evidence showed that spinal orthoses can help improve patient rehabilitation outcomes, and they are used in current practice. However, in the committee's experience, not all trauma populations see a benefit (for example, older people) and spinal orthoses can cause adverse events if improperly fitted. Healthcare professionals should be aware that these devices may be poorly tolerated and know when to discuss problems with the surgical team. Because of these issues with the evidence, the committee made a research recommendation on spinal orthoses for older people.
## How the recommendations might affect services
The recommendations reflect current practice. Splints and orthoses are commonly used and are all low cost. Bespoke splints are easily made in a treatment room and would not need any additional resources.
Return to recommendations
# Management of swelling and oedema, and scars
Recommendations 1.11.34 to 1.11.44
## Why the committee made the recommendations
Swelling is a common side effect of traumatic injury, but there are symptoms that will need treatment from healthcare professionals (for example, signs of deep vein thrombosis). No evidence was found, so the committee used their knowledge and experience to recommend a programme of elevation and exercises to prevent and reduce any swelling associated with trauma. Compression bandages can be used to help this. However, providing appropriate compression is a skill. Therefore, the committee recommended specialist supervision for this.
No evidence was found on the psychological aspects of scarring after traumatic injury. Based on their experience, the committee recommended several measures to encourage people to adjust to their new appearance, reassure them of expected recovery sensations and provide information about scar management. For children and young people, the committee recommended performing any painful treatments away from their hospital bed. This encourages them to associate their bed with security, an important factor in their hospital experience.
Evidence was found for massage as a treatment for scar tissue. This will help desensitise the area, and increase tissue mobility (and therefore maintain range of movement).
In the committee's experience, scar management knowledge is not very prevalent in non-specialist healthcare settings. Therefore, they recommended referring people to specialist services if they have scars or skin grafts that need complex treatment (for example, contracture across joints that limits movement).
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Nutritional supplementation
Recommendations 1.11.45 to 1.11.52
## Why the committee made the recommendations
The evidence for nutritional supplementation was of very low quality. However, the committee agreed that there is a lack of awareness about the nutritional risks and needs following traumatic injury. People need more calories after traumatic injury, to help with healing. However, they often have complications that can affect eating habits or nutrient absorption. To address these issues and the lack of awareness around nutritional supplementation, the committee made recommendations based on their own experience.
The committee made a specific recommendation for people with burns in combination with other traumatic injuries because they are at increased risk of losing significant muscle mass, weight and strength for a prolonged period, because of the long-lasting effect of the hypermetabolic response.
## How the recommendations might affect services
The recommendations are in line with current practice and will not need additional resources to implement.
Return to recommendations
# Cognitive rehabilitation
Recommendations 1.12.1 to 1.12.7
## Why the committee made the recommendations
There was no evidence in this area. However, in the committee's experience, trauma-related cognitive functioning problems can be upsetting for people and affect their decision making and participation. Because of this, the committee believed it is important to reassure people that these problems are usually temporary. When problems are not temporary, the committee recommended adapting rehabilitation therapy to take account of this and to help the person participate in therapy and assessments.
As another aspect of helping people with cognitive difficulties to participate, the committee highlighted information needs and formats to use. The committee were also keen to emphasise the need to share this information with the person's family or carers, because they can play an important part in helping the person understand and recall key messages.
The committee agreed on additional steps to follow for children and young people, to ensure that their education providers accommodate their changing needs.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Psychological rehabilitation
Recommendations 1.13.1 to 1.13.7
## Why the committee made the recommendations
The committee used their knowledge and experience to make recommendations on psychological rehabilitation. They highlighted the importance of reassuring people that the acute stress response is common and normally temporary, because it can be very distressing. Outside of the acute stress response, the committee identified several other psychological issues, to raise awareness among professionals and encourage good practice.
Because of low quality evidence, the committee based the recommendations on psychological support on their own experience. They agreed that 'one size does not fit all' within psychological and psychosocial therapies and felt it was important to offer psychological and emotional support that is tailored to a person's rehabilitation goals, needs and preferences.
The committee recommended that any treatment for psychological disorders should form part of a complete rehabilitation package, and not be kept separate. This will allow better communication and coordination of physical and mental healthcare.
No evidence of benefit was found for family support interventions. However, in the committee's experience, involving family can be beneficial.
## How the recommendations might affect services
The recommendations reinforce current practice and refer to existing NICE guidelines, so should not need additional resources to implement. Most team members specialising in the management of major trauma are equipped to provide psychological and emotional support. Being more aware of psychological problems may result in more referrals to psychology services.
Return to recommendations
# Rehabilitation after limb-threatening injury – early assessment, decision making and support
Recommendations 1.14.1 to 1.14.4
## Why the committee made the recommendations
There was no evidence in this area. The committee agreed based on their experience who should be involved from the multidisciplinary team and what the discussions needed to cover.
Although no evidence was identified, the committee recommended psychological support before limb amputation because of the life-changing nature of the procedures. Psychological and emotional support can improve outcomes after surgery (such as emotional wellbeing and pain management).
The committee recommended involving limb reconstruction and prosthetic specialists early on, because amputation and limb reconstruction can be life-changing and traumatic.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Rehabilitation after limb reconstruction
Recommendations 1.14.5 to 1.14.7
## Why the committee made the recommendations
There was no evidence identified but, based on their own experience, the committee agreed that rehabilitation should start as early as possible after surgery to reduce the risk of complications that may delay the person's recovery, and to maintain range of movement after limb reconstruction. Because of the complexity of limb reconstruction, the committee did not recommend a specific programme but suggested certain interventions that could be used to accomplish this.
The committee also agreed that psychological support should continue after limb reconstruction surgery, to help the person adjust to their appearance and manage pain.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Rehabilitation after limb loss or amputation
Recommendations 1.14.8 and 1.14.9
## Why the committee made the recommendations
There was no evidence but, based on their own experience, the committee agreed that rehabilitation should start as early as possible after surgery to reduce the risk of complications that may delay the person's recovery. People should usually be referred to the amputee and prosthetic rehabilitation team before their surgery, but the committee acknowledged that sometimes there is not enough time so they would need to be referred afterwards.
The committee also agreed that psychological support should continue after limb loss and amputation to help the person adjust to their appearance and manage pain (for example, mirror therapy).
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended. More people being referred to amputee and prosthetic rehabilitation before surgery may cause an initial increase in early referrals, but this will be offset by fewer people being referred later in rehabilitation.
Return to recommendations
# Pain management after limb loss or amputation
Recommendations 1.14.10 to 1.14.12
## Why the committee made the recommendations
The committee agreed that pain management should be discussed before surgery because pain after limb loss or amputation can be difficult to treat, and managing pain effectively after surgery can increase participation in the rehabilitation process. Additionally, people with poor perioperative pain control have an increased risk of phantom limb pain in the long term. There was also evidence that mirror therapy (a type of graded motor imagery therapy) is an effective and inexpensive non-pharmacological treatment for phantom limb pain after limb loss or amputation.
## How the recommendations might affect services
The recommendations enforce current practice and are not expected to be difficult to implement. Mirror therapy is relatively cheap and easy to implement. Other forms of graded motor imagery therapy are less commonly used and should be delivered by staff with appropriate skills, potentially resulting in extra training costs where it is currently not available. There may be an increased level of referrals to specialised pain management teams, depending on the complexity of pain management plans. However, this will be offset by increased participation in rehabilitation after surgery and therefore better outcomes.
Return to recommendations
# Residual limb oedema and shaping after limb loss or amputation
Recommendations 1.14.13 to 1.14.15
## Why the committee made the recommendations
There was no evidence so the committee based the recommendations on their knowledge and experience. They highlighted the benefit of elevation and compression therapy in managing residual limb oedema by reducing swelling and facilitating prosthetics fitting. They also agreed that:
limb swelling should be avoided when using early walking aids because this can delay prosthetics fitting and rehabilitation
residual limb (stump) boards on wheelchairs can provide support to keep the limb elevated for people with a below-the-knee amputation.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Range of movement and strengthening after limb loss or amputation
Recommendation 1.14.16
## Why the committee made the recommendation
The committee used their knowledge and experience to recommend providing range of movement exercises to help prevent complications and optimise functional outcomes.
## How the recommendation might affect services
The recommendation reflects current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Functional independence after limb loss or amputation
Recommendations 1.14.17 and 1.14.18
## Why the committee made the recommendations
Although there was some evidence identified about waiting until prosthetics had been fitted before starting rehabilitation, this disagreed with the committee's knowledge and experience. They argued that the best way to maintain and improve the person's range of movement after limb loss or amputation is by starting rehabilitation therapy as early as possible. Rehabilitation should not be delayed by waiting for prosthetics to be fitted because the maintenance and improvement of range of movement will help prevent complications and optimise functional outcomes.
The committee also agreed that wheelchairs should be provided early, along with appropriate accessories such as anti-tippers and residual limb (stump) boards. Wheelchairs should be adjusted to accommodate the changes in the person's weight distribution after limb loss or amputation. By providing appropriately fitted and adjusted wheelchairs as early as possible, a person's independence and mobility will be increased and they will be better able to engage in activities of daily living. There was no evidence, so the committee used their knowledge and experience to make the recommendation on wheelchairs.
## How the recommendations might affect services
There might be an increased number of referrals to physiotherapists and occupational therapists in order for wheelchairs to be individually fitted and adjusted. However, the committee discussed that the increased mobility and independence will result in an increased engagement with rehabilitation, leading to better rehabilitation outcomes. Overall, the recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Psychological support after limb loss, amputation or limb reconstruction
Recommendations 1.14.19 to 1.14.22
## Why the committee made the recommendations
Although there was no evidence, the committee used their experience and knowledge to discuss how continuing psychological support after limb reconstruction, loss or amputation can help the person come to terms with their appearance and manage pain.
The committee recommended actively monitoring children and young people for emerging emotional and psychological impact. This is because childhood and young adulthood is a period of change for anyone, and children who have had limb reconstruction, loss or amputation may experience it differently to the general paediatric population (for example, altered body image may become more important during puberty).
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Continuing rehabilitation after limb reconstruction, limb loss or amputation and after discharge
Recommendations 1.14.23 to 1.14.26
## Why the committee made the recommendations
The rehabilitation plan should be reviewed at key points to ensure it is updated with any changes in the person's goals, circumstance or needs. For children and young people, physical growth may cause complications around the residual limb or prosthetic fitting. The committee recommended referral to specialist assessment when this occurs, in order to prevent any adverse effects.
Based on their experience, the committee recommended psychological and emotional support after trauma to help a person adjust to their altered body image, manage pain and cope with the possibility of further procedures.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
Return to recommendations
# Rehabilitation after spinal cord injury – referral, assessment and general principles
Recommendations 1.15.1 to 1.15.8
## Why the committee made the recommendations
The committee discussed their experience with early treatment of traumatic spinal cord injury in emergency departments and how this can affect rehabilitation. Studies involving spinal cord injury treatment in the emergency department were not included in the evidence reviews because of an existing NICE guideline on spinal injury: assessment and initial management. However, the committee highlighted several areas of acute treatment that can affect rehabilitation after traumatic injury.
Because of competing clinical interests, certain aspects of spinal cord injury management are often overlooked in emergency healthcare settings. The committee highlighted the importance of timely contact with regional specialist spinal cord injury centres and the national spinal injuries database to establish a partnership of care with specialist healthcare professionals that will continue throughout the rehabilitation journey. An American Spinal Injury Association (ASIA) chart should also be completed early to identify a current reference point for future assessments.
The committee reflected on the additional issues that people encounter after spinal cord injury because of the chronic nature of the injury and resulting disabilities (for example, bowel, bladder and sexual function). External support networks are very important during spinal cord injury rehabilitation, with family members (and carers or friends, if appropriate) being invited into healthcare discussions and rehabilitation goals. Vocational, educational, recreational and home adjustments may be needed after discharge. By starting these conversations and arrangements early in the rehabilitation process, any modifications can be in place and rehabilitation can be better tailored to an individual, creating a smoother transfer back into the community. Ongoing contact with hospital rehabilitation teams should be maintained to ensure a continued progress review to inform outpatient rehabilitation planning.
The committee discussed the additional complications that children and young people might experience after spinal cord injury because they are still growing. Spinal growth patterns, skeletal growth and nutrition need to be closely monitored in children and young people. Complications in any of these areas can cause additional barriers to rehabilitation, and will become more difficult (if not impossible) to treat as the child or young person stops growing.
## How the recommendations might affect practice
The recommendations reinforce current practice and are in line with the NICE guideline on spinal injury. The benefits of increased care coordination will offset the extra time that professionals might need to follow the recommendations. ASIA charts can be difficult to administer reliably, and staff with appropriate skills should complete assessments, potentially resulting in some extra training costs.
Return to recommendations
# Bladder and bowel function
Recommendations 1.15.9 to 1.15.12
## Why the committee made the recommendations
The committee agreed that bladder and bowel management is important because the medical consequences from undetected bladder and bowel malfunction can be severe. Complications include renal tract damage, bowel perforation and respiratory distress. The committee used their knowledge and experience to recommend several measures to monitor and maintain bladder and bowel function. Although keeping people nil by mouth is a common practice while assessing bowel function, the committee highlighted that delays in this assessment should be minimised in order to prevent issues with nutrition and discomfort during rehabilitation.
## How the recommendations might affect practice
There is variation in bladder and bowel management, so the recommendations should lead to greater consistency and improve care. Monitoring bladder and bowel function will involve additional time, but should have benefits in reducing complications, avoiding delays in starting and continuing rehabilitation, and improving patient outcomes.
Return to recommendations
# Respiratory function, swallowing and speech
Recommendations 1.15.13 to 1.15.17
## Why the committee made the recommendations
Spinal cord injury can cause problems with speech and swallowing, so the committee agreed that people should be nil by mouth until they have been assessed for aspiration risk. They used their expertise to highlight groups of people that are at a particularly high risk, and should be assessed early. Referral to specialists may be needed.
Maintaining respiratory function is essential after a spinal cord injury because the injury may have damaged the chest muscles used in respiration. Without treatment, this could lead to respiratory failure and severe complications. It can also delay rehabilitation until the person is clinically stable enough to start it, and may mean they also need chest physiotherapy to be added to their care plan. Respiratory function should be assessed in line with the NICE guideline on spinal injury to determine baseline function and mark progress. The committee highlighted that children and young people can find it difficult to complete these assessments (particularly forced vital capacity ), and these should be performed and interpreted in accordance with their age and ability. The committee used their experience to recommend several protective interventions to assist with respiratory function after spinal cord injury.
## How the recommendations might affect services
Monitoring respiratory function after a spinal cord injury will involve additional time, but should have benefits in preventing complications caused by compromised respiratory function, avoiding delays in starting and continuing rehabilitation, and improving outcomes. Prophylactic respiratory support will potentially reduce the need for additional chest rehabilitation further down the pathway.
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# Preventing complications
Recommendations 1.15.18 to 1.15.20
## Why the committee made the recommendations
The extended periods of bed rest and immobilisation following spinal cord injury can lead to a wide variety of complications, which can delay rehabilitation. There was no evidence so the committee based the recommendations on their knowledge and experience.
Skin management is a particular area of concern because of decreased mobilisation coupled with reduced physical sensation. People can develop deep pressure ulcers very quickly, which need to be treated before rehabilitation can start.
Blood pressure monitoring is important after spinal cord injury because people are at risk of developing autonomic dysreflexia (in high-level spinal cord injury) and orthostatic hypotension. Autonomic dysreflexia has severe consequences (for example, strokes, encephalopathy, brain haemorrhages and heart attacks) and should be managed as a medical emergency. Orthostatic hypotension has less severe complications but, because it is triggered when changing positions, can affect engagement with rehabilitation exercises.
## How the recommendations might affect services
The recommendations reinforce current practice and should not need additional resources to implement. Additional education might be needed for healthcare professionals on the best way to inform people with spinal cord injury about skin and pressure management.
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# Maintaining mobility and movement
Recommendations 1.15.21 to 1.15.33
## Why the committee made the recommendations
The committee agreed that it is important to maintain mobility and range of motion after a spinal cord injury. However, they also recognised that the large variety of spinal cord injury disabilities and needs means that this should be considered on a case-by-case basis. Because of this complexity, the committee stressed that specialist advice should be sought when needed (for example, the appropriateness of wrist splints for people with a spinal cord injury involving C6). Spinal orthoses have conflicting results in different people, and can hinder certain rehabilitation programmes. Therefore, the committee recommended referring to surgical teams in these cases, to explore other avenues of treatment.
There was some evidence on the benefit of specialist equipment and rehabilitation techniques to maintain mobility and range of motion. The committee agreed that these should be considered on a case-by-case basis, aligning interventions with rehabilitation needs and goals.
Spasticity is an important area to treat for people with spinal cord injury, to prevent losing range of joint movement and contractures. There was some evidence on baclofen (an oral antispastic medication) and botulinum toxin type A to manage spasticity after a spinal cord injury. Referral to a multidisciplinary team specialised in spasticity management may be needed.
Length of bed rest after spinal cord injury varies throughout different NHS trusts, and is an area that the committee were keen to standardise. However, because of the lack of evidence identified, they were unable to make any strong recommendations and made a research recommendation on the optimal length of bed rest to inform future guideline updates.
## How the recommendations might affect services
More people with spinal cord injury might be referred to specialist services. Any additional cost will be offset by more people achieving their long-term rehabilitation goals because of earlier specialist input. There might be some additional costs for training healthcare staff, and some services might need to procure specialist equipment to help with mobility, upper limb function and independent walking. Although some equipment, like robotics, can be expensive, the committee agreed a range of effective interventions. There is flexibility within the recommendations about the use of a range of assistive devices and techniques.
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# Low mood and psychological support
Recommendations 1.15.34 to 1.15.37
## Why the committee made the recommendations
There was conflicting quantitative evidence on using psychosocial interventions after spinal cord injury, with some studies reporting beneficial outcomes and some finding no difference. The committee argued that this was low quality evidence, and that their experience and expertise agreed with the beneficial impact of psychological interventions. However, because they have already made recommendations on psychological interventions for rehabilitation after traumatic injury, they used this section of the guideline to make recommendations that are specific to people with spinal cord injury.
People with spinal cord injury have increased rates of low mood and psychological trauma, and this can affect engagement with rehabilitation. Access to a psychologist with experience in traumatic spinal cord injury and rehabilitation is not guaranteed outside of specialised spinal units, so the committee made a recommendation to address this. Active monitoring is recommended for children and young people because childhood and young adulthood is a period of change for anyone, and children and young people with a spinal cord injury could be affected in different ways to the general paediatric population (for example, altered body image becoming more important during puberty).
## How the recommendations might affect services
The recommendations reinforce current practice and should not need additional resources to implement. If multidisciplinary teams are more aware of low mood and psychological trauma in people with a spinal injury, they may make more referrals for psychological support.
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# Rehabilitation after nerve injury – general principles
Recommendations 1.16.1 to 1.16.3
## Why the committee made the recommendations
Nerve injuries may be hidden; for instance, when the person has multiple injuries, a cognitive impairment, a head injury, is in critical care or has a pre-existing neurological condition. These obvious injuries could distract clinicians from recognising subtler nerve injury, and neurological deficit caused by nerve injury can be mistakenly assumed to be due to a pre-existing neurological condition. In addition, diagnosis of nerve injury may not be possible if the person is unconscious, and nerve function cannot be assessed on limbs that are splinted. The committee highlighted the need to assess the peripheral nerves of the affected limb to identify the informed nerve and functional deficit.
The committee highlighted the importance of assessing the risks to tissue viability if there is sensory or motor loss secondary to peripheral nerve injury, to manage the risk and not jeopardise the person's functional recovery.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice might need to be amended.
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# Therapies and referral
Recommendations 1.16.4 to 1.16.9
## Why the committee made the recommendations
Based on the evidence and their experience, the committee emphasised the need to start rehabilitation therapy to maintain range of movement and regain function after nerve injury. This is because nerve injury can cause the joint to rest in an unnatural position and lead to fixed deformity from contracture of the capsule and muscle. Providing vocational therapy while the recovery is ongoing can help the person return to normal activities such as work.
Nerve function should be assessed regularly for symptoms of recovery, which will affect the components and intensity of the nerve rehabilitation programme. It should not be a static programme. For people who have a poor prognosis, a referral to a specialist peripheral nerve injury service should be made because these services are better equipped to deal with the complex needs of peripheral nerve injury.
People recovering from nerve injury may experience low mood, anxiety and lack of motivation, because recovery may be a lengthy process. To ensure that specialist psychological support is available for people who may need it, the rehabilitation team should have access to a psychologist with trauma and rehabilitation experience.
## How the recommendations might affect practice
Sensory interventions (including mirror therapy) and hydrotherapy are not widely available and this could have some resource implications. However, hydrotherapy would only be offered if pool facilities were available, and mirror therapy and other sensory interventions are relatively inexpensive and easy to implement. All of the above interventions can play a part in stimulating and aiding functional recovery, and can lead to a quicker recovery, help with pain management, and improve the person's health-related quality of life.
Healthcare professionals may need training to conduct nerve conduction studies reliably, but this will save costs further down the care pathway. There may be more referrals to specialist peripheral nerve injury services.
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# Rehabilitation after chest injury
Recommendations 1.17.1 to 1.17.12
## Why the committee made the recommendations
There was no evidence identified. However, the committee discussed the importance of starting rehabilitation as soon as possible to avoid further complications. They also discussed the need for regular assessment of pain and highlighted pain management options. This is because pain is a contributing factor for much of the morbidity associated with chest injury, and the appropriateness of pain management options may vary between people with chest injury.
For people with chest trauma, the committee highlighted the need for movement in order to optimise their respiratory function and prevent deconditioning. They further highlighted a range of rehabilitation therapies to use in preventing respiratory difficulties because this is a key component of chest trauma rehabilitation. The committee are aware that the availability of these therapies may differ between services, and different therapies may be preferred by different people.
Because of the concerns over possible injury causes and underlying pathologies, the committee highlighted the need to assess people with rib fractures, in order to inform future treatment and prevent recurrence. The committee recognise stiffness of the upper limbs as a common complication and discussed measures to prevent compromised function.
The committee recommended referring people with complex chest injuries that affect communication and swallowing skills to speech and language therapy to prevent speech decline and swallowing difficulties.
The committee also recommended providing information that will help people to return to normal life and explain how to seek help for different problems that may arise because rehabilitation for chest injuries can take a long time, causing stress and worry.
## How the recommendations might affect services
The recommendations reflect current practice, but where there are regional variations, practice will need to be amended.
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{'Context': "Traumatic injury is a significant cause of early death and morbidity – particularly in the working population. Major trauma is the biggest cause of death in children and adults under the age of\xa040.\n\nThis guideline defines traumatic injury as any injury that requires admission to hospital at the time of injury. This could include musculoskeletal injuries, visceral injuries, nerve injuries, soft tissue damage, spinal injury, limb reconstruction and limb loss. Minor injuries can also lead to a hospital admission.\n\nThis guideline does not cover the management of traumatic brain injury, except in relation to early screening for onward referral and the coordination of services for people with multiple injuries, one of which may be traumatic brain injury. The specialist assessment and delivery of rehabilitation services for traumatic brain injury will be covered in a new NICE guideline on rehabilitation for chronic neurological disorders including traumatic brain injury.\n\nIn England, 45,000\xa0people are affected by very severe or major trauma every year. A further 500,000\xa0people (included in the population for this guideline) experience less severe trauma, and a proportion of those will need hospital admission because of pre-existing conditions, disability, frailty, or because the functional impact of injuries and environmental factors means that they will not be able to manage in their own home.\n\nTrauma affects all age groups, but there are 2\xa0peaks: younger age and older age. People may have different rehabilitation needs that reflect different functional expectations and priorities. Trauma can negatively affect quality of life, both physically and mentally. It can lead to problems with mobility, pain, breathing, swallowing, eating, drinking, toileting, cognitive function, speech, language and communication, sensory problems, and can lead to depression, anxiety and other psychological difficulties. These issues can similarly have a social and financial impact on the person, as well as on their family and carers. The impact of these problems may be influenced by pre-existing conditions.\n\nAfter a traumatic injury, people need rehabilitation assessment and interventions that take account of any pre-existing conditions and focus on helping them regain optimum function and independence as quickly as possible.\n\nThis guideline focuses on people with complex rehabilitation needs after a traumatic injury. The defined population in this guideline has not been based on the severity of the injury (sometimes measured using an injury severity score) but on the complexity of the rehabilitation need, taking into account existing conditions and circumstances that will impact rehabilitation. Complex needs cover multiple needs, and will involve coordinated multidisciplinary input from at least 2\xa0allied health professional disciplines, which may include rehabilitation medicine, and could also include:\n\nvocational or educational social support for the person to return to their previous functional level, including return to work, school or college\n\nemotional, psychological and psychosocial support\n\nequipment or adaptations\n\nongoing recovery from injury that may change the person's rehabilitation needs (for example, restrictions of weight-bearing, cast immobilisation in fracture clinic)\n\nfurther surgery and readmissions to hospital.\n\nCurrently, people who meet 'major trauma' criteria should have a rehabilitation assessment and prescription carried out during the hospital admission. Further assessments are performed over time to capture changing needs. For people who do not meet major trauma criteria (currently those with an injury severity score of less than\xa09), the pathway for rehabilitation is less clear.\n\nThere are limitations in access to the appropriate rehabilitation services for people after trauma, which may be related to geography, age, injury type or rehabilitation need. There is significant variation in practice, with no national network of services.\n\nImprovement in survival rates resulting from the introduction of major trauma networks in 2012 has led to an increased need for rehabilitation.\n\nMilitary experience has shown better outcomes with improved rehabilitation, where early and intensive rehabilitation has been shown to improve function, pain, quality of life and mental health outcomes. It can also improve outcomes for carers of those affected by traumatic injury.\n\nCosts of treatment after a traumatic injury are high in the acute phase, and there are also long-term care costs to the NHS through ongoing treatment. Social care costs may be high for people who need ongoing care and support in the community. There are wider costs to the community if people are unable to return to work or education. Rehabilitation may be able to reduce these costs through improving overall function. Interventions may improve outcomes at a number of stages.\n\nThere are several NICE guidelines about the assessment, treatment and management of specific injuries for adults and children. There is guidance about service delivery, assessment and management of major trauma, and rehabilitation after critical illness and stroke. There are also guidelines about the transition between hospital and home, from children's to adults' services, and about home care services.", 'How to use this guideline': 'All the recommendations apply to all people with complex rehabilitation needs after a traumatic injury, regardless of age or the nature of the injury, unless:\n\nthe recommendation specifically states that it is for adults only, or children and young people only or\n\nthe recommendation or section of the guideline specifically states that it is for people with a particular injury.\n\nThe following sections provide a pathway from assessment through to goal setting, agreeing and coordinating the delivery of a rehabilitation plan and programmes of therapy, and coordinating and organising rehabilitation at and following discharge:\n\nInitial assessment and early interventions for people with complex rehabilitation needs\n\nMultidisciplinary team rehabilitation needs assessment\n\nSetting rehabilitation goals\n\nDeveloping a rehabilitation plan and making referrals\n\nRehabilitation programmes of therapies and treatments\n\nPrinciples for sharing information and involving family and carers\n\nCoordination of rehabilitation care in hospital:\n\n\n\nFrom admission to hospital\n\nWhen transferring between services and settings\n\n\n\nCoordination of rehabilitation care at discharge\n\nSupporting access and participation in education, work and community (adjustment and goal settings)\n\nCommissioning and organisation of rehabilitation services\n\nThe rehabilitation therapies and interventions included in the following sections apply to ALL people with complex rehabilitation needs after a traumatic injury:\n\nPhysical rehabilitation\n\nCognitive rehabilitation\n\nPsychological rehabilitation\n\nThe following injury-specific sections should be read in conjunction with the sections on physical rehabilitation, cognitive rehabilitation and psychological rehabilitation:\n\nRehabilitation after limb reconstruction, limb loss or amputation\n\nRehabilitation after spinal cord injury\n\nRehabilitation after nerve injury\n\nRehabilitation after chest injury', 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Initial assessment and early interventions for people with complex rehabilitation needs\n\nBe aware that the severity of a person's traumatic injury does not necessarily correlate with the complexity of their rehabilitation needs, so assess the impact of the injury using a person-centred, individualised and holistic approach at all stages of their care pathway.\n\nAfter a traumatic injury, assess the person's rehabilitation needs as an integral part of their care pathway from admission. This may include:\n\ndiscussing findings from early rehabilitation assessments with the person, and their family members or carers (as appropriate)\n\nhelping the person, and their family members or carers (as appropriate), to think about preferred rehabilitation goals to inform shared decision making about medical or surgical options\n\ninvolving rehabilitation specialists (ideally including a consultant in rehabilitation) alongside acute care teams to discuss the implications for rehabilitation depending on different medical and surgical options.\n\nAll practitioners involved in the person's care should provide immediate psychological and emotional support for people who are mentally distressed and/or cognitively impaired after a traumatic injury. Request additional support and/or advice from psychology services as needed.\n\nAfter a traumatic injury:\n\nAvoid delays in acute treatment so that rehabilitation can start as soon as possible, for example, to maintain movement.\n\nStart rehabilitation when the person is ready and able to engage and participate (see also recommendation 1.2.5). For people who lack capacity to engage in making decisions about their rehabilitation, follow the NICE guideline on decision making and mental capacity.\n\nProvide access to rehabilitation therapies:\n\nbefore surgery, to maintain respiratory function and functional abilities (if surgery is delayed) and\n\nas soon as possible after surgery (starting ideally no later than the following day).\n\nAs soon as possible after the traumatic injury, assess how the person's physical impairments might affect their ability to engage in activities of daily living. Involve occupational therapy for:\n\ninput and advice on therapies and referral for aids and\n\nequipment and adaptations.\n\nAs soon as possible after a traumatic injury, start to assess whether the person has new or existing cognitive, hearing, visual or communication impairments or emotional difficulties that might affect their ability to engage in rehabilitation and in activities of daily living. Involve occupational therapy, psychology and speech and language therapy as appropriate.\n\nUse equipment as appropriate to encourage movement (for example, walking aids and transfer devices) and to protect the injury (for example, splints or orthotics).\n\nAsk about the person's diet and nutrition, including their weight, eating habits and any use of health supplements such as vitamins and minerals or high-calorie drinks.\n\nEnsure that the initial assessment checks to see if the person can swallow safely. Also see recommendation 1.11.51 and the NICE guideline on nutrition support for adults.\n\nAssess the person's risk of malnutrition using, for example, the Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP) score in children and young people under 16\xa0years and, for example, the Malnutrition Universal Screening Tool (MUST) score for adults (see the section on screening for malnutrition and the risk of malnutrition in hospital and the community in the NICE guideline on nutrition support for adults).\n\nMonitor the person's nutritional intake and weight throughout their hospital stay, provide nutrition support in line with the NICE guideline on nutrition support for adults, and refer for a specialist dietitian review if needed.\n\nComplete a safeguarding assessment for children, young people and vulnerable adults after a traumatic injury, taking into account any known or suspected non-accidental injury. (Also see the NICE guidelines on child abuse and neglect and child maltreatment, and the Care Act\xa02014.)\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on initial assessment and early interventions for people with complex rehabilitation needs\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury\n\nevidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Multidisciplinary team rehabilitation needs assessment\n\nThe multidisciplinary team should complete a personalised and holistic rehabilitation needs assessment in partnership with the person and their family members or carers (as appropriate), which should include:\n\nphysical functioning (see the section on assessing physical functioning)\n\ncognitive functioning (see the section on assessing cognitive functioning)\n\npsychological functioning (see the section on assessing psychological functioning).\n\nIn addition to the holistic rehabilitation needs assessment in recommendation 1.2.1, the multidisciplinary team should complete specialist assessments for the following injuries:\n\nfor limb injuries, see the section on rehabilitation after limb reconstruction, limb loss or amputation\n\nfor nerve injuries, see the section on rehabilitation after nerve injury\n\nfor spinal injuries, see the section on rehabilitation after spinal cord injury\n\nfor chest injuries, see the section on rehabilitation after chest injury.\n\nAlways think about the mechanism of injury and whether the person may have had a head injury. Be aware that the symptoms of traumatic brain injury can be subtle and regular screening may be necessary. If there are clinical symptoms, refer the person for a specialist assessment with healthcare professionals with expertise in traumatic brain injury rehabilitation. See also the NICE guideline on head injury.\n\nThe multidisciplinary team involved in assessing people's rehabilitation needs in hospital should consist of healthcare professionals and practitioners with expertise in rehabilitation after traumatic injury. Depending on the nature of the injury, the setting for assessment and treatment, the age of the person and other pre-existing health or care issues, the multidisciplinary team could involve:\n\nsurgeons, rehabilitation medicine specialists, intensive care specialists, elderly care specialists and/or paediatricians (as appropriate)\n\nallied health professionals such as occupational therapists, physiotherapists, dietitians, orthotists and speech and language therapists\n\npractitioner psychologists\n\nspecialist nurses\n\nplay therapists\n\npharmacists\n\na trauma coordinator and/or rehabilitation coordinator\n\nwhen planning discharge:\n\n\n\na social worker\n\na discharge coordinator.\n\n\n\nThe multidisciplinary team should assess the person's rehabilitation needs as soon as possible after the traumatic injury, when measures are being taken to optimise their ability to engage in the assessment process. These measures include:\n\npain management\n\nresolution of infections\n\nresolution of acute confusion or delirium\n\nconsideration of psychological wellbeing\n\nmaking available hearing aids, glasses, dentures and other orthodontic appliances\n\naccess to communication aids (if needed)\n\naccess to interpreters (for example, for people who do not speak English)\n\nhaving in place drug or alcohol dependence withdrawal management\n\nrestarting long-term medications to maintain physical and mental health; see also the NICE guideline on medicines optimisation.\n\nBe aware that traumatic injury may affect sexual function. Discuss this with people at assessment and review, and seek specialist advice about sexual function, fertility issues and psychological support.\n\nIf a person lacks mental capacity, carry out a rehabilitation needs assessment based on the principles of best interests decision making, as set out in the NICE guideline on decision making and mental capacity.\n\nAs part of the rehabilitation needs assessment, the multidisciplinary team should ask about the person's pre-injury activities, for example:\n\nthe person's background, personal history, relationships, work, education, meaningful activities, spiritual and religious practices, and hobbies and interests\n\nusual activities of daily living, including mobility and other physical activity\n\nmotivational factors such as the person's lifestyle, previous ability, future aspirations, priorities and core values.\n\nThe multidisciplinary team should allow adequate time to:\n\nliaise with the clinical team managing any pre-existing, long-term conditions that may affect rehabilitation\n\ncomplete the rehabilitation needs assessment, which should include a detailed and accurate analysis of the person's injuries, impairments, goals and likely rehabilitation needs and\n\ndiscuss the findings together, to reduce the need to repeat questions and to improve the efficiency of the assessment process.\n\nWhen discussing rehabilitation needs with people, and their family members or carers (as appropriate):\n\nbe sensitive about the timing because pain, confusion, fatigue and trauma can make it more difficult for people to absorb and retain information\n\ngive people sufficient time to process information about their injuries and rehabilitation options, to help them adjust after the traumatic injury and engage more readily in the rehabilitation therapy\n\nif people ask for information about the likely long-term prognosis, recognise that this may be difficult to predict and should only be discussed with the person after multidisciplinary team review.\n\nUse validated tools (for example, the rehabilitation complexity scale [RCS], patient categorisation tool [PCAT], complex needs checklist [CNC] or post-ICU presentation screen [PICUPS]), in the rehabilitation needs assessment to determine the need for early referral to specialist rehabilitation units.\n\nRegularly reassess (using clinical assessment and validated tools) whether referral for specialised rehabilitation is still needed and what other referrals may now be needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multidisciplinary team rehabilitation needs assessment\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury\n\nevidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Assessing physical functioning\n\nAs part of the rehabilitation needs assessment after a traumatic injury, the multidisciplinary team should assess the person's pre-injury and current physical functioning, which should include:\n\nassessing pain management to enable physical rehabilitation activities to begin\n\na comprehensive neuromusculoskeletal assessment to identify physical impairments such as nerve injury, muscle imbalance and proprioception problems\n\nassessing upper and lower limb function and the impact of the injury on the person's ability to move and use walking aids (if needed)\n\nassessing and recording the range of movement for each joint affected\n\nasking about any problems with balance or dizziness and other vestibular symptoms (either pre-existing or new), and considering assessment for benign paroxysmal positional vertigo (BPPV) and for head injury\n\nif the traumatic injury has been caused by a fall, asking about previous falls and considering a falls risk assessment in line with the section on multifactorial risk assessment in the NICE guideline on falls\n\nassessing pre-existing or newly acquired vision or hearing problems\n\nassessing whether there are any new difficulties with communication, speech and language\n\nassessing ability to do transfers, for example, to move from lying to sitting, and sitting to standing\n\nassessing trunk control and core stability (if relevant)\n\nassessing ability to move and level of aerobic fitness and/or exercise tolerance\n\nassessing skin care, wound care and pressure area management\n\nfor children and young people, asking about previous developmental attainment and functioning.\n\nRefer the person for a specialist assessment if the multidisciplinary team does not have appropriate skills or expertise to perform the assessment needed. Examples are:\n\nto determine when and how splints and orthoses should be used, taking into account that people with complex traumatic injuries may need bespoke splints or orthoses\n\nif they have external fixation for lower limb fractures\n\nif they have sensory loss or nerve injury (see the section on rehabilitation after nerve injury).\n\nAssess the person for factors that may affect their ability to engage in rehabilitation. These may include balance and coordination issues (neurovestibular disorders), and newly acquired vision or hearing loss. Refer for specialist assessment and management as needed. Also see the section on sudden or rapid onset of hearing loss in the NICE guideline on hearing loss in adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing physical functioning\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Assessing cognitive functioning\n\nPlease note this guideline does not cover assessment or specific rehabilitation interventions for people with traumatic brain injuries. See recommendation 1.2.3 in the section on multidisciplinary team rehabilitation needs assessment.\n\nBe aware that even if there has been no brain injury, problems with cognitive functioning are common after a traumatic injury because of the psychological shock and trauma.\n\nAs part of the rehabilitation needs assessment after a traumatic injury, the multidisciplinary team should ask about any cognitive problems, for example:\n\nconfusion\n\ndisorientation\n\nslowed thinking and/or slowed processing of information\n\nwithdrawal\n\nmemory problems\n\nagitation\n\ncommunication, speech or language changes (for example, withdrawal or selective mutism).\n\nIf a person has problems with cognitive functioning after a traumatic injury, investigate for other causes such as:\n\npre-existing cognitive impairment or dementia (see the NICE guideline on dementia)\n\ndelirium (for example, alcohol or drug misuse, drug toxicity or opiate-related confusion, infection or sepsis, or hypoxia; see the NICE guideline on delirium)\n\nbehavioural problems or learning disabilities (see the NICE guideline on challenging behaviour and learning disabilities)\n\ntraumatic brain injury (this may not show up on scans immediately and further investigations will be needed if it is suspected; see also recommendation\xa01.2.3).\n\nIf a person has problems with cognitive functioning after a traumatic injury and the potential causes in recommendation 1.2.18 have been ruled out, assess the person's:\n\norientation to time, place, person and situation\n\nability to follow simple instructions\n\nability to recall information and communicate it correctly after a short period of time.\n\nIf the assessment in recommendation 1.2.19 confirms difficulties with cognitive functioning, refer the person to an occupational therapist, practitioner psychologist (ideally a neuropsychologist) or a speech and language therapist (as appropriate) for a specialist cognitive assessment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing cognitive functioning\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.2: cognitive interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Assessing psychological functioning\n\nAs part of the rehabilitation needs assessment after a traumatic injury, the multidisciplinary team should ask about psychological and psychosocial risk factors, for example:\n\npast or present mental health problems, such as anxiety or depression\n\npast or present mental illness or psychiatric treatment\n\nhistory of traumatic brain injury\n\nhistory of self-harm or suicide attempts\n\nany experience of domestic violence or abuse\n\nany safeguarding concerns (if the person is a child or a vulnerable adult)\n\nexcessive alcohol consumption or recreational drug use\n\nthe circumstances of the injury, for example, self-harm or a violent crime\n\nsocial factors that mean the person may need additional support, for example, if the person is socially isolated, homeless, a refugee or recent migrant, if they have difficulty reading or speaking English, or if they have learning disabilities or other needs.\n\nAs part of the rehabilitation needs assessment after a traumatic injury, look for indicators of psychological problems (including lack of engagement with rehabilitation) beyond that of an acute stress response (see recommendation 1.13.1). Take into account any psychological and psychosocial risk factors (see recommendation 1.2.21) and, if needed, refer the person for a psychological assessment with a practitioner psychologist (with relevant expertise in physical trauma and rehabilitation) or a member of the liaison psychiatry team to inform their rehabilitation plan and goals.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessing psychological functioning\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Setting rehabilitation goals\n\nAlso see the section on supporting access and participation in education, work and community (adjustment and goal setting).\n\nAgree short-term and long-term rehabilitation goals with the person and their family members or carers (as appropriate), and review them regularly based on:\n\nwhat is most important to the person and what they most value\n\nactivities that are meaningful for the person and relate to what is important\n\na strengths-based approach, which builds on positive function and ability\n\nthe person's home circumstances\n\nthe person's aspirations about returning to work or education, and their preferred timeframe\n\ndeveloping the knowledge, skills and confidence to manage their own health and wellbeing\n\nan understanding that there may be setbacks as well as gains, so goals should be flexible.\n\nWhen setting long-term rehabilitation goals, agree small steps so that progress can be monitored in a way that is meaningful and motivational for the person.\n\nMembers of the multidisciplinary team involved in setting rehabilitation goals should be skilled and competent in:\n\nhelping people identify goals that are right for them\n\nunderstanding how the psychological impact of trauma can affect goal setting and rehabilitation planning.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on setting rehabilitation goals\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Developing a rehabilitation plan and making referrals\n\nUse the rehabilitation needs assessment (see the section on multidisciplinary team rehabilitation needs assessment) and the person's rehabilitation goals (see the section on setting rehabilitation goals) to develop a rehabilitation plan for the person (this may be in the form of a rehabilitation prescription). The rehabilitation plan should include:\n\ninformation about the person's injuries\n\nthe person's short-term and long-term rehabilitation goals (see the section on setting rehabilitation goals)\n\ninformation about the person's needs and preferences\n\na suggested rehabilitation programme of therapies and treatments (see the section on rehabilitation programmes of therapies and treatments)\n\nhow the rehabilitation programme of therapies and treatments will be delivered\n\ninformation and sources of further information about returning to vocational or leisure activities\n\ninformation about associated risks, responsibilities, and possible legal issues about returning to driving and sources of specific advice (for example, the DVLA [Driver and Vehicle Licensing Agency])\n\ninformation about referrals or sources of further information\n\nany follow-up arrangements (especially when transferring to home or community settings)\n\nwho the rehabilitation plan should be shared with (with the person's consent) and details about any information that the person wants to remain confidential\n\ndetails of a rehabilitation coordinator or key worker, and the lead healthcare professional involved in the person's care.\n\nThe rehabilitation plan should be:\n\na tailored and personalised journey towards the person's agreed goals, focusing on what is important to them\n\ndeveloped with the person, and their family members or carers (as appropriate)\n\nbased on advice and input from all members of the multidisciplinary team\n\nwritten in clear English\n\na single document or file\n\nshared with the person, their families and carers (as appropriate), the person's GP, and healthcare professionals involved in their ongoing care\n\nregularly updated in partnership with the person to reflect their progress, goals, ongoing needs and key contact information, particularly at key points of transition in care.\n\nWhere it is not possible or appropriate for the person to have access to all of the information in a rehabilitation plan, ensure that important components of the plan are included in a summarised patient-held document that is regularly updated with progress, appointment times and contact details.\n\nIf there are aspects of the rehabilitation plan that the multidisciplinary team cannot implement, the rehabilitation coordinator or another senior member of the multidisciplinary team should make appropriate referrals without delay, including referrals to specialised rehabilitation services.\n\nManage the care of adults with fragility fractures of the femur within a specialist pathway involving orthogeriatricians. Also see the NICE guideline on hip fracture.\n\nIf an older person with a traumatic injury is on a care pathway that does not routinely involve geriatrician support, consider referral to an orthogeriatrician, a surgical liaison or a perioperative physician (as appropriate).\n\nFor adults with a fragility fracture, assess bone health and refer as necessary, for example, to a specialist bone health clinic or outpatient service. Also see the NICE guideline on osteoporosis.\n\nIf a traumatic injury has been caused by a fall, ask the person about previous falls, and consider a falls risk assessment and a referral to a community falls service (as appropriate). Also see the section on multifactorial risk assessment in the NICE guideline on falls.\n\nAssess all adults over\xa065 who have a traumatic injury for their risk of falls in line with the recommendations on multifactorial risk assessment in the NICE guideline on falls.\n\nProvide information about, or refer people to, services that may help prevent future injury, such as falls prevention, safeguarding services, domestic abuse services, violence prevention programmes, and condition-specific support organisations.\n\nFor people admitted to hospital with violent injuries related to suspected criminal activity, consider a violence prevention programme and follow-up as part of their rehabilitation plans. This could include psychological support (for example, counselling), substance abuse rehabilitation, employment or education training, group sessions, family development, liaison with the police, social worker involvement, and rehousing, when needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on developing a rehabilitation plan and making referrals\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury\n\nevidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community.\n\nLoading. Please wait.\n\n# Rehabilitation programmes of therapies and treatments\n\n## General principles for rehabilitation programmes\n\nRehabilitation programmes of therapies and treatments should:\n\nform part of the person's rehabilitation plan, and be tailored to their individual needs (see the section on developing a rehabilitation plan and making referrals)\n\nfocus on outcomes (for example, return to work, school or leisure activities) and be based on the person's short-term and long-term rehabilitation goals (see the section on setting rehabilitation goals)\n\ninclude educational material to help people understand the nature of their injuries, to promote self-care and to prepare them for any long-term or intensive periods of rehabilitation (for example, sleep, pacing activities and pain management)\n\ninclude (as appropriate) physical, cognitive and psychological therapies and treatments such as physiotherapy, exercise, occupational therapy, psychology and orthotics, as well as injury-specific therapies and treatments; see the sections on:\n\n\n\nphysical rehabilitation\n\ncognitive rehabilitation\n\npsychological rehabilitation\n\nrehabilitation after limb reconstruction, limb loss or amputation\n\nrehabilitation after spinal cord injury\n\nrehabilitation after nerve injury\n\nrehabilitation after chest injury\n\n\n\ninclude access to specialist services to address complex issues such as fertility and endocrine concerns\n\ninclude (as appropriate) a combination of group and individual sessions as well as the development of a self-management rehabilitation programme (see the section on supporting access and participation in education, work and community [adjustment and goal setting])\n\ninclude and document regular progress reviews and a final assessment to review outcomes, update the rehabilitation plan and detail any ongoing rehabilitation needs for onward referrals to GP, outpatient and/or community services\n\ninclude post-programme follow-up, in person or virtually.\n\nTailor the start time, frequency, intensity and duration of the rehabilitation programme to have the most beneficial effect on the person's recovery (for example, a short period of intensive rehabilitation at an important time point might be better than weekly sessions over a long period).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on general principles for rehabilitation programmes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Intensive rehabilitation programmes\n\nIn the post-acute period, consider an intensive (for example, 3\xa0weeks) inpatient or outpatient (including residential) rehabilitation programme for adults, young people and children with complex injuries and rehabilitation needs if such an intervention is likely to have a significant impact on change in function (for example, it could result in return to work or education and living independently).\n\nWhen providing intensive rehabilitation programmes:\n\noffer education and learning materials (see the section on guided self-managed rehabilitation) to prepare people for intensive rehabilitation, for example, 1\xa0week of remote learning followed by a (for example, 3‑week) residential or outpatient programme\n\nanswer questions, such as those relating to the person's injuries and rehabilitation\n\nconsider delivering rehabilitation therapies with regular breaks (for example, only during weekdays to allow for rest periods at weekends and time to review progress)\n\ncommunicate any changes to the rehabilitation plan with the local team following the intensive period of rehabilitation.\n\nStart an intensive rehabilitation programme at the appropriate time for the person, taking into account:\n\nthat the timing and nature of rehabilitation therapies and treatments will depend on issues such as bone and soft tissue healing, weight-bearing, and removal of weight-bearing restrictions\n\nthe person's psychological and emotional wellbeing, levels of adjustment and engagement with the rehabilitation process.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intensive rehabilitation programmes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Guided self-managed rehabilitation\n\nConsider guided self-managed rehabilitation to allow the person to engage in rehabilitation in their own time and by their own schedule, working with rehabilitation healthcare professionals and practitioners, with regular reviews to check on progress, provide ongoing reassurance and answer queries.\n\nAs part of a self-management rehabilitation programme, consider providing a tailored package of online education and learning materials for people after a traumatic injury, which could include information on:\n\nmovement and physical activity\n\nenergy conservation and pacing\n\nsleep\n\nactivities of daily living\n\nwork, social activities and hobbies\n\nnutrition and diet\n\npain management and medicines\n\nwound healing\n\nmental health\n\nlocal and national sources of information\n\npeer support services, including local and national groups. For people who cannot access the internet, explore alternative ways to provide these materials.\n\nIf people are following a self-management rehabilitation programme, consider arranging follow-up appointments and regular reviews with rehabilitation healthcare professionals and practitioners to check on self-managed progress, provide ongoing reassurance and answer new queries.\n\nFor children, young people and vulnerable adults, offer additional support to develop and deliver a self-management programme that takes into account their communication needs, their own views and priorities and (for children) their developmental stage.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on guided self-managed rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments\n\nMonitor the person's progress after starting rehabilitation. Use tools such as patient-reported outcome measures (PROMs) and clinician-reported outcome measures (CROMs) for adults; parent- and child-reported measures for children and young people; and consider using tools that involve family members and carers. Additional specific clinical assessments may be used as appropriate.\n\nEncourage people to record information about their injuries, treatments and rehabilitation therapy options (for example, using a diary as part of their rehabilitation plan) to assist discussions and shared decision making.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community.\n\nLoading. Please wait.\n\n# Principles for sharing information and involving family and carers\n\nInvolve people, and their families and carers (as appropriate), in assessments, in planning their coordination of care and in making decisions at all stages of the rehabilitation process. This should include discussing medical or surgical treatment options, discussing findings from assessments, setting goals, discussing potential discharge destinations and examining the different rehabilitation options after discharge.\n\nEncourage and support children and young people to be actively involved in decision making about their rehabilitation to the best of their ability.\n\nBe aware that encouragement from family members, carers, friends and healthcare professionals can all have a positive effect on a person's rehabilitation after a traumatic injury, so involve the person's family members, carers and friends (as appropriate) as much as possible throughout the person's rehabilitation journey.\n\nIn discussions and when giving information to people, and their family members or carers (as appropriate), use clear language, and tailor the timing, content and delivery of information to the needs and preferences of the person. Information should be:\n\nspecific to the person's injuries\n\noffered in face-to-face (in person or remotely by video link) discussions, and in a suitable format, for example, digital, printed, braille or Easy Read\n\noffered throughout the person's care\n\npersonalised and sensitive\n\nsupportive and respectful\n\nevidence-based and consistent between healthcare professionals.For more guidance on communication, providing information (including different formats and languages) and shared decision making, see the NICE guidelines on patient experience in adult NHS services, babies, children and young people's experience of healthcare, decision making and mental capacity and shared decision making.\n\nBe aware that if a person has severe and complex rehabilitation needs after a traumatic injury, if they have had a brain injury or if they have problems with cognitive functioning after a traumatic injury, information giving may need to be enhanced and reinforced by:\n\nrepeating information on several occasions\n\nproviding information in a suitable format (for example, Easy Read)\n\ngiving information in the presence of family members or carers (as appropriate).\n\nBe aware that people who lack mental capacity may be legally entitled to professional advocacy (see the Mental Capacity Act 2005), as may people who have care and support needs (see the Care Act 2014). Also see the NICE guideline on decision making and mental capacity.\n\nAdvise carers about their right to a carer's assessment, an assessment for replacement care, and other support (see the NICE guideline on supporting adult carers for recommendations on identifying, assessing and meeting the caring, physical and mental health needs of families and carers).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles for sharing information and involving family and carers\xa0.\n\nFull details of the evidence and the committee's discussion are:\n\nevidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Coordination of rehabilitation care in hospital\n\n## From admission to hospital\n\nWhere possible, provide continuity of staff throughout the person's rehabilitation pathway.\n\nAssign a named rehabilitation coordinator or key worker to oversee the person's care as soon as possible and within 72\xa0hours of admission. Ensure that the person knows who their rehabilitation coordinator or key worker is, how they will coordinate care, and how they can be contacted.\n\nThe trauma team should agree the core members of the rehabilitation multidisciplinary team who will establish an injury management plan and start developing a rehabilitation plan and goals. See recommendation 1.2.4 for details of the multidisciplinary team after hospital admission.\n\nA member of the rehabilitation multidisciplinary team should discuss the person's rehabilitation at daily trauma meetings or ward rounds.\n\nWhere assessment identifies the need for specialist rehabilitation (see the section on multidisciplinary team rehabilitation needs assessment), complete the referral to specialist rehabilitation units as soon as possible.\n\nUse a unique identifier, preferably the NHS number if this is known, when exchanging clinical information about the person's assessment, rehabilitation plan, onward referral, transition between services, discharge to community services, and all aspects of their care pathway.\n\n## When transferring between services and settings\n\nMake follow-up appointments with acute teams (if needed) for people moving from an acute unit to rehabilitation services, and ensure that the person is informed before they are transferred.\n\nWhen people transfer between service providers or settings (for example, wards, hospitals and inpatient rehabilitation facilities), share information (with the person's consent) by providing a detailed verbal and written or online handover (for example, the rehabilitation plan and the person's progress against it) and let the person know this has been done. Ensure information is promptly communicated:\n\nto those coordinating and delivering rehabilitation in the new setting or service\n\nto the person, and family members and carers (as appropriate)\n\nto any other service providers involved in the person's care and support.\n\nThe detailed handover and report should include oral and online or printed information about:\n\nall of the person's injuries\n\ndifferent treatment options and their benefits and risks\n\nthe person's current rehabilitation plan and goals\n\nthe person's cultural, language and communication needs\n\npsychological approaches to managing pain and fatigue, if relevant\n\nbeneficial activities, and activities to avoid\n\nhow to manage activities of daily living, including self-care and re-engaging with everyday life\n\nplans for returning to work or school, housing and benefits, and driving, if relevant\n\nhow to recognise possible problems or complications, and what to do\n\nlocal support groups, opportunities to access peer support, online forums and national charities, and how to get in touch with them\n\nservices that provide independent legal, financial, employment and welfare advice\n\nadvice for the family or carers about:\n\n\n\nwhat to expect and how to support the person at home\n\nthe impact of the traumatic injury on family members and carers, and how they can get support.\n\n\n\nWhen people transfer between service providers or settings, discuss with them:\n\ntheir expected recovery pathway\n\nwhat might happen if recovery is slower than expected\n\nthe emotional impact of living with possible long-term symptoms and treatments.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on coordination of rehabilitation care in hospital\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Coordination of rehabilitation care at discharge\n\n## Discharge planning and a multidisciplinary approach\n\nConsider early, multidisciplinary discharge planning to ensure appropriate and smooth discharge and transition to outpatient and community services.\n\nReassess the person's needs and review the rehabilitation plan before discharge to ensure that their needs are addressed alongside any long-term, existing health conditions or disabilities.\n\nBe aware that family members and carers can play a key role in the smooth transition to outpatient and community services. If the person consents and their family members or carers agree, actively involve them in the transition process.\n\nGive people information and support at the earliest opportunity if they need to apply for funded equipment for use after discharge from hospital (for example, wheelchairs) because applications can take time to process and may delay the person's discharge.\n\nFor children and young people, arrange a meeting between the school or education setting, 1\xa0or more members of the multidisciplinary team, and their parents or carers, to inform the education provider about the changes to the environment and education plan that the child or young person may need to meet their education and support needs. This should take into account transport needs.\n\nAdvise people that further help with funding for equipment, assistive technology, environmental adaptations and other forms of support with rehabilitation might be available for their home, education and workplace settings (for example, through local authorities, the education, health and care plan, Access to Work grants, voluntary sector grants and the Department for Work and Pensions).\n\nGive people, and their family members or carers (as appropriate), information about services that provide independent legal, financial, employment and welfare advice (for example, Citizens Advice).\n\nIf a person has significant ongoing and complex medical and therapy needs, offer a gradual and incremental return into the community, for example, transfer to a local hospital, a stepdown bed or a pre-discharge visit to home, to reduce the distress of the sudden loss of support as an inpatient.\n\nEnsure that ongoing advice about pain management, including a plan to reduce analgesia, is discussed with the person and passed onto the person's GP or another lead clinician. See also the NICE guideline on medicines optimisation.\n\nWhere possible, arrange joint inpatient and community team home visits with the person before discharge, especially for people with significant ongoing needs.\n\nIf there are any concerns about how the person will manage at home after they are discharged, consider overnight or weekend visits home before discharge, depending on their needs, preferences and home circumstances.\n\nWhen arranging overnight or weekend visits home, involve the person in discussing the possible risks and how to manage them, especially if they live alone.\n\n## Planning for rehabilitation and other support following discharge\n\nIf a person is likely to have continuing health and social care needs after discharge to home:\n\ninform relevant healthcare professionals, social care practitioners and education practitioners (as appropriate)\n\nestablish the person's eligibility for funded social care support, including for families and carers\n\nuse the NHS continuing healthcare checklist, to establish the person's eligibility for a full continuing healthcare assessment before discharge\n\nfor children and young people, establish their eligibility for emergency education funding for short-term support at school and for funded support through an education, health and social care plan (if appropriate). Also see the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.\n\nOffer a multidisciplinary approach to meet the person's rehabilitation and social care needs that is coordinated, consistent and as integrated as possible, to support the person, and their family or carer (as appropriate), through transfer from inpatient to outpatient rehabilitation services.\n\nDocument in the rehabilitation plan and handover report how rehabilitation after discharge will be delivered (see recommendations 1.7.7 to 1.7.9 for what should be included). When transferring the person to outpatient and community settings (including home), also include:\n\nwhether ongoing support and follow-up after discharge is needed, for example, community rehabilitation, referrals and review appointments\n\nwhen community rehabilitation appointments will be likely to take place.\n\nFor people who will have significant ongoing needs after discharge:\n\narrange a pre-discharge planning meeting with community practitioners who will be involved in the person's rehabilitation, care and support (for example, therapists, social workers and care coordinators)\n\nencourage pre-discharge visits by community practitioners to meet the person, and their family or carer (as appropriate)\n\nconsider organising a joint 'handover' appointment between the inpatient multidisciplinary team and community practitioners at the point of discharge.\n\nLiaise with community teams (such as community and voluntary sector providers, physiotherapists and occupational therapists, education support, and special educational needs coordinators in schools and nurseries for children and young people) to agree a staged return to the workplace or education. (See also the NICE guideline on transition between inpatient hospital settings and community or care home settings for adults with social care needs.)\n\nWhen planning discharge, address potential barriers that may prevent the person accessing rehabilitation in the community. For example, ensure that they can travel to and access the location of treatments, and ensure that the timing and length of appointments will be manageable for them.\n\nIf a person cannot travel to rehabilitation appointments, offer telephone or video consultations, or rehabilitation in the person's home.\n\nConsider arranging telephone or video consultations or rehabilitation in the person's home, rather than in a clinic or hospital setting (for example, if the person needs help to learn to live independently in their own home).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on coordination of rehabilitation care at discharge\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review A.1/A.2: identification and assessment of rehabilitation needs after traumatic injury\n\nevidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## A single point of contact, key contact and key worker after discharge\n\nAt discharge from hospital, provide people and their family or carers (as appropriate) with a single point of contact at the hospital for information, help and advice for a limited time period (for example, 3\xa0months).\n\nIf people need ongoing rehabilitation and other health and social care support after discharge, the inpatient multidisciplinary team and community practitioners should agree who will be the key contact after discharge when contact with the hospital is no longer appropriate (see recommendation 1.8.23). This person may be a GP, rehabilitation physician, special educational needs coordinator, allied health professional, family support worker, social worker, case manager, disability paediatrician or speciality-specific coordinator, for example, a neuro\xa0navigator.\n\nIf people have complex or long-term conditions or social care needs, consider appointing a key worker as a direct source of advice, support and signposting. This should be a healthcare or social care professional with knowledge and expertise about inpatient or community-based rehabilitation and support, including education or training support for children and young people.\n\nFor young people who are transitioning between children's and adults' services, see recommendations about the role of the named worker in the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on a single point of contact, key contact and key worker after discharge\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Supporting access and participation in education, work and community (adjustment and goal setting)\n\nAlso see the section on setting rehabilitation goals.\n\nHelp and support the person to adjust after a traumatic injury by asking them and their family members or carers (as appropriate) about:\n\ntheir life, hobbies, occupation, usual activities, and personal and family history, and finding out what is important to them\n\ntheir views and feelings about their injuries and rehabilitation options\n\nthe support they think they will need by asking about their views and feelings\n\nallowing time for adjustment and considering this before starting any new rehabilitation therapies or interventions.\n\nSupport the person to achieve realistic rehabilitation goals for life skills, work-related training or education (see the section on setting rehabilitation goals). Support should be tailored to the person's needs and may include:\n\nproviding equipment and adaptations (for example, wheelchairs and seating)\n\nincreasing independence in activities of daily living (for example, personal care, dressing and bathing, housework, shopping, food preparation, eating and drinking, managing money, how to access carers' and disability benefits and grants, driving or using public transport)\n\nwork-related training (for example, careers advice and retraining)\n\nadvice from job centres (for example, disability employment advisers and access to work scheme)\n\naccess to adult education settings\n\naccess to education for children and young people (for example, special educational needs and disabilities [SEND] adjustments in school, or new school placements).\n\nRevisit rehabilitation goals with the person at regular intervals and align them with ongoing emotional and psychological adjustment.\n\nGive people information about opportunities for engaging in daily meaningful activity (for example, hobbies, social activities or voluntary work) while they are in the process of a staged return to work.\n\nAdapt rehabilitation activities to promote social interaction and participation in the person's normal activities of daily living consistent with the person's lifestyle and preferences.\n\nProvide information for the person's employer or education provider about:\n\nthe person's rehabilitation needs and\n\nhow they can make adjustments to support the person's rehabilitation goals, for example, a staged or part-time return to work or education, and/or amended duties.\n\nSee the section on workplace culture and policies in the NICE guideline on workplace health: long-term sickness absence and capability to work for recommendations about vocational support and returning to work.\n\nProvide information for early years settings or schools about the child or young person's rehabilitation needs, and the adjustments needed to enable their return to education and sports, for example, a staged return.\n\nGive children and young people, and their families and carers (as appropriate), information about educational support and return to school.\n\nFor young people who are starting to access support from adult rehabilitation services, see the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nCommunity practitioners should offer emotional and psychological support to adults and their families and carers to help with lifestyle adjustments and the effects of the traumatic injury (for example, prolonged hospitalisations), and support their gradual return to work, education, social roles and leisure activities.\n\nThe team around the child should offer emotional and psychological support to children, young people and their families and carers to help with lifestyle adjustments and the effects of the traumatic injury (for example, prolonged hospitalisations), and support their gradual return to education, play, social and leisure activities.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting access and participation in education, work and community (adjustment and goal setting)\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review B.4: rehabilitation interventions relating to participation in society for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Commissioning and organisation of rehabilitation services\n\n## Commissioning\n\nWhen planning, commissioning and coordinating the delivery of rehabilitation and related services (for example, social care and the voluntary sector), commissioners and providers should design services with whole care pathways in mind, from acute treatment and inpatient rehabilitation through to community provision, including specialised and non-specialised elements.\n\nEnsure collaboration between commissioners from different commissioning bodies to ensure seamless provision, for example, to include specialist community, vocational and educational rehabilitation provision for people after a traumatic injury, including those transferring between children's and adults' services.\n\nEnsure that it is clear locally who has overall designated commissioning responsibility for rehabilitation services.\n\nCommissioners and providers should ensure that rehabilitation services for people after a traumatic injury:\n\nmeet the needs of people of all ages and at all stages of rehabilitation\n\nare developed and co‑designed in collaboration with the people who use rehabilitation services and the healthcare professionals who work within them\n\nare outcome-focused and relevant for the people who use them.\n\nConsider commissioning intensive (for example, 3‑week) residential or outpatient rehabilitation programmes for people of all ages in addition to existing rehabilitation pathways, for example, as a tertiary service for trauma rehabilitation within the trauma network.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on commissioning\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Organisation\n\nEstablish care networks (for example, trauma networks) and clear guidance on coordination and communication between rehabilitation settings and services to meet the needs of the local population across different aspects of rehabilitation service commissioning.\n\nRehabilitation units should maintain an online directory of care pathways, rehabilitation facilities and voluntary sector services (including recreational facilities) so that practitioners have access to up-to-date information and contact details to pass on to people with complex rehabilitation needs.\n\nIf community treatments and services remain uncertain at the point of discharge, give people and their families and carers (as appropriate) information about rehabilitation community and social services available in their local area and from national support networks, and how they can access these.\n\nOffer networking opportunities between different rehabilitation, social care and related services to enhance inter-service awareness and working relationships.\n\nConsider technology-enabled follow-up, support and rehabilitation sessions if people request more local, accessible therapy or if rehabilitation practitioners are not available in their area, for example, in rural areas.\n\nConsider group rehabilitation sessions to allow people to interact with peers, share experiences and to provide valuable support.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on organisation\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D.1 (service coordination): inpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.3 (service coordination): barriers and facilitators to accessing rehabilitation services following discharge to the community.\n\nLoading. Please wait.\n\n## Rehabilitation skills, knowledge and expertise in the workforce\n\nEnsure that staff working with people with complex rehabilitation needs have specialist skills, knowledge and expertise in the person's injuries, the complexity of their rehabilitation needs and goals, and the stages of their recovery journey.\n\nEnsure that hospital staff have access to supervision and training to develop their specialist knowledge in the management and rehabilitation of traumatic injuries.\n\nEnsure that community rehabilitation practitioners have access to training expertise, advice or peer support from specialist services, especially where specific rehabilitation interventions or services are not widely available. For example, healthcare professionals such as speech and language therapists, practitioner psychologists and consultants with specialist knowledge of specific injuries and complex rehabilitation could work together with general rehabilitation staff working in community-based rehabilitation services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation skills, knowledge and expertise in the workforce\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D.2 (service coordination): inpatient to outpatient settings for people with complex rehabilitation needs after traumatic injury\n\nevidence review D.4 (service coordination): support needs and preferences following discharge to outpatient or community rehabilitation services for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Physical rehabilitation\n\n## Physical rehabilitation – early interventions and principles\n\nProvide personalised exercises as soon as possible after a traumatic injury to maintain and improve muscle function, strength and range of movement.\n\nProactively support people in managing their pain, and ensure that they have adequate analgesia so that rehabilitation can go ahead.\n\nChoose a pain scale appropriate for the person, taking into account a range of factors such as their developmental age, cognitive ability, any communication difficulties and their first language.\n\nIf needed, provide aids, splints or orthotics to maintain range of movement or protect the injury (for example, an ankle-foot orthosis, knee brace or spinal orthosis).\n\nUse clinical judgement and expertise to determine the frequency and dose of the prescribed exercises because this is vital to the success of the interventions, and will differ depending on the individual needs and goals.\n\nBefore starting weight-bearing exercises, be aware of the effects of low blood pressure (for example, postural hypotension or vasovagal syncope [fainting]) and monitor the person for hypotensive symptoms when starting therapy.\n\nMinimise adverse effects of low blood pressure and loss of postural reflexes by:\n\noptimising the person's bed position and using strategies such as thromboembolic stockings\n\nensuring adequate hydration\n\ncarrying out a medication review\n\nusing abdominal binders and tilt tables.\n\nBe aware that traumatic injury that requires intubation, or causes facial trauma, oedema or loss of dentition may lead to a voice disorder, decreased speech intelligibility and/or swallowing difficulties. Consider early referral to appropriate professionals as needed; this may include maxillofacial specialists, dental services, ear, nose and throat services, or speech and language therapy.\n\nPromote independence with activities of daily living, in particular personal activities of daily living, and consider referral to occupational therapy if needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical rehabilitation – early interventions and principles\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Early weight-bearing\n\nThe surgical team should define and document the person's weight-bearing status at the earliest opportunity after a traumatic injury, and inform the rehabilitation multidisciplinary team, explaining the reasons for restricted weight-bearing, what limits should be put in place and for how long.\n\nStart a programme of weight-bearing exercises, including exercises through play for children and young people, as soon as possible after a traumatic injury to encourage mobility and maintain postural reflexes, muscle mass, strength and function.\n\nFor people with lower limb injuries, start a programme of targeted weight-bearing exercises, including exercises through play for children and young people, to improve range of movement of the affected joint(s), improve muscle activation, and improve strength and balance. Aim to progress the person's function with weight-bearing tasks such as mobility, ability to move from sitting to standing, and ability to lateral step.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on early weight-bearing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Aerobic and strengthening exercises\n\nAs soon as possible after a traumatic injury, start a tailored exercise programme to help with reconditioning, fitness, strengthening, balance, proprioception and vestibular function, irrespective of the person's age, stage of rehabilitation or combination of injuries. The exercise programme:\n\ncould be self-directed and/or delivered as one-to-one sessions or in a group\n\nshould include resistance training, core strengthening exercises and general aerobic fitness\n\nshould include task-specific balance training if needed\n\nshould be incorporated into the usual play activities for children\n\nshould be tailored to the person's needs and goals (for example, the frequency of the sessions and the exercises involved).\n\nConsider a continued programme of aerobic exercise when agreeing a rehabilitation plan and at appropriate points along the rehabilitation pathway.\n\nFor people with limited lower limb mobility or immobility after a traumatic injury, consider a programme of upper body aerobic training or seated exercises.\n\nTailor the aerobic exercise programme to the person's interests to help with personal commitment and adherence, and depending on the nature of their traumatic injuries.\n\nDo not withhold aerobic exercise programmes from older people after a traumatic injury.\n\nAfter discharge from hospital after a traumatic injury, offer people a home exercise programme that includes aerobic and strengthening exercises, and review their progress at outpatient clinics or key worker appointments.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on aerobic and strengthening exercises\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Gait training and re-education\n\nFor people who are unable to weight-bear (because of clinical restrictions or pre-existing conditions), start an exercise programme as soon as possible after the traumatic injury to reduce the impact of non-weight-bearing and to optimise the transition to gait training when possible.\n\nAs soon as possible after a traumatic injury and once weight-bearing can begin, start a gait re-education programme that:\n\naims to restore gait patterns\n\nincludes passive stretches and range of movement exercises\n\nreduces the impact of non-weight-bearing on joints and muscles.\n\nFor people who need a non-weight-bearing period after a traumatic injury:\n\nassess muscle weakness and joint range of movement as soon as possible after the non-weight-bearing period ends and\n\nstart an exercise programme aimed at muscle strengthening and gait progression.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on gait training and re-education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Manual therapies and maintaining joint range of movement\n\nProvide a programme of passive, active assisted or active range of movement exercises for all affected joints.\n\nConsider a programme of targeted stretching techniques in addition to the standard range of movement exercise programme in recommendation 1.11.22.\n\nIf the person is unable to engage in range of movement exercises independently, consider using controlled motion devices to help with range of movement at the knee and ankle joints.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on manual therapies and maintaining joint range of movement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Splinting and orthotics\n\nRegularly review the use of splints (as part of donning [putting on] and doffing [taking off]), cautiously increasing the length of time the splint is in use to ensure that it is still appropriate and that there are not complications such as nerve injury or pressure sores.\n\nEnsure that the person, and their families and carers (as appropriate), know how to put on and take off their orthoses and splints, when to wear them and when to seek advice.\n\nFor people with lower limb fractures or nerve injuries, consider an orthosis (for example, a dorsi-wedge in a moon boot or an ankle-foot orthosis) if there is a risk of loss of ankle range of movement.\n\nFor people with external fixation for lower limb fractures, carry out specialised splinting to maintain ankle range of movement.\n\nMonitor the pressure effects on skin by orthoses or splints, particularly in people with reduced cutaneous sensation and/or recent skin graft or flaps. Seek advice from tissue viability services and/or plastic surgery specialists as needed.\n\nBe aware that spinal orthoses, such as cervical collars and thoraco-lumbar spinal orthoses, may be poorly tolerated by some people, particularly older people or those with delirium, cognitive impairment or dementia.\n\nIf spinal orthoses are causing problems (such as pain, pressure sores, or swallowing or breathing difficulties) or are significantly affecting the person's ability to engage with rehabilitation, inform the relevant surgical team.\n\nIf splints or braces are used to immobilise and protect joints, avoid positions that may result in loss of function or complications in the future.\n\nFor people with upper limb injuries that affect range of movement in their hands and fingers, offer bespoke (thermoplastic) splints as early as clinically possible to maintain range of movement. Refer people with complex hand injuries to a hand therapy specialist, as appropriate.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on splinting and orthotics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Management of swelling and oedema, and scars\n\nDiscuss with people what swelling to expect after a traumatic injury. Explain how to monitor swelling on a daily basis, and advise them about signs or symptoms that they should seek medical advice for.\n\nConsider alternative medical causes for unexpected swelling such as deep vein thrombosis, and investigate as necessary.\n\nStart a programme of circulation exercises and elevate the person's affected limb to prevent and reduce swelling after a traumatic injury, for example, by using elevating leg rests for wheelchairs.\n\nConsider providing compression bandaging under specialist supervision, for example, from a specialist in hand therapy.\n\nHelp the person desensitise themselves to their injury by encouraging them to:\n\nlook at the affected area\n\ngently touch the affected area\n\nmove their affected limb.\n\nFor children and young people, keep their hospital bed as a 'safe' space, and carry out potentially painful scar management techniques such as massage, or other painful treatments, away from their bed if possible.\n\nReassure people that unpleasant sensations (for example, pain and itchiness) in the area of wounds or skin injuries are normal after a traumatic injury, and may change as recovery progresses.\n\nDiscuss and give people information about scar management such as keeping the wound out of direct sunlight for 1\xa0year, and using recommended emollients.\n\nProvide a massage programme for scar tissue after healing, to desensitise the affected area and increase tissue mobility.\n\nConsider referral for specialist treatments for people with problematic scars such as hypertrophy or contracture across joints.\n\nIf the person's injuries and scars have had a significant psychological impact on them, consider referral to psychology services and/or signpost to appropriate support groups. See also the section on assessing psychological functioning and the section on psychological rehabilitation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of swelling and oedema, and scars\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Nutritional supplementation\n\nMonitor the person's intake of adequate food and drink to maintain weight, taking into account the effects of post-surgical anorexia, pain medications, constipation and nausea, and the increased calorific needs of healing.\n\nRegularly and proactively review the person's nutritional needs and the dietary plan for effective rehabilitation. See recommendations in the NICE guideline on nutrition support for adults.\n\nFollowing assessment by a dietitian specialising in trauma care, consider supplementation of dietary protein for people who are frail, have gastrointestinal health issues or have multiple injuries.\n\nInvolve specialist dietitians when considering dietary protein requirements for people with severe kidney impairment.\n\nFor people with a fragility fracture, measure vitamin\xa0D levels and consider a supplement. Also see the recommendations in the NICE guideline on osteoporosis: assessing the risk of fragility fracture and the NICE guideline on vitamin\xa0D: supplement use in specific population groups.\n\nFor people with burns in combination with other traumatic injuries, regularly monitor their weight and involve a dietitian with experience of burns, for example, if the person's weight fluctuates or they are at risk of losing muscle mass and strength.\n\nIf there are concerns about safe swallowing and risk of aspiration (see recommendation 1.1.10), keep the person nil by mouth and carry out a swallowing assessment by an appropriately trained healthcare professional as soon as possible. If immediate assessment is not available, maintain hydration and nutrition by non-oral means. Also see the NICE guideline on nutrition support for adults.\n\nInvolve a dietitian and nutrition team for treatments to maintain nutritional supply, for example, a nasogastric tube, percutaneous endoscopic gastrostomy (PEG), radiologically inserted percutaneous gastrostomy (RIG) or parenteral nutrition (PN).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on nutritional supplementation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Cognitive rehabilitation\n\nPlease note this guideline does not cover assessment or specific rehabilitation interventions for people with traumatic brain injuries. See recommendation 1.2.3 in the section on multidisciplinary team rehabilitation needs assessment.\n\nReassure people that most trauma-related problems with cognitive functioning are temporary.\n\nAdapt rehabilitation therapy to the person's current cognitive function and emotional needs, taking into account any problems with motor development and skills, and any coexisting neurodevelopmental conditions.\n\nIf problems with cognitive functioning persist, get worse or recur, carry out further assessments to understand the cause.\n\nIf a person has problems with cognitive functioning after a traumatic injury, provide information:\n\nusing clear language\n\nwith the timing, content and delivery tailored to the person's needs and preferences\n\nin a suitable format (for example, Easy Read)\n\nwith written plans to aid recall\n\nthat uses pictures, symbols and objects of reference\n\nwith calendar or diary prompts for sessions or appointments.\n\nShare information with family members or carers (as appropriate) so they can help the person understand the key messages and aid recall.\n\nFor children and young people:\n\nask parents and carers if there are any pre-injury cognitive issues, for example, any known special educational needs\n\nliaise with their education provider if information about their pre-injury cognitive performance is needed\n\ninform education providers and teachers, including those in the hospital setting, about the child or young person's needs and any problems with cognitive functioning.\n\nBe aware that after a traumatic injury, people may present with fluctuations in mental capacity, and that this may affect decision making. See the NICE guideline on decision making and mental capacity.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on cognitive rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.2: cognitive interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Psychological rehabilitation\n\nReassure people that short-term psychological problems in the form of an acute stress response are common after a traumatic injury. Symptoms can last for 4\xa0to 6\xa0weeks and may include:\n\ndisturbed sleep\n\nintrusive thoughts and memories\n\nnightmares\n\nbedwetting in children\n\nflashbacks\n\nlow mood\n\nanxiety.\n\nBe aware that:\n\nthere is an ongoing risk of low mood in people after a traumatic injury\n\npsychological problems and mental distress commonly accompany ongoing emotional and psychological adjustments, for example, as a result of life-changing injuries\n\npsychological problems and mental distress can recur or deteriorate when a person is discharged home or transferred to another setting\n\nanxiety, depression and post-traumatic stress disorder (PTSD) can occur or recur at any time after a traumatic injury.\n\nDiscuss psychological support with the person, and their family members or carers (as appropriate), and offer psychological and emotional support that is tailored to their rehabilitation goals, needs and preferences as part of an overall rehabilitation treatment programme.\n\nIf the person's rehabilitation is adversely affected by their psychological problems (for example, if the person is struggling to engage with the rehabilitation process), refer them urgently to psychology services for psychological assessment and treatment, ideally to a practitioner psychologist with appropriate expertise with physical trauma and rehabilitation.\n\nAsk about thoughts of self-harm and suicide regularly, as part of psychological assessment, and particularly at key milestones such as hospital discharge and changes of setting.\n\nThe multidisciplinary team should regularly check for signs and symptoms of anxiety, depression and PTSD when reviewing the person's progress against rehabilitation goals and plans.\n\nTreat PTSD, anxiety, and depression in adults, children and young people as part of an overall coordinated rehabilitation treatment package, and in line with the NICE guidelines on:\n\npost-traumatic stress disorder\n\nsocial anxiety disorder\n\ngeneralised anxiety disorder and panic disorder in adults\n\ndepression in adults\n\ndepression in adults with a chronic physical health problem\n\ndepression in children and young people\n\nservice user experience in adult mental health.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Rehabilitation after limb reconstruction, limb loss or amputation\n\nThis section covers specific rehabilitation for people after limb reconstruction, limb loss or amputation. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to spinal cord injury, nerve injury or chest injury.\n\n## Rehabilitation after limb-threatening injury – early assessment, decision making and support\n\nDiscuss limb reconstruction and/or amputation with the person, and their family members or carers (as appropriate), when making decisions about treatment pathways and assessing rehabilitation options. Recognise that, for some people who have had a complex limb-threatening injury, amputation may be the option that best delivers the person's most important rehabilitation goals.\n\nMembers of a specialist multidisciplinary team (for example, a limb reconstruction team or prosthetics team) alongside the trauma rehabilitation team should discuss the implications of the following, as part of assessing rehabilitation needs, as soon as possible with the person, and their family members or carers (as appropriate):\n\nrehabilitation pathways\n\npain management\n\nrecovery timescales\n\nlong-term expectations\n\nimpact on daily life, for example, work, hobbies, activities, education and play.\n\nWhen amputation is being considered and if time permits before surgery, a member or members of the specialist multidisciplinary team with expertise in prosthetic prescription and rehabilitation should carry out a pre-amputation rehabilitation assessment and consultation.\n\nOffer psychological support before limb reconstruction or amputation (see the section on psychological support).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after limb-threatening injury – early assessment, decision making and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Rehabilitation after limb reconstruction\n\nAfter limb reconstruction, start rehabilitation therapy as early as possible (ideally the day after surgery) to maintain range of movement. This may include:\n\nsplinting\n\nexercise\n\npain management\n\nswelling and oedema management\n\nhand therapy\n\nmobility\n\npositioning.\n\nAvoid early rapid irreversible loss of range of movement after limb reconstruction by ensuring that the person carries out range of movement exercises for the affected joint and other joints to optimise recovery and avoid contractures.\n\nContinue psychological and emotional support after limb reconstruction (see the section on psychological support).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after limb reconstruction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Rehabilitation after limb loss or amputation\n\nAfter limb loss or amputation, refer the person to the amputee and prosthetic rehabilitation service as soon as possible if the referral was not made before the surgery.\n\nAfter limb loss or amputation, start rehabilitation therapy as early as possible and ideally the day after surgery. This may include:\n\npain management (see the section on pain management)\n\nresidual limb oedema and shaping (see the section on residual limb oedema and shaping)\n\nrange of movement and strengthening exercises (see the section on range of movement and strengthening)\n\nfunctional independence, including play for children (see the section on functional independence)\n\npsychological support (see the section on psychological support).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after limb loss or amputation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\nPlan analgesia with the person before surgery, and ensure that their pain is managed after surgery so that they can effectively participate in rehabilitation therapies.\n\nManage the different types of pain that can develop, for example, phantom limb pain, neurogenic pain, psychogenic pain, myogenic pain and complex regional pain, and refer the person to a specialist pain team if needed.\n\nConsider visualisation interventions such as graded motor imagery or mirror therapy to manage phantom limb pain in people who have had an amputation or limb loss after trauma.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain management after limb loss or amputation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\nManage residual limb oedema using elevation and compression therapy to reduce swelling and improve shaping in preparation for prosthetics fitting.\n\nFor people with a below-knee amputation, keep the limb elevated using a residual limb (stump) board when using a wheelchair.\n\nAvoid residual limb swelling when using walking aids, for example, by using crutches or a frame with the limb in a dependent position.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on residual limb oedema and shaping after limb loss or amputation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\nMaintain and improve range of movement and strength after limb loss or amputation (particularly in hip flexors, hip abductors and knee flexors) by starting rehabilitation therapy that includes:\n\nexercise\n\nmobility, including early walking aids (for example, amputee-specific early walking aids) after surgery when the wound has settled\n\npositioning.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on range of movement and strengthening after limb loss or amputation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\nDo not wait for prosthetics to be fitted before starting rehabilitation after limb loss or amputation.\n\nEnsure that wheelchairs:\n\nare provided as early as possible\n\ninclude appropriate accessories (for example, anti-tippers and residual limb [stump] boards)\n\nare adjusted to accommodate the changes in the person's weight distribution after limb loss or amputation.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on functional independence after limb loss or amputation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Psychological support after limb loss, amputation or limb reconstruction\n\nContinue psychological support and ensure that the multidisciplinary team has access to a practitioner psychologist with appropriate expertise in physical trauma and rehabilitation, ideally with experience of working with people with limb loss, amputation or limb reconstruction.\n\nFor children, consider play or play therapy when offering psychological and emotional support.\n\nFor children and young people, the team around the child should actively monitor for any emerging emotional difficulties as the child or young person grows and develops (for example, moving schools, puberty and emotional relationships).\n\nTake into account the long-term psychological impact of change in body image as a result of injury for all people and the psychological impact for children and young people as they grow.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological support after limb loss, amputation or limb reconstruction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Continuing rehabilitation after limb reconstruction, limb loss or amputation and after discharge\n\nWhen completing a rehabilitation plan (see the section on developing a rehabilitation plan and making referrals) for people after limb reconstruction, limb loss or amputation, ensure that the following are always included in the person's rehabilitation programme:\n\nexercise and mobility\n\npsychological and emotional support\n\nreferral and signposting to support groups\n\npin-site review (for limb reconstruction)\n\nframe adjustment (for limb reconstruction)\n\nprosthetics team review, if relevant.\n\nThe specialist multidisciplinary team should offer psychological and emotional support to enable the person to adjust to their altered body image, manage pain and cope with the possibility that they may need further procedures. Psychological and emotional support should involve:\n\nlistening carefully and validating feelings\n\nsupporting reflection and reasoning around realistic goals and care\n\nsupporting planning\n\noffering feedback about progress towards goals.\n\nCarry out reviews of the rehabilitation plan (for example, equipment, home environment, clothing and footwear needs) at key points, for example:\n\nat discharge\n\nwhen an external-fixation frame is removed\n\nwhen weight-bearing status changes\n\nwhen prosthetics are changed\n\nwhen the person starts to go outside\n\nwhen the person starts to return to education, work or community activities\n\nif the person is readmitted because of complications.(Also see the section on monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments.)\n\nFor children and young people, monitor the impact of growth on the residual limb and prosthetic fitting, and refer without delay for specialist assessment when there are changes.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on continuing rehabilitation after limb reconstruction, limb loss or amputation and after discharge\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.1: specific programmes and packages in amputation for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Rehabilitation after spinal cord injury\n\nThis section covers specific rehabilitation for people after spinal cord injury. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to limb injury, nerve injury or chest injury.\n\nThese recommendations focus on the rehabilitation and supportive needs of people with spinal cord injury (after initial acute assessment) who are not currently in a regional specialist spinal cord injury centre. See also the NICE guideline on spinal injury: assessment and initial management.\n\n## Rehabilitation after spinal cord injury – referral, assessment and general principles\n\nFor people with a spinal cord injury:\n\nensure that ongoing contact with the regional specialist spinal cord injury centre is made in line with the recommendations on communication with tertiary services in the NICE guideline on spinal injury and\n\nrefer using the national spinal injuries database within 24\xa0hours of the diagnosis.\n\nSeek advice from the regional specialist spinal cord injury centre outreach team throughout the person's inpatient stay and at discharge to support their rehabilitation.\n\nA healthcare professional with appropriate clinical skills should complete an assessment using an American Spinal Injury Association (ASIA) chart as soon as possible after a spinal cord injury, and repeat this as clinically indicated.\n\nBe aware that spinal cord injury may affect areas of physical function including bowel, bladder and sexual function, and seek specialist advice as appropriate (see also recommendation 1.2.6 in the multidisciplinary team rehabilitation needs assessment section).\n\nRefer children and young people with a spinal cord injury:\n\nto specialist play services to support their emotional and physical development and wellbeing\n\nto education services to support their ongoing educational development.\n\nFor children and young people, monitor growth and nutrition throughout the rehabilitation process.\n\nWhen discharge planning for children and young people after a spinal cord injury, ensure that meetings take place early and involve the child or young person, and their parents and carers (as appropriate), together with the local education authority, specialist play services and multidisciplinary teams involved in their care.\n\nAfter hospital discharge, consider ongoing contact between the rehabilitation team and the person, and their family members and carers (as appropriate), with education and a structured review of progress in rehabilitation as part of outpatient follow-up. This could be offered by telephone or video link.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after spinal cord injury – referral, assessment and general principles\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Bladder and bowel function\n\nAssess and manage bladder function after a spinal cord injury as follows:\n\nprotect upper renal function at all times by maintaining safe bladder emptying (inserting a urinary catheter if necessary), and ensuring that people understand and use bladder management techniques as a key part of their rehabilitation (see also the monitoring and surveillance section in the NICE guideline on urinary incontinence in neurological disease)\n\nidentify acute kidney injury in line with the NICE guideline on acute kidney injury\n\nidentify renal tract stones (see also the NICE guideline on urinary incontinence in neurological disease).\n\nRegularly assess and manage bowel function after a spinal cord injury as follows:\n\nassess anal tone and sensation\n\nstart and review a bowel management plan that includes laxatives, enemas, suppositories and manual evacuation, depending on the level and severity of the spinal injury.\n\nKeep the person nil by mouth until their bowel function has been assessed because of the risk of neurogenic bowel stasis and aspiration pneumonia. Avoid unnecessary delays to assessing bowel function to avoid prolonged periods of nil by mouth.\n\nFor younger children, ask their parents and carers (as appropriate), about their pre-injury continence skills, and take their age and ability into account when assessing and managing bladder and bowel function.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bladder and bowel function\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Respiratory function, swallowing and speech\n\nKeep the person nil by mouth until their risk of aspiration has been assessed (see recommendation 1.11.51).\n\nBe aware that people with cervical spine injuries and those managed on flat bed rest, are particularly at risk of swallowing and speech difficulties and should be assessed early for risk of aspiration.\n\nAssess and manage respiratory function (taking into account age and ability when assessing children and young people) as follows:\n\nuse spirometry to measure vital capacity in line with the NICE guideline on spinal injury\n\nconsider prophylactic respiratory support with, for example, active cycle of breathing techniques, incentive spirometry, intermittent positive pressure breathing (IPPB) or non-invasive ventilation (NIV), to maintain forced vital capacity (FVC) and prevent chest complications\n\nconsider use of cough-assist techniques or devices.\n\nConsider critical care management for people with a high-level spinal injury.\n\nAssess voice quality and refer to a speech and language therapist and/or ear, nose and throat specialist as needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on respiratory function, swallowing and speech\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Preventing complications\n\nAssess skin and pressure care after a spinal cord injury as follows:\n\nstart a 24‑hour positioning and turning programme and use a pressure mattress if appropriate (ensuring that the spinal column has been assessed as mechanically stable) or indicated and\n\ngive information about skin protection for people with sensory deficits.\n\nBe aware of the risk of autonomic dysreflexia, and treat it as a medical emergency.\n\nBe aware that most people who have had a spinal cord injury will develop orthostatic hypotension, which can affect their participation in rehabilitation. Consider interventions to optimise blood pressure, for example, medication review, graduated positioning, abdominal binders and compression stockings.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preventing complications\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Maintaining mobility and movement\n\nFor people with a spinal cord injury who are using a spinal orthosis (for example, cervical collar or thoraco-lumbar spinal orthosis), regularly assess them for complications such as pain, pressure sores, swallowing or breathing difficulties (particularly in older people or those with dementia or delirium).\n\nIf spinal orthoses are causing side effects or are significantly affecting the person's engagement with rehabilitation, inform the relevant surgical team.\n\nMaintain joint range of motion after a spinal cord injury and consider early use of splints and orthoses.\n\nSeek specialist advice about hand splints for people with a higher level cervical spinal injury to maintain tenodesis grasp and release ability where indicated; for example, do not splint into wrist extension if there is C6 involvement.\n\nConsider interventions (for example, progressive sitting, tilt table) to increase mobility and aid early sitting as soon as possible after a spinal cord injury.\n\nConsider additional techniques and specialised equipment (for example, functional electrical stimulation, gait orthoses, bodyweight-supported gait training and robotic devices) to promote mobility, upper limb function and independent walking.\n\nAssess people's needs and refer them to specialist services without delay if assistive technology, such as environmental control systems, is needed.\n\nFor adults, treat spasticity to prevent losing range of joint movement and avoid contractures.\n\nFor adults, consider oral medications to treat spasticity or botulinum toxin type\xa0A targeted muscle injections, depending on the clinical circumstances. In January 2022, botulinum toxin type\xa0A was an off-label use for some of the available brands. See individual summaries of product characteristics and NICE's information on prescribing medicines.\n\nStop oral medications and targeted muscle injections for spasticity if there is no benefit at the maximum tolerated dose. (Explain to the person that special precautions may be needed when stopping certain medicines.)\n\nIf spasticity is causing significant impairments in mobility, posture or function, and initial treatments are unsuccessful, refer the person to a multidisciplinary team experienced in the management of spasticity for assessment and treatment planning.\n\nFor children and young people, assess spasticity and follow the recommendations in the NICE guideline on spasticity in under\xa019s.\n\nBe aware that pre-pubertal children have a high risk of early or late onset kyphoscoliosis, so monitor their spinal shape and curvature at regular intervals and refer early for specialist assessment if needed.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on maintaining mobility and movement\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review B.1: physical interventions for people with complex rehabilitation needs after traumatic injury\n\nevidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Low mood and psychological support\n\nBe aware that there is significant risk of low mood and psychological trauma for people with spinal injury, and that this may have an impact on rehabilitation.\n\nConsider psychological support after spinal cord injury, and ensure that the multidisciplinary team has access to a practitioner psychologist with appropriate expertise in physical trauma and rehabilitation, ideally with experience of working with people with spinal cord injury.\n\nFor children and young people, the team around the child should actively monitor for any emerging emotional difficulties as the child or young person grows and develops (for example, moving schools, puberty and emotional relationships).\n\nTake into account the long-term psychological impact of change in body image as a result of injury for all people and for children and young people as they grow.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on low mood and psychological support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.2: specific programmes and packages in nerve injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Rehabilitation after nerve injury\n\nThis section covers specific rehabilitation for people after nerve injury. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to limb injury, spinal cord injury or chest injury.\n\n## Rehabilitation after nerve injury – general principles\n\nBe aware that nerve injuries may be hidden, particularly if the person:\n\nhas multiple injuries\n\nhas a cognitive impairment or a learning disability\n\nhas a head injury\n\nis in critical care (adults) or paediatric intensive care (children and young people)\n\nhas a pre-existing neurological condition or injury\n\nhas a complex fracture.\n\nIf nerve injury is suspected, assess the peripheral nerves of the affected limb to identify the involved nerve and functional deficit. The surgical team should decide whether early surgical intervention is necessary (see also the section on assessing physical functioning).\n\nBe aware of the risk to tissue viability if there is sensory or motor loss secondary to peripheral nerve injury.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after nerve injury – general principles\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.2: specific programmes and packages in nerve injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Therapies and referral\n\nAfter nerve injury, start rehabilitation therapy to maintain range of movement and regain function. This may include:\n\nsplinting\n\nexercise (passive and active range of movement)\n\nplay therapy (for children)\n\npain management\n\nsensory interventions (including mirror therapy, electrical stimulation and hand therapy)\n\nhydrotherapy (where available)\n\nfunctional or vocational therapy.\n\nRegularly assess for signs of nerve recovery and review the programme of therapy as needed.\n\nConsider nerve conduction or a specialist opinion to help determine prognosis and guide future therapy and management if early surgical intervention was not needed and:\n\nthere are no signs of nerve recovery 6\xa0weeks after the injury or\n\nif recovery is not as expected.\n\nFor people who have a poor prognosis for recovery after rehabilitation therapy and nerve conduction studies, consider referral to a specialist peripheral nerve injury service, for example, for surgery.\n\nBe aware that people recovering from nerve injury may experience low mood, anxiety and lack of motivation because recovery may be a lengthy and ambiguous process (for example, because of uncertainty about the long-term prognosis).\n\nConsider psychological support after nerve injury, and ensure that the multidisciplinary team has access to a practitioner psychologist with appropriate expertise in physical trauma and rehabilitation, ideally with experience of working with people with nerve injury.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on therapies and referral\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.2: specific programmes and packages in nerve injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Rehabilitation after chest injury\n\nThis section covers specific rehabilitation for people after chest injury. The recommendations in this section should be read together with all the recommendations in the rest of the guideline apart from those specific to limb injury, spinal cord injury or nerve injury.\n\nStart rehabilitation after chest injury as soon as possible to optimise respiratory function and prevent deconditioning.\n\nAssess pain regularly and provide adequate analgesia to allow people to be able to breathe deeply, cough, start moving around early and participate in rehabilitation activities.\n\nIf oral or intravenous analgesia is inadequate to enable people to breathe deeply, cough or start engaging in rehabilitation, consider early neuraxial (for example, epidural catheter) or regional (for example, paravertebral, erector spinae plane or serratus anterior blocks) analgesia delivered by an appropriately qualified healthcare professional.\n\nEncourage people with chest trauma to start moving around as soon as it is safe to do so, to optimise respiratory function and prevent deconditioning.\n\nOffer a range of rehabilitation therapies to prevent atelectasis and promote deep breathing and secretion clearance. Therapies may include:\n\nsupported cough to brace chest wall\n\nactive cycle breathing technique\n\nincentive spirometry\n\nportable intermittent positive pressure breathing (IPPB) devices.\n\nBe aware that stiffness of the upper limbs is a common complication of chest and rib injury on the affected side.\n\nThe multidisciplinary team should discuss the risks and benefits of the use of spinal orthoses in people with a combination of spine injury and rib fracture.\n\nPrevent stiffness of the upper limbs with range of movement exercises and advice about maintaining function. Encourage children to play to maintain their range of movement.\n\nGive people information about what they can do to help themselves return to their normal activities of daily life (for example, how to increase their exercise tolerance), and how to seek help if they are worried about problems such as:\n\npain\n\nshortness of breath\n\nfatigue\n\ncough.\n\nAssess adults presenting with rib fractures for their risk of fragility fracture in line with NICE's guideline on osteoporosis.\n\nIf people have complex chest injuries that affect communication and swallowing skills, consider referral to speech and language therapy.\n\nConsider assessing children and young people with rib fractures for bone density disorder and for the possibility of non-accidental injury (see recommendation 1.1.13 on safeguarding).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rehabilitation after chest injury\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C.4: specific programmes and packages in chest injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Complex rehabilitation needs\n\nComplex rehabilitation needs cover multiple needs due to traumatic injury or injuries (polytrauma), and will involve coordinated multidisciplinary input from 2\xa0or more allied health professional disciplines.\n\n## Controlled motion device\n\nA device that gently flexes and extends the knee joint (usually after surgery) to allow the joint to bend without the person needing to exert any effort. Sometimes called a continuous passive motion machine.\n\n## Key worker\n\nA key worker is a named member of clinical staff (for example, a senior nurse, physiotherapist or occupational therapist) assigned at each stage of the care pathway who coordinates the person's rehabilitation and care; this may continue post-discharge. They act as a single point of contact for the person and their family and carers, and will support liaison with other services, such as social care. The person who fulfils this role may be different along the pathway, for example, following hospital discharge. This role may also be performed by case managers or case coordinators, who would coordinate care as well as liaise with insurers and legal teams, particularly following discharge.\n\nFor major trauma, the role of key worker is defined further in recommendation 1.6.3 in the NICE guideline on major trauma: service delivery.\n\n## Neurovestibular disorders\n\nDizziness or problems with balance caused by damage to parts of the inner ear and/or the brain that process the sensory information involved with controlling balance and eye movements.\n\n## Orthostatic hypotension\n\nLow blood pressure on changing position from lying to sitting, and sitting to standing.\n\n## Practitioner psychologists\n\nThe definition of practitioner psychologists is based on the Health and Care Professions Council (HCPC) registration criteria and standards of proficiency.\n\n## Pre-amputation rehabilitation assessment and consultation\n\nThis follows the principles of the initial rehabilitation assessment in the section on assessment and early interventions for people with complex rehabilitation needs, and also takes into account implications for rehabilitation such as recovery timescales, quality of life and goal setting for different surgical options that may include amputation of all or part of the limb, or reconstructive surgery of the limb. Decisions about surgical interventions would affect the kind of rehabilitation interventions and therapies the person would need, the timescales involved and their personal goals.\n\n## Rehabilitation coordinator\n\nRehabilitation coordinators are rehabilitation specialists, for example, allied health professionals such as physiotherapists, occupational therapists, speech and language therapists, or clinicians who play an active role in the multidisciplinary team. They are usually responsible for decisions about rehabilitation treatment options at the beginning of the pathway and for the implementation of the pathway, including referral or transfer to other services. They are usually part of the team that delivers the rehabilitation care, and the lead contact for the person receiving care.\n\n## Rehabilitation plan\n\nThis may be in the form of a rehabilitation prescription. It may also come in different versions such as the rehabilitation passport, which is a patient-held document, and may be a simplified version of the plan. It is carried with the person and also communicated between rehabilitation teams and updated accordingly and used to document information about injuries and rehabilitation treatments in an accessible format.\n\n## Single point of contact\n\nA single point of hospital contact following discharge may be a key worker, trauma coordinator or a rehabilitation coordinator, or it may simply be a link to a unit, team or person that formed part of the person's rehabilitation care while in hospital. The point of contact may not be able to offer advice directly but can seek information and input from others if this is needed for a defined period post-discharge.\n\n## Specialised rehabilitation services\n\nSpecialised elements of care pathways would include options for people with complex rehabilitation needs, for example, level\xa01, level\xa02a and level\xa02b units within a local area.\n\n## Strengths-based approach\n\nStrengths-based (or asset-based) approaches focus on the person's strengths (including personal strengths, and social and community networks) and not on their deficits. Strengths-based practice is holistic and multidisciplinary, and works with the individual person to promote their wellbeing.\n\n## Team around the child\n\nA group of professionals who work with an individual child or young person with a disability or complex needs who come together to share information and agree a plan – along with parents and carers – to meet the child's needs. The emphasis should be on the needs of the child and the aim is to provide joined-up support.\n\n## Trauma coordinator\n\nThis person would work closely with the multidisciplinary team to coordinate the patient pathway between relevant specialties involved in the treatment, including acute surgical and medical teams and rehabilitation, from admission to discharge, particularly for people with highly complex traumatic injuries and rehabilitation needs. They offer clinical advice and sometimes this role is performed by a nurse and is sometimes called a nurse coordinator. This role may also include the responsibilities of a key worker, liaising with family and carers, especially in the early stages of the pathway.\n\n## Traumatic injury\n\nThis includes multiple, major and severe injuries, sometimes referred to as polytrauma, and any musculoskeletal, visceral, nerve, soft tissue, spinal or limb injury that requires admission to hospital at the time of injury.\n\n## Vocational therapy\n\nFocuses on the rehabilitation interventions needed to help people with long-term health conditions or disabilities return to or stay in work, education or training. This may involve adapting working conditions, job roles or retraining.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Effectiveness of intensive rehabilitation in adults\n\nWhat is the effectiveness and cost effectiveness of intensive rehabilitation programmes in adults with complex rehabilitation needs after a traumatic injury?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on intensive rehabilitation programmes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Effectiveness of intensive rehabilitation in children and young people\n\nWhat is the effectiveness and cost effectiveness of intensive rehabilitation programmes in children and young people with complex rehabilitation needs after a traumatic injury?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on intensive rehabilitation programmes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Thoracic lumbar sacral orthoses in older people\n\nWhat are the benefits and harms of using thoracic lumbar sacral orthoses in older people with thoraco-lumbar vertebral fractures?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on splinting and orthotics\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.1: physical interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Self-management materials\n\nWhat is the effectiveness and cost effectiveness of rehabilitation programmes combined with self-management materials, compared with rehabilitation programmes alone, in people with complex rehabilitation needs after a traumatic injury?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on guided self-managed rehabilitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B.3: psychological and psychosocial interventions for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.\n\n## Length of bed rest after spinal cord injury\n\nWhat is the effectiveness and cost effectiveness of short-term bed rest compared with long-term bed rest on functional outcomes in people with complex rehabilitation needs after traumatic injury that involves the spinal column or spinal cord injury?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on maintaining mobility and movement\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C.3: specific programmes and packages in spinal cord injury for people with complex rehabilitation needs after traumatic injury.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect services.\n\n# Initial assessment and early interventions for people with complex rehabilitation needs\n\nRecommendations 1.1.1 to 1.1.13\n\n## Why the committee made the recommendations\n\nRehabilitation can be a long journey, and people will need different interventions and will aim for different endpoints. Because of this, the committee agreed that healthcare professionals should think about each person's individual rehabilitation needs and what is important to them, and take into account their personal strengths, lifestyle and goals, rather than being primarily driven by the nature of the injury.\n\nPsychological and emotional support is important immediately after the injury, to help the person come to terms with their experience and engage with rehabilitation assessment, early interventions and goal-setting discussions.\n\nThere was evidence that avoiding delays in acute treatment can improve the effectiveness of early rehabilitation interventions. In the committee's view, early assessments and interventions are also important so that healthcare professionals have up-to-date information and can plan and start rehabilitation promptly. Nutritional assessment (including swallowing safety) is an important factor (particularly in soft tissue healing) but is often overlooked.\n\nThe person's longer-term rehabilitation goals should be taken into account when discussing treatment options because these can affect decisions made about the timing and nature of rehabilitation. For example, if a person has upper and lower limb injuries, they might not have surgical treatment of their upper limb injuries because they want to use crutches to help with weight-bearing during rehabilitation for their lower limb injuries.\n\n## How the recommendations might affect practice\n\nThe recommendations will not involve a major change in practice and are consistent with existing NICE guidelines. Healthcare professionals might need to spend more time assessing how traumatic injuries affect all aspects of a person's life, and explaining the implications of different medical and surgical treatments on rehabilitation. Spending time on initial assessment and early treatment immediately after a traumatic injury will lead to a better tailored rehabilitation plan and goals, which will save time later on. Generally, all professionals involved in the person's care following a traumatic injury will already be equipped to provide psychological and emotional support.\n\nReturn to recommendations\n\n# Multidisciplinary team rehabilitation needs assessment\n\nRecommendations 1.2.1 to 1.2.12\n\n## Why the committee made the recommendations\n\nThere was no evidence in this area, so the committee made recommendations based on their knowledge and experience. They agreed that a comprehensive approach to needs assessment is vital to meet all aspects of the person's care needs, including personal history, usual activities and potential motivations. They also highlighted injuries or conditions that may need to be assessed by specialists who are better equipped to meet complex care needs.\n\nThe committee specified the healthcare professionals who should be members of the multidisciplinary team. These members of the multidisciplinary team do not necessarily have to be available all the time, but should be able to contribute when needed.\n\nThe committee suggested ways to help people engage in the assessment process because people can have problems with engagement after a traumatic injury. The timing of the needs assessment is also an important aspect of this, because pain, fatigue and confusion can make it difficult for people to understand what is happening. They may need more time than normal to process information and adjust after the trauma. This is particularly important for people with cognitive impairment or brain injuries.\n\nThe committee agreed that time was needed for members of the multidisciplinary team to work with clinical teams to fully understand the person's rehabilitation needs and in particular consider the impact of pre-existing conditions so that this could inform a tailored rehabilitation programme. The committee were keen to highlight the importance of validated outcome tools and checklists because these can help identify people who need to be referred to a specialist service early, which can prevent delays in rehabilitation.\n\n## How the recommendations might affect services\n\nIt is standard practice to have multidisciplinary teams conduct needs assessments. Staff might need additional training on how to use assessment tools, and some extra time might be needed as a result of the recommendations. However, this will be offset by the benefits of appropriate and timely care, increased care coordination, and better outcomes. Overall, the recommendations reinforce current practice and are in line with other guidance.\n\nReturn to recommendations\n\n# Assessing physical functioning\n\nRecommendations 1.2.13 to 1.2.15\n\n## Why the committee made the recommendations\n\nThe committee discussed the importance of assessing physical functioning as part of the rehabilitation needs assessment after a traumatic injury. There was no evidence in this area so the committee agreed, based on their knowledge and experience, that the assessment should include both pre-injury and current levels of physical functioning to inform rehabilitation goals. Referrals to specialists may be needed as part of this. The person's current level of physical functioning will serve as a baseline for initial rehabilitation needs and to monitor changes.\n\n## How the recommendations might affect services\n\nThe recommendations are not expected to have a large resource impact or be difficult to implement, although extra time might be needed to complete the comprehensive assessment. There may also be more referrals to specialist services. However, the involvement of specialist services at the assessment stage will identify needs earlier and reduce unmet care needs.\n\nReturn to recommendations\n\n# Assessing cognitive functioning\n\nRecommendations 1.2.16 to 1.2.20\n\n## Why the committee made the recommendations\n\nThere was no evidence in this area. However, the committee believed that recommendations are needed because problems with cognitive functioning are common after a traumatic injury (even without brain injury). The committee also highlighted some of the cognitive problems the multidisciplinary team should consider as part of the rehabilitation needs assessment, because these may not show up on scans immediately.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice may need to be amended. Some extra time might be needed to complete the comprehensive assessment. There may also be more referrals to specialist services. However, the involvement of specialist services at the assessment stage will identify needs earlier and reduce unmet care needs.\n\nReturn to recommendations\n\n# Assessing psychological functioning\n\nRecommendations 1.2.21 and 1.2.22\n\n## Why the committee made the recommendations\n\nThere was no evidence in this area, so the committee made recommendations based on their knowledge and experience. They recommended asking about past risk factors to help inform future rehabilitation goals, and current risk factors to help form a baseline for initial rehabilitation needs and monitor changes.\n\nSome people may need additional support because they react to trauma in different ways, have different barriers to rehabilitation, and may have different responses to psychological and psychosocial interventions. Because of this, the committee recommended referral to a practitioner psychologist with trauma and rehabilitation experience when needed.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended. Some extra time might be needed to complete the comprehensive assessment, and there might also be more referrals to specialist services. However, the involvement of specialist services at the assessment stage will identify needs earlier and reduce unmet care needs.\n\nReturn to recommendations\n\n# Setting rehabilitation goals\n\nRecommendations 1.3.1 to 1.3.3\n\n## Why the committee made the recommendations\n\nBased on qualitative evidence, the committee highlighted the need to agree patient-focused short- and long-term goals with people. They also recommended that these goals are reviewed regularly, to ensure a flexible approach that takes people's concerns into account.\n\nAgreeing small steps as part of long-term rehabilitation goals ensures that efforts are consistently made towards achieving these goals.\n\nThe committee highlighted skills and competencies needed by the multidisciplinary team, to ensure that staff have the right training.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended. Some additional professional time might be needed to explore psychological and psychosocial risk factors.\n\nReturn to recommendations\n\n# Developing a rehabilitation plan and making referrals\n\nRecommendations 1.4.1 to 1.4.11\n\n## Why the committee made the recommendations\n\nThere was convincing qualitative evidence on patient education, communication between settings, and follow-up. Combining this with their own knowledge and experience, the committee recommended several key components of a successful and comprehensive rehabilitation plan. This should be a single document that can be shared between people undergoing rehabilitation, families or carers, and healthcare professionals. It should be an evolving document, detailing a person's rehabilitation journey and any changes in goals and needs. The committee reflected that it is not always possible or appropriate for people to have access to all of a rehabilitation plan, and therefore recommended that a separate patient-held document be provided if this is the case.\n\nThe committee agreed that preventing recurrence of traumatic injury should form an essential component of the rehabilitation plan. Prevention is covered in several other NICE guidelines, so the committee made recommendations that supplement and refer to these guidelines.\n\nThere was strong qualitative evidence from both healthcare professionals and people undergoing rehabilitation that reducing delays leads to better coordination of care and rehabilitation outcomes. Based on this, the committee made a recommendation on referrals for parts of the plan that the multidisciplinary team cannot implement themselves. The committee also used their experience to recommend that older people have access to orthogeriatricians, surgical support or perioperative physicians. This is important because the needs of older people with traumatic injuries are complex, and it will prevent delays further on in rehabilitation.\n\nLimited evidence showed that violence intervention programmes might reduce hospital admissions. There was also convincing economic evidence that such programmes represent value for money. The committee agreed that the effectiveness evidence combined with economic evidence was sufficient to support a recommendation on violence reduction interventions.\n\n## How the recommendations might affect services\n\nPractitioners should already be producing these rehabilitation plans, but some extra time might be needed to ensure they fulfil the expectations set out in these recommendations. However, this will be offset by reducing problems with the suitability of the plan further down the line, because the more it is tailored for the person, the more effective it will be at helping the person achieve their goals. The recommendations outline good practice points and should make practice more consistent. Having a clear rehabilitation plan will make the whole process more efficient and potentially reduce the amount of extra support people need (for example, asking the team for more information because they do not understand the rehabilitation plan).\n\nCurrently, violence reduction interventions are mainly funded by the voluntary sector, so the recommendation on these may represent a change in practice. However, any cost increase will be offset by a potential reduction in future NHS and personal social service costs (for example, readmissions as a result of violent crime).\n\nReturn to recommendations\n\n# General principles for rehabilitation programmes\n\nRecommendations 1.5.1 and 1.5.2\n\n## Why the committee made the recommendations\n\nEvidence showed that rehabilitation programmes should be tailored to a person's needs and rehabilitation goals to maximise their effectiveness. There is no 'one-size-fits-all' programme. Instead, they should be multidisciplinary and developed in conjunction with healthcare professionals and people undergoing rehabilitation, to ensure they are relevant to a person's everyday life. The committee used their knowledge and experience to recommend the content of rehabilitation programmes. There was also evidence on education materials, showing that they can help people learn about their trauma and rehabilitation in their own time, increasing their engagement in the process.\n\n## How the recommendations might affect services\n\nThe recommendations reinforce current practice and should not be difficult to implement. Education materials on rehabilitation already exist in healthcare settings, but they might need to be changed into a suitable format for people undergoing rehabilitation.\n\nReturn to recommendations\n\n# Intensive rehabilitation programmes\n\nRecommendations 1.5.3 to 1.5.5\n\n## Why the committee made the recommendations\n\nThere was no evidence on what to include in an intensive rehabilitation programme. Based on their own experience and expert testimony, the committee made a recommendation on general good practice principles.\n\nThere was also no evidence relating to the timing or intensity of rehabilitation. The committee were aware, based on their own experience and expert testimony, that delivering rehabilitation at the right time and providing short blocks of intensive rehabilitation might improve patient outcomes, leading to a quicker recovery and return to work. They gave the example of a 3‑week residential rehabilitation programme because economic modelling indicated that this type of programme could be cost effective. However, the committee agreed that an intensive rehabilitation programme would be appropriate only for the most severe injuries and complex needs, when a significant impact on rehabilitation outcomes is likely. Such an approach to rehabilitation may also reduce the health and social care costs associated with longer-term care and rehabilitation.\n\nThe expert witness supported the use of education materials before intensive rehabilitation starts, to prepare people for the programme.\n\nThe committee made research recommendations on the effectiveness of intensive rehabilitation in adults and the effectiveness of intensive rehabilitation in children and young people.\n\n## How the recommendations might affect services\n\nThe recommendations are in line with current practice and should have little impact on resources. Intensive rehabilitation is already available for some people (for example, people who have lost a limb). Because rehabilitation services are already being carried out, intensive rehabilitation could be delivered through service redesign and repurposing of existing funds and resources rather than introducing them as completely new resources. Intensive rehabilitation would potentially represent value for money as per the economic model. Also, only a small group of people with the most severe injuries would be eligible for an intensive rehabilitation programme.\n\nOn education, existing materials for guided self-management rehabilitation could be used for intensive rehabilitation. This has the potential to reduce the amount of extra support people need, freeing up professionals for other work.\n\nReturn to recommendations\n\n# Guided self-managed rehabilitation\n\nRecommendations 1.5.6 to 1.5.9\n\n## Why the committee made the recommendations\n\nEvidence showed that self-management programmes are appreciated because they give people the flexibility to perform exercises at times most suitable for them. The committee used their experience and knowledge to recommend several possible components of a self-management programme.\n\nGuided self-management rehabilitation was identified in the qualitative literature, as well as expert witness testimony and committee experience, but not in the quantitative literature. The committee made a research recommendation on self-management rehabilitation interventions to better inform future guideline development.\n\n## How the recommendations might affect services\n\nGuided self-managed rehabilitation is not provided consistently across the country. In areas where it is not currently provided, extra professional time might be needed for planning, particularly for children, young people and vulnerable adults. There may also be costs from adopting self-managed rehabilitation programmes to different settings.\n\nFor trusts that do not like sharing their content using external content-sharing services, there may be costs from hosting programme content on their own server. However, much of the content could be standardised for most people using guided self-managed rehabilitation, so the costs for creating the plans would be mostly one‑off. These programmes could be developed at a national level, reducing costs to individual services.\n\nGuided self-managed rehabilitation programmes have the potential to reduce the amount of extra support people need, freeing up professionals for other work.\n\nReturn to recommendations\n\n# Monitoring progress against the rehabilitation plan, goals and programme of therapies and treatments\n\nRecommendations 1.5.10 and 1.5.11\n\n## Why the committee made the recommendations\n\nIn the committee's experience, rehabilitation plans and goals can only be helpful to people if progress is monitored consistently and accurately. There are many tools that can be used for this; the choice depends on the person's rehabilitation goals and the type of trauma. Because of this variation, the committee did not recommend specific measurement tools.\n\nFor some people, family members and carers will need to be involved in monitoring progress (for example, for young children or vulnerable adults). The paediatric professionals on the committee recommended using a measurement tool that includes both children- and parent-reported measures for this population. Another way to monitor progress is to use the person's own views. There was some evidence that supported asking people to record information to assist discussions and shared decision making while describing subjective measurements that are hard to quantify (for example, their motivation to continue rehabilitation).\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended. Some additional professional time may be needed to complete tools to monitor progress (for example, patient-reported outcome measures [PROMs]).\n\nReturn to recommendations\n\n# Principles for sharing information and involving family and carers\n\nRecommendations 1.6.1 to 1.6.7\n\n## Why the committee made the recommendations\n\nOne theme that appeared throughout the evidence was the importance of giving clear and consistent verbal and written information to people undergoing rehabilitation. Evidence showed that this communication should be tailored to a person's injury, needs and goals. If information was too general, people felt poorly prepared and less supported by healthcare staff and services.\n\nPeople should be given sufficient time to process information in order for them to adjust after trauma and explore their rehabilitation options thoroughly. This is particularly important for people with cognitive impairment or brain injuries, and they may need professionals to repeat information to them.\n\nAlong with good evidence, the committee used their knowledge and experience to highlight the central role that families, carers and friends can have in encouraging and supporting people through rehabilitation.\n\n## How the recommendations might affect services\n\nThe recommendations reinforce current practice and are in line with current guidance and legislation. Some extra time might be needed to consistently involve people and their families and carers in planning. Services might need to develop multiple templates for different communication formats. However, this will be offset by the benefits of people understanding their options, increased engagement and potentially better outcomes.\n\nReturn to recommendations\n\n# Coordination of rehabilitation care in hospital\n\nRecommendations 1.7.1 to 1.7.10\n\n## Why the committee made the recommendations\n\nThe committee agreed with the evidence that multidisciplinary teams should be formed early. Evidence showed that delays in rehabilitation can cause poorer outcomes. In order to reduce this, the committee recommended that referrals to specialist rehabilitation services be made as soon as possible. Similarly, the committee recommended follow-up appointments with acute teams when people move to rehabilitation units to further reduce delays.\n\nThere was conflicting evidence on how people feel about receiving information from many different specialists. This may be confusing to people, and specialists may have difficulty prioritising different clinical perspectives. The committee believed that named rehabilitation coordinators or key workers are needed to help reduce this confusion. These should be assigned within 72\xa0hours of admission because this is the time limit for starting a trauma prescription for major trauma patients.\n\nThere was evidence that providing continuity of staff enhances coordination by building trust and rapport between healthcare staff and the people they are caring for. However, the committee were aware that this is not always possible.\n\nThere was good evidence about the importance of prompt and consistent communication when transferring people between inpatient settings. Using their experience and knowledge, the committee agreed recommendations to improve communication between settings, including the use of unique identifiers.\n\nEvidence showed that coordination is improved when a person is educated in their rehabilitation, because they are more engaged. The evidence also showed that coordination is improved when family members and carers receive this information, because they frequently act as a support network for people undergoing rehabilitation. The committee understood the important role that families and friends can fulfil, but were aware of the potential safeguarding concerns around this issue. Therefore, they recommended that this information is only provided to additional people if appropriate, and only with a person's consent.\n\nThe committee agreed that families and carers be advised about the support that is available to them at a time that can be confusing and distressing.\n\n## How the recommendations might affect services\n\nMultidisciplinary teams are a standard way of working. Having a named rehabilitation coordinator might lead to an increased workload for the coordinator, but this can be limited by daily conversations within the team and delegating responsibilities. Key workers are already routinely assigned to people with complex health and social care needs.\n\nThere may be more referrals as a result of involving specialist rehabilitation services earlier in the trauma pathway, but this will ensure timely care with a reduction in disability and will support optimal physical, cognitive and emotional recovery for patients. Most services have established processes and templates for handover. Where this is not the case, services will have to spend time creating them. Additionally, technology might need to be updated to ensure systems are compatible with those used by other services.\n\nReturn to recommendations\n\n# Coordination of rehabilitation care at discharge\n\nRecommendations 1.8.1 to 1.8.20\n\n## Why the committee made the recommendations\n\nDischarge home from inpatient settings is often a time of great stress and apprehension for people with a traumatic injury because they are facing a large reduction in monitoring and support from healthcare staff. The recommendations emphasise the importance of making sure that plans are in place, eventualities are covered and people have all the information they need.\n\nThere was evidence that early planning for discharge is needed to take into account the person's needs and preferences, contact relevant services to arrange necessary adjustments, and allow enough time to reassess the rehabilitation plan before discharge. For children and young people returning to education, a meeting between healthcare professionals, education staff and parents or carers should be arranged to discuss new education and support needs. This also gives time to address any potential barriers the person might face in using community rehabilitation services.\n\nThere was good evidence on the importance of providing adequate information to people and their families or carers before discharge. This should not be limited to immediate medical information, but should be as comprehensive as possible. The committee used the evidence and their own knowledge and experience to identify information that should be provided. Evidence also showed that including family members and carers in discharge planning can lead to a smoother transition back into the community. The committee agreed that it is important to include family and carers, but they should only be involved if all parties consent.\n\nThere was good evidence, supported by the committee's knowledge and experience, that people who have help with organising their access to rehabilitation services are more likely to use them. In the committee's experience, complex funding is a barrier to receiving equipment that a person may need once discharged. Similarly, there are many different services that a person may need to work with after a traumatic injury (for example, legal services and welfare advice). In order to prevent delays in discharge, information on these organisations should also be provided as soon as possible, to avoid delays in the application process.\n\nThere was evidence that people can find a gradual return home helpful, beginning with overnight or weekend visits home before final discharge. This allows people to adjust to being in their home with their new needs, identifying areas that might need further rehabilitation and multidisciplinary team input before permanently going home. The committee acknowledged that this is not appropriate for everyone, but should be discussed as part of discharge planning. Home visits were also identified as being good practice to highlight any potential risks and allow people to have a fully informed discussion about what would benefit them.\n\nThe need for flexibility in rehabilitation appointments after discharge was a key theme in the evidence, because people face certain barriers to access (for example, time constraints, or travel to and from rehabilitation appointments). The committee agreed that arranging rehabilitation sessions at home rather than in a clinic or hospital can help, by decreasing travel and waiting times. Based on the evidence and their experience, the committee also recommended alternative consultation formats (for example, phone or video), to increase the flexibility of rehabilitation appointments.\n\n## How the recommendations might affect services\n\nAdditional time might be needed to compile information and discuss it with people and their support networks. However, by giving comprehensive information before discharge, there will be a decreased need to contact healthcare professionals with rehabilitation questions, and potentially reduced visits and readmissions to inpatient services.\n\nAdditional professional time might be needed to cover early discharge planning, checking access to community rehabilitation services, liaising with education providers and organising home visits. The recommendations imply more coordination between inpatient teams and other health and social care services, which will take more time. However, this additional time spent will result in patients feeling more supported, increasing their confidence in services and improving outcomes. There is a potential resource impact from staggering discharge through overnight or weekend visits home. However, this would only be needed in exceptional cases.\n\nTelephone or video consultations may result in a greater uptake of some services, because people may find remote attendance easier. However, services would have planned to provide in-person consultations for these people anyway, so there should be no overall resource impact.\n\nReturn to recommendations\n\n# A single point of contact, key contact and key worker after discharge\n\nRecommendations 1.8.21 to 1.8.24\n\n## Why the committee made the recommendations\n\nThere was good evidence that people benefit from having a single point of contact after discharge from hospital (for example, a discharge coordinator, a phone line or an email contact). Having a team or a professional as a single point of contact can build rapport and trust, increasing the person's confidence in accessing outpatient and community rehabilitation services. It also reduces communication delays or duplication. This contact can also provide injury-specific information and information about local rehabilitation services, help people organise their rehabilitation, and advocate for them. This should be provided for a limited time after discharge in order to provide a secure and safe transition of care. The committee gave an example of 3\xa0months, which was designed to encompass the transition period while still providing a stimulus to ensure healthcare is properly transferred to the appropriate setting.\n\nBased on both the evidence and their own experience, the committee recommended appointing a key contact or key worker for people with continued or complex health and social care needs after discharge. Because of the increased level of support these people might need, a one-to-one relationship will increase trust and rapport, which will benefit patients and healthcare professionals.\n\n## How the recommendations might affect practice\n\nMultiple healthcare professionals within the team have access to the relevant patient information and could therefore act as a point of contact, and so this would not need additional resources. Having a single point of contact may reduce the workload of case managers that are routinely assigned to people with complex healthcare and social care needs.\n\nKey worker roles would be filled by existing healthcare or social care professionals. However, there may be more pressure on their time.\n\nReturn to recommendations\n\n# Supporting access and participation in education, work and community after discharge (adjustment and goal setting)\n\nRecommendations 1.9.1 to 1.9.12\n\n## Why the committee made the recommendations\n\nThere was evidence showing that people appreciate psychological and emotional support to adjust to social roles (for example, parenting or other family roles, relationships, intimacy), access meaningful activities for day-to-day living, and return to work, education and training. This is in line with the committee's own knowledge and experience. In the committee's experience, it is difficult to predict the outcome of rehabilitation, and making realistic goals is essential (for example, some people will not be able to return to the same type of work and will need retraining). The committee agreed that it is beneficial for people to continue with their normal activities and hobbies as part of their rehabilitation therapy. Even if adjustments are needed, this improves participation in social activities, counteracts the social isolation people may feel after traumatic injury, and makes rehabilitation goals more tangible. And the longer a person is not undertaking their everyday activities, the more difficult it is for them to return to the same level as before their injury.\n\nThere was good evidence on the importance of providing adequate information to people and their families before discharge. Evidence also showed that people often rely on family, carers and friends to help them navigate the multiple appointments and services needed during rehabilitation.\n\n## How the recommendations might affect services\n\nMore time might be needed to develop a rapport with people, to find out what goals are most important to them and to tailor support needs to them. Additional time may also be needed in order to provide information to employers or education providers.\n\nAll team members involved in the care of an individual provide emotional and psychological support, so this would not be an additional cost.\n\nReturn to recommendations\n\n# Commissioning\n\nRecommendations 1.10.1 to 1.10.5\n\n## Why the committee made the recommendations\n\nThe qualitative and quantitative evidence identified aspects of planning, commissioning and coordinating that were important to the successful delivery of rehabilitation services. The committee agreed that rehabilitation services should collaborate and use joined-up commissioning approaches to provide a whole pathway rehabilitation. Based on their knowledge and experience, and limited qualitative evidence, the committee identified general principles that commissioners and providers should consider when planning, commissioning and coordinating rehabilitation services. Because these services will have different commissioners, collaboration and good communication will be needed.\n\nThere was no evidence on intensity of rehabilitation, so the committee took expert witness testimony on this. They expanded on the points raised by the expert witness to recommend providing an intensive rehabilitation programme. The committee recommended commissioning this as a tertiary service because it would only be appropriate for some people. This way, the service would be best designed to meet the needs of their local population.\n\nBased on the qualitative evidence and their experience, the committee agreed that it is essential for an identified commissioner to have overall responsibility for local rehabilitation services, to avoid confusion and subsequent commissioning and budget errors.\n\n## How the recommendations might affect services\n\nThe recommendations are in line with current practice and should have little impact on resources. Where practice differs, there may be some resource implications, because services will need to set up frameworks for more collaborative and integrated commissioning. Intensive rehabilitation is already commissioned for some patient groups (for example, people who have lost a limb).\n\nReturn to recommendations\n\n# Organisation\n\nRecommendations 1.10.6 to 1.10.11\n\n## Why the committee made the recommendations\n\nThere was qualitative evidence showing that establishing care networks and pathways between different settings encourages conversation, allows services to share advice and support each other, and can help identify gaps in local provision.\n\nThere was qualitative evidence on the usefulness of an electronic directory of care pathways, rehabilitation facilities and voluntary sector services. Some trauma units already have these in place, but directories are often out of date or incomplete. Accessing this information is also often difficult.\n\nThere was qualitative evidence showing the importance of community and social services for overall rehabilitation and recovery. Non-medical rehabilitative services are wide-ranging and can include social care, housing, home adaptation, transport, and sports and recreational facilities. The committee made a recommendation to make sure that people and their families or carers know these other services exist.\n\nThere was qualitative evidence showing that continuity of care increases when various professionals involved are aware of other areas of rehabilitation and can network with each other. There was also qualitative evidence on the importance of professionals in generalised medical settings having access to networking opportunities. This allows greater familiarity between professionals and improves cooperation.\n\nThere was qualitative evidence showing that technology and telehealth can be suitable methods of improving flexibility and availability of specialist appointments. This can be particularly useful in rural areas, because qualitative evidence showed that these areas are underserved by specialist rehabilitation services. However, not everyone has the equipment needed for remote consultations, so they cannot completely replace face-to-face consultations.\n\nThere was qualitative evidence showing that socialising and interacting with peers can promote rehabilitation uptake and counteract isolation. In the committee's experience, group rehabilitation sessions are a good way for people to get peer support. This was supported by expert witness testimony. However, peer support might not be suitable for everyone (for example, some people may feel discouraged if they are not progressing at the same rate as others).\n\n## How the recommendations might affect services\n\nMore resources may be needed to establish care networks and pathways. However, there are already examples of this in the NHS. Some trauma units already have electronic directories of care pathways, rehabilitation facilities and voluntary sector services. Services may need to do more to keep these up-to-date.\n\nMost professionals already have opportunities for networking. However, practice may need to change for some services where this is not the case (for example, in rural areas).\n\nTelehealth is becoming more common and does not need any specialist equipment.\n\nGroup rehabilitation sessions may represent a change in practice for some services.\n\nReturn to recommendations\n\n# Rehabilitation skills, knowledge and expertise in the workforce\n\nRecommendations 1.10.12 to 1.10.14\n\n## Why the committee made the recommendations\n\nThe evidence identified a disparity in access to specialist rehabilitation services, depending on location (for example, rural areas are underserved) and individual needs (for example, if a person is not able to leave their home). A lack of rehabilitation knowledge within non-specialist healthcare services adversely impacts a person's trust in their rehabilitation services. The committee agreed that training is needed to address this. Community rehabilitation practitioners in general healthcare services should also have access to specialist rehabilitation support. This would not need to be full time, and could be provided remotely. Peer support and networking opportunities are also recommended. These will improve communication between professionals in different areas of healthcare and improve coordination for people undergoing rehabilitation.\n\n## How the recommendations might affect services\n\nSpecialist rehabilitation professionals might need to spend more time providing peer support to general services. This could be done in low-cost ways, for example, virtual meetings. If non-specialist healthcare professionals are better supported, people's needs are more likely to be met locally and there will be less pressure on specialist services. Time and resources might be needed to provide more training for non-specialists. However, this will also reduce demand on specialist services.\n\nReturn to recommendations\n\n# Physical rehabilitation – early interventions and principles\n\nRecommendations 1.11.1 to 1.11.9\n\n## Why the committee made the recommendations\n\nThere was conflicting evidence on the frequency and intensity of prescribed exercises because of the wide range of possible exercises, wide range of trauma and wide range of populations covered by the evidence. The committee agreed, based on their knowledge and experience, that healthcare professionals should set the frequency and intensity of rehabilitation exercises depending on the person's rehabilitation goals, but that these should be started as soon as possible. Analgesia may be needed to allow people to participate in rehabilitation. The committee also highlighted the importance of minimising the effects of low blood pressure when undergoing physical rehabilitation. This risk is increased because the person would need to change positions to perform certain rehabilitation exercises. Independence in performing everyday tasks should be encouraged, to prevent loss of these skills.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended. There may be more referrals to occupational therapy as a result of encouraging independence with activities of daily living. However, occupational therapists are already available in these settings, and this should not have a significant resource impact or be difficult to implement.\n\nReturn to recommendations\n\n# Early weight-bearing\n\nRecommendations 1.11.10 to 1.11.12\n\n## Why the committee made the recommendations\n\nThe committee agreed with the evidence and current practice that weight-bearing exercises should be started as soon as possible. In their experience, this is important to encourage mobility and maintain postural reflexes, muscle mass, strength and function.\n\nDecisions about weight-bearing should be led by the surgical team because it will be affected by any potential surgeries. However, bed rest can be harmful to muscle function, skin integrity, postural reflexes and respiratory function (especially in older people), and should be avoided as far as possible for most people with traumatic injury. The surgical team should communicate when a person is able to weight-bear as early as possible to keep bed rest to a minimum and so that weight-bearing can start without delay.\n\nLower limb injuries will affect a person's mobility, which affects their ability to participate in weight-bearing rehabilitation exercises to a greater extent than upper limb injuries, so the committee recommended a targeted weight-bearing programme. This programme should aim to progress the person's function with weight-bearing tasks such as mobility, ability to move from sitting to standing, and ability to lateral step (which is particularly important for people to maintain independence after discharge).\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice and are not expected to need additional resources to implement. Some additional time might be needed for communication between medical and surgical teams.\n\nReturn to recommendations\n\n# Aerobic and strengthening interventions\n\nRecommendations 1.11.13 to 1.11.18\n\n## Why the committee made the recommendations\n\nThere was evidence showing the importance of aerobic and strengthening exercises in rehabilitation after traumatic injury. These exercises lead to better rehabilitation outcomes in several different trauma populations. The committee supplemented this evidence with their own knowledge and experience to recommend several aspects that healthcare professionals should consider when designing aerobic and strengthening rehabilitation programmes. The recommendations cover general components rather than specific exercises because the evidence did not clearly show which exercises were best, and because the recommendations need to be applicable to a wide range of traumatic injuries. The committee also recommended tailoring aerobic and strengthening exercises to each person's interests, to make the exercises more enjoyable and to encourage people to take part.\n\nThe committee agreed that the exercise programme should begin as early as possible to limit the loss of muscle tone and physical fitness. Evidence showed that upper body aerobic training can improve rehabilitation outcomes in people with lower limb injuries. The committee discussed how for older people, fitness and strengthening programmes can help to optimise respiratory function, increase endurance when doing rehabilitation exercises, and improve mobility.\n\nFinally, the committee stressed that these exercise rehabilitation programmes should be continued after people are discharged home, to ensure that their physical strength and fitness does not stagnate or decrease. Regular reviews should be carried out during rehabilitation appointments in order to gauge whether the programme components are still appropriate for people's rehabilitation needs, and to change them if not.\n\n## How the recommendations might affect services\n\nThe recommendations are not expected to have a significant resource impact or be difficult to implement. However, extra time may be needed to tailor exercise programmes to each person's preferences.\n\nCurrently, some physiotherapists do not offer aerobic exercise programmes to older people who are frail. For these physiotherapists, there will be a change in practice and there may be a greater uptake of aerobic exercise in older people. Older people would already be working with a physiotherapist, so this will only change the type of exercise used and there will be no additional costs for services.\n\nReturn to recommendations\n\n# Gait training and re-education\n\nRecommendations 1.11.19 to 1.11.21\n\n## Why the committee made the recommendations\n\nAlthough there was evidence to show that gait re-education did not improve rehabilitation outcomes, the committee disagreed with these findings. In their knowledge and experience, gait re-education is a very effective rehabilitation tool, particularly for muscle strengthening. In people who are not mobile, gait re-education can still be introduced early but should be focused on reducing the impact of non-weight-bearing. This will maintain the current level of functioning and mobility, so people are ready to undertake weight-bearing gait re-education as soon as possible.\n\n## How the recommendations might affect services\n\nAt some hospitals, physiotherapists do not get patients into their physiotherapy unit until they can weight-bear fully. These physiotherapists will need to change their practice. Overall, the recommendations are not expected to have a significant resource impact or be challenging to implement.\n\nReturn to recommendations\n\n# Manual therapies and maintaining joint range of movement\n\nRecommendations 1.11.22 to 1.11.24\n\n## Why the committee made the recommendations\n\nThere are a variety of range of movement exercises that can be used for rehabilitation, with different levels of assistance depending on ability. Controlled motion devices should be considered if people are not able to perform exercises independently. The committee agreed that range of movement is particularly important during rehabilitation. Targeted stretching is a good method of preventing loss of movement, particularly after exercises, when muscles tighten as a response to activation.\n\n## How the recommendations might affect services\n\nThe committee were aware of the potential resource impact of recommending specific controlled motion devices to assist range of motion. Generally, these devices are rarely used (and mostly only in hospitals to help with knee injury). However, once acquired, these devices can be used by multiple people. Overall, the recommendations are not expected to have a large resource impact or be difficult to implement.\n\nReturn to recommendations\n\n# Splinting and orthotics\n\nRecommendations 1.11.25 to 1.11.33\n\n## Why the committee made the recommendations\n\nEvidence showed a benefit from orthoses in rehabilitation after trauma. No evidence was found on splinting. The committee combined the available evidence with their experience and knowledge to recommend several specialised splints and orthoses, and to warn about positions known to cause complications and loss of function later on in recovery.\n\nBecause of their complexity, the committee recommended bespoke splints for people with hand injuries, as well as referral to a hand therapy specialist. 'Off-the-rack' splints can be ill-fitting and cause lost range of movement in the hands and fingers.\n\nRegular review of splints is recommended because splinting can have adverse effects if not monitored carefully (for example, pressure sores). This risk is increased in people with reduced skin sensation and recent skin graft or flaps, so splints and orthoses may be contraindicated and specialist advice may be needed. People (and families and carers, if appropriate) should receive education on how to wear splints or orthoses to limit adverse effects and when to seek professional advice.\n\nEvidence showed that spinal orthoses can help improve patient rehabilitation outcomes, and they are used in current practice. However, in the committee's experience, not all trauma populations see a benefit (for example, older people) and spinal orthoses can cause adverse events if improperly fitted. Healthcare professionals should be aware that these devices may be poorly tolerated and know when to discuss problems with the surgical team. Because of these issues with the evidence, the committee made a research recommendation on spinal orthoses for older people.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice. Splints and orthoses are commonly used and are all low cost. Bespoke splints are easily made in a treatment room and would not need any additional resources.\n\nReturn to recommendations\n\n# Management of swelling and oedema, and scars\n\nRecommendations 1.11.34 to 1.11.44\n\n## Why the committee made the recommendations\n\nSwelling is a common side effect of traumatic injury, but there are symptoms that will need treatment from healthcare professionals (for example, signs of deep vein thrombosis). No evidence was found, so the committee used their knowledge and experience to recommend a programme of elevation and exercises to prevent and reduce any swelling associated with trauma. Compression bandages can be used to help this. However, providing appropriate compression is a skill. Therefore, the committee recommended specialist supervision for this.\n\nNo evidence was found on the psychological aspects of scarring after traumatic injury. Based on their experience, the committee recommended several measures to encourage people to adjust to their new appearance, reassure them of expected recovery sensations and provide information about scar management. For children and young people, the committee recommended performing any painful treatments away from their hospital bed. This encourages them to associate their bed with security, an important factor in their hospital experience.\n\nEvidence was found for massage as a treatment for scar tissue. This will help desensitise the area, and increase tissue mobility (and therefore maintain range of movement).\n\nIn the committee's experience, scar management knowledge is not very prevalent in non-specialist healthcare settings. Therefore, they recommended referring people to specialist services if they have scars or skin grafts that need complex treatment (for example, contracture across joints that limits movement).\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Nutritional supplementation\n\nRecommendations 1.11.45 to 1.11.52\n\n## Why the committee made the recommendations\n\nThe evidence for nutritional supplementation was of very low quality. However, the committee agreed that there is a lack of awareness about the nutritional risks and needs following traumatic injury. People need more calories after traumatic injury, to help with healing. However, they often have complications that can affect eating habits or nutrient absorption. To address these issues and the lack of awareness around nutritional supplementation, the committee made recommendations based on their own experience.\n\nThe committee made a specific recommendation for people with burns in combination with other traumatic injuries because they are at increased risk of losing significant muscle mass, weight and strength for a prolonged period, because of the long-lasting effect of the hypermetabolic response.\n\n## How the recommendations might affect services\n\nThe recommendations are in line with current practice and will not need additional resources to implement.\n\nReturn to recommendations\n\n# Cognitive rehabilitation\n\nRecommendations 1.12.1 to 1.12.7\n\n## Why the committee made the recommendations\n\nThere was no evidence in this area. However, in the committee's experience, trauma-related cognitive functioning problems can be upsetting for people and affect their decision making and participation. Because of this, the committee believed it is important to reassure people that these problems are usually temporary. When problems are not temporary, the committee recommended adapting rehabilitation therapy to take account of this and to help the person participate in therapy and assessments.\n\nAs another aspect of helping people with cognitive difficulties to participate, the committee highlighted information needs and formats to use. The committee were also keen to emphasise the need to share this information with the person's family or carers, because they can play an important part in helping the person understand and recall key messages.\n\nThe committee agreed on additional steps to follow for children and young people, to ensure that their education providers accommodate their changing needs.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Psychological rehabilitation\n\nRecommendations 1.13.1 to 1.13.7\n\n## Why the committee made the recommendations\n\nThe committee used their knowledge and experience to make recommendations on psychological rehabilitation. They highlighted the importance of reassuring people that the acute stress response is common and normally temporary, because it can be very distressing. Outside of the acute stress response, the committee identified several other psychological issues, to raise awareness among professionals and encourage good practice.\n\nBecause of low quality evidence, the committee based the recommendations on psychological support on their own experience. They agreed that 'one size does not fit all' within psychological and psychosocial therapies and felt it was important to offer psychological and emotional support that is tailored to a person's rehabilitation goals, needs and preferences.\n\nThe committee recommended that any treatment for psychological disorders should form part of a complete rehabilitation package, and not be kept separate. This will allow better communication and coordination of physical and mental healthcare.\n\nNo evidence of benefit was found for family support interventions. However, in the committee's experience, involving family can be beneficial.\n\n## How the recommendations might affect services\n\nThe recommendations reinforce current practice and refer to existing NICE guidelines, so should not need additional resources to implement. Most team members specialising in the management of major trauma are equipped to provide psychological and emotional support. Being more aware of psychological problems may result in more referrals to psychology services.\n\nReturn to recommendations\n\n# Rehabilitation after limb-threatening injury – early assessment, decision making and support\n\nRecommendations 1.14.1 to 1.14.4\n\n## Why the committee made the recommendations\n\nThere was no evidence in this area. The committee agreed based on their experience who should be involved from the multidisciplinary team and what the discussions needed to cover.\n\nAlthough no evidence was identified, the committee recommended psychological support before limb amputation because of the life-changing nature of the procedures. Psychological and emotional support can improve outcomes after surgery (such as emotional wellbeing and pain management).\n\nThe committee recommended involving limb reconstruction and prosthetic specialists early on, because amputation and limb reconstruction can be life-changing and traumatic.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Rehabilitation after limb reconstruction\n\nRecommendations 1.14.5 to 1.14.7\n\n## Why the committee made the recommendations\n\nThere was no evidence identified but, based on their own experience, the committee agreed that rehabilitation should start as early as possible after surgery to reduce the risk of complications that may delay the person's recovery, and to maintain range of movement after limb reconstruction. Because of the complexity of limb reconstruction, the committee did not recommend a specific programme but suggested certain interventions that could be used to accomplish this.\n\nThe committee also agreed that psychological support should continue after limb reconstruction surgery, to help the person adjust to their appearance and manage pain.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Rehabilitation after limb loss or amputation\n\nRecommendations 1.14.8 and 1.14.9\n\n## Why the committee made the recommendations\n\nThere was no evidence but, based on their own experience, the committee agreed that rehabilitation should start as early as possible after surgery to reduce the risk of complications that may delay the person's recovery. People should usually be referred to the amputee and prosthetic rehabilitation team before their surgery, but the committee acknowledged that sometimes there is not enough time so they would need to be referred afterwards.\n\nThe committee also agreed that psychological support should continue after limb loss and amputation to help the person adjust to their appearance and manage pain (for example, mirror therapy).\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended. More people being referred to amputee and prosthetic rehabilitation before surgery may cause an initial increase in early referrals, but this will be offset by fewer people being referred later in rehabilitation.\n\nReturn to recommendations\n\n# Pain management after limb loss or amputation\n\nRecommendations 1.14.10 to 1.14.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that pain management should be discussed before surgery because pain after limb loss or amputation can be difficult to treat, and managing pain effectively after surgery can increase participation in the rehabilitation process. Additionally, people with poor perioperative pain control have an increased risk of phantom limb pain in the long term. There was also evidence that mirror therapy (a type of graded motor imagery therapy) is an effective and inexpensive non-pharmacological treatment for phantom limb pain after limb loss or amputation.\n\n## How the recommendations might affect services\n\nThe recommendations enforce current practice and are not expected to be difficult to implement. Mirror therapy is relatively cheap and easy to implement. Other forms of graded motor imagery therapy are less commonly used and should be delivered by staff with appropriate skills, potentially resulting in extra training costs where it is currently not available. There may be an increased level of referrals to specialised pain management teams, depending on the complexity of pain management plans. However, this will be offset by increased participation in rehabilitation after surgery and therefore better outcomes.\n\nReturn to recommendations\n\n# Residual limb oedema and shaping after limb loss or amputation\n\nRecommendations 1.14.13 to 1.14.15\n\n## Why the committee made the recommendations\n\nThere was no evidence so the committee based the recommendations on their knowledge and experience. They highlighted the benefit of elevation and compression therapy in managing residual limb oedema by reducing swelling and facilitating prosthetics fitting. They also agreed that:\n\nlimb swelling should be avoided when using early walking aids because this can delay prosthetics fitting and rehabilitation\n\nresidual limb (stump) boards on wheelchairs can provide support to keep the limb elevated for people with a below-the-knee amputation.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Range of movement and strengthening after limb loss or amputation\n\nRecommendation 1.14.16\n\n## Why the committee made the recommendation\n\nThe committee used their knowledge and experience to recommend providing range of movement exercises to help prevent complications and optimise functional outcomes.\n\n## How the recommendation might affect services\n\nThe recommendation reflects current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Functional independence after limb loss or amputation\n\nRecommendations 1.14.17 and 1.14.18\n\n## Why the committee made the recommendations\n\nAlthough there was some evidence identified about waiting until prosthetics had been fitted before starting rehabilitation, this disagreed with the committee's knowledge and experience. They argued that the best way to maintain and improve the person's range of movement after limb loss or amputation is by starting rehabilitation therapy as early as possible. Rehabilitation should not be delayed by waiting for prosthetics to be fitted because the maintenance and improvement of range of movement will help prevent complications and optimise functional outcomes.\n\nThe committee also agreed that wheelchairs should be provided early, along with appropriate accessories such as anti-tippers and residual limb (stump) boards. Wheelchairs should be adjusted to accommodate the changes in the person's weight distribution after limb loss or amputation. By providing appropriately fitted and adjusted wheelchairs as early as possible, a person's independence and mobility will be increased and they will be better able to engage in activities of daily living. There was no evidence, so the committee used their knowledge and experience to make the recommendation on wheelchairs.\n\n## How the recommendations might affect services\n\nThere might be an increased number of referrals to physiotherapists and occupational therapists in order for wheelchairs to be individually fitted and adjusted. However, the committee discussed that the increased mobility and independence will result in an increased engagement with rehabilitation, leading to better rehabilitation outcomes. Overall, the recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Psychological support after limb loss, amputation or limb reconstruction\n\nRecommendations 1.14.19 to 1.14.22\n\n## Why the committee made the recommendations\n\nAlthough there was no evidence, the committee used their experience and knowledge to discuss how continuing psychological support after limb reconstruction, loss or amputation can help the person come to terms with their appearance and manage pain.\n\nThe committee recommended actively monitoring children and young people for emerging emotional and psychological impact. This is because childhood and young adulthood is a period of change for anyone, and children who have had limb reconstruction, loss or amputation may experience it differently to the general paediatric population (for example, altered body image may become more important during puberty).\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Continuing rehabilitation after limb reconstruction, limb loss or amputation and after discharge\n\nRecommendations 1.14.23 to 1.14.26\n\n## Why the committee made the recommendations\n\nThe rehabilitation plan should be reviewed at key points to ensure it is updated with any changes in the person's goals, circumstance or needs. For children and young people, physical growth may cause complications around the residual limb or prosthetic fitting. The committee recommended referral to specialist assessment when this occurs, in order to prevent any adverse effects.\n\nBased on their experience, the committee recommended psychological and emotional support after trauma to help a person adjust to their altered body image, manage pain and cope with the possibility of further procedures.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Rehabilitation after spinal cord injury – referral, assessment and general principles\n\nRecommendations 1.15.1 to 1.15.8\n\n## Why the committee made the recommendations\n\nThe committee discussed their experience with early treatment of traumatic spinal cord injury in emergency departments and how this can affect rehabilitation. Studies involving spinal cord injury treatment in the emergency department were not included in the evidence reviews because of an existing NICE guideline on spinal injury: assessment and initial management. However, the committee highlighted several areas of acute treatment that can affect rehabilitation after traumatic injury.\n\nBecause of competing clinical interests, certain aspects of spinal cord injury management are often overlooked in emergency healthcare settings. The committee highlighted the importance of timely contact with regional specialist spinal cord injury centres and the national spinal injuries database to establish a partnership of care with specialist healthcare professionals that will continue throughout the rehabilitation journey. An American Spinal Injury Association (ASIA) chart should also be completed early to identify a current reference point for future assessments.\n\nThe committee reflected on the additional issues that people encounter after spinal cord injury because of the chronic nature of the injury and resulting disabilities (for example, bowel, bladder and sexual function). External support networks are very important during spinal cord injury rehabilitation, with family members (and carers or friends, if appropriate) being invited into healthcare discussions and rehabilitation goals. Vocational, educational, recreational and home adjustments may be needed after discharge. By starting these conversations and arrangements early in the rehabilitation process, any modifications can be in place and rehabilitation can be better tailored to an individual, creating a smoother transfer back into the community. Ongoing contact with hospital rehabilitation teams should be maintained to ensure a continued progress review to inform outpatient rehabilitation planning.\n\nThe committee discussed the additional complications that children and young people might experience after spinal cord injury because they are still growing. Spinal growth patterns, skeletal growth and nutrition need to be closely monitored in children and young people. Complications in any of these areas can cause additional barriers to rehabilitation, and will become more difficult (if not impossible) to treat as the child or young person stops growing.\n\n## How the recommendations might affect practice\n\nThe recommendations reinforce current practice and are in line with the NICE guideline on spinal injury. The benefits of increased care coordination will offset the extra time that professionals might need to follow the recommendations. ASIA charts can be difficult to administer reliably, and staff with appropriate skills should complete assessments, potentially resulting in some extra training costs.\n\nReturn to recommendations\n\n# Bladder and bowel function\n\nRecommendations 1.15.9 to 1.15.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that bladder and bowel management is important because the medical consequences from undetected bladder and bowel malfunction can be severe. Complications include renal tract damage, bowel perforation and respiratory distress. The committee used their knowledge and experience to recommend several measures to monitor and maintain bladder and bowel function. Although keeping people nil by mouth is a common practice while assessing bowel function, the committee highlighted that delays in this assessment should be minimised in order to prevent issues with nutrition and discomfort during rehabilitation.\n\n## How the recommendations might affect practice\n\nThere is variation in bladder and bowel management, so the recommendations should lead to greater consistency and improve care. Monitoring bladder and bowel function will involve additional time, but should have benefits in reducing complications, avoiding delays in starting and continuing rehabilitation, and improving patient outcomes.\n\nReturn to recommendations\n\n# Respiratory function, swallowing and speech\n\nRecommendations 1.15.13 to 1.15.17\n\n## Why the committee made the recommendations\n\nSpinal cord injury can cause problems with speech and swallowing, so the committee agreed that people should be nil by mouth until they have been assessed for aspiration risk. They used their expertise to highlight groups of people that are at a particularly high risk, and should be assessed early. Referral to specialists may be needed.\n\nMaintaining respiratory function is essential after a spinal cord injury because the injury may have damaged the chest muscles used in respiration. Without treatment, this could lead to respiratory failure and severe complications. It can also delay rehabilitation until the person is clinically stable enough to start it, and may mean they also need chest physiotherapy to be added to their care plan. Respiratory function should be assessed in line with the NICE guideline on spinal injury to determine baseline function and mark progress. The committee highlighted that children and young people can find it difficult to complete these assessments (particularly forced vital capacity [FVC]), and these should be performed and interpreted in accordance with their age and ability. The committee used their experience to recommend several protective interventions to assist with respiratory function after spinal cord injury.\n\n## How the recommendations might affect services\n\nMonitoring respiratory function after a spinal cord injury will involve additional time, but should have benefits in preventing complications caused by compromised respiratory function, avoiding delays in starting and continuing rehabilitation, and improving outcomes. Prophylactic respiratory support will potentially reduce the need for additional chest rehabilitation further down the pathway.\n\nReturn to recommendations\n\n# Preventing complications\n\nRecommendations 1.15.18 to 1.15.20\n\n## Why the committee made the recommendations\n\nThe extended periods of bed rest and immobilisation following spinal cord injury can lead to a wide variety of complications, which can delay rehabilitation. There was no evidence so the committee based the recommendations on their knowledge and experience.\n\nSkin management is a particular area of concern because of decreased mobilisation coupled with reduced physical sensation. People can develop deep pressure ulcers very quickly, which need to be treated before rehabilitation can start.\n\nBlood pressure monitoring is important after spinal cord injury because people are at risk of developing autonomic dysreflexia (in high-level spinal cord injury) and orthostatic hypotension. Autonomic dysreflexia has severe consequences (for example, strokes, encephalopathy, brain haemorrhages and heart attacks) and should be managed as a medical emergency. Orthostatic hypotension has less severe complications but, because it is triggered when changing positions, can affect engagement with rehabilitation exercises.\n\n## How the recommendations might affect services\n\nThe recommendations reinforce current practice and should not need additional resources to implement. Additional education might be needed for healthcare professionals on the best way to inform people with spinal cord injury about skin and pressure management.\n\nReturn to recommendations\n\n# Maintaining mobility and movement\n\nRecommendations 1.15.21 to 1.15.33\n\n## Why the committee made the recommendations\n\nThe committee agreed that it is important to maintain mobility and range of motion after a spinal cord injury. However, they also recognised that the large variety of spinal cord injury disabilities and needs means that this should be considered on a case-by-case basis. Because of this complexity, the committee stressed that specialist advice should be sought when needed (for example, the appropriateness of wrist splints for people with a spinal cord injury involving C6). Spinal orthoses have conflicting results in different people, and can hinder certain rehabilitation programmes. Therefore, the committee recommended referring to surgical teams in these cases, to explore other avenues of treatment.\n\nThere was some evidence on the benefit of specialist equipment and rehabilitation techniques to maintain mobility and range of motion. The committee agreed that these should be considered on a case-by-case basis, aligning interventions with rehabilitation needs and goals.\n\nSpasticity is an important area to treat for people with spinal cord injury, to prevent losing range of joint movement and contractures. There was some evidence on baclofen (an oral antispastic medication) and botulinum toxin type\xa0A to manage spasticity after a spinal cord injury. Referral to a multidisciplinary team specialised in spasticity management may be needed.\n\nLength of bed rest after spinal cord injury varies throughout different NHS trusts, and is an area that the committee were keen to standardise. However, because of the lack of evidence identified, they were unable to make any strong recommendations and made a research recommendation on the optimal length of bed rest to inform future guideline updates.\n\n## How the recommendations might affect services\n\nMore people with spinal cord injury might be referred to specialist services. Any additional cost will be offset by more people achieving their long-term rehabilitation goals because of earlier specialist input. There might be some additional costs for training healthcare staff, and some services might need to procure specialist equipment to help with mobility, upper limb function and independent walking. Although some equipment, like robotics, can be expensive, the committee agreed a range of effective interventions. There is flexibility within the recommendations about the use of a range of assistive devices and techniques.\n\nReturn to recommendations\n\n# Low mood and psychological support\n\nRecommendations 1.15.34 to 1.15.37\n\n## Why the committee made the recommendations\n\nThere was conflicting quantitative evidence on using psychosocial interventions after spinal cord injury, with some studies reporting beneficial outcomes and some finding no difference. The committee argued that this was low quality evidence, and that their experience and expertise agreed with the beneficial impact of psychological interventions. However, because they have already made recommendations on psychological interventions for rehabilitation after traumatic injury, they used this section of the guideline to make recommendations that are specific to people with spinal cord injury.\n\nPeople with spinal cord injury have increased rates of low mood and psychological trauma, and this can affect engagement with rehabilitation. Access to a psychologist with experience in traumatic spinal cord injury and rehabilitation is not guaranteed outside of specialised spinal units, so the committee made a recommendation to address this. Active monitoring is recommended for children and young people because childhood and young adulthood is a period of change for anyone, and children and young people with a spinal cord injury could be affected in different ways to the general paediatric population (for example, altered body image becoming more important during puberty).\n\n## How the recommendations might affect services\n\nThe recommendations reinforce current practice and should not need additional resources to implement. If multidisciplinary teams are more aware of low mood and psychological trauma in people with a spinal injury, they may make more referrals for psychological support.\n\nReturn to recommendations\n\n# Rehabilitation after nerve injury – general principles\n\nRecommendations 1.16.1 to 1.16.3\n\n## Why the committee made the recommendations\n\nNerve injuries may be hidden; for instance, when the person has multiple injuries, a cognitive impairment, a head injury, is in critical care or has a pre-existing neurological condition. These obvious injuries could distract clinicians from recognising subtler nerve injury, and neurological deficit caused by nerve injury can be mistakenly assumed to be due to a pre-existing neurological condition. In addition, diagnosis of nerve injury may not be possible if the person is unconscious, and nerve function cannot be assessed on limbs that are splinted. The committee highlighted the need to assess the peripheral nerves of the affected limb to identify the informed nerve and functional deficit.\n\nThe committee highlighted the importance of assessing the risks to tissue viability if there is sensory or motor loss secondary to peripheral nerve injury, to manage the risk and not jeopardise the person's functional recovery.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice might need to be amended.\n\nReturn to recommendations\n\n# Therapies and referral\n\nRecommendations 1.16.4 to 1.16.9\n\n## Why the committee made the recommendations\n\nBased on the evidence and their experience, the committee emphasised the need to start rehabilitation therapy to maintain range of movement and regain function after nerve injury. This is because nerve injury can cause the joint to rest in an unnatural position and lead to fixed deformity from contracture of the capsule and muscle. Providing vocational therapy while the recovery is ongoing can help the person return to normal activities such as work.\n\nNerve function should be assessed regularly for symptoms of recovery, which will affect the components and intensity of the nerve rehabilitation programme. It should not be a static programme. For people who have a poor prognosis, a referral to a specialist peripheral nerve injury service should be made because these services are better equipped to deal with the complex needs of peripheral nerve injury.\n\nPeople recovering from nerve injury may experience low mood, anxiety and lack of motivation, because recovery may be a lengthy process. To ensure that specialist psychological support is available for people who may need it, the rehabilitation team should have access to a psychologist with trauma and rehabilitation experience.\n\n## How the recommendations might affect practice\n\nSensory interventions (including mirror therapy) and hydrotherapy are not widely available and this could have some resource implications. However, hydrotherapy would only be offered if pool facilities were available, and mirror therapy and other sensory interventions are relatively inexpensive and easy to implement. All of the above interventions can play a part in stimulating and aiding functional recovery, and can lead to a quicker recovery, help with pain management, and improve the person's health-related quality of life.\n\nHealthcare professionals may need training to conduct nerve conduction studies reliably, but this will save costs further down the care pathway. There may be more referrals to specialist peripheral nerve injury services.\n\nReturn to recommendations\n\n# Rehabilitation after chest injury\n\nRecommendations 1.17.1 to 1.17.12\n\n## Why the committee made the recommendations\n\nThere was no evidence identified. However, the committee discussed the importance of starting rehabilitation as soon as possible to avoid further complications. They also discussed the need for regular assessment of pain and highlighted pain management options. This is because pain is a contributing factor for much of the morbidity associated with chest injury, and the appropriateness of pain management options may vary between people with chest injury.\n\nFor people with chest trauma, the committee highlighted the need for movement in order to optimise their respiratory function and prevent deconditioning. They further highlighted a range of rehabilitation therapies to use in preventing respiratory difficulties because this is a key component of chest trauma rehabilitation. The committee are aware that the availability of these therapies may differ between services, and different therapies may be preferred by different people.\n\nBecause of the concerns over possible injury causes and underlying pathologies, the committee highlighted the need to assess people with rib fractures, in order to inform future treatment and prevent recurrence. The committee recognise stiffness of the upper limbs as a common complication and discussed measures to prevent compromised function.\n\nThe committee recommended referring people with complex chest injuries that affect communication and swallowing skills to speech and language therapy to prevent speech decline and swallowing difficulties.\n\nThe committee also recommended providing information that will help people to return to normal life and explain how to seek help for different problems that may arise because rehabilitation for chest injuries can take a long time, causing stress and worry.\n\n## How the recommendations might affect services\n\nThe recommendations reflect current practice, but where there are regional variations, practice will need to be amended.\n\nReturn to recommendations"}
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https://www.nice.org.uk/guidance/ng211
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This guideline covers complex rehabilitation needs after traumatic injury, including assessment and goal setting, rehabilitation plans and programmes, physical, psychological and cognitive rehabilitation, rehabilitation for specific injuries, coordination of rehabilitation in hospital, at discharge and in the community, and commissioning and organising rehabilitation services.
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f27fec29eb964c5975c0e24a55d3d48cf8642886
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nice
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Selpercatinib for previously treated RET fusion-positive advanced non-small-cell lung cancer
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Selpercatinib for previously treated RET fusion-positive advanced non-small-cell lung cancer
Evidence-based recommendations on selpercatinib (Retsevmo) for previously treated RET fusion-positive advanced non-small-cell lung cancer in adults.
# Recommendations
Selpercatinib is recommended for use within the Cancer Drugs Fund as an option for treating RET fusion-positive advanced non-small-cell lung cancer (NSCLC) in adults who need systemic therapy after immunotherapy, platinum-based chemotherapy or both. It is recommended only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect treatment with selpercatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
People with RET fusion-positive advanced NSCLC are usually offered docetaxel if they need systemic therapy after previous treatment. Sometimes they may be offered docetaxel with nintedanib.
Clinical trial evidence suggests some benefit for selpercatinib, but this is highly uncertain because the trial has not been running long enough. Also, selpercatinib is not directly compared with another treatment in the trial. It is compared indirectly with other treatments, but the results from this are also highly uncertain. Because of this, the estimates of cost effectiveness are very uncertain and selpercatinib cannot be recommended for routine use in the NHS.
Selpercatinib could be cost effective if further data shows that people live longer with treatment. Data from the trial of selpercatinib and from NHS practice would help address the uncertainty about clinical effectiveness. Selpercatinib is therefore recommended for use in the Cancer Drugs Fund.# Information about selpercatinib
# Marketing authorisation indication
Selpercatinib (Retsevmo, Eli Lilly) has a conditional marketing authorisation 'for the treatment of adults with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for 60 capsules of selpercatinib (80 mg) is £4,680 (excluding VAT; BNF online, accessed July 2021). The company's estimated cost for a 28‑day cycle of selpercatinib is £8,736.00.
The company has a commercial arrangement. This makes selpercatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 1 issue was resolved during the technical engagement stage, and agreed that including genetic testing costs in the model was appropriate.
It discussed issues 1 to 13, which were identified in the ERG report. It also discussed the possibility of commissioning selpercatinib through the Cancer Drugs Fund.
# New targeted treatment
## People with RET fusion-positive advanced non-small-cell lung cancer would welcome a new treatment
The patient and clinical experts explained that the symptoms of advanced non-small-cell lung cancer (NSCLC; including breathlessness, cough, and weight loss) are hard to treat. Typical treatments for RET fusion-positive advanced NSCLC in the NHS are chemotherapy (such as platinum doublet chemotherapy) and immunotherapy (such as pembrolizumab). The clinical expert and the Cancer Drugs Fund clinical lead from NHS England explained that, for previously treated RET fusion-positive NSCLC, docetaxel is the main treatment. But they also explained that some people may also be offered nintedanib with docetaxel, and that these are the only standard treatments for this indication. They explained that use of docetaxel with nintedanib is decreasing because of its limited benefit and increased side effects compared with docetaxel alone. This leaves few options for people with RET fusion-positive advanced NSCLC. Selpercatinib is the first treatment targeted at RET fusion-positive advanced NSCLC and has shown high response rates in some people with this tumour type. The committee concluded that people with RET fusion-positive NSCLC would welcome the introduction of selpercatinib as a treatment option.
# Comparators
## The relevant comparators are docetaxel alone and docetaxel with nintedanib
In its original submission, the company provided evidence for a range of comparators based on the NICE scope for this appraisal. Through clinical advice and discussion at technical engagement, the company refined the list of comparators down to docetaxel alone and docetaxel with nintedanib. The ERG suggested that pemetrexed with carboplatin, and platinum doublet chemotherapy remained relevant comparators. The committee discussed atezolizumab as well. The company explained that advice to both itself and ERG had been clear that people would most likely have immunotherapies first. The company said it was advised that people who have immunotherapies first are not then offered them second line, meaning this class of therapy is irrelevant for this indication. The company said it was also advised that pemetrexed with carboplatin and platinum doublet chemotherapy are rarely used second line. The committee concluded that docetaxel was the main comparator and that docetaxel with nintedanib was also an appropriate comparator for people with RET fusion-positive NSCLC.
# Clinical evidence
## The direct clinical evidence for selpercatinib is uncertain because it depends on 1 single-arm study
The evidence for selpercatinib comes from the LIBRETTO‑001 clinical trial. This is a single-arm, open-label, multicentre phase 1 to 2 trial including people with advanced solid tumours with RET activations. The primary outcome of the trial is objective response rate. Secondary outcomes include progression-free survival (PFS), overall survival (OS) and health-related quality of life. A total of 329 people with RET fusion-positive advanced NSCLC were enrolled, and:
data from 253 people was used in the analyses
people were enrolled with second-line advanced NSCLC that had been treated with platinum chemotherapy (known as the integrated analysis set )
data from 105 people was used in the first data cut (described as the primary analysis set).In the primary analysis set, the objective response rate was 63.8% and the median PFS was 16.53 months. Other trial results were confidential, but the company reported evidence that showed similar results for the primary analysis set and IAS groups. The ERG stated that the small number of survival events in LIBRETTO‑001 and the short follow-up times meant that there was uncertainty around the impact of selpercatinib on survival. Also, some PFS and OS data was not evaluable. The company was able to provide additional evidence from a later data cut. This gave about 3 more months of data, the results from which were consistent with the results from the IAS. However, the ERG considered that this did not overcome the uncertainty because the data was still immature. The ERG also noted that the company had not included this additional data in its cost-effectiveness modelling using its original data set. The committee agreed that basing the evidence on 1 single-arm study meant that there was uncertainty in the data for selpercatinib, particularly because the data was immature.
## The trial population is generalisable to the NHS population
The trial population included people who had had platinum chemotherapy, some people who had also had immunotherapy, and some people who had also had a multikinase inhibitor (MKI) such as cabozantinib. The ERG said it would have been more appropriate to provide data for people who had only had chemotherapy and people who had only had immunotherapy. The ERG also said people were unlikely to be offered MKIs in the NHS as part of treatment for RET fusion-positive NSCLC. This is because MKIs do not have a UK marketing authorisation for this indication specifically. The clinical expert said the trial population did reflect the NHS population for this indication. The company provided data to show that the trial groups who had and had not had MKI treatment had similar responses. The ERG acknowledged that the data for the IAS MKI‑naive group was similar to the data for the IAS overall. The committee accepted that the LIBRETTO‑001 trial population was generalisable to the NHS population of people with RET fusion-positive advanced NSCLC.
## Recommendations in this technology appraisal should apply to people with squamous and non-squamous advanced NSCLC
The marketing authorisation for selpercatinib does not differentiate between people with squamous and non-squamous advanced NSCLC. However, because of the rarity of RET gene fusions in squamous NSCLC, clinical advice, and the very small number of people with squamous NSCLC in the LIBRETTO‑001 trial, the company did not present any evidence on using selpercatinib to treat these tumours. The clinical expert said they might expect some difference in the effectiveness of selpercatinib in treating squamous advanced NSCLC. This is because people with squamous NSCLC may be older, have a higher chance of being smokers and be less fit. However, the clinical expert expected there would still be some level of response. The Cancer Drugs Fund clinical lead said that the NHS would expect to follow the same recommendation for people with squamous advanced NSCLC as for people with non-squamous advanced NSCLC. The committee agreed that the recommendations in this technology appraisal would apply to both squamous and non-squamous advanced NSCLC. This is because of the wording of the marketing authorisation and because the squamous population is so small.
# Indirect treatment comparison
## The populations included in the trials used in the network meta-analyses (NMAs) are relevant for the indirect treatment comparison (ITC)
Because LIBRETTO‑001 was a single-arm trial, an ITC was needed to establish the relative efficacy of selpercatinib. The ERG stated that trials used for the ITC were unlikely to have contained substantial numbers of people with RET fusion-positive advanced NSCLC. This was because the mutation is rare (1% to 2% of people with NSCLC). Also, testing was not done for RET fusion status in these trials, which the company acknowledged as a limitation of the data. The company did its ITC using NMA. This method allows for the relative effects estimated in different studies to be pooled if studies are sufficiently similar. To overcome the limitations noted by the ERG, and to ensure the selected trials were comparable, a suitable cohort of people was needed as a control arm for LIBRETTO‑001. The company simulated a control arm (that is, people having docetaxel with placebo), referred to as the pseudo-control arm, by using data from the REVEL NSCLC randomised controlled trial. The aim was to allow for the LIBRETTO‑001 data to be compared with the other trials in the ITC. The committee noted that the other trial data was not adjusted for RET status. The clinical expert said that the effect of RET fusion on treatment effectiveness for people with advanced NSCLC is unknown. However, the clinical expert thought it may become clear over time as more testing is carried out for this form of lung cancer. The committee accepted that, in the absence of a direct comparator population with RET fusion-positive NSCLC, the NMA trial populations were relevant for the ITC.
## Removing the adjustment for RET status from the simulated control arm for docetaxel is appropriate
In the company's original submission, the Flatiron clinic-genomic database was used to provide a range of prognostic factors (such as RET fusion status, age, smoking history and cancer histology). This was to adjust the control arm extracted from the REVEL randomised controlled trial to match the LIBRETTO‑001 population. The company said this process had generated a relevant control arm for LIBRETTO‑001, simulating the effect of using docetaxel with placebo to treat RET fusion-positive advanced NSCLC. The ERG said the methods used by the company needed multiple statistical steps, and each step created additional uncertainty. The company changed its approach after technical engagement, and the ERG pointed out that several issues either remained or had been created by using the new propensity score-matching approach. It also pointed out that the additional data provided by the company from a later point of the LIBRETTO‑001 trial had not been used in the NMAs. Doing this would have ensured as much data as possible was informing the ITC. The ERG emphasised that there was still too much uncertainty in the NMAs to make conclusions on the relative efficacy of selpercatinib and the comparators. The committee agreed that simulating the control arm using the company's approach did generate uncertainty for the relative efficacy of selpercatinib. It agreed that, in principle, using a simulated control arm was acceptable. The committee considered that there was not enough evidence to understand the effect of RET fusion status on survival. So, it thought that the relative clinical-effectiveness estimates may have lacked validity. In response to consultation, the company reported new evidence from the scientific literature. It argued this showed that RET fusion status was not prognostic, so the simulated control arm should be generated without adjustment for RET status. The company provided updated survival results for the simulated control arm without adjustment for RET status. It used these results in its NMA. The ERG said that scientific literature identified by the company was not designed to show whether RET fusion status was prognostic, and that the results were not conclusive. However, it thought that the analysis from the company that had shown its results without adjusting the simulated comparator for RET fusion status could be informative. The ERG said that there were still several issues in addition to those with the generation of the revised simulated control arm. These included:
statistical concerns about the violation of the proportional hazards assumption in some of the trials in the NMA
that the people in the trials (other than LIBRETTO‑001) were not tested for RET fusion-positive status
that fewer people were included in the company's propensity score-matching approach than in its original approach.The clinical expert commented that there is uncertainty about whether RET status does affect outcomes. However, the clinical expert explained that, in their experience, they would expect RET fusion-positive NSCLC to respond similarly to treatment as other forms of NSCLC. The clinical expert also reminded the committee that people with RET fusion mutations tend to access treatment at an earlier age, which would improve outcomes. The ERG emphasised that it was not possible to mitigate all uncertainty in estimating the effect of selpercatinib and the simulated control arm. The Cancer Drugs Fund clinical lead commented that there is uncertainty about the prognostic effects of RET fusion mutations. However, they noted that the company had adjusted the data for other covariates, such as demographic factors, that are known to affect survival. The committee concluded that, based on the limited data available, it was appropriate to remove the adjustment for RET status from the simulated control arm. But it also noted that significant uncertainty remained from this and other sources.
# The company's economic model
## The company's model is appropriate for decision making
The company used a partitioned-survival economic model that included 3 health states: progression-free, progressed and death. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for NSCLC, including:
NICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic non-small-cell lung cancer after chemotherapy
NICE's technology appraisal guidance on osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer
NICE's technology appraisal guidance on nivolumab for advanced non-squamous non-small-cell lung cancer after chemotherapy.The committee concluded that the company's economic model was suitable for decision making.
## The company's survival extrapolations for people having selpercatinib are plausible but uncertain
In the company's original submission, extrapolation of PFS and OS for selpercatinib came from LIBRETTO‑001 and the NMA (see section 3.6). The different extrapolation distributions were ranked using statistical methods, and also considered by clinical advisers to the company. The company based its conclusions for the selpercatinib arm on the Spline/Knot1 OS extrapolation. This was because its clinical advisers believed this extrapolation fitted most closely to their expectation of clinical reality, even though it was not objectively the best fit. The committee noted that clinical expert opinions drew little on experience of the rare RET fusion-positive form of NSCLC. It also noted that there is little long-term experience of using selpercatinib in the NHS. The ERG said that selection based on clinical advice rather than statistical tests, was open to bias. The direction and magnitude of any bias was not clear from the data. The ERG did not select a preferred alternative base-case extrapolation function because it thought the data and NMAs were too uncertain to make this possible. It noted that the Gompertz alternative extrapolation would match the clinical evidence most closely, and would be just as appropriate a selection of extrapolation as Spline/Knot1. However, it noted that it resulted in substantially different cost-effectiveness results. A different approach was used for PFS with selpercatinib, in that the stratified Gompertz distribution was used to fit the data. The committee discussed the differences in the extrapolated OS estimations presented and that this was, in part, caused by the short follow up of the LIBRETTO‑001 trial. The ERG said that, based on its inspection of extrapolations fit to the LIBRETTO‑001 data, OS for selpercatinib appeared to have been overestimated by the company. The clinical expert and Cancer Drugs Fund clinical lead supported this view. The committee acknowledged the uncertainty in PFS and OS estimates, particularly in the wide range of extrapolations for selpercatinib. In response to consultation, the company provided updated survival extrapolations for selpercatinib based on the results from its updated NMA and presented the updated results. It was again possible to fit a wide range of extrapolations to the data. The company repeated the process used in its original submission for choosing extrapolation curves. It selected the stratified Gompertz distribution for PFS, and the unstratified Gompertz for OS. The ERG commented that, based on the selpercatinib Kaplan–Meier curve of the data in LIBRETTO‑001, the extrapolated OS for selpercatinib appeared to have been overestimated. The ERG reiterated that several other distributions also fitted the data. The Cancer Drugs Fund clinical lead and clinical expert commented that the 5‑year survival estimates appeared to be similar to those seen in clinical practice for other targeted lung cancer therapies. They explained that the predicted survival may have been high, for example, the 38.8% survival predicted at 5 years using the company's Gompertz extrapolation. But they thought that this was plausible based on experience with other targeted treatments. The company acknowledged that its revised PFS and OS extrapolations may still have overestimated the effect of selpercatinib. However, it commented that the uncertainty could have been reduced with more mature data from LIBRETTO‑001. The committee concluded that there was still uncertainty about long-term survival with selpercatinib and that more mature data from LIBRETTO‑001 would provide more robust long-term survival estimates. However, it agreed that, based on the opinions of the clinical expert and the Cancer Drugs Fund clinical lead, the survival benefits from selpercatinib at 5 years were not unreasonable. So, the committee concluded that it was appropriate to consider the company's survival estimates for selpercatinib in its decision making.
## The modelled OS for the simulated control arm is plausible but there is still uncertainty
In the company's original submission, the estimates of PFS and OS for docetaxel came from the simulated control arm and NMA (see section 3.6 and section 3.7). The ERG considered that the extrapolation of survival in the control arm was likely to have been longer than expected in clinical practice. The clinical expert said they would have expected OS to be about 9 to 10 months for docetaxel, rather than the higher values seen in the survival extrapolations in the original submission. They explained that it is feasible that people with RET fusion-positive advanced NSCLC could have greater OS than people with other forms of advanced NSCLC. This is particularly because they tend to be younger and non-smokers, which might explain some of the higher-than-expected OS in the docetaxel arm. However, they noted that there was no evidence to support this. The company explained that the increase in OS from 9 months in the simulated control arm was because of the adjustment processes for RET fusion status used in its generation. The committee agreed that the survival estimates for the control arm were implausibly long, and that this would mean the conclusions based on the model were not robust. In response to consultation, the company provided revised survival extrapolations for the simulated control arm without adjustment for RET fusion status. The company considered that the updated survival extrapolations fitted more closely to the clinical expert's estimates (that is, 9 to 10 months). The ERG reiterated its opinion that there was still a lot of uncertainty. It did not think that simply removing the adjustment for RET fusion status would have accounted for all the uncertainty (see section 3.7). The ERG thought that the company had succeeded in reducing survival estimates for the simulated control arm, which had been considered to be too high. However, it pointed out that, because of limited data, the long-term survival for this group was still uncertain. The clinical expert considered the revised survival extrapolations to be more plausible. This was because of the low number of people in the stimulated control arm who were expected to be alive at 5 years and beyond. The committee agreed that the company's revised survival extrapolations for the simulated control arm were clinically plausible and appropriate for decision making. However, it also agreed that the survival estimates were still uncertain. This was because of the lack of evidence on whether RET status is a prognostic factor, so whether it should have been adjusted for in the stimulated control arm.
## The economic model should use time to discontinuation (TTD) when calculating the cost of selpercatinib
The original company model used PFS to calculate the cost of selpercatinib. The ERG said that using an extrapolation based on the TTD data in LIBRETTO‑001 would be more accurate. The company subsequently used an estimate for TTD in its updated model. The ERG preferred to incorporate a parametric extrapolation for TTD into the original model. The company stated that the ERG's approach overestimated TTD, and therefore costs, because the data was immature. The clinical expert said that the costs of selpercatinib would be higher if estimated using TTD rather than PFS. The reason is that it is common for a treatment to be continued even if there is disease progression because progression does not mean there is no benefit from the treatment. This could be because:
an initially large tumour is substantially reduced, so progression of this tumour would be less than without treatment or
-r more secondary tumours have progressed but there is still a positive effect on the primary tumour from having the treatment.The clinical expert advised that it would be unlikely that people would still be on the treatment 2 years after progression. In response to consultation, the company provided further information on its original approach. It explained that it had got the mean time from progression to stopping treatment from the LIBRETTO‑001 trial. It then added this value to the PFS curve to calculate cost of selpercatinib. The company also provided scenario analyses for various fixed time points between PFS and stopping treatment with selpercatinib. It based this on LIBRETTO‑001 data to show that modelling TTD might overestimate the time on treatment, and so overestimate costs of selpercatinib. The ERG considered that this did not include new evidence. It reminded the committee that TTD is the usual basis for calculating costs in other NICE technology appraisals. The ERG also highlighted that more data was available for TTD than OS. So, it thought that there could have been an inconsistency in the company's arguments that OS data was sufficiently reliable to use within the economic model but not TTD data. The clinical expert said that people would continue using selpercatinib for as long as it was beneficial. The clinical expert explained that there would not be a single predicable value for time from progression to stopping treatment. The Cancer Drugs Fund clinical lead said that the company's scenario analysis comparing PFS extrapolations with various TTD extrapolations showed an inconsistency between the company's separate results for OS and TTD. This inconsistency resulted in a longer OS but shorter TTD (the results are confidential and cannot be reported here). When the details of the results were considered by the committee and the experts, they were not plausible. The Cancer Drugs Fund clinical lead considered that the expected OS for people with RET fusion-positive NSCLC closely aligned with the ERG's TTD extrapolation. The company considered that this extrapolation of TTD was an overestimate. It thought that the uncertainty associated with TTD could be reduced with further data from the ongoing trial and validation from external data. The committee noted consultation comments had stated that it would be inconsistent with previous NICE technology appraisals to use PFS rather than TTD. It concluded that the cost of selpercatinib should be based on an extrapolation of the TTD data in LIBRETTO‑001.
## The cost of genetic testing for RET fusions should be incorporated into the economic model
The company did not include costs for genetic testing for RET fusions into its original cost-effectiveness model. This was because it expects such testing to be done routinely within the NHS. The Cancer Drugs Fund clinical lead confirmed that testing for RET fusions is available in the NHS as a fluorescent in-situ hybridisation test. However, access to this test is not routine or part of normal screening at the NHS Genomic Medicine Service. The clinical expert said that next-generation sequencing screening panels would be adapted to include testing for RET fusions when possible. However, at the time of this appraisal for selpercatinib, this was not considered routine. Therefore, NHS England provided a suitable cost per test to the company, and the company included this in its economic model. The committee noted the response to consultation from a commentator that the cost of testing should have been shown as a percentage of the overall testing costs. The commentator said that this percentage should have represented the additional costs compared with the testing costs without testing for RET fusion status. The committee agreed that incorporating the cost of genetic testing for RET fusions was appropriate.
# Utility values in the economic model
## The progressed disease (PD) utility value used by the company is acceptable in the absence of more robust data
The ERG pointed out that the company's approach to utility values used in the model was inconsistent. In general, the company took its utility values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous non-small-cell lung cancer after chemotherapy. However, it used the utility value for PD of 0.688 from the company's base-case analysis in the nivolumab appraisal, rather than that appraisal committee's preferred value for PD of 0.569. The ERG was concerned that 0.688 was high, preferring 0.569. For the appraisal of selpercatinib, the company collected health-related quality-of-life data in the LIBRETTO‑001 trial. However, it used the European Organisation for Research and Treatment of Cancer (EORTC) QLQ‑C30 questionnaire rather than EQ‑5D to collect this data. The company followed a method reported in the literature to map EORTC to EQ‑5D, and the calculated PD value was higher than 0.688. So, the company decided to use the midpoint between 0.569 and 0.688 in its model, which was 0.628. The ERG said this approach was arbitrary and maintained its view that the utility value of 0.569 from the nivolumab appraisal was appropriate for this population. The clinical expert stated that people with RET fusion-positive advanced NSCLC tend to be younger and have never smoked. So, they thought it was feasible they might have generally higher utility values than people with other forms of lung cancer. The committee decided that the PD value of 0.628 used by the company in the revised model was acceptable for decision making in absence of more robust data.
# Cost-effectiveness estimates
## The most plausible incremental cost-effectiveness ratio (ICER) is outside the range normally considered a cost-effective use of NHS resources
In response to consultation, the company presented a revised base case, which included an updated commercial arrangement for selpercatinib. The pairwise ICER was:
£55,119 per quality-adjusted life year (QALY) gained for selpercatinib compared with docetaxel
£48,800 per QALY gained for selpercatinib compared with docetaxel plus nintedanib (not accounting for the confidential discount which applies to nintedanib and increases the ICER).The ERG did a fully incremental analysis. This was a combined single analysis in which nintedanib with docetaxel was compared with docetaxel alone, which was then compared with selpercatinib alone. In this analysis, docetaxel alone and selpercatinib alone 'extendedly dominated' docetaxel with nintedanib (that is, nintedanib with docetaxel was less effective and had a higher ICER than selpercatinib). This meant the relevant comparison was between docetaxel and selpercatinib. The company also presented scenario analyses using its revised PFS curves for calculating the cost of selpercatinib. In these, the ICERs ranged from £54,006 to £59,540 per QALY gained for selpercatinib compared with docetaxel (see section 3.11). The ERG made 1 change to the base case. It modelled the costs of selpercatinib based on TTD rather than PFS. The ERG's pairwise ICERs were £76,210 per QALY gained for selpercatinib compared with docetaxel, and £71,978 per QALY gained for selpercatinib compared with docetaxel with nintedanib (not accounting for the confidential discount that applies to nintedanib, which increases the ICER). The ERG maintained that the data underpinning the cost-effectiveness model was uncertain because of the issues mentioned in section 3.3, section 3.6, section 3.7, section 3.9 and section 3.10. The committee acknowledged the large range of plausible ICERs because of data immaturity and modelling assumptions. It was aware that modelling the cost of selpercatinib based on TTD rather than PFS was a key driver of cost effectiveness. It reiterated its opinion that the cost of selpercatinib should have been based on TTD rather than PFS. It therefore concluded that the most plausible ICERs for selpercatinib compared with docetaxel would be closer to the ERG's ICER of £76,210 per QALY gained. This was because this ICER incorporated its preferred assumption. It concluded that this was outside the range normally considered a cost-effective use of NHS resources.
## There are no additional benefits that are not captured in the cost-effectiveness analysis
The committee noted that, unlike docetaxel, selpercatinib is an oral drug, and it specifically targets RET fusion-positive NSCLC. It agreed that selpercatinib would be beneficial. The committee considered that the model structure should have been able to capture the benefits and costs of selpercatinib in terms of health-related quality of life and QALYs gained. It did not think that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.
# End of life
## Life expectancy for people with RET fusion-positive NSCLC having standard care is less than 2 years
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the company's original submission, the base-case estimate for the median OS for people offered docetaxel was less than 24 months, and an estimate of the mean was not provided. However, the company explained that it thought this to be an overestimate compared with clinical expert opinion, which was 9 to 10 months. The ERG's estimates for OS for people offered docetaxel with or without nintedanib were higher than those of the company, that is, above 24 months. The company thought that the ERG's extrapolations for survival were overestimates. The committee noted the comments from the clinical expert. It considered that the expected survival of people with RET fusion-positive advanced NSCLC who were not offered selpercatinib might be much less than 24 months in practice. In the company's response to consultation, the modelled estimates for OS with docetaxel (without adjustment for RET status in the simulated control arm) were closer to the survival estimates expected by the clinical expert. The ERG reiterated that there was a lack of data to show that removing the adjustment for RET status was the correct approach, so there was still uncertainty. The committee accepted that there was uncertainty in how the simulated control arm was generated. But it agreed that the updated OS results for docetaxel were plausible and concluded that the short life expectancy criterion was met.
## Selpercatinib is likely to extend life by more than 3 months
In its original base case, the company estimated that selpercatinib would extend life expectancy by much more than 3 months (the company's modelled estimates are confidential and cannot be presented here). The ERG thought that this was feasible according to the data, but highly uncertain because of the difference between clinical expert opinion and company estimates. The committee recalled its concerns about the uncertainty in the OS estimates generated using the company's original model. It concluded that the company's estimate of extending life expectancy was not reliable and so the life extension criterion was not met. This was because of its concerns with the original NMA and the lack of robust results from the model. In response to consultation, the company presented updated OS estimates for selpercatinib and the simulated control arm based on the generation of the revised control arm, and updated NMAs. A wide range of extrapolations could be made from the results, so the committee agreed that there was uncertainty about the extent of the additional survival gain from selpercatinib compared with the simulated control arm. However, it concluded that it was likely that people having selpercatinib would benefit from an extension to life of more than 3 months.
# Conclusion
## Selpercatinib is not recommended for routine use in the NHS
The committee was aware that the evidence base will necessarily be weaker for some rare indications such as RET fusion-positive advanced NSCLC because of the low number of people with the condition. The committee recalled that there are no targeted treatments currently available for RET fusion-positive advanced NSCLC, as discussed in section 3.1. It noted the clinical- and cost-effectiveness evidence was highly uncertain because of the immaturity of the data from the LIBRETTO‑001 trial. It also noted that there was still uncertainty about the ITC using NMAs based on the simulated control arm. Selpercatinib met NICE's end of life criteria. However, the committee's preferred ICER was well above the range normally considered a cost-effective use of NHS resources, even considering the end of life criteria. Therefore, it could not recommend selpercatinib for routine use for previously treated RET fusion-positive advanced NSCLC.
# Cancer Drugs Fund
## Selpercatinib should be included in the Cancer Drugs Fund
Having concluded that selpercatinib could not be recommended for routine use, the committee then considered whether it could be recommended for treating RET fusion-positive advanced NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):
The company had expressed that it thought the Cancer Drugs Fund may be appropriate for selpercatinib.
The key uncertainties were the accuracy and clinical feasibility of the extrapolations of OS, PFS and TTD for selpercatinib. Further data collection in the ongoing LIBRETTO‑001 trial may reduce the uncertainties in the OS, PFS and TTD extrapolations (see section 3.9).
Further data collection in the ongoing LIBRETTO‑001 trial would not reduce the uncertainty in the OS and PFS extrapolations for docetaxel, which are based on the simulated control arm. Data from other sources might confirm the effect of RET fusion status on survival in people with advanced NSCLC but would not remove other sources of uncertainty. The committee agreed that this uncertainty would not be fully resolved by data collection in the Cancer Drugs Fund (see section 3.10).The company proposed a confidential commercial arrangement for use of selpercatinib within the Cancer Drugs Fund. The committee noted there was uncertainty about the extrapolations of OS, PFS and TTD for selpercatinib, and the extrapolations of OS and PFS for docetaxel, which were based on the simulated control arm. However, it was satisfied that, with the commercial access agreement applied, selpercatinib has plausible potential to be cost effective (the cost-effectiveness estimates are confidential and cannot be reported here). The committee concluded that selpercatinib met the criteria for inclusion in the Cancer Drugs Fund. It therefore recommended the drug for use within the Cancer Drugs Fund for treating RET fusion-positive advanced NSCLC in adults who need systemic therapy after immunotherapy, platinum-based chemotherapy or both, if the conditions in the managed access agreement are followed. It also stated that, when the guidance is next reviewed, the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out in section 3.14.
|
{'Recommendations': 'Selpercatinib is recommended for use within the Cancer Drugs Fund as an option for treating RET fusion-positive advanced non-small-cell lung cancer (NSCLC) in adults who need systemic therapy after immunotherapy, platinum-based chemotherapy or both. It is recommended only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect treatment with selpercatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPeople with RET fusion-positive advanced NSCLC are usually offered docetaxel if they need systemic therapy after previous treatment. Sometimes they may be offered docetaxel with nintedanib.\n\nClinical trial evidence suggests some benefit for selpercatinib, but this is highly uncertain because the trial has not been running long enough. Also, selpercatinib is not directly compared with another treatment in the trial. It is compared indirectly with other treatments, but the results from this are also highly uncertain. Because of this, the estimates of cost effectiveness are very uncertain and selpercatinib cannot be recommended for routine use in the NHS.\n\nSelpercatinib could be cost effective if further data shows that people live longer with treatment. Data from the trial of selpercatinib and from NHS practice would help address the uncertainty about clinical effectiveness. Selpercatinib is therefore recommended for use in the Cancer Drugs Fund.', 'Information about selpercatinib': "# Marketing authorisation indication\n\nSelpercatinib (Retsevmo, Eli Lilly) has a conditional marketing authorisation 'for the treatment of adults with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for 60\xa0capsules of selpercatinib (80\xa0mg) is £4,680 (excluding VAT; BNF online, accessed July\xa02021). The company's estimated cost for a 28‑day cycle of selpercatinib is £8,736.00.\n\nThe company has a commercial arrangement. This makes selpercatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 1\xa0issue was resolved during the technical engagement stage, and agreed that including genetic testing costs in the model was appropriate.\n\nIt discussed issues 1\xa0to\xa013, which were identified in the ERG report. It also discussed the possibility of commissioning selpercatinib through the Cancer Drugs Fund.\n\n# New targeted treatment\n\n## People with RET fusion-positive advanced non-small-cell lung cancer would welcome a new treatment\n\nThe patient and clinical experts explained that the symptoms of advanced non-small-cell lung cancer (NSCLC; including breathlessness, cough, and weight loss) are hard to treat. Typical treatments for RET fusion-positive advanced NSCLC in the NHS are chemotherapy (such as platinum doublet chemotherapy) and immunotherapy (such as pembrolizumab). The clinical expert and the Cancer Drugs Fund clinical lead from NHS England explained that, for previously treated RET fusion-positive NSCLC, docetaxel is the main treatment. But they also explained that some people may also be offered nintedanib with docetaxel, and that these are the only standard treatments for this indication. They explained that use of docetaxel with nintedanib is decreasing because of its limited benefit and increased side effects compared with docetaxel alone. This leaves few options for people with RET fusion-positive advanced NSCLC. Selpercatinib is the first treatment targeted at RET fusion-positive advanced NSCLC and has shown high response rates in some people with this tumour type. The committee concluded that people with RET fusion-positive NSCLC would welcome the introduction of selpercatinib as a treatment option.\n\n# Comparators\n\n## The relevant comparators are docetaxel alone and docetaxel with nintedanib\n\nIn its original submission, the company provided evidence for a range of comparators based on the NICE scope for this appraisal. Through clinical advice and discussion at technical engagement, the company refined the list of comparators down to docetaxel alone and docetaxel with nintedanib. The ERG suggested that pemetrexed with carboplatin, and platinum doublet chemotherapy remained relevant comparators. The committee discussed atezolizumab as well. The company explained that advice to both itself and ERG had been clear that people would most likely have immunotherapies first. The company said it was advised that people who have immunotherapies first are not then offered them second line, meaning this class of therapy is irrelevant for this indication. The company said it was also advised that pemetrexed with carboplatin and platinum doublet chemotherapy are rarely used second line. The committee concluded that docetaxel was the main comparator and that docetaxel with nintedanib was also an appropriate comparator for people with RET fusion-positive NSCLC.\n\n# Clinical evidence\n\n## The direct clinical evidence for selpercatinib is uncertain because it depends on 1\xa0single-arm study\n\nThe evidence for selpercatinib comes from the LIBRETTO‑001 clinical trial. This is a single-arm, open-label, multicentre phase\xa01 to\xa02 trial including people with advanced solid tumours with RET activations. The primary outcome of the trial is objective response rate. Secondary outcomes include progression-free survival (PFS), overall survival (OS) and health-related quality of life. A total of 329\xa0people with RET fusion-positive advanced NSCLC were enrolled, and:\n\ndata from 253\xa0people was used in the analyses\n\npeople were enrolled with second-line advanced NSCLC that had been treated with platinum chemotherapy (known as the integrated analysis set [IAS])\n\ndata from 105\xa0people was used in the first data cut (described as the primary analysis set).In the primary analysis set, the objective response rate was 63.8% and the median PFS was 16.53\xa0months. Other trial results were confidential, but the company reported evidence that showed similar results for the primary analysis set and IAS groups. The ERG stated that the small number of survival events in LIBRETTO‑001 and the short follow-up times meant that there was uncertainty around the impact of selpercatinib on survival. Also, some PFS and OS data was not evaluable. The company was able to provide additional evidence from a later data cut. This gave about 3 more months of data, the results from which were consistent with the results from the IAS. However, the ERG considered that this did not overcome the uncertainty because the data was still immature. The ERG also noted that the company had not included this additional data in its cost-effectiveness modelling using its original data set. The committee agreed that basing the evidence on 1\xa0single-arm study meant that there was uncertainty in the data for selpercatinib, particularly because the data was immature.\n\n## The trial population is generalisable to the NHS population\n\nThe trial population included people who had had platinum chemotherapy, some people who had also had immunotherapy, and some people who had also had a multikinase inhibitor (MKI) such as cabozantinib. The ERG said it would have been more appropriate to provide data for people who had only had chemotherapy and people who had only had immunotherapy. The ERG also said people were unlikely to be offered MKIs in the NHS as part of treatment for RET fusion-positive NSCLC. This is because MKIs do not have a UK marketing authorisation for this indication specifically. The clinical expert said the trial population did reflect the NHS population for this indication. The company provided data to show that the trial groups who had and had not had MKI treatment had similar responses. The ERG acknowledged that the data for the IAS MKI‑naive group was similar to the data for the IAS overall. The committee accepted that the LIBRETTO‑001 trial population was generalisable to the NHS population of people with RET fusion-positive advanced NSCLC.\n\n## Recommendations in this technology appraisal should apply to people with squamous and non-squamous advanced NSCLC\n\nThe marketing authorisation for selpercatinib does not differentiate between people with squamous and non-squamous advanced NSCLC. However, because of the rarity of RET gene fusions in squamous NSCLC, clinical advice, and the very small number of people with squamous NSCLC in the LIBRETTO‑001 trial, the company did not present any evidence on using selpercatinib to treat these tumours. The clinical expert said they might expect some difference in the effectiveness of selpercatinib in treating squamous advanced NSCLC. This is because people with squamous NSCLC may be older, have a higher chance of being smokers and be less fit. However, the clinical expert expected there would still be some level of response. The Cancer Drugs Fund clinical lead said that the NHS would expect to follow the same recommendation for people with squamous advanced NSCLC as for people with non-squamous advanced NSCLC. The committee agreed that the recommendations in this technology appraisal would apply to both squamous and non-squamous advanced NSCLC. This is because of the wording of the marketing authorisation and because the squamous population is so small.\n\n# Indirect treatment comparison\n\n## The populations included in the trials used in the network meta-analyses (NMAs) are relevant for the indirect treatment comparison (ITC)\n\nBecause LIBRETTO‑001 was a single-arm trial, an ITC was needed to establish the relative efficacy of selpercatinib. The ERG stated that trials used for the ITC were unlikely to have contained substantial numbers of people with RET fusion-positive advanced NSCLC. This was because the mutation is rare (1% to 2% of people with NSCLC). Also, testing was not done for RET fusion status in these trials, which the company acknowledged as a limitation of the data. The company did its ITC using NMA. This method allows for the relative effects estimated in different studies to be pooled if studies are sufficiently similar. To overcome the limitations noted by the ERG, and to ensure the selected trials were comparable, a suitable cohort of people was needed as a control arm for LIBRETTO‑001. The company simulated a control arm (that is, people having docetaxel with placebo), referred to as the pseudo-control arm, by using data from the REVEL NSCLC randomised controlled trial. The aim was to allow for the LIBRETTO‑001 data to be compared with the other trials in the ITC. The committee noted that the other trial data was not adjusted for RET status. The clinical expert said that the effect of RET fusion on treatment effectiveness for people with advanced NSCLC is unknown. However, the clinical expert thought it may become clear over time as more testing is carried out for this form of lung cancer. The committee accepted that, in the absence of a direct comparator population with RET fusion-positive NSCLC, the NMA trial populations were relevant for the ITC.\n\n## Removing the adjustment for RET status from the simulated control arm for docetaxel is appropriate\n\nIn the company's original submission, the Flatiron clinic-genomic database was used to provide a range of prognostic factors (such as RET fusion status, age, smoking history and cancer histology). This was to adjust the control arm extracted from the REVEL randomised controlled trial to match the LIBRETTO‑001 population. The company said this process had generated a relevant control arm for LIBRETTO‑001, simulating the effect of using docetaxel with placebo to treat RET fusion-positive advanced NSCLC. The ERG said the methods used by the company needed multiple statistical steps, and each step created additional uncertainty. The company changed its approach after technical engagement, and the ERG pointed out that several issues either remained or had been created by using the new propensity score-matching approach. It also pointed out that the additional data provided by the company from a later point of the LIBRETTO‑001 trial had not been used in the NMAs. Doing this would have ensured as much data as possible was informing the ITC. The ERG emphasised that there was still too much uncertainty in the NMAs to make conclusions on the relative efficacy of selpercatinib and the comparators. The committee agreed that simulating the control arm using the company's approach did generate uncertainty for the relative efficacy of selpercatinib. It agreed that, in principle, using a simulated control arm was acceptable. The committee considered that there was not enough evidence to understand the effect of RET fusion status on survival. So, it thought that the relative clinical-effectiveness estimates may have lacked validity. In response to consultation, the company reported new evidence from the scientific literature. It argued this showed that RET fusion status was not prognostic, so the simulated control arm should be generated without adjustment for RET status. The company provided updated survival results for the simulated control arm without adjustment for RET status. It used these results in its NMA. The ERG said that scientific literature identified by the company was not designed to show whether RET fusion status was prognostic, and that the results were not conclusive. However, it thought that the analysis from the company that had shown its results without adjusting the simulated comparator for RET fusion status could be informative. The ERG said that there were still several issues in addition to those with the generation of the revised simulated control arm. These included:\n\nstatistical concerns about the violation of the proportional hazards assumption in some of the trials in the NMA\n\nthat the people in the trials (other than LIBRETTO‑001) were not tested for RET fusion-positive status\n\nthat fewer people were included in the company's propensity score-matching approach than in its original approach.The clinical expert commented that there is uncertainty about whether RET status does affect outcomes. However, the clinical expert explained that, in their experience, they would expect RET fusion-positive NSCLC to respond similarly to treatment as other forms of NSCLC. The clinical expert also reminded the committee that people with RET fusion mutations tend to access treatment at an earlier age, which would improve outcomes. The ERG emphasised that it was not possible to mitigate all uncertainty in estimating the effect of selpercatinib and the simulated control arm. The Cancer Drugs Fund clinical lead commented that there is uncertainty about the prognostic effects of RET fusion mutations. However, they noted that the company had adjusted the data for other covariates, such as demographic factors, that are known to affect survival. The committee concluded that, based on the limited data available, it was appropriate to remove the adjustment for RET status from the simulated control arm. But it also noted that significant uncertainty remained from this and other sources.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company used a partitioned-survival economic model that included 3\xa0health states: progression-free, progressed and death. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for NSCLC, including:\n\nNICE's technology appraisal guidance on atezolizumab for treating locally advanced or metastatic non-small-cell lung cancer after chemotherapy\n\nNICE's technology appraisal guidance on osimertinib for untreated EGFR mutation-positive non-small-cell lung cancer\n\nNICE's technology appraisal guidance on nivolumab for advanced non-squamous non-small-cell lung cancer after chemotherapy.The committee concluded that the company's economic model was suitable for decision making.\n\n## The company's survival extrapolations for people having selpercatinib are plausible but uncertain\n\nIn the company's original submission, extrapolation of PFS and OS for selpercatinib came from LIBRETTO‑001 and the NMA (see section\xa03.6). The different extrapolation distributions were ranked using statistical methods, and also considered by clinical advisers to the company. The company based its conclusions for the selpercatinib arm on the Spline/Knot1 OS extrapolation. This was because its clinical advisers believed this extrapolation fitted most closely to their expectation of clinical reality, even though it was not objectively the best fit. The committee noted that clinical expert opinions drew little on experience of the rare RET fusion-positive form of NSCLC. It also noted that there is little long-term experience of using selpercatinib in the NHS. The ERG said that selection based on clinical advice rather than statistical tests, was open to bias. The direction and magnitude of any bias was not clear from the data. The ERG did not select a preferred alternative base-case extrapolation function because it thought the data and NMAs were too uncertain to make this possible. It noted that the Gompertz alternative extrapolation would match the clinical evidence most closely, and would be just as appropriate a selection of extrapolation as Spline/Knot1. However, it noted that it resulted in substantially different cost-effectiveness results. A different approach was used for PFS with selpercatinib, in that the stratified Gompertz distribution was used to fit the data. The committee discussed the differences in the extrapolated OS estimations presented and that this was, in part, caused by the short follow up of the LIBRETTO‑001 trial. The ERG said that, based on its inspection of extrapolations fit to the LIBRETTO‑001 data, OS for selpercatinib appeared to have been overestimated by the company. The clinical expert and Cancer Drugs Fund clinical lead supported this view. The committee acknowledged the uncertainty in PFS and OS estimates, particularly in the wide range of extrapolations for selpercatinib. In response to consultation, the company provided updated survival extrapolations for selpercatinib based on the results from its updated NMA and presented the updated results. It was again possible to fit a wide range of extrapolations to the data. The company repeated the process used in its original submission for choosing extrapolation curves. It selected the stratified Gompertz distribution for PFS, and the unstratified Gompertz for OS. The ERG commented that, based on the selpercatinib Kaplan–Meier curve of the data in LIBRETTO‑001, the extrapolated OS for selpercatinib appeared to have been overestimated. The ERG reiterated that several other distributions also fitted the data. The Cancer Drugs Fund clinical lead and clinical expert commented that the 5‑year survival estimates appeared to be similar to those seen in clinical practice for other targeted lung cancer therapies. They explained that the predicted survival may have been high, for example, the 38.8% survival predicted at 5\xa0years using the company's Gompertz extrapolation. But they thought that this was plausible based on experience with other targeted treatments. The company acknowledged that its revised PFS and OS extrapolations may still have overestimated the effect of selpercatinib. However, it commented that the uncertainty could have been reduced with more mature data from LIBRETTO‑001. The committee concluded that there was still uncertainty about long-term survival with selpercatinib and that more mature data from LIBRETTO‑001 would provide more robust long-term survival estimates. However, it agreed that, based on the opinions of the clinical expert and the Cancer Drugs Fund clinical lead, the survival benefits from selpercatinib at 5\xa0years were not unreasonable. So, the committee concluded that it was appropriate to consider the company's survival estimates for selpercatinib in its decision making.\n\n## The modelled OS for the simulated control arm is plausible but there is still uncertainty\n\nIn the company's original submission, the estimates of PFS and OS for docetaxel came from the simulated control arm and NMA (see section\xa03.6 and\xa0section 3.7). The ERG considered that the extrapolation of survival in the control arm was likely to have been longer than expected in clinical practice. The clinical expert said they would have expected OS to be about 9\xa0to 10\xa0months for docetaxel, rather than the higher values seen in the survival extrapolations in the original submission. They explained that it is feasible that people with RET fusion-positive advanced NSCLC could have greater OS than people with other forms of advanced NSCLC. This is particularly because they tend to be younger and non-smokers, which might explain some of the higher-than-expected OS in the docetaxel arm. However, they noted that there was no evidence to support this. The company explained that the increase in OS from 9\xa0months in the simulated control arm was because of the adjustment processes for RET fusion status used in its generation. The committee agreed that the survival estimates for the control arm were implausibly long, and that this would mean the conclusions based on the model were not robust. In response to consultation, the company provided revised survival extrapolations for the simulated control arm without adjustment for RET fusion status. The company considered that the updated survival extrapolations fitted more closely to the clinical expert's estimates (that is, 9\xa0to 10\xa0months). The ERG reiterated its opinion that there was still a lot of uncertainty. It did not think that simply removing the adjustment for RET fusion status would have accounted for all the uncertainty (see section\xa03.7). The ERG thought that the company had succeeded in reducing survival estimates for the simulated control arm, which had been considered to be too high. However, it pointed out that, because of limited data, the long-term survival for this group was still uncertain. The clinical expert considered the revised survival extrapolations to be more plausible. This was because of the low number of people in the stimulated control arm who were expected to be alive at 5\xa0years and beyond. The committee agreed that the company's revised survival extrapolations for the simulated control arm were clinically plausible and appropriate for decision making. However, it also agreed that the survival estimates were still uncertain. This was because of the lack of evidence on whether RET status is a prognostic factor, so whether it should have been adjusted for in the stimulated control arm.\n\n## The economic model should use time to discontinuation (TTD) when calculating the cost of selpercatinib\n\nThe original company model used PFS to calculate the cost of selpercatinib. The ERG said that using an extrapolation based on the TTD data in LIBRETTO‑001 would be more accurate. The company subsequently used an estimate for TTD in its updated model. The ERG preferred to incorporate a parametric extrapolation for TTD into the original model. The company stated that the ERG's approach overestimated TTD, and therefore costs, because the data was immature. The clinical expert said that the costs of selpercatinib would be higher if estimated using TTD rather than PFS. The reason is that it is common for a treatment to be continued even if there is disease progression because progression does not mean there is no benefit from the treatment. This could be because:\n\nan initially large tumour is substantially reduced, so progression of this tumour would be less than without treatment or\n\nor more secondary tumours have progressed but there is still a positive effect on the primary tumour from having the treatment.The clinical expert advised that it would be unlikely that people would still be on the treatment 2\xa0years after progression. In response to consultation, the company provided further information on its original approach. It explained that it had got the mean time from progression to stopping treatment from the LIBRETTO‑001 trial. It then added this value to the PFS curve to calculate cost of selpercatinib. The company also provided scenario analyses for various fixed time points between PFS and stopping treatment with selpercatinib. It based this on LIBRETTO‑001 data to show that modelling TTD might overestimate the time on treatment, and so overestimate costs of selpercatinib. The ERG considered that this did not include new evidence. It reminded the committee that TTD is the usual basis for calculating costs in other NICE technology appraisals. The ERG also highlighted that more data was available for TTD than OS. So, it thought that there could have been an inconsistency in the company's arguments that OS data was sufficiently reliable to use within the economic model but not TTD data. The clinical expert said that people would continue using selpercatinib for as long as it was beneficial. The clinical expert explained that there would not be a single predicable value for time from progression to stopping treatment. The Cancer Drugs Fund clinical lead said that the company's scenario analysis comparing PFS extrapolations with various TTD extrapolations showed an inconsistency between the company's separate results for OS and TTD. This inconsistency resulted in a longer OS but shorter TTD (the results are confidential and cannot be reported here). When the details of the results were considered by the committee and the experts, they were not plausible. The Cancer Drugs Fund clinical lead considered that the expected OS for people with RET fusion-positive NSCLC closely aligned with the ERG's TTD extrapolation. The company considered that this extrapolation of TTD was an overestimate. It thought that the uncertainty associated with TTD could be reduced with further data from the ongoing trial and validation from external data. The committee noted consultation comments had stated that it would be inconsistent with previous NICE technology appraisals to use PFS rather than TTD. It concluded that the cost of selpercatinib should be based on an extrapolation of the TTD data in LIBRETTO‑001.\n\n## The cost of genetic testing for RET fusions should be incorporated into the economic model\n\nThe company did not include costs for genetic testing for RET fusions into its original cost-effectiveness model. This was because it expects such testing to be done routinely within the NHS. The Cancer Drugs Fund clinical lead confirmed that testing for RET fusions is available in the NHS as a fluorescent in-situ hybridisation test. However, access to this test is not routine or part of normal screening at the NHS Genomic Medicine Service. The clinical expert said that next-generation sequencing screening panels would be adapted to include testing for RET fusions when possible. However, at the time of this appraisal for selpercatinib, this was not considered routine. Therefore, NHS England provided a suitable cost per test to the company, and the company included this in its economic model. The committee noted the response to consultation from a commentator that the cost of testing should have been shown as a percentage of the overall testing costs. The commentator said that this percentage should have represented the additional costs compared with the testing costs without testing for RET fusion status. The committee agreed that incorporating the cost of genetic testing for RET fusions was appropriate.\n\n# Utility values in the economic model\n\n## The progressed disease (PD) utility value used by the company is acceptable in the absence of more robust data\n\nThe ERG pointed out that the company's approach to utility values used in the model was inconsistent. In general, the company took its utility values from NICE's technology appraisal guidance on nivolumab for advanced non-squamous non-small-cell lung cancer after chemotherapy. However, it used the utility value for PD of 0.688 from the company's base-case analysis in the nivolumab appraisal, rather than that appraisal committee's preferred value for PD of 0.569. The ERG was concerned that 0.688 was high, preferring 0.569. For the appraisal of selpercatinib, the company collected health-related quality-of-life data in the LIBRETTO‑001 trial. However, it used the European Organisation for Research and Treatment of Cancer (EORTC) QLQ‑C30 questionnaire rather than EQ‑5D to collect this data. The company followed a method reported in the literature to map EORTC to EQ‑5D, and the calculated PD value was higher than 0.688. So, the company decided to use the midpoint between 0.569 and 0.688 in its model, which was 0.628. The ERG said this approach was arbitrary and maintained its view that the utility value of 0.569 from the nivolumab appraisal was appropriate for this population. The clinical expert stated that people with RET fusion-positive advanced NSCLC tend to be younger and have never smoked. So, they thought it was feasible they might have generally higher utility values than people with other forms of lung cancer. The committee decided that the PD value of 0.628 used by the company in the revised model was acceptable for decision making in absence of more robust data.\n\n# Cost-effectiveness estimates\n\n## The most plausible incremental cost-effectiveness ratio (ICER) is outside the range normally considered a cost-effective use of NHS resources\n\nIn response to consultation, the company presented a revised base case, which included an updated commercial arrangement for selpercatinib. The pairwise ICER was:\n\n£55,119 per quality-adjusted life year (QALY) gained for selpercatinib compared with docetaxel\n\n£48,800 per QALY gained for selpercatinib compared with docetaxel plus nintedanib (not accounting for the confidential discount which applies to nintedanib and increases the ICER).The ERG did a fully incremental analysis. This was a combined single analysis in which nintedanib with docetaxel was compared with docetaxel alone, which was then compared with selpercatinib alone. In this analysis, docetaxel alone and selpercatinib alone 'extendedly dominated' docetaxel with nintedanib (that is, nintedanib with docetaxel was less effective and had a higher ICER than selpercatinib). This meant the relevant comparison was between docetaxel and selpercatinib. The company also presented scenario analyses using its revised PFS curves for calculating the cost of selpercatinib. In these, the ICERs ranged from £54,006 to £59,540 per QALY gained for selpercatinib compared with docetaxel (see section\xa03.11). The ERG made 1\xa0change to the base case. It modelled the costs of selpercatinib based on TTD rather than PFS. The ERG's pairwise ICERs were £76,210 per QALY gained for selpercatinib compared with docetaxel, and £71,978 per QALY gained for selpercatinib compared with docetaxel with nintedanib (not accounting for the confidential discount that applies to nintedanib, which increases the ICER). The ERG maintained that the data underpinning the cost-effectiveness model was uncertain because of the issues mentioned in section\xa03.3,\xa0section 3.6,\xa0section 3.7,\xa0section 3.9\xa0and\xa0section 3.10. The committee acknowledged the large range of plausible ICERs because of data immaturity and modelling assumptions. It was aware that modelling the cost of selpercatinib based on TTD rather than PFS was a key driver of cost effectiveness. It reiterated its opinion that the cost of selpercatinib should have been based on TTD rather than PFS. It therefore concluded that the most plausible ICERs for selpercatinib compared with docetaxel would be closer to the ERG's ICER of £76,210 per QALY gained. This was because this ICER incorporated its preferred assumption. It concluded that this was outside the range normally considered a cost-effective use of NHS resources.\n\n## There are no additional benefits that are not captured in the cost-effectiveness analysis\n\nThe committee noted that, unlike docetaxel, selpercatinib is an oral drug, and it specifically targets RET fusion-positive NSCLC. It agreed that selpercatinib would be beneficial. The committee considered that the model structure should have been able to capture the benefits and costs of selpercatinib in terms of health-related quality of life and QALYs gained. It did not think that it had not been presented with evidence of any additional benefits that were not captured in the measurement of QALYs.\n\n# End of life\n\n## Life expectancy for people with RET fusion-positive NSCLC having standard care is less than 2\xa0years\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the company's original submission, the base-case estimate for the median OS for people offered docetaxel was less than 24\xa0months, and an estimate of the mean was not provided. However, the company explained that it thought this to be an overestimate compared with clinical expert opinion, which was 9\xa0to 10\xa0months. The ERG's estimates for OS for people offered docetaxel with or without nintedanib were higher than those of the company, that is, above 24\xa0months. The company thought that the ERG's extrapolations for survival were overestimates. The committee noted the comments from the clinical expert. It considered that the expected survival of people with RET fusion-positive advanced NSCLC who were not offered selpercatinib might be much less than 24\xa0months in practice. In the company's response to consultation, the modelled estimates for OS with docetaxel (without adjustment for RET status in the simulated control arm) were closer to the survival estimates expected by the clinical expert. The ERG reiterated that there was a lack of data to show that removing the adjustment for RET status was the correct approach, so there was still uncertainty. The committee accepted that there was uncertainty in how the simulated control arm was generated. But it agreed that the updated OS results for docetaxel were plausible and concluded that the short life expectancy criterion was met.\n\n## Selpercatinib is likely to extend life by more than 3\xa0months\n\nIn its original base case, the company estimated that selpercatinib would extend life expectancy by much more than 3\xa0months (the company's modelled estimates are confidential and cannot be presented here). The ERG thought that this was feasible according to the data, but highly uncertain because of the difference between clinical expert opinion and company estimates. The committee recalled its concerns about the uncertainty in the OS estimates generated using the company's original model. It concluded that the company's estimate of extending life expectancy was not reliable and so the life extension criterion was not met. This was because of its concerns with the original NMA and the lack of robust results from the model. In response to consultation, the company presented updated OS estimates for selpercatinib and the simulated control arm based on the generation of the revised control arm, and updated NMAs. A wide range of extrapolations could be made from the results, so the committee agreed that there was uncertainty about the extent of the additional survival gain from selpercatinib compared with the simulated control arm. However, it concluded that it was likely that people having selpercatinib would benefit from an extension to life of more than 3\xa0months.\n\n# Conclusion\n\n## Selpercatinib is not recommended for routine use in the NHS\n\nThe committee was aware that the evidence base will necessarily be weaker for some rare indications such as RET fusion-positive advanced NSCLC because of the low number of people with the condition. The committee recalled that there are no targeted treatments currently available for RET fusion-positive advanced NSCLC, as discussed in section\xa03.1. It noted the clinical- and cost-effectiveness evidence was highly uncertain because of the immaturity of the data from the LIBRETTO‑001 trial. It also noted that there was still uncertainty about the ITC using NMAs based on the simulated control arm. Selpercatinib met NICE's end of life criteria. However, the committee's preferred ICER was well above the range normally considered a cost-effective use of NHS resources, even considering the end of life criteria. Therefore, it could not recommend selpercatinib for routine use for previously treated RET fusion-positive advanced NSCLC.\n\n# Cancer Drugs Fund\n\n## Selpercatinib should be included in the Cancer Drugs Fund\n\nHaving concluded that selpercatinib could not be recommended for routine use, the committee then considered whether it could be recommended for treating RET fusion-positive advanced NSCLC within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):\n\nThe company had expressed that it thought the Cancer Drugs Fund may be appropriate for selpercatinib.\n\nThe key uncertainties were the accuracy and clinical feasibility of the extrapolations of OS, PFS and TTD for selpercatinib. Further data collection in the ongoing LIBRETTO‑001 trial may reduce the uncertainties in the OS, PFS and TTD extrapolations (see section\xa03.9).\n\nFurther data collection in the ongoing LIBRETTO‑001 trial would not reduce the uncertainty in the OS and PFS extrapolations for docetaxel, which are based on the simulated control arm. Data from other sources might confirm the effect of RET fusion status on survival in people with advanced NSCLC but would not remove other sources of uncertainty. The committee agreed that this uncertainty would not be fully resolved by data collection in the Cancer Drugs Fund (see section\xa03.10).The company proposed a confidential commercial arrangement for use of selpercatinib within the Cancer Drugs Fund. The committee noted there was uncertainty about the extrapolations of OS, PFS and TTD for selpercatinib, and the extrapolations of OS and PFS for docetaxel, which were based on the simulated control arm. However, it was satisfied that, with the commercial access agreement applied, selpercatinib has plausible potential to be cost effective (the cost-effectiveness estimates are confidential and cannot be reported here). The committee concluded that selpercatinib met the criteria for inclusion in the Cancer Drugs Fund. It therefore recommended the drug for use within the Cancer Drugs Fund for treating RET fusion-positive advanced NSCLC in adults who need systemic therapy after immunotherapy, platinum-based chemotherapy or both, if the conditions in the managed access agreement are followed. It also stated that, when the guidance is next reviewed, the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out in section\xa03.14."}
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https://www.nice.org.uk/guidance/ta760
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Evidence-based recommendations on selpercatinib (Retsevmo) for previously treated RET fusion-positive advanced non-small-cell lung cancer in adults.
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85cf9d00f825d78bb2d0050f0d3b2b98c19d2500
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nice
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Cabotegravir with rilpivirine for treating HIV-1
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Cabotegravir with rilpivirine for treating HIV-1
Evidence-based recommendations on cabotegravir (Vocabria) with rilpivirine (Rekambys) for treating HIV-1 in adults. This includes adults with virological suppression (HIV-1 RNA fewer than 50 copies/ml) on a stable antiretroviral regimen, and without any evidence of viral resistance to, and no previous virological failure with, any non-nucleoside reverse transcriptase inhibitors or integrase inhibitors.
# Recommendations
Cabotegravir with rilpivirine is recommended, within its marketing authorisation, as an option for treating HIV‑1 infection in adults:
with virological suppression (HIV‑1 RNA fewer than 50 copies/ml) on a stable antiretroviral regimen and
without any evidence of viral resistance to, and no previous virological failure with, any non-nucleoside reverse transcriptase inhibitors or integrase inhibitors. It is recommended only if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Current treatment for HIV‑1 is antiretroviral regimens taken as tablets (orally) each day. The aim is to keep the number of virus particles in the blood (the viral load) so low that it cannot be detected, so that the virus cannot be transmitted between people. Cabotegravir with rilpivirine is the first long-acting antiretroviral injection available for HIV‑1.
Clinical trial results show that cabotegravir with rilpivirine is as effective as oral antiretrovirals at keeping the viral load lower than 50 copies/ml of blood. It is unclear whether there would be a difference in adherence between long-acting injections and daily oral tablets. The most likely cost-effectiveness estimate is likely to be within what NICE normally considers an acceptable use of NHS resources. So, cabotegravir with rilpivirine is recommended.# Information about cabotegravir with rilpivirine
# Marketing authorisation indication
Cabotegravir (Vocabria, Viiv Healthcare) with rilpivirine (Rekambys, Janssen) is indicated 'for the treatment of HIV‑1 infection in adults who are virologically suppressed (HIV‑1 RNA fewer than 50 copies/ml) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with, agents of the NNRTI and INI class'.
# Dosage in the marketing authorisation
The dosage schedules are available in the summary of product characteristics for cabotegravir and the summary of product characteristics for rilpivirine.
# Price
The list price for cabotegravir is £638.57 for a 30‑day pack of oral tablets and £1,197.02 for the bi‑monthly (every 2 months) intramuscular injection vial (excluding VAT). The list price for rilpivirine is £200.27 for a 30‑day pack of oral tablets and £440.47 for the bi‑monthly intramuscular injection vial (excluding VAT). The company has a commercial arrangement (simple discount patient access scheme). This makes cabotegravir with rilpivirine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Viiv Healthcare, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that none of the issues were resolved after technical engagement. It recognised that there were remaining areas of uncertainty associated with the analyses presented (see ERG report, table 1.1, page 12) and took these into account in its decision making. It discussed issues 1 to 10, which were outstanding after the technical engagement stage.
# The condition
## HIV is not curable and people living with it currently need to take daily medication for life
The committee heard from the clinical and community experts (alternative term for patient expert) that HIV is a retrovirus that attacks the human immune system, specifically macrophages and CD4+ T cells. The HIV‑1 subtype accounts for most infections worldwide and can be acquired through sexual contact, breastfeeding, broken skin, or injections using contaminated equipment or substances. People living with HIV‑1 that is untreated are at risk of their immune system gradually weakening, which can lead to opportunistic infections and cancers that further deteriorate their health. Despite scientific advances, HIV is still incurable, but the virus can be controlled by modern treatment. The current treatment regimens are oral antiretroviral therapies (ART) taken daily. There are several classes of antiretroviral agents that act on different phases of the HIV‑1 virus life cycle either by disrupting its ability to enter the human host cells or to multiply. The ARTs used in the NHS include the following classes of drugs:
nucleoside reverse transcriptase inhibitors (NRTIs)
non-nucleoside reverse transcriptase inhibitors (NNRTIs)
protease inhibitors (PIs)
fusion inhibitors
integrase inhibitors (INI or INSTIs)
CCR5 antagonists.Therapy involves a combination of different agents, either as single- or multi-tablet regimens that must be taken every day for the rest of a person's life. The clinical experts told the committee that the aim is to suppress the virus to undetectable levels in the blood (defined as HIV‑1 RNA fewer than 50 copies/ml) because then it becomes untransmissible. The clinical experts explained that treatment success with current daily oral treatments is mainly determined by adherence, which is influenced by drug side effects and psychosocial issues. They explained that although adherence is important, perfect adherence is not needed to have an undetectable viral load with modern treatments, and current therapy is highly effective. The community experts explained that adherence can be difficult in some cases because of drug-related side effects, toxicity, and other psychosocial issues such as stigma or changes in lifestyle. They also explained that a reduction in adherence might put people living with HIV‑1 at risk of developing viral rebound or resistance to antiretrovirals. The committee concluded that HIV‑1 is not curable and people living with it currently need to take daily medication for life.
## Stigma remains an issue for people living with HIV, and can have a negative impact on people's health and relationships
One of the community experts said that because people need to take their medication for life, their daily tablets serve as a constant reminder of their HIV status. This reminder can be distressing for some people because it is linked to stigma and having HIV‑1. The expert expanded on the stigma around HIV; for some people it triggers the fear of having to disclose their status if people discover their tablets, which can easily happen when living in shared accommodation or taking medication in a public setting. The expert explained that the fear of unwanted disclosure happens constantly throughout people's lives. Stigma can present in various forms, including self-stigma based on negative self-beliefs, anticipated stigma when individuals expect negative treatment based on their HIV status, and discrimination. The community experts explained that although things have improved over the last decade, stigma is a key barrier to people with HIV living fulfilled and happy lives. The committee understood that people's friendships, trust in others and the quality of their relationships in every sphere of life has more effect than anything else on mental health, physical health and how long we live. For this reason, stigma has a negative impact on personal, social, occupational and healthcare relationships. Furthermore, the community experts explained that stigma can sometimes affect adherence to oral regimens because individuals may miss a dose if they do not feel comfortable taking their medication in front of other people. The committee acknowledged these difficulties and concluded that stigma remains an issue for people living with HIV and can have a negative impact on people's health and relationships.
# New treatment option
## Cabotegravir with rilpivirine would be beneficial for people who find daily tablets challenging or who would prefer an injectable regimen
Long-acting cabotegravir and long-acting rilpivirine (referred to as 'cabotegravir with rilpivirine' from here onwards) is administered as 2 separate intramuscular injections. The dosing regimen starts with a 28‑day oral lead‑in, followed by monthly injections for 2 months. Thereafter, injections are given every 2 months. Cabotegravir is an INSTI and rilpivirine is an NNRTI. The company explained that it is intended to be a new alternative treatment option instead of daily oral ARTs. The clinical experts explained that, even though cabotegravir with rilpivirine has a lower frequency of dosing, people would need to visit an HIV clinic more often than with current oral ARTs because it is administered in the clinic. The clinical and community experts stated that cabotegravir with rilpivirine could be an effective alternative when treatment adherence to a daily oral regimen is affected either by side effects, when oral intake is impaired, or when lifestyle interferes with following a daily regimen. This is particularly important because people with HIV‑1 need to maintain their medication regimen to prevent viral rebound or developing resistance to ART. The community experts stressed that there is a huge appetite for an injectable treatment because taking tablets every day can be challenging. The committee noted that to be eligible for cabotegravir with rilpivirine, people must already have virological suppression on a stable antiretroviral regimen, so it may not be appropriate for people who have poor adherence. The company explained that long-acting treatments have improved adherence in other disease areas, so it is plausible that this would also be true for HIV. It considered that cabotegravir with rilpivirine would be particularly valuable for people with good levels of adherence but who might struggle to maintain this over time. The committee concluded that cabotegravir with rilpivirine would be a valuable treatment option for people who have adequate levels of adherence but who find daily tablets challenging or who would prefer an injectable regimen.
# Comparators
## Choice of oral ART depends on regional availability and individual need
There is currently no NICE technology appraisal guidance on treating HIV. NHS England's guide on best practice in HIV prescribing and multidisciplinary teams provides support to clinicians in treating HIV and managing multidisciplinary team discussions. It aims to provide access to antiretroviral therapy to anyone living with HIV, promote informed choice, help with shared decision making, and support therapy. The clinical expert explained that the clinical management of the condition is led by standard principles. The expert said that people living with HIV‑1 have treatment at commissioned hospitals with specialist HIV clinics. In these clinics, people are given an antiretroviral regimen and are regularly seen until their HIV‑1 is stable on a treatment routine. Once the viral load is suppressed, people would normally visit the HIV clinic 2 or 3 times per year for a routine follow up. The clinical and commissioning experts added that there is regional variation in antiretroviral prescribing, and that there are different prices for each drug in each region. Consequently, prescribing depends on individual need, and regional cost and availability. The committee concluded that the choice of oral ART depends on regional availability and individual need.
## The company included relevant oral antiretroviral therapies
The comparator in the scope was 'antiretroviral treatment (established clinical management such as integrase inhibitors)'. The company chose the oral ARTs that most people living with HIV‑1 switch to when they have virological suppression, because these would be the treatments used by the people who could potentially use cabotegravir with rilpivirine. It considered these treatments as a group (sometimes referred to as a 'basket' comparator) rather than comparing cabotegravir and rilpivirine with each oral antiretroviral individually. Given the variability in ART used across the country, the committee considered this approach to be appropriate, because the oral ARTs are all considered similar in efficacy (see section 3.6). The regimens included in the company's comparator group were:
emtricitabine with tenofovir alafenamide plus dolutegravir
emtricitabine with tenofovir alafenamide plus raltegravir
abacavir, dolutegravir and lamivudine
dolutegravir with lamivudine
dolutegravir with rilpivirine
bictegravir, emtricitabine and tenofovir alafenamide
doravirine, lamivudine and tenofovir disoproxil fumarate
darunavir, cobicistat, emtricitabine and tenofovir alafenamide
emtricitabine, rilpivirine and tenofovir alafenamide.The company explained that it selected these treatments based on treatment switches captured by market data. The clinical experts confirmed that these treatments are normally used in NHS practice for people who have virological suppression and need to switch treatment for non-virological reasons, and therefore it was appropriate for the company to include them. However, a clinical expert was concerned that dolutegravir plus tenofovir and emtricitabine was excluded, because it is widely prescribed. In its submission, the company explained that people normally switch away from this treatment because of toxicity concerns. The committee concluded that the oral ARTs included in the group of comparators were relevant.
## All oral antiretroviral therapies have similar efficacy
The company assumed that all oral ART regimens have similar efficacy. It explained that the large number of non-inferiority studies available on this subject supports this, and that this assumption was confirmed by a clinical expert. Also, the company's pivotal trials used 2 NRTIs and an INSTI plus an NNRTI or PI (ATLAS), and an NRTI, INSTI and an NRTI (FLAIR), so it considered the treatment efficacy to be generalisable to the NHS. The ERG was satisfied that, given the very high efficacy of current oral ARTs, the company's assumption that they all have similar efficacy was appropriate. There was a general agreement among the clinical experts that all oral ARTs have similar efficacy. The committee concluded that all oral ARTs have similar efficacy.
# Clinical effectiveness
## It is unlikely that including case control studies in the company's systematic review would affect the cost-effectiveness results
The company did a systematic review to identify literature on clinical effectiveness and safety outcomes. The company included evidence from randomised control trials and excluded case-control studies. The ERG was concerned that relevant data might have been missed by excluding case-control studies. The company stated that given the high volumes of literature on HIV, priority was given to randomised controlled trials, which are the gold standard in the evidence hierarchy. The company also stressed that including case-control studies would not have led to a different conclusion. The clinical experts agreed with the company and expressed no concerns, because the available evidence came from randomised controlled trials. The ERG explained that it had other concerns about the company's search strategy, including language and date limits, and search sensitivity. It would have preferred searches specifically for safety data but agreed that given the large amount of HIV literature about safety, it is unlikely that anything new would have been identified. The committee considered there to be minor limitations associated with the company's systematic review, but it was unlikely that important studies were missed. The committee concluded that it is unlikely that including case-control studies would have affected the cost-effectiveness results.
## The comparator ARTs in the ATLAS and FLAIR clinical trials are generalisable to the NHS
The company's key clinical evidence for long-acting cabotegravir with rilpivirine came from ATLAS, FLAIR and ATLAS‑2M. These were phase 3 randomised, controlled, open-label, non-inferiority trials in people living with HIV‑1. ATLAS and FLAIR compared monthly cabotegravir and rilpivirine with daily oral ARTs. ATLAS included 618 adults who had virological suppression on a stable regimen containing 2 NRTIs plus an INSTI, an NNRTI or a PI for at least 6 months. The comparator in ATLAS was 2 NRTIs plus an INSTI, 2 NRTIs plus a PI, or 2 NRTIs plus an NNRTI. FLAIR included 566 adults who had no previous experience of ART. There was a 20‑week induction with current oral ART (abacavir /dolutegravir/lamivudine), then people were randomised to have monthly cabotegravir with rilpivirine or continue the induction regimen. The ERG noted that the oral ARTs used in the comparator arms of ATLAS and FLAIR may not be fully representative of the drugs normally used in the NHS in England. The company explained that the regimens used as comparators in ATLAS and FLAIR are considered to have comparable efficacy to currently used regimens in the NHS. It supported this by explaining that non-inferiority trials are the norm for ART in HIV (see section 3.6). To further support its assumption of generalisability to the NHS, the company submitted information about how the components used in the ATLAS oral ART arm were similar to drugs prescribed in the UK. The company had consulted an expert who stated that he had no reservations about the generalisability of the results of the company's trials to the NHS. At technical engagement, a representative from a professional organisation explained that most individuals would take an NRTI with either an NNRTI, INSTI or PI. This was similar to the comparator arm of ATLAS (in ATLAS, people in the comparator arm took 2 NRTIs plus an INSTI and an NNRTI or a PI). The committee concluded that the comparator ARTs in the ATLAS and FLAIR clinical trials are generalisable to the NHS.
## Long-acting cabotegravir with rilpivirine is non-inferior to oral ARTs
ATLAS and FLAIR aimed to show non-inferiority to oral ARTs with a pre-specified non-inferiority margin of 4%. The primary outcome in both trials was the proportion of people with HIV‑1 RNA 50 or more copies/ml at week 48. The company presented results from a pre-specified pooled analysis of ATLAS and FLAIR, explaining that the trials had similar designs. The primary end point was met in this pooled analysis, with 11 of 591 people (1.9%) in the monthly cabotegravir with rilpivirine arm, and 10 of 591 people in the oral ART arm, with HIV‑1 RNA 50 or more copies/ml at week 48. The adjusted difference in the proportion of people with HIV‑1 RNA 50 or more copies/ml at week 48 was 0.16% (95% confidence interval -1.35 to -1.67). The clinical experts confirmed that cabotegravir with rilpivirine is considered similar in effectiveness to the current oral ARTs. The committee concluded that long-acting cabotegravir with rilpivirine is non-inferior to oral ARTs.
## Long-acting cabotegravir with rilpivirine is as effective when taken every 2 months compared with when taken every 1 month
The ATLAS‑2M clinical trial aimed to show that cabotegravir with rilpivirine every 2 months is non-inferior to cabotegravir with rilpivirine every 1 month. The trial included 1,020 adults who had virological suppression. People were randomised to have long-acting cabotegravir with rilpivirine either monthly or bi‑monthly (every 2 months) for 100 weeks. About half of the people enrolled were from the ongoing ATLAS study and the rest were new. The primary outcome was met at week 48. The results showed that 5 of 523 (1.0%) in the monthly cabotegravir with rilpivirine arm, and 9 of 522 (1.7%) in the bi‑monthly arm had HIV‑1 RNA 50 or more copies/ml at week 48. The adjusted difference in the proportion of people with HIV‑1 RNA 50 or more copies/ml at week 48 was 0.8% (95% CI -0.6 to 2.2). The pre-specified non-inferiority margin assigned to note the difference between the 2 interventions was 4%. The clinical experts were satisfied that cabotegravir with rilpivirine every 2 months is non-inferior to monthly cabotegravir with rilpivirine. The committee recognised that long-acting cabotegravir with rilpivirine is as effective when taken every 2 months compared with when taken every 1 month.
## An indirect treatment comparison is appropriate in the absence of head-to-head trial data
The company submitted an indirect treatment comparison (ITC) of long-acting cabotegravir with rilpivirine every 2 months compared with oral ARTs. The ERG stated that the lack of a head-to-head comparison restricts the comparability of the 2 interventions. The company agreed with the ERG in that an ITC cannot replace evidence from head-to-head studies but explained that there are no head-to-head trials of cabotegravir with rilpivirine every 2 months and oral ARTs. A stakeholder at technical engagement said that the efficacy of cabotegravir with rilpivirine every 1 month is already established as being non-inferior to oral ARTs, so it is uncertain if a direct comparison would add value. The committee concluded that there is no direct evidence comparing long-acting cabotegravir with rilpivirine every 2 months with oral ARTs, so an ITC was appropriate.
## Results of indirect treatment comparisons using pooled data and meta-analysed data are similar
The company combined results from ATLAS and FLAIR in a pre-specified pooled analysis and used the pooled results in an ITC. The outcomes included in the company's ITC were the relative risk of having more than 50 HIV RNA copies/ml, the relative risk of having fewer than 50 HIV RNA copies/ml, and the relative risk of having an adverse event leading to stopping treatment. The relative risk of having more than 50 HIV RNA copies/ml with cabotegravir and rilpivirine compared with oral antiretroviral treatments was 1.10 (95% CI 0.25 to 4.90). The relative risk of having fewer than 50 HIV RNA copies/ml was 1.01 (95% CI 0.95 to 1.06). The ERG considered there to be substantial differences between the ATLAS and FLAIR studies and explained that the studies should have been meta-analysed rather than pooled. After technical engagement, the company submitted results of an ITC in which the ATLAS and FLAIR data had been combined in a meta-analysis, then used in an ITC. The relative risks of having a viral load of fewer than 50 copies/ml and more than 50 copies/ml were very similar across the ITC using the meta-analysed ATLAS and FLAIR data and the analysis using the pooled data. However, the ERG highlighted that the relative risk of having an adverse event leading to stopping treatment was higher with cabotegravir and rilpivirine compared with oral ART in the non-pooled data analysis. The committee concluded that the results of the ITCs using pooled data and meta-analysed data are similar.
## The ERG disagrees with the company's interpretation of non-inferiority for the ITC, but this has no implications for cost-effectiveness results
The company considered that cabotegravir and rilpivirine every 2 months is non-inferior to current ARTs. However, the ERG noted that the ITC was imprecise and not designed as a non-inferiority analysis with defined non-inferiority margins, and non-significance cannot be interpreted as non-inferiority. The ERG's interpretation of the ITC results was that there is no evidence that cabotegravir with rilpivirine every 2 months is inferior to current ART, and it is uncertain whether cabotegravir with rilpivirine every 2 months is non-inferior to current ART. However, the ERG clarified that this issue relates only to the wording and interpretation, rather than the estimation of results, so there would be no effect on the cost-effectiveness results. The company claimed that guidance on the interpretation of non-inferiority within the context of ITC methodology is still under development and that there is no single accepted method. Furthermore, the company stated that the conclusions on comparative effectiveness had been interpreted correctly in the context of HIV regimens and the basis for their efficacy. The committee concluded that the ERG disagreed with the company's interpretation of non-inferiority, but that this has no implications for the cost-effectiveness results.
## Cabotegravir with rilpivirine is generally well tolerated in clinical trials, but is associated with injection site reactions
The most commonly reported adverse events in ATLAS‑2M for long-acting cabotegravir with rilpivirine were injection site pain, injection site nodule and induration. Most people with injection site reactions reported them as being mostly mild (grade 1 or 2). The median duration for injection site reactions was 3 days, but in some cases, they lasted more than 14 days (monthly 6% and bi‑monthly 4%). In this trial, drug-related adverse events leading to withdrawal were slightly higher in the monthly arm (11%) than in the bi‑monthly arm (8%). In the pooled ATLAS and FLAIR analysis, the findings showed that adverse events were more prevalent in people who had monthly injections of cabotegravir and rilpivirine than in people who had oral ARTs (86% and 75%, respectively). The most frequently reported adverse event related to cabotegravir with rilpivirine was injection site pain (pooled ATLAS and FLAIR, monthly injections 76%). The rate of adverse events leading to withdrawal from treatment in ATLAS and FLAIR (pooled) was similar for cabotegravir with rilpivirine and oral ARTs (3% and 2%, respectively). The committee concluded that cabotegravir with rilpivirine was generally well tolerated in the clinical trials but is associated with injection site reactions.
# Cost-effectiveness analysis
## The company's model is acceptable for decision making
The company presented a hybrid Markov state-transition model with a decision tree process. The model used clinical data from ATLAS‑2M for virological response (HIV RNA fewer than 50 copies/ml) and immunological response (increase in CD4+ cell count) for both cabotegravir with rilpivirine and oral ART. In the model, people with HIV were at risk of experiencing treatment failure, reaching or maintaining virological suppression, or having an adverse event that could lead to viral resistance or withdrawal from therapy. It also included an internal decision tree process that differentiated between individuals who stopped treatment because of virological reasons and those who stopped for non-virological reasons. The treatment switching process was allocated by the model's decision tree. This informed the overall cohort results once individuals had transitioned through the appropriate subsequent treatments. Clinical efficacy was driven by virological response (HIV RNA fewer than 50 copies/ml), immunological response (increase in CD4+ cell count) and whether there was a change in therapy line use or resistance development. The company assumed there was no difference in efficacy between cabotegravir and rilpivirine and oral antiretroviral therapy, but assumed differences in adherence and utility values between the treatments. In the model, the adherence input affected viral suppression, which then affected the monthly probability of viral rebound. The impact of reduced adherence translated into experiencing a higher probability of viral rebound and switching to a different treatment each month. The committee noted that the company's model structure appropriately represented the natural history of the disease. But, it was concerned that if the assumptions about the consequences of non-adherence were not appropriate, the benefit of cabotegravir with rilpivirine may have been overestimated (see section 3.16). The committee concluded that the structure of the model was acceptable for decision making.
## The model should not include a reduction in adherence for oral antiretroviral therapy
In its original base case, the company assumed that 25.6% of people do not adhere to treatment with oral ARTs. It explained that this value was obtained from the SWEET study. The company updated this assumption to 17.85% after technical engagement because this is a mid-point value between the company's original value and the ERG's preferred estimate of 10.1%. The ERG obtained its estimate from Sherr et al. (2010). The ERG explained that a range of 87% to 93% for average lifetime adherence is plausible. Regarding adherence to long-acting cabotegravir with rilpivirine, the company used the adherence rate of 98% at 96 weeks from the ATLAS‑2M clinical trial. The company assumed that adherence to cabotegravir with rilpivirine would not differ in clinical practice to that seen in the trial setting. It explained that it is difficult to estimate adherence to HIV treatment regimens, especially because people's adherence varies through their lifetime. The clinical expert agreed with the company that it is difficult to calculate adherence, but suggested that viral suppression could be a reliable surrogate marker. The expert further explained that people in the UK have extremely high rates of virological suppression and that recent studies have shown that undetectable viral blood levels can be maintained even if adherence to oral ARTs is reduced to 75%. The clinical experts also noted that the company's analysis modelled a pessimistic adherence scenario for oral ART, compared with an optimistic scenario for cabotegravir with rilpivirine. The committee agreed it was problematic that the company had used randomised clinical trial data to inform the model adherence input for cabotegravir with rilpivirine but had assumed that oral ARTs would have lower rates of adherence than seen in the trials. The clinical experts highlighted that individuals who would take long-acting injectable ARTs could also experience difficulties adhering to it and that the consequences of not adhering may be worse. This is because long-acting injectable doses have a much longer gap in between administrations. Nevertheless, this was not captured in the company's model. The clinical experts explained that individuals who miss doses of injections are at higher risk of developing drug resistance and virological failure than people who miss a tablet. The committee also expressed concerns about the fact that differences in adherence assumptions drive differences in life years gained in the model. It considered it unrealistic that somebody would live longer if they have cabotegravir and rilpivirine injections compared with oral ART, especially given the high rates of treatment success with modern oral ART. The committee understood the difficulties with obtaining adherence inputs for the model, but considered it had not seen any evidence to convince it that there is a difference in adherence between cabotegravir with rilpivirine and oral ART. The committee concluded that the model should not include a reduction in adherence for oral ART compared with long-acting injectable ART.
## Modelling a linear relationship between adherence and risk of virological failure may not be appropriate
The company explained that, once it had obtained its estimate for the level of adherence, it used this in a direct linear regression equation from a published paper by Ross et al. (2015). From this formula, an adjustment factor was derived, which was then applied to the trial-reported viral suppression rate, thereby linking rates of adherence with rates of viral suppression in the model. The company confirmed that this approach means that there is a direct linear relationship between viral suppression and adherence in the model, and people begin to lose effect if they do not adhere perfectly to treatment. A clinical expert responded that a linear relationship between adherence and risk of virological failure does not happen in real life. They explained that in clinical practice, there is a threshold effect, which is getting progressively lower with modern treatments. However, the committee recalled that the model should not include a reduction in adherence for oral antiretrovirals compared with long-acting injectables (see section 3.16). It considered that updating the model to incorporate its preference for a threshold effect would be unlikely to affect decision making if the adherence reduction for oral antiretrovirals was removed. The committee concluded that modelling a linear relationship between adherence and risk of virological failure may not be appropriate.
## The company's approach to costing the grouped comparator is acceptable
The company used a simple average of the prices of the individual treatments to calculate the overall cost of the grouped comparator (see section 3.5 for a list of included treatments). For decision-making purposes, Commercial Medicines Unit prices were used to cost the comparators, which included a confidential discount and better reflected the cost incurred by the NHS than the list prices. When different regional prices were available for a comparator, 3 scenarios were considered to explore the uncertainty:
using a simple average of the prices across the regions
using the single lowest of the regional prices
using the single highest of the regional prices.These different pricing scenarios for the comparators were then used to calculate the average price for the grouped comparator. When deciding on the most appropriate regional pricing scenario, the committee considered variations in the availability and pricing of ARTs across regions in England. It had not seen evidence on antiretroviral therapy use within the different regions. For this reason, the committee decided that a simple average of the Commercial Medicines Unit prices across regions best reflected the price paid by the NHS in England. By contrast, the lowest and highest regional price scenarios would unlikely represent the true price paid by the NHS due to the regional variations. The committee queried whether the annual cost of the comparator (when using a simple average of the prices across the regions) was similar to the annual costs seen in the NHS. The clinical expert confirmed that the approximate annual cost of therapy used in the NHS was similar to the average price of the comparator when using a simple average of the prices across the regions (the prices are confidential so cannot be reported here). The committee considered that the company's approach to costing the comparator was appropriate, and the average of the regional Commercial Medicines Unit prices should be used. The committee concluded that the company's approach to costing the grouped comparator is acceptable.
## The assumption of a utility advantage for cabotegravir with rilpivirine is uncertain
The company's modelled health states were stratified by CD4+ cell count. The utility values defined by CD4+ cell count were retrieved from the literature. The company used published values from Kauf et al. (2008), which were derived from 5 open-label studies in 1,327 individuals who had treatment with oral ART. The company explained that it was unable to use utility values from the clinical trials for these health states because of the CD4+ cell stratification boundaries used in each health state. It also explained that it would not have been possible to collect health-related quality-of-life data for all the health-state categories in the model. The company clarified that SF‑12 health questionnaires were collected in the ATLAS and FLAIR clinical trials. Although these could not be used to estimate health-state utilities, it was possible to use them to estimate a difference in utility between cabotegravir with rilpivirine and oral ARTs. The company used mapping to generate SF‑6 data from SF‑12 data, then derived a utility advantage for cabotegravir with rilpivirine. The value is confidential so cannot be reported here. This was then applied to the health-state utility values in the economic model. The ERG added that the utility advantage in the model is applied continuously for as long as people are on the treatment and that although it is a small value, it has a large impact on the results. The committee expressed its concerns about the uncertainty around the utility gain, but it was conscious of the issues around stigma that might be reflected in the utility advantage presented. The committee recalled that some people with HIV have a negative experience with oral medication on a day-to-day basis. Individuals experience the psychological consequences of living in a society in which stigma-related issues are still prevalent, the fear of unwanted disclosure if their tablets are seen, and the burden of a constant reminder of their HIV status from their daily tablets. The committee considered that medication alone cannot reduce stigma associated with the disease but can help with the cognitive load of self-managing HIV. The committee concluded that there may be a utility advantage for cabotegravir with rilpivirine because it may be valued by people concerned about stigma and disclosure of their HIV status, and it reduces the burden of taking daily tablets. However, it also concluded that the company's modelled utility advantage is uncertain.
## Implementation issues may need to be considered by the NHS
The clinical experts explained that currently NHS services are not set up to offer treatment with an intramuscular long-acting antiretroviral drug, so are not ready to cope with the demand of increased visits. They emphasised that people would have to attend the clinics more frequently when having treatment with cabotegravir and rilpivirine than they would with oral ARTs. The community expert stressed that there are advantages and disadvantages associated with visiting the clinic more frequently, and that the increased number of visits with cabotegravir and rilpivirine should not be seen only as a negative. Visiting the clinic more often means there are more opportunities to signpost people to local support services. Clinical experts explained that costs of setting up additional clinics may need to be considered. They also explained there are other costs associated with cabotegravir with rilpivirine treatment. These include follow up for people who have missed appointments and providing people with oral bridging therapy to maintain viral suppression levels in the case of missed injections. The company suggested that the uptake of the new technology would not be immediate and that it would increase over several years, allowing time for its implementation. The committee understood that the company's model included the costs for an assumed 15 minutes for a nurse to administer the 2 intramuscular injections, but did not include any other implementation or administration costs. The committee recalled that the company offered support with the implementation of this technology in clinics, but the extent of that resource was unclear. The committee considered that the NHS may need to consider implementation issues, including whether its services need to be adapted to ensure cabotegravir and rilpivirine can be administered. However, it concluded that it had not seen any evidence to suggest that the time needed for the NHS to comply with the recommendations should be amended.
# Cost-effectiveness results
## Cabotegravir with rilpivirine is likely to be a cost-effective use of NHS resources
NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee agreed that an acceptable ICER would be towards the higher end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) because of the unmet need for an alternative to daily tablets and stigma-related issues. Because of confidential commercial arrangements for cabotegravir with rilpivirine and comparator treatments, the exact cost-effectiveness results cannot be reported here. In the company's base case, which assumed a 17.85% reduction in adherence for oral ART, the cost-effectiveness estimate for cabotegravir with rilpivirine compared with oral ART for HIV‑1 was within what NICE normally considers an acceptable use of NHS resources. However, the committee would have preferred to see an analysis with a 0% reduction in adherence for oral ART (see section 3.16). When the committee's preferred non-adherence assumption of 0% was applied, the cost-effectiveness estimate increased but remained below £30,000 per QALY gained. It concluded that its preferred ICER was in the range that could be considered cost-effective.
# Innovation
## The innovative quality of long-acting antiretroviral injections is taken into account in the cost effectiveness
The committee considered whether cabotegravir and rilpivirine could be considered innovative, and whether the company's economic analysis had captured all associated health-related benefits. The committee was aware that cabotegravir with rilpivirine is the first long-acting antiretroviral injectable available for people with HIV and agreed with the company that there is an unmet need for an alternative to current oral ARTs. The committee considered that the dosing frequency and method of administration had been captured by the utility benefit associated with treatment. It concluded that it had taken this innovative quality into account when considering the cost effectiveness of long-acting cabotegravir and rilpivirine.
# Equalities
## HIV-1 disproportionately affects some populations, but this cannot be addressed in a technology appraisal
The committee noted potential equality issues raised during the NICE scoping and appraisal process. HIV‑1 disproportionately affects some populations such as gay, bisexual and trans people, people of black African family background, people from countries with a high community prevalence, people who are homeless, and people who inject drugs. The company confirmed that there is no evidence of a difference in the effect of cabotegravir with rilpivirine in any population with protected characteristics and the guidance would apply equally to all groups for whom there was evidence presented. Also, the committee noted that differences in incidence of a condition in different groups cannot be addressed in this technology appraisal.
## The committee took into account lifestyle factors that may affect people's ability to have treatment
At technical engagement, clinical and community groups noted that lifestyle factors may affect people's ability to attend clinics or adhere to their medication. People with chaotic lifestyles (for example people who are homeless, in prison, or who use drugs) may struggle to keep up with daily oral medication because it needs to be taken at the same time each day, with food, whereas long-acting injections may not suit people who cannot easily access their clinic for appointments. The committee was not presented with evidence relating to adherence for people with different lifestyle factors, but took this issue into account in its decision making.
## The committee took into account in its decision making that some people struggle to take oral treatments
The committee acknowledged that some people struggle to take their oral medication because of psychological or social reasons, and some people have difficulty swallowing or absorption issues. It was unclear whether this technology would benefit these people because the committee had not been presented with the necessary information about the current comparator treatments for this population to make a decision. However, the committee took this issue into account for its decision making.
## It is not possible to address needle phobia in this technology appraisal
The committee noted that even though this technology is a helpful alternative to current standard of care, it might not be suitable for individuals who have needle phobia. Needle phobia was not considered in the company's clinical- or cost-effectiveness evidence. The committee did not consider this to be an equalities issue and did not consider it possible to address needle phobia in this technology appraisal.
## The benefit of long-acting antiretrovirals for stigma related to taking daily tablets for HIV is included in the modelling
The committee was aware of the stigma associated with HIV. It acknowledged that long-acting antiretrovirals could remove the stigma-related concerns associated with daily tablets, for example the fear of unwanted disclosure if tablets are seen, and the burden of a constant reminder of HIV status (see section 3.2). However, the committee considered this benefit had been taken into account in the modelled utility advantage for cabotegravir with rilpivirine compared with oral ART (see section 3.19).
# Conclusion
## Cabotegravir with rilpivirine is recommended for routine commissioning
The committee recommended cabotegravir with rilpivirine, within its marketing authorisation, for treating HIV‑1 infection in adults with virological suppression (HIV‑1 RNA fewer than 50 copies/ml) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no previous virological failure with, any NNRTIs or INIs. The committee acknowledged that cabotegravir with rilpivirine meets an unmet need for people living with HIV‑1 by offering an alternative to daily oral regimens. There was uncertainty about the size of the utility advantage for cabotegravir with rilpivirine over daily oral ART. Despite this uncertainty, the committee considered that a utility advantage was plausible because cabotegravir with rilpivirine may be valued by people concerned about stigma and disclosure of their HIV status, and it reduces the burden of taking daily tablets (see section 3.19). The committee considered it was acceptable for the company to assume in its model that long-acting cabotegravir with rilpivirine and oral ARTs have the same efficacy. But it was not appropriate to assume that adherence is greater with cabotegravir with rilpivirine compared with oral ARTs. The committee acknowledged other factors including the innovative nature of cabotegravir with rilpivirine, the daily burden of taking tablets, the equalities issues raised (see section 3.23) and the negative impact that stigma has on the lives of people living with HIV. But it recalled that this was captured in the cost-effectiveness calculation (see section 3.19). Using the committee's preferred adherence assumption (see section 3.16), the most plausible ICER for cabotegravir and rilpivirine compared with oral ART was lower than £30,000 per QALY gained. The committee concluded that the cost-effectiveness estimates were unlikely to exceed its acceptable maximum even though some uncertainties remained. Taking all this into account, the committee concluded that cabotegravir with rilpivirine is likely to be a cost-effective use of NHS resources for treating HIV‑1, so it is recommended.
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{'Recommendations': 'Cabotegravir with rilpivirine is recommended, within its marketing authorisation, as an option for treating HIV‑1 infection in adults:\n\nwith virological suppression (HIV‑1 RNA fewer than 50\xa0copies/ml) on a stable antiretroviral regimen and\n\nwithout any evidence of viral resistance to, and no previous virological failure with, any non-nucleoside reverse transcriptase inhibitors or integrase inhibitors. It is recommended only if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nCurrent treatment for HIV‑1 is antiretroviral regimens taken as tablets (orally) each day. The aim is to keep the number of virus particles in the blood (the viral load) so low that it cannot be detected, so that the virus cannot be transmitted between people. Cabotegravir with rilpivirine is the first long-acting antiretroviral injection available for HIV‑1.\n\nClinical trial results show that cabotegravir with rilpivirine is as effective as oral antiretrovirals at keeping the viral load lower than 50\xa0copies/ml of blood. It is unclear whether there would be a difference in adherence between long-acting injections and daily oral tablets. The most likely cost-effectiveness estimate is likely to be within what NICE normally considers an acceptable use of NHS resources. So, cabotegravir with rilpivirine is recommended.', 'Information about cabotegravir with rilpivirine': "# Marketing authorisation indication\n\nCabotegravir (Vocabria, Viiv Healthcare) with rilpivirine (Rekambys, Janssen) is indicated 'for the treatment of HIV‑1 infection in adults who are virologically suppressed (HIV‑1 RNA fewer than 50\xa0copies/ml) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no prior virological failure with, agents of the NNRTI and INI class'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedules are available in the summary of product characteristics for cabotegravir and the summary of product characteristics for rilpivirine.\n\n# Price\n\nThe list price for cabotegravir is £638.57 for a 30‑day pack of oral tablets and £1,197.02 for the bi‑monthly (every 2\xa0months) intramuscular injection vial (excluding VAT). The list price for rilpivirine is £200.27 for a 30‑day pack of oral tablets and £440.47 for the bi‑monthly intramuscular injection vial (excluding VAT). The company has a commercial arrangement (simple discount patient access scheme). This makes cabotegravir with rilpivirine available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Viiv Healthcare, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that none of the issues were resolved after technical engagement. It recognised that there were remaining areas of uncertainty associated with the analyses presented (see ERG report, table\xa01.1, page\xa012) and took these into account in its decision making. It discussed issues\xa01\xa0to\xa010, which were outstanding after the technical engagement stage.\n\n# The condition\n\n## HIV is not curable and people living with it currently need to take daily medication for life\n\nThe committee heard from the clinical and community experts (alternative term for patient expert) that HIV is a retrovirus that attacks the human immune system, specifically macrophages and CD4+ T\xa0cells. The HIV‑1 subtype accounts for most infections worldwide and can be acquired through sexual contact, breastfeeding, broken skin, or injections using contaminated equipment or substances. People living with HIV‑1 that is untreated are at risk of their immune system gradually weakening, which can lead to opportunistic infections and cancers that further deteriorate their health. Despite scientific advances, HIV is still incurable, but the virus can be controlled by modern treatment. The current treatment regimens are oral antiretroviral therapies (ART) taken daily. There are several classes of antiretroviral agents that act on different phases of the HIV‑1 virus life cycle either by disrupting its ability to enter the human host cells or to multiply. The ARTs used in the NHS include the following classes of drugs:\n\nnucleoside reverse transcriptase inhibitors (NRTIs)\n\nnon-nucleoside reverse transcriptase inhibitors (NNRTIs)\n\nprotease inhibitors (PIs)\n\nfusion inhibitors\n\nintegrase inhibitors (INI or INSTIs)\n\nCCR5 antagonists.Therapy involves a combination of different agents, either as single- or multi-tablet regimens that must be taken every day for the rest of a person's life. The clinical experts told the committee that the aim is to suppress the virus to undetectable levels in the blood (defined as HIV‑1 RNA fewer than 50\xa0copies/ml) because then it becomes untransmissible. The clinical experts explained that treatment success with current daily oral treatments is mainly determined by adherence, which is influenced by drug side effects and psychosocial issues. They explained that although adherence is important, perfect adherence is not needed to have an undetectable viral load with modern treatments, and current therapy is highly effective. The community experts explained that adherence can be difficult in some cases because of drug-related side effects, toxicity, and other psychosocial issues such as stigma or changes in lifestyle. They also explained that a reduction in adherence might put people living with HIV‑1 at risk of developing viral rebound or resistance to antiretrovirals. The committee concluded that HIV‑1 is not curable and people living with it currently need to take daily medication for life.\n\n## Stigma remains an issue for people living with HIV, and can have a negative impact on people's health and relationships\n\nOne of the community experts said that because people need to take their medication for life, their daily tablets serve as a constant reminder of their HIV status. This reminder can be distressing for some people because it is linked to stigma and having HIV‑1. The expert expanded on the stigma around HIV; for some people it triggers the fear of having to disclose their status if people discover their tablets, which can easily happen when living in shared accommodation or taking medication in a public setting. The expert explained that the fear of unwanted disclosure happens constantly throughout people's lives. Stigma can present in various forms, including self-stigma based on negative self-beliefs, anticipated stigma when individuals expect negative treatment based on their HIV status, and discrimination. The community experts explained that although things have improved over the last decade, stigma is a key barrier to people with HIV living fulfilled and happy lives. The committee understood that people's friendships, trust in others and the quality of their relationships in every sphere of life has more effect than anything else on mental health, physical health and how long we live. For this reason, stigma has a negative impact on personal, social, occupational and healthcare relationships. Furthermore, the community experts explained that stigma can sometimes affect adherence to oral regimens because individuals may miss a dose if they do not feel comfortable taking their medication in front of other people. The committee acknowledged these difficulties and concluded that stigma remains an issue for people living with HIV and can have a negative impact on people's health and relationships.\n\n# New treatment option\n\n## Cabotegravir with rilpivirine would be beneficial for people who find daily tablets challenging or who would prefer an injectable regimen\n\nLong-acting cabotegravir and long-acting rilpivirine (referred to as 'cabotegravir with rilpivirine' from here onwards) is administered as 2\xa0separate intramuscular injections. The dosing regimen starts with a 28‑day oral lead‑in, followed by monthly injections for 2\xa0months. Thereafter, injections are given every 2\xa0months. Cabotegravir is an INSTI and rilpivirine is an NNRTI. The company explained that it is intended to be a new alternative treatment option instead of daily oral ARTs. The clinical experts explained that, even though cabotegravir with rilpivirine has a lower frequency of dosing, people would need to visit an HIV clinic more often than with current oral ARTs because it is administered in the clinic. The clinical and community experts stated that cabotegravir with rilpivirine could be an effective alternative when treatment adherence to a daily oral regimen is affected either by side effects, when oral intake is impaired, or when lifestyle interferes with following a daily regimen. This is particularly important because people with HIV‑1 need to maintain their medication regimen to prevent viral rebound or developing resistance to ART. The community experts stressed that there is a huge appetite for an injectable treatment because taking tablets every day can be challenging. The committee noted that to be eligible for cabotegravir with rilpivirine, people must already have virological suppression on a stable antiretroviral regimen, so it may not be appropriate for people who have poor adherence. The company explained that long-acting treatments have improved adherence in other disease areas, so it is plausible that this would also be true for HIV. It considered that cabotegravir with rilpivirine would be particularly valuable for people with good levels of adherence but who might struggle to maintain this over time. The committee concluded that cabotegravir with rilpivirine would be a valuable treatment option for people who have adequate levels of adherence but who find daily tablets challenging or who would prefer an injectable regimen.\n\n# Comparators\n\n## Choice of oral ART depends on regional availability and individual need\n\nThere is currently no NICE technology appraisal guidance on treating HIV. NHS England's guide on best practice in HIV prescribing and multidisciplinary teams provides support to clinicians in treating HIV and managing multidisciplinary team discussions. It aims to provide access to antiretroviral therapy to anyone living with HIV, promote informed choice, help with shared decision making, and support therapy. The clinical expert explained that the clinical management of the condition is led by standard principles. The expert said that people living with HIV‑1 have treatment at commissioned hospitals with specialist HIV clinics. In these clinics, people are given an antiretroviral regimen and are regularly seen until their HIV‑1 is stable on a treatment routine. Once the viral load is suppressed, people would normally visit the HIV clinic 2\xa0or\xa03\xa0times per year for a routine follow up. The clinical and commissioning experts added that there is regional variation in antiretroviral prescribing, and that there are different prices for each drug in each region. Consequently, prescribing depends on individual need, and regional cost and availability. The committee concluded that the choice of oral ART depends on regional availability and individual need.\n\n## The company included relevant oral antiretroviral therapies\n\nThe comparator in the scope was 'antiretroviral treatment (established clinical management such as integrase inhibitors)'. The company chose the oral ARTs that most people living with HIV‑1 switch to when they have virological suppression, because these would be the treatments used by the people who could potentially use cabotegravir with rilpivirine. It considered these treatments as a group (sometimes referred to as a 'basket' comparator) rather than comparing cabotegravir and rilpivirine with each oral antiretroviral individually. Given the variability in ART used across the country, the committee considered this approach to be appropriate, because the oral ARTs are all considered similar in efficacy (see section\xa03.6). The regimens included in the company's comparator group were:\n\nemtricitabine with tenofovir alafenamide plus dolutegravir\n\nemtricitabine with tenofovir alafenamide plus raltegravir\n\nabacavir, dolutegravir and lamivudine\n\ndolutegravir with lamivudine\n\ndolutegravir with rilpivirine\n\nbictegravir, emtricitabine and tenofovir alafenamide\n\ndoravirine, lamivudine and tenofovir disoproxil fumarate\n\ndarunavir, cobicistat, emtricitabine and tenofovir alafenamide\n\nemtricitabine, rilpivirine and tenofovir alafenamide.The company explained that it selected these treatments based on treatment switches captured by market data. The clinical experts confirmed that these treatments are normally used in NHS practice for people who have virological suppression and need to switch treatment for non-virological reasons, and therefore it was appropriate for the company to include them. However, a clinical expert was concerned that dolutegravir plus tenofovir and emtricitabine was excluded, because it is widely prescribed. In its submission, the company explained that people normally switch away from this treatment because of toxicity concerns. The committee concluded that the oral ARTs included in the group of comparators were relevant.\n\n## All oral antiretroviral therapies have similar efficacy\n\nThe company assumed that all oral ART regimens have similar efficacy. It explained that the large number of non-inferiority studies available on this subject supports this, and that this assumption was confirmed by a clinical expert. Also, the company's pivotal trials used 2\xa0NRTIs and an INSTI plus an NNRTI or PI (ATLAS), and an NRTI, INSTI and an NRTI (FLAIR), so it considered the treatment efficacy to be generalisable to the NHS. The ERG was satisfied that, given the very high efficacy of current oral ARTs, the company's assumption that they all have similar efficacy was appropriate. There was a general agreement among the clinical experts that all oral ARTs have similar efficacy. The committee concluded that all oral ARTs have similar efficacy.\n\n# Clinical effectiveness\n\n## It is unlikely that including case control studies in the company's systematic review would affect the cost-effectiveness results\n\nThe company did a systematic review to identify literature on clinical effectiveness and safety outcomes. The company included evidence from randomised control trials and excluded case-control studies. The ERG was concerned that relevant data might have been missed by excluding case-control studies. The company stated that given the high volumes of literature on HIV, priority was given to randomised controlled trials, which are the gold standard in the evidence hierarchy. The company also stressed that including case-control studies would not have led to a different conclusion. The clinical experts agreed with the company and expressed no concerns, because the available evidence came from randomised controlled trials. The ERG explained that it had other concerns about the company's search strategy, including language and date limits, and search sensitivity. It would have preferred searches specifically for safety data but agreed that given the large amount of HIV literature about safety, it is unlikely that anything new would have been identified. The committee considered there to be minor limitations associated with the company's systematic review, but it was unlikely that important studies were missed. The committee concluded that it is unlikely that including case-control studies would have affected the cost-effectiveness results.\n\n## The comparator ARTs in the ATLAS and FLAIR clinical trials are generalisable to the NHS\n\nThe company's key clinical evidence for long-acting cabotegravir with rilpivirine came from ATLAS, FLAIR and ATLAS‑2M. These were phase\xa03 randomised, controlled, open-label, non-inferiority trials in people living with HIV‑1. ATLAS and FLAIR compared monthly cabotegravir and rilpivirine with daily oral ARTs. ATLAS included 618\xa0adults who had virological suppression on a stable regimen containing 2\xa0NRTIs plus an INSTI, an NNRTI or a PI for at least 6\xa0months. The comparator in ATLAS was 2\xa0NRTIs plus an INSTI, 2\xa0NRTIs plus a PI, or 2\xa0NRTIs plus an NNRTI. FLAIR included 566\xa0adults who had no previous experience of ART. There was a 20‑week induction with current oral ART (abacavir /dolutegravir/lamivudine), then people were randomised to have monthly cabotegravir with rilpivirine or continue the induction regimen. The ERG noted that the oral ARTs used in the comparator arms of ATLAS and FLAIR may not be fully representative of the drugs normally used in the NHS in England. The company explained that the regimens used as comparators in ATLAS and FLAIR are considered to have comparable efficacy to currently used regimens in the NHS. It supported this by explaining that non-inferiority trials are the norm for ART in HIV (see section\xa03.6). To further support its assumption of generalisability to the NHS, the company submitted information about how the components used in the ATLAS oral ART arm were similar to drugs prescribed in the UK. The company had consulted an expert who stated that he had no reservations about the generalisability of the results of the company's trials to the NHS. At technical engagement, a representative from a professional organisation explained that most individuals would take an NRTI with either an NNRTI, INSTI or PI. This was similar to the comparator arm of ATLAS (in ATLAS, people in the comparator arm took 2\xa0NRTIs plus an INSTI and an NNRTI or a PI). The committee concluded that the comparator ARTs in the ATLAS and FLAIR clinical trials are generalisable to the NHS.\n\n## Long-acting cabotegravir with rilpivirine is non-inferior to oral ARTs\n\nATLAS and FLAIR aimed to show non-inferiority to oral ARTs with a pre-specified non-inferiority margin of 4%. The primary outcome in both trials was the proportion of people with HIV‑1 RNA 50\xa0or more copies/ml at week\xa048. The company presented results from a pre-specified pooled analysis of ATLAS and FLAIR, explaining that the trials had similar designs. The primary end point was met in this pooled analysis, with 11\xa0of 591\xa0people (1.9%) in the monthly cabotegravir with rilpivirine arm, and 10\xa0of 591\xa0people in the oral ART arm, with HIV‑1 RNA 50\xa0or more copies/ml at week\xa048. The adjusted difference in the proportion of people with HIV‑1 RNA 50\xa0or more copies/ml at week\xa048 was 0.16% (95% confidence interval [CI] -1.35 to -1.67). The clinical experts confirmed that cabotegravir with rilpivirine is considered similar in effectiveness to the current oral ARTs. The committee concluded that long-acting cabotegravir with rilpivirine is non-inferior to oral ARTs.\n\n## Long-acting cabotegravir with rilpivirine is as effective when taken every 2\xa0months compared with when taken every 1\xa0month\n\nThe ATLAS‑2M clinical trial aimed to show that cabotegravir with rilpivirine every 2\xa0months is non-inferior to cabotegravir with rilpivirine every 1\xa0month. The trial included 1,020\xa0adults who had virological suppression. People were randomised to have long-acting cabotegravir with rilpivirine either monthly or bi‑monthly (every 2\xa0months) for 100\xa0weeks. About half of the people enrolled were from the ongoing ATLAS study and the rest were new. The primary outcome was met at week\xa048. The results showed that 5 of 523 (1.0%) in the monthly cabotegravir with rilpivirine arm, and 9 of 522 (1.7%) in the bi‑monthly arm had HIV‑1 RNA 50\xa0or more copies/ml at week\xa048. The adjusted difference in the proportion of people with HIV‑1 RNA 50\xa0or more copies/ml at week\xa048 was 0.8% (95% CI -0.6 to 2.2). The pre-specified non-inferiority margin assigned to note the difference between the 2\xa0interventions was 4%. The clinical experts were satisfied that cabotegravir with rilpivirine every 2\xa0months is non-inferior to monthly cabotegravir with rilpivirine. The committee recognised that long-acting cabotegravir with rilpivirine is as effective when taken every 2\xa0months compared with when taken every 1\xa0month.\n\n## An indirect treatment comparison is appropriate in the absence of head-to-head trial data\n\nThe company submitted an indirect treatment comparison (ITC) of long-acting cabotegravir with rilpivirine every 2\xa0months compared with oral ARTs. The ERG stated that the lack of a head-to-head comparison restricts the comparability of the 2\xa0interventions. The company agreed with the ERG in that an ITC cannot replace evidence from head-to-head studies but explained that there are no head-to-head trials of cabotegravir with rilpivirine every 2\xa0months and oral ARTs. A stakeholder at technical engagement said that the efficacy of cabotegravir with rilpivirine every 1\xa0month is already established as being non-inferior to oral ARTs, so it is uncertain if a direct comparison would add value. The committee concluded that there is no direct evidence comparing long-acting cabotegravir with rilpivirine every 2\xa0months with oral ARTs, so an ITC was appropriate.\n\n## Results of indirect treatment comparisons using pooled data and meta-analysed data are similar\n\nThe company combined results from ATLAS and FLAIR in a pre-specified pooled analysis and used the pooled results in an ITC. The outcomes included in the company's ITC were the relative risk of having more than 50\xa0HIV RNA copies/ml, the relative risk of having fewer than 50\xa0HIV RNA copies/ml, and the relative risk of having an adverse event leading to stopping treatment. The relative risk of having more than 50\xa0HIV RNA copies/ml with cabotegravir and rilpivirine compared with oral antiretroviral treatments was 1.10 (95% CI 0.25 to 4.90). The relative risk of having fewer than 50\xa0HIV RNA copies/ml was 1.01 (95% CI 0.95 to 1.06). The ERG considered there to be substantial differences between the ATLAS and FLAIR studies and explained that the studies should have been meta-analysed rather than pooled. After technical engagement, the company submitted results of an ITC in which the ATLAS and FLAIR data had been combined in a meta-analysis, then used in an ITC. The relative risks of having a viral load of fewer than 50\xa0copies/ml and more than 50\xa0copies/ml were very similar across the ITC using the meta-analysed ATLAS and FLAIR data and the analysis using the pooled data. However, the ERG highlighted that the relative risk of having an adverse event leading to stopping treatment was higher with cabotegravir and rilpivirine compared with oral ART in the non-pooled data analysis. The committee concluded that the results of the ITCs using pooled data and meta-analysed data are similar.\n\n## The ERG disagrees with the company's interpretation of non-inferiority for the ITC, but this has no implications for cost-effectiveness results\n\nThe company considered that cabotegravir and rilpivirine every 2\xa0months is non-inferior to current ARTs. However, the ERG noted that the ITC was imprecise and not designed as a non-inferiority analysis with defined non-inferiority margins, and non-significance cannot be interpreted as non-inferiority. The ERG's interpretation of the ITC results was that there is no evidence that cabotegravir with rilpivirine every 2\xa0months is inferior to current ART, and it is uncertain whether cabotegravir with rilpivirine every 2\xa0months is non-inferior to current ART. However, the ERG clarified that this issue relates only to the wording and interpretation, rather than the estimation of results, so there would be no effect on the cost-effectiveness results. The company claimed that guidance on the interpretation of non-inferiority within the context of ITC methodology is still under development and that there is no single accepted method. Furthermore, the company stated that the conclusions on comparative effectiveness had been interpreted correctly in the context of HIV regimens and the basis for their efficacy. The committee concluded that the ERG disagreed with the company's interpretation of non-inferiority, but that this has no implications for the cost-effectiveness results.\n\n## Cabotegravir with rilpivirine is generally well tolerated in clinical trials, but is associated with injection site reactions\n\nThe most commonly reported adverse events in ATLAS‑2M for long-acting cabotegravir with rilpivirine were injection site pain, injection site nodule and induration. Most people with injection site reactions reported them as being mostly mild (grade\xa01 or\xa02). The median duration for injection site reactions was 3\xa0days, but in some cases, they lasted more than 14\xa0days (monthly 6% and bi‑monthly 4%). In this trial, drug-related adverse events leading to withdrawal were slightly higher in the monthly arm (11%) than in the bi‑monthly arm (8%). In the pooled ATLAS and FLAIR analysis, the findings showed that adverse events were more prevalent in people who had monthly injections of cabotegravir and rilpivirine than in people who had oral ARTs (86% and 75%, respectively). The most frequently reported adverse event related to cabotegravir with rilpivirine was injection site pain (pooled ATLAS and FLAIR, monthly injections 76%). The rate of adverse events leading to withdrawal from treatment in ATLAS and FLAIR (pooled) was similar for cabotegravir with rilpivirine and oral ARTs (3% and 2%, respectively). The committee concluded that cabotegravir with rilpivirine was generally well tolerated in the clinical trials but is associated with injection site reactions.\n\n# Cost-effectiveness analysis\n\n## The company's model is acceptable for decision making\n\nThe company presented a hybrid Markov state-transition model with a decision tree process. The model used clinical data from ATLAS‑2M for virological response (HIV RNA fewer than 50\xa0copies/ml) and immunological response (increase in CD4+ cell count) for both cabotegravir with rilpivirine and oral ART. In the model, people with HIV were at risk of experiencing treatment failure, reaching or maintaining virological suppression, or having an adverse event that could lead to viral resistance or withdrawal from therapy. It also included an internal decision tree process that differentiated between individuals who stopped treatment because of virological reasons and those who stopped for non-virological reasons. The treatment switching process was allocated by the model's decision tree. This informed the overall cohort results once individuals had transitioned through the appropriate subsequent treatments. Clinical efficacy was driven by virological response (HIV RNA fewer than 50\xa0copies/ml), immunological response (increase in CD4+ cell count) and whether there was a change in therapy line use or resistance development. The company assumed there was no difference in efficacy between cabotegravir and rilpivirine and oral antiretroviral therapy, but assumed differences in adherence and utility values between the treatments. In the model, the adherence input affected viral suppression, which then affected the monthly probability of viral rebound. The impact of reduced adherence translated into experiencing a higher probability of viral rebound and switching to a different treatment each month. The committee noted that the company's model structure appropriately represented the natural history of the disease. But, it was concerned that if the assumptions about the consequences of non-adherence were not appropriate, the benefit of cabotegravir with rilpivirine may have been overestimated (see section\xa03.16). The committee concluded that the structure of the model was acceptable for decision making.\n\n## The model should not include a reduction in adherence for oral antiretroviral therapy\n\nIn its original base case, the company assumed that 25.6% of people do not adhere to treatment with oral ARTs. It explained that this value was obtained from the SWEET study. The company updated this assumption to 17.85% after technical engagement because this is a mid-point value between the company's original value and the ERG's preferred estimate of 10.1%. The ERG obtained its estimate from Sherr et al. (2010). The ERG explained that a range of 87% to 93% for average lifetime adherence is plausible. Regarding adherence to long-acting cabotegravir with rilpivirine, the company used the adherence rate of 98% at 96\xa0weeks from the ATLAS‑2M clinical trial. The company assumed that adherence to cabotegravir with rilpivirine would not differ in clinical practice to that seen in the trial setting. It explained that it is difficult to estimate adherence to HIV treatment regimens, especially because people's adherence varies through their lifetime. The clinical expert agreed with the company that it is difficult to calculate adherence, but suggested that viral suppression could be a reliable surrogate marker. The expert further explained that people in the UK have extremely high rates of virological suppression and that recent studies have shown that undetectable viral blood levels can be maintained even if adherence to oral ARTs is reduced to 75%. The clinical experts also noted that the company's analysis modelled a pessimistic adherence scenario for oral ART, compared with an optimistic scenario for cabotegravir with rilpivirine. The committee agreed it was problematic that the company had used randomised clinical trial data to inform the model adherence input for cabotegravir with rilpivirine but had assumed that oral ARTs would have lower rates of adherence than seen in the trials. The clinical experts highlighted that individuals who would take long-acting injectable ARTs could also experience difficulties adhering to it and that the consequences of not adhering may be worse. This is because long-acting injectable doses have a much longer gap in between administrations. Nevertheless, this was not captured in the company's model. The clinical experts explained that individuals who miss doses of injections are at higher risk of developing drug resistance and virological failure than people who miss a tablet. The committee also expressed concerns about the fact that differences in adherence assumptions drive differences in life years gained in the model. It considered it unrealistic that somebody would live longer if they have cabotegravir and rilpivirine injections compared with oral ART, especially given the high rates of treatment success with modern oral ART. The committee understood the difficulties with obtaining adherence inputs for the model, but considered it had not seen any evidence to convince it that there is a difference in adherence between cabotegravir with rilpivirine and oral ART. The committee concluded that the model should not include a reduction in adherence for oral ART compared with long-acting injectable ART.\n\n## Modelling a linear relationship between adherence and risk of virological failure may not be appropriate\n\nThe company explained that, once it had obtained its estimate for the level of adherence, it used this in a direct linear regression equation from a published paper by Ross et al. (2015). From this formula, an adjustment factor was derived, which was then applied to the trial-reported viral suppression rate, thereby linking rates of adherence with rates of viral suppression in the model. The company confirmed that this approach means that there is a direct linear relationship between viral suppression and adherence in the model, and people begin to lose effect if they do not adhere perfectly to treatment. A clinical expert responded that a linear relationship between adherence and risk of virological failure does not happen in real life. They explained that in clinical practice, there is a threshold effect, which is getting progressively lower with modern treatments. However, the committee recalled that the model should not include a reduction in adherence for oral antiretrovirals compared with long-acting injectables (see section\xa03.16). It considered that updating the model to incorporate its preference for a threshold effect would be unlikely to affect decision making if the adherence reduction for oral antiretrovirals was removed. The committee concluded that modelling a linear relationship between adherence and risk of virological failure may not be appropriate.\n\n## The company's approach to costing the grouped comparator is acceptable\n\nThe company used a simple average of the prices of the individual treatments to calculate the overall cost of the grouped comparator (see section\xa03.5 for a list of included treatments). For decision-making purposes, Commercial Medicines Unit prices were used to cost the comparators, which included a confidential discount and better reflected the cost incurred by the NHS than the list prices. When different regional prices were available for a comparator, 3\xa0scenarios were considered to explore the uncertainty:\n\nusing a simple average of the prices across the regions\n\nusing the single lowest of the regional prices\n\nusing the single highest of the regional prices.These different pricing scenarios for the comparators were then used to calculate the average price for the grouped comparator. When deciding on the most appropriate regional pricing scenario, the committee considered variations in the availability and pricing of ARTs across regions in England. It had not seen evidence on antiretroviral therapy use within the different regions. For this reason, the committee decided that a simple average of the Commercial Medicines Unit prices across regions best reflected the price paid by the NHS in England. By contrast, the lowest and highest regional price scenarios would unlikely represent the true price paid by the NHS due to the regional variations. The committee queried whether the annual cost of the comparator (when using a simple average of the prices across the regions) was similar to the annual costs seen in the NHS. The clinical expert confirmed that the approximate annual cost of therapy used in the NHS was similar to the average price of the comparator when using a simple average of the prices across the regions (the prices are confidential so cannot be reported here). The committee considered that the company's approach to costing the comparator was appropriate, and the average of the regional Commercial Medicines Unit prices should be used. The committee concluded that the company's approach to costing the grouped comparator is acceptable.\n\n## The assumption of a utility advantage for cabotegravir with rilpivirine is uncertain\n\nThe company's modelled health states were stratified by CD4+ cell count. The utility values defined by CD4+ cell count were retrieved from the literature. The company used published values from Kauf et al. (2008), which were derived from 5\xa0open-label studies in 1,327\xa0individuals who had treatment with oral ART. The company explained that it was unable to use utility values from the clinical trials for these health states because of the CD4+ cell stratification boundaries used in each health state. It also explained that it would not have been possible to collect health-related quality-of-life data for all the health-state categories in the model. The company clarified that SF‑12 health questionnaires were collected in the ATLAS and FLAIR clinical trials. Although these could not be used to estimate health-state utilities, it was possible to use them to estimate a difference in utility between cabotegravir with rilpivirine and oral ARTs. The company used mapping to generate SF‑6 data from SF‑12 data, then derived a utility advantage for cabotegravir with rilpivirine. The value is confidential so cannot be reported here. This was then applied to the health-state utility values in the economic model. The ERG added that the utility advantage in the model is applied continuously for as long as people are on the treatment and that although it is a small value, it has a large impact on the results. The committee expressed its concerns about the uncertainty around the utility gain, but it was conscious of the issues around stigma that might be reflected in the utility advantage presented. The committee recalled that some people with HIV have a negative experience with oral medication on a day-to-day basis. Individuals experience the psychological consequences of living in a society in which stigma-related issues are still prevalent, the fear of unwanted disclosure if their tablets are seen, and the burden of a constant reminder of their HIV status from their daily tablets. The committee considered that medication alone cannot reduce stigma associated with the disease but can help with the cognitive load of self-managing HIV. The committee concluded that there may be a utility advantage for cabotegravir with rilpivirine because it may be valued by people concerned about stigma and disclosure of their HIV status, and it reduces the burden of taking daily tablets. However, it also concluded that the company's modelled utility advantage is uncertain.\n\n## Implementation issues may need to be considered by the NHS\n\nThe clinical experts explained that currently NHS services are not set up to offer treatment with an intramuscular long-acting antiretroviral drug, so are not ready to cope with the demand of increased visits. They emphasised that people would have to attend the clinics more frequently when having treatment with cabotegravir and rilpivirine than they would with oral ARTs. The community expert stressed that there are advantages and disadvantages associated with visiting the clinic more frequently, and that the increased number of visits with cabotegravir and rilpivirine should not be seen only as a negative. Visiting the clinic more often means there are more opportunities to signpost people to local support services. Clinical experts explained that costs of setting up additional clinics may need to be considered. They also explained there are other costs associated with cabotegravir with rilpivirine treatment. These include follow up for people who have missed appointments and providing people with oral bridging therapy to maintain viral suppression levels in the case of missed injections. The company suggested that the uptake of the new technology would not be immediate and that it would increase over several years, allowing time for its implementation. The committee understood that the company's model included the costs for an assumed 15\xa0minutes for a nurse to administer the 2\xa0intramuscular injections, but did not include any other implementation or administration costs. The committee recalled that the company offered support with the implementation of this technology in clinics, but the extent of that resource was unclear. The committee considered that the NHS may need to consider implementation issues, including whether its services need to be adapted to ensure cabotegravir and rilpivirine can be administered. However, it concluded that it had not seen any evidence to suggest that the time needed for the NHS to comply with the recommendations should be amended.\n\n# Cost-effectiveness results\n\n## Cabotegravir with rilpivirine is likely to be a cost-effective use of NHS resources\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee agreed that an acceptable ICER would be towards the higher end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) because of the unmet need for an alternative to daily tablets and stigma-related issues. Because of confidential commercial arrangements for cabotegravir with rilpivirine and comparator treatments, the exact cost-effectiveness results cannot be reported here. In the company's base case, which assumed a 17.85% reduction in adherence for oral ART, the cost-effectiveness estimate for cabotegravir with rilpivirine compared with oral ART for HIV‑1 was within what NICE normally considers an acceptable use of NHS resources. However, the committee would have preferred to see an analysis with a 0% reduction in adherence for oral ART (see section\xa03.16). When the committee's preferred non-adherence assumption of 0% was applied, the cost-effectiveness estimate increased but remained below £30,000 per QALY gained. It concluded that its preferred ICER was in the range that could be considered cost-effective.\n\n# Innovation\n\n## The innovative quality of long-acting antiretroviral injections is taken into account in the cost effectiveness\n\nThe committee considered whether cabotegravir and rilpivirine could be considered innovative, and whether the company's economic analysis had captured all associated health-related benefits. The committee was aware that cabotegravir with rilpivirine is the first long-acting antiretroviral injectable available for people with HIV and agreed with the company that there is an unmet need for an alternative to current oral ARTs. The committee considered that the dosing frequency and method of administration had been captured by the utility benefit associated with treatment. It concluded that it had taken this innovative quality into account when considering the cost effectiveness of long-acting cabotegravir and rilpivirine.\n\n# Equalities\n\n## HIV-1 disproportionately affects some populations, but this cannot be addressed in a technology appraisal\n\nThe committee noted potential equality issues raised during the NICE scoping and appraisal process. HIV‑1 disproportionately affects some populations such as gay, bisexual and trans people, people of black African family background, people from countries with a high community prevalence, people who are homeless, and people who inject drugs. The company confirmed that there is no evidence of a difference in the effect of cabotegravir with rilpivirine in any population with protected characteristics and the guidance would apply equally to all groups for whom there was evidence presented. Also, the committee noted that differences in incidence of a condition in different groups cannot be addressed in this technology appraisal.\n\n## The committee took into account lifestyle factors that may affect people's ability to have treatment\n\nAt technical engagement, clinical and community groups noted that lifestyle factors may affect people's ability to attend clinics or adhere to their medication. People with chaotic lifestyles (for example people who are homeless, in prison, or who use drugs) may struggle to keep up with daily oral medication because it needs to be taken at the same time each day, with food, whereas long-acting injections may not suit people who cannot easily access their clinic for appointments. The committee was not presented with evidence relating to adherence for people with different lifestyle factors, but took this issue into account in its decision making.\n\n## The committee took into account in its decision making that some people struggle to take oral treatments\n\nThe committee acknowledged that some people struggle to take their oral medication because of psychological or social reasons, and some people have difficulty swallowing or absorption issues. It was unclear whether this technology would benefit these people because the committee had not been presented with the necessary information about the current comparator treatments for this population to make a decision. However, the committee took this issue into account for its decision making.\n\n## It is not possible to address needle phobia in this technology appraisal\n\nThe committee noted that even though this technology is a helpful alternative to current standard of care, it might not be suitable for individuals who have needle phobia. Needle phobia was not considered in the company's clinical- or cost-effectiveness evidence. The committee did not consider this to be an equalities issue and did not consider it possible to address needle phobia in this technology appraisal.\n\n## The benefit of long-acting antiretrovirals for stigma related to taking daily tablets for HIV is included in the modelling\n\nThe committee was aware of the stigma associated with HIV. It acknowledged that long-acting antiretrovirals could remove the stigma-related concerns associated with daily tablets, for example the fear of unwanted disclosure if tablets are seen, and the burden of a constant reminder of HIV status (see section\xa03.2). However, the committee considered this benefit had been taken into account in the modelled utility advantage for cabotegravir with rilpivirine compared with oral ART (see section\xa03.19).\n\n# Conclusion\n\n## Cabotegravir with rilpivirine is recommended for routine commissioning\n\nThe committee recommended cabotegravir with rilpivirine, within its marketing authorisation, for treating HIV‑1 infection in adults with virological suppression (HIV‑1 RNA fewer than 50\xa0copies/ml) on a stable antiretroviral regimen without present or past evidence of viral resistance to, and no previous virological failure with, any NNRTIs or INIs. The committee acknowledged that cabotegravir with rilpivirine meets an unmet need for people living with HIV‑1 by offering an alternative to daily oral regimens. There was uncertainty about the size of the utility advantage for cabotegravir with rilpivirine over daily oral ART. Despite this uncertainty, the committee considered that a utility advantage was plausible because cabotegravir with rilpivirine may be valued by people concerned about stigma and disclosure of their HIV status, and it reduces the burden of taking daily tablets (see section\xa03.19). The committee considered it was acceptable for the company to assume in its model that long-acting cabotegravir with rilpivirine and oral ARTs have the same efficacy. But it was not appropriate to assume that adherence is greater with cabotegravir with rilpivirine compared with oral ARTs. The committee acknowledged other factors including the innovative nature of cabotegravir with rilpivirine, the daily burden of taking tablets, the equalities issues raised (see section\xa03.23) and the negative impact that stigma has on the lives of people living with HIV. But it recalled that this was captured in the cost-effectiveness calculation (see section\xa03.19). Using the committee's preferred adherence assumption (see section\xa03.16), the most plausible ICER for cabotegravir and rilpivirine compared with oral ART was lower than £30,000 per QALY gained. The committee concluded that the cost-effectiveness estimates were unlikely to exceed its acceptable maximum even though some uncertainties remained. Taking all this into account, the committee concluded that cabotegravir with rilpivirine is likely to be a cost-effective use of NHS resources for treating HIV‑1, so it is recommended."}
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https://www.nice.org.uk/guidance/ta757
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Evidence-based recommendations on cabotegravir (Vocabria) with rilpivirine (Rekambys) for treating HIV-1 in adults. This includes adults with virological suppression (HIV-1 RNA fewer than 50 copies/ml) on a stable antiretroviral regimen, and without any evidence of viral resistance to, and no previous virological failure with, any non-nucleoside reverse transcriptase inhibitors or integrase inhibitors.
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6dafcbcd290d233d221954c7a9639db22ea55b4d
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nice
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Solriamfetol for treating excessive daytime sleepiness caused by narcolepsy
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Solriamfetol for treating excessive daytime sleepiness caused by narcolepsy
Evidence-based recommendations on solriamfetol (Sunosi) for treating excessive daytime sleepiness caused by narcolepsy in adults.
# Recommendations
Solriamfetol is recommended as an option for treating excessive daytime sleepiness in adults with narcolepsy with or without cataplexy. This is only if modafinil and either dexamfetamine or methylphenidate have not worked well enough or are not suitable.
This recommendation is not intended to affect treatment with solriamfetol that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Excessive daytime sleepiness caused by narcolepsy is usually first treated with modafinil, then dexamfetamine or methylphenidate. Availability of other treatments such as sodium oxybate and pitolisant varies in clinics across England. If available, they're normally used after modafinil and dexamfetamine or methylphenidate.
Clinical trial evidence shows that solriamfetol reduces excessive daytime sleepiness compared with placebo. It does not show a difference in quality of life but this is not certain because of the way that quality of life was assessed in the trial. There is no data comparing solriamfetol with dexamfetamine or methylphenidate. And there is no direct data comparing it with sodium oxybate or pitolisant. There is some indirect data but it is from only a small number of short trials. So solriamfetol's clinical effectiveness compared with these treatments is uncertain.
The cost-effectiveness estimates for solriamfetol compared with dexamfetamine or methylphenidate are highly uncertain, because they were based only on assumptions. And they're likely to be higher than what NICE normally considers acceptable. But solriamfetol is cost effective compared with pitolisant and sodium oxybate. So solriamfetol is recommended if modafinil and dexamfetamine or methylphenidate have not worked well enough or are not suitable to control excessive daytime sleepiness caused by narcolepsy.# Information about solriamfetol
# Marketing authorisation indication
Solriamfetol (Sunosi, Jazz Pharmaceuticals) has a marketing authorisation 'to improve wakefulness and reduce excessive daytime sleepiness in adult patients with narcolepsy (with or without cataplexy)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for solriamfetol is £177.52 for a 75 mg 28‑day pack and £248.64 for a 150 mg 28‑day pack (BNF online accessed October 2021). Costs may vary in different settings because of negotiated procurement discounts.# Committee discussion
The appraisal committee considered evidence submitted by Jazz Pharmaceuticals, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
It recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision-making. It discussed the following issues: treatment pathway, comparators, generalisability of clinical trial evidence, indirect treatment comparison, subgroup analysis, dosing splits, treatment discontinuation and healthcare resource use (see the technical report issues 1 to 9), which were outstanding after the technical engagement stage.
# The condition
## Narcolepsy substantially affects many aspects of daily life and people with narcolepsy would welcome a new treatment option
Excessive daytime sleepiness and other symptoms of narcolepsy can significantly affect the quality of life of people with the condition. According to the patient experts, as well as excessive daytime sleepiness, symptoms include cataplexy, sleep paralysis and poor sleep quality. As a result people with the condition often feel extremely tired throughout the day. The patient experts said their narcolepsy affects their physical and mental wellbeing and every aspect of daily life, including education, employment, maintaining a social life, carrying out everyday activities and the ability to drive. They said it can also affect family members. The patient experts said that narcolepsy can be unpredictable, because symptoms and treatment effectiveness can differ significantly from person to person. They also said that the condition was difficult to manage with current treatments and that a new treatment option would be welcomed. The clinical and patient experts pointed out that diagnosis can be delayed in clinical practice because it is not always easy to identify. The committee concluded that narcolepsy is a debilitating disease that significantly affects many aspects of daily life and that people with narcolepsy would welcome a new treatment option.
# Treatment pathway and comparators
## Dexamfetamine and methylphenidate are standard treatments after modafinil; access to pitolisant and sodium oxybate varies
The clinical experts said that narcolepsy symptoms vary widely, and the characteristics and comorbidities of each person need to be considered when making treatment decisions (see section 3.1). This means that treatments for narcolepsy vary depending on the person. They explained that modafinil is currently the established first-line treatment for excessive daytime sleepiness caused by narcolepsy in NHS clinical practice in England. The clinical experts explained that treatment options after modafinil vary because of different access to some treatments in different centres. Options include dexamfetamine, methylphenidate, sodium oxybate and pitolisant. Only sodium oxybate, pitolisant and dexamfetamine have marketing authorisations in the UK for narcolepsy. The clinical experts said that sodium oxybate is used primarily when cataplexy symptoms are severe in people with narcolepsy. However, they also explained that sodium oxybate and pitolisant are not always available in clinics across England, and access can be restricted. The committee was aware that sodium oxybate and pitolisant had not been appraised by NICE for treating narcolepsy. The clinical experts said that sodium oxybate is available for children who have narcolepsy with cataplexy through NHS England's national commissioning policy, but this policy does not include adults. They explained that treatment with pitolisant or sodium oxybate can require an individual funding request, which is often rejected. This meant that if someone's condition did not respond to dexamfetamine or methylphenidate, which are widely available treatments after modafinil, no more treatments may be available. At consultation the company provided further information on pitolisant and sodium oxybate's availability, saying that clinical experts had advised them that they are widely used in the NHS. The company also provided NHS formulary data to show that both treatments were used across various regions of England. The ERG agreed that pitolisant and sodium oxybate are used but noted that they are usually subject to restrictions such as the number of prior treatments. Some regions require individual funding requests. At consultation, the company and other consultees highlighted that a Regional Medicines Optimisation Committee had published a commissioning statement for sodium oxybate and another was planned for pitolisant. The committee noted that the commissioning statement recommended considering sodium oxybate as a third or later line treatment. The committee acknowledged that modafinil is the standard first-line treatment and that there is considerable variation in the use and availability of treatments after modafinil. The committee concluded that dexamfetamine and methylphenidate were the established treatments for narcolepsy in NHS practice after modafinil, and that access to pitolisant and sodium oxybate varies.
## The comparators for solriamfetol depend on the treatment pathway
The NICE scope listed modafinil, dexamfetamine, methylphenidate, pitolisant and sodium oxybate as comparators to solriamfetol. Although the marketing authorisation for solriamfetol does not require previous treatments, the company positioned solriamfetol as a second-line treatment after modafinil. The clinical experts agreed that this was appropriate given that modafinil is the established first-line treatment for excessive daytime sleepiness caused by narcolepsy. They said solriamfetol may also be used third or fourth line depending on baseline characteristics and comorbidities. The committee agreed with the company that modafinil was not an appropriate comparator. The company considered dexamfetamine, methylphenidate, pitolisant and sodium oxybate to be appropriate comparators to solriamfetol. Because of the limited data available for dexamfetamine and methylphenidate, the company focused its clinical and cost effectiveness submission on a comparison with pitolisant and sodium oxybate, and only provided a comparison with dexamfetamine and methylphenidate as scenario analyses. The committee acknowledged that there is limited data for dexamfetamine and methylphenidate, but concluded that they were the most relevant second-line comparators. It also noted that pitolisant and sodium oxybate are usually given third line or later if available (see section 3.2). The committee agreed that pitolisant and sodium oxybate could be considered relevant third-line comparators, despite some variability in access. The committee concluded that the relevant comparators for solriamfetol depend on their position in the treatment pathway.
# Clinical evidence
## TONES 2 results are generalisable to people with excessive daytime sleepiness caused by narcolepsy seen in the NHS
TONES 2 was a randomised 12‑week trial comparing solriamfetol against placebo in people with narcolepsy. Results from this trial inform the efficacy of solriamfetol in the network meta-analysis (NMA; see section 3.6) and therefore its cost effectiveness. They showed that solriamfetol significantly reduced excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) compared with placebo after 12 weeks (ESS changes of -2.2 and -3.8 compared with placebo for solriamfetol 75 mg and 150 mg doses respectively). However, there was no significant change between trial arms in terms of EQ‑5D utilities, functional outcomes of sleep questionnaire score (FOSQ‑10; disease-specific measure) or the physical or mental health component scales of the SF‑36 (see section 3.11). The trial was primarily carried out in the US and Canada. The proportion of patients in the trial with cataplexy and the proportion of patients whose condition had previously been treated with modafinil were lower than in NHS clinical practice. In addition, small numbers of patients were randomised to each solriamfetol dose (59 patients had 75 mg and 59 had 150 mg). The ERG and clinical experts explained that, although there were some differences between TONES 2 and the narcolepsy population in NHS practice in England, they considered that the results were generalisable. The committee concluded that the results from TONES 2 were generalisable to the population seen in NHS clinical practice.
## Subgroup analysis by prior modafinil and cataplexy status is informative but limited by the data available
The company provided a TONES 2 analysis that was stratified by 2 subgroups: prior modafinil and cataplexy status. The ERG said that the prior modafinil subgroup reflected the company's positioning of solriamfetol as a post-modafinil treatment. But it was based on small numbers of patients (exact numbers are academic in confidence and cannot be reported here) and therefore the subgroups may be underpowered. The clinical experts said that the lower proportion of modafinil use in TONES 2 may be because the trial was primarily done in the US and Canada. The company pointed out that the results showed solriamfetol effectiveness did not differ significantly depending on whether modafinil had been taken previously. But the trial was not powered to detect differences in effectiveness by this subgroup. The clinical experts said that there were fewer people in TONES 2 with cataplexy than in NHS practice. The company explained that this was likely to be because of the small numbers in the trial or because the trial excluded people who did not stop their anticataplexy treatment. It also explained that solriamfetol was not thought to affect cataplexy symptoms, and the main aim was to improve wakefulness and reduce excessive daytime sleepiness. The committee recalled that the patient experts explained that narcolepsy can involve other symptoms, for example cataplexy, which can also substantially affect quality of life (see section 3.1). The ERG said that the subgroup analysis from TONES 2 showed no clear difference in outcomes between people with narcolepsy with cataplexy and without it in terms of ESS reduction. It noted however that effectiveness could still differ between these groups. The company said that it was not possible to include subgroups in the indirect comparison because the comparator treatment trials did not report results by these groups (see section 3.6) and pointed out that neither of the subgroup analyses changed the cost-effectiveness conclusions. The committee agreed that the subgroup analysis by prior modafinil use and cataplexy status was informative because it added some certainty to solriamfetol's clinical effectiveness after modafinil and for narcolepsy with cataplexy. But it concluded that it was limited by the data available.
# Indirect treatment comparison
## The indirect treatment comparison between solriamfetol, pitolisant and sodium oxybate is limited by the data available and adds uncertainty to the analysis
Because TONES 2 only included a placebo comparator, the company used an NMA to indirectly compare solriamfetol with pitolisant and sodium oxybate. Only one NMA (which estimated mean change in the ESS) was used in the cost-effectiveness analysis to compare solriamfetol with comparators through a common placebo comparator. The results from the random effects model showed that the mean ESS change 95% credible intervals had a wide range and crossed 0 for comparisons between solriamfetol 150 mg and pitolisant (at a dose of less than 40 mg), sodium oxybate (4.5 g, 6 g and 9 g doses), solriamfetol 75 mg and placebo. This meant that ESS change comparisons between solriamfetol 150 mg and comparators were not considered to be statistically different using the random effects model. The ERG noted that the NMA was limited to a small number of trials and that there were high levels of heterogeneity between the included trials, which meant there was substantial uncertainty in its results. The clinical experts said that it was difficult to say if any treatment in the NMA was more effective than another in treating excessive daytime sleepiness caused by narcolepsy. The indirect treatment comparison was also limited by the inability to compare potentially important subgroups, such as previous modafinil use or cataplexy status (see section 3.5). The NMA was further limited to an 8‑week timepoint because of the maximum length of comparator trials. The ERG's clinical experts explained that this may underestimate the effectiveness of sodium oxybate, which can take up to 12 weeks to show a response. The committee concluded that the indirect treatment comparison between solriamfetol, pitolisant and sodium oxybate is limited by the data available and adds uncertainty to the analysis.
## Comparisons with dexamfetamine or methylphenidate are highly uncertain because there is no clinical trial data for them
The company explained that it found no clinical trial evidence to estimate the effectiveness of dexamfetamine or methylphenidate and therefore these treatments could not be included in the indirect treatment comparison. The committee considered that the lack of trial evidence to inform comparisons between dexamfetamine and methylphenidate was a key uncertainty in the analysis. This is because these treatments are commonly used after modafinil as second-line options and therefore are the most relevant comparators at this part of the pathway (see section 3.2 and section 3.3). At consultation, the company said that the clinical experts they interviewed could not provide estimates for the efficacy of dexamfetamine or methylphenidate. The company therefore presented a cost-effectiveness scenario analysis for solriamfetol compared with dexamfetamine and methylphenidate using a range of assumed ESS reductions. It assumed dexamfetamine and methylphenidate reduced ESS scores by the same amount as 4.5 g sodium oxybate did in the company's NMA (see section 3.6). The ERG noted that 4.5 g sodium oxybate had the lowest ESS reduction in the NMA. The committee also noted that this assumed dexamfetamine and methylphenidate were only marginally more effective than placebo. The company also provided a sensitivity analysis that varied the assumed ESS reductions for dexamfetamine and methylphenidate. The committee noted that this limited any comparison between solriamfetol and dexamfetamine and methylphenidate to one based on assumed differences in ESS reduction between these treatments, which made results highly uncertain. The committee concluded that the analysis comparing solriamfetol with dexamfetamine and methylphenidate is limited by the data available and adds a high level of uncertainty to the analysis.
# Treatment discontinuation due to adverse events
## Discontinuation due to adverse events for solriamfetol, pitolisant and sodium oxybate is similar but uncertain for dexamfetamine and methylphenidate
Information on adverse events leading to discontinuation of treatment for solriamfetol comes from the TONES 2 and TONES 5 (long-term follow up) trials. In TONES 2 the incidence of adverse events that led to discontinuation was low at 12 weeks (1.7%, 1.7% and 5.1% for placebo, solriamfetol 75 mg, and solriamfetol 150 mg, respectively). In TONES 5, discontinuation due to adverse events was 10.2% for people with narcolepsy; however, 56.8% of these events were in the first 4 weeks of treatment. The company did an NMA estimating the rate of adverse events of solriamfetol, pitolisant and sodium oxybate at 8 weeks using TONES 2 data for solriamfetol (see section 3.6). This showed that these rates were similar across all treatments except for the higher dose of solriamfetol (150 mg). The company said that the rates of discontinuation due to adverse events were low with no significant differences between treatments. The company noted that there was no clinical trial evidence to allow dexamfetamine or methylphenidate to be included in this NMA. The committee accepted that adverse events resulting in discontinuation in the NMA were similar for solriamfetol, pitolisant and sodium oxybate, but the rates for dexamfetamine and methylphenidate were uncertain because of a lack of data.
# The economic model
## Response to treatment is not based only on the Epworth Sleepiness Scale in clinical practice but there may not be appropriate alternatives
Improvements in excessive daytime sleepiness and response to treatment were estimated in the company's analysis by the reduction in ESS from baseline. The company explained that it only used the ESS because there was no appropriate alternative measure. The clinical experts explained that a response to treatment is normally defined by consulting with the person having treatment, not just by ESS reduction. The company assumed that a reduction in the ESS by 3 points or more would equal a response to treatment in the model, and this determined if people remained on treatment beyond 8 weeks. The clinical experts said that, although an ESS reduction of 3 may be appropriate, there is no consensus on what a clinically relevant ESS reduction is, and it varies from person to person. The ESS reduction threshold was tested in a scenario analysis by the ERG, which noted that the choice of ESS reduction threshold did not significantly affect cost-effectiveness results. The committee concluded that using the ESS alone to determine response to treatment is unlikely to reflect clinical practice but there may not be appropriate alternative measures.
## The treatment pathway after modafinil is not fully captured in the company's model
The company model included a decision tree, which estimated the proportion of people who have a treatment response at 8 weeks (see section 3.6). After this timepoint, the company used a Markov model in which people who have a treatment response were assumed to continue treatment until they stop because of a loss of response or an adverse event (see section 3.13). People continuing treatment were assumed to have the same level of reduction in mean ESS as measured at 8 weeks. The company positioned solriamfetol as second-line treatment and did not model any later lines of treatment after treatment stops. The company explained that the modelling approach was limited by the available evidence base. The committee agreed that the lack of evidence made it difficult to model the complexity of the narcolepsy treatment pathway. But it also noted that the model did not include people having treatment after second line, which was a limitation in the analysis. The clinical experts said that if treatment with second-line dexamfetamine or methylphenidate was not effective, people with excessive daytime sleepiness caused by narcolepsy may not have access to pitolisant or sodium oxybate (see section 3.2 and section 3.3). These people may remain on dexamfetamine or methylphenidate, potentially trying a higher dose or a combination of treatments, which could provide a small benefit. At consultation, the company provided a scenario analysis that assumed some people continue these treatments without seeing any ESS reduction. The ERG noted that people may remain on treatment with solriamfetol despite a lack of response if there were no other treatments, so provided a scenario analysis for this. The committee noted that the company's base case only included comparisons against pitolisant and sodium oxybate, which were usually given third line or later in the treatment pathway if available (see sections 3.2 and 3.3). The committee concluded that the treatment pathway after modafinil was not fully captured in the company's model.
## Changes in quality of life may not be adequately captured by mapping the Epworth Sleepiness Scale to the EQ-5D
TONES 2 collected data on a range of quality-of-life measures including the EQ‑5D‑5L. After 12 weeks there was no significant change in EQ‑5D utility values between patients who had solriamfetol (75 mg or 150 mg) or placebo. The committee also recalled that there was no statistical difference between TONES 2 arms in terms of the FOSQ‑10 (disease-specific measure) or the physical or mental health component scales of the SF‑36 (see section 3.4). The company explained that the EQ‑5D was not sensitive to changes in quality of life in people with excessive daytime sleepiness caused by narcolepsy because the measure does not include a sleep domain. It also noted that the trial was not long enough to capture changes in quality of life. The company therefore developed a mapping algorithm that estimated EQ‑5D values based on ESS scores using data from the National Health and Wellness Survey (NHWS). The company also provided an analysis that used the alternative mapping approach published by McDaid et al. (2007). The ERG considered that the company's approach was appropriate given the lack of alternative data. But it noted that mapping from the ESS may underestimate the impact of treatments on quality of life in this condition. At the second meeting the company updated its mapping approach to include only UK EQ‑5D tariff values, which the ERG agreed with. The committee noted that the results estimated from both the NHWS and the McDaid mapping were associated with uncertainty. It also acknowledged that the estimated relative differences in quality-adjusted life years (QALYs) between treatments were very similar for each mapping approach. The committee concluded that mapping from the ESS to the EQ‑5D may not adequately capture changes in quality of life but the mapping analysis was acceptable for decision-making.
## A range of dosing assumptions in the analysis is appropriate to account for the variability in clinical practice
All treatments for narcolepsy are available in different doses, which vary in cost and effectiveness. These different dose options were weighted, based on assumptions, to inform cost-effectiveness comparisons between solriamfetol and other treatments. The company's original base case assumed the proportions of people taking 75 mg and 150 mg doses of solriamfetol were the same as reported in French prescribing data. After consultation the company updated these proportions based on more recent German sales data. (These figures are commercial in confidence and cannot be reported here.) The ERG noted that the cost-effectiveness conclusions were not sensitive to solriamfetol dose split assumptions. The clinical experts explained that it is also difficult to estimate the most likely dose split in NHS clinical practice for the comparator treatments. At consultation the company presented a scenario analysis using doses of 40 mg for dexamfetamine (instant release tablet) and methylphenidate (modified release capsule). The company explained that it was difficult to determine which dose was the most appropriate, and that its estimate was conservative. The committee considered that the scenario analysis may have overestimated the cost of methylphenidate and dexamfetamine and noted that other formulations and doses with lower costs were available. The committee considered that the most appropriate dose splits were uncertain, particularly for dexamfetamine and methylphenidate, but a range of dosing assumptions in the analysis is appropriate to account for the variability in clinical practice.
## The treatment discontinuation due to adverse events assumptions are uncertain for analysis involving dexamfetamine and methylphenidate
The company assumed that discontinuation due to adverse events at 8 weeks was the same for each treatment, based on the NMA, which did not show a statistical difference in rates between solriamfetol, pitolisant and sodium oxybate (see section 3.8). There was no long-term clinical trial evidence to inform treatment discontinuation due to adverse events for any comparator treatment in the analysis after 8 weeks. So, the company assumed in its economic model that all treatments were discontinued because of an adverse event at the same rate from 8 weeks onwards (an annual rate of 4.4%, which assumes the rate at week 4 in TONES 5 is similar to the rate at week 8; see section 3.8). The ERG agreed that this simplifying assumption was appropriate because there was no robust evidence to inform long-term discontinuation rates due to adverse events. The clinical experts said that dexamfetamine and methylphenidate were associated with higher rates of adverse events, for example cardiovascular adverse events, than other treatments in the analysis. After consultation the company said that clinical experts advised them that adverse event rates were likely to be higher for dexamfetamine and methylphenidate than solriamfetol, but there was no robust evidence to inform this. The company also provided a scenario analysis in which dexamfetamine and methylphenidate were assumed to increase mortality. The ERG noted that the sources the company provided to support excess mortality with these treatments did not refer to mortality rates. Therefore, it did not consider this scenario to be robust. The ERG did a scenario analysis that assumed higher treatment discontinuation rates for dexamfetamine and methylphenidate. The committee agreed that they may be associated with higher rates of discontinuation due to adverse events. But it noted that it was difficult to determine the appropriate rate to use. The committee concluded that assumptions about treatment discontinuation due to adverse events were uncertain for dexamfetamine and methylphenidate.
## It is appropriate to include the costs of healthcare resource use because of adverse events in the analysis for dexamfetamine and methylphenidate
The company only included the costs of drug acquisition in its original cost-effectiveness analysis. The company pointed out that the number of serious adverse events in the clinical evidence was low and that adverse events from solriamfetol treatment tended to occur early, be mild in nature and resolve quickly (see section 3.8). The clinical and patient experts explained that treatment with dexamfetamine or methylphenidate would be associated with higher healthcare resource use costs because they are associated with more adverse events (see section 3.13). The committee acknowledged that it was difficult to estimate healthcare resource use because of the lack of available data. But it agreed that the economic modelling did not account fully for the likely increased healthcare resource use from adverse events from dexamfetamine and methylphenidate and likely underestimated the costs of these treatments. After consultation the company updated its scenario analysis to include adverse event costs for dexamfetamine and methylphenidate based on analysis of their summary of product characteristics (SmPC) and the Medicines and Healthcare products Regulatory Agency (MHRA) yellow card scheme data. The ERG agreed with including these costs and noted that, although the analysis was uncertain, it did not believe the company had overestimated these costs. The committee concluded that including the costs of adverse events for dexamfetamine and methylphenidate was appropriate.
# Cost-effectiveness estimates
## Solriamfetol is a cost-effective use of NHS resources after modafinil and either dexamfetamine or methylphenidate
The company's and ERG's base case compared solriamfetol with pitolisant and sodium oxybate. Comparisons with dexamfetamine and methylphenidate were included in a scenario analysis. The company's and ERG's base case assumptions included:
response defined as an ESS reduction of 3 or more (see section 3.9)
EQ-5D utility values estimated from using the ESS score using a novel mapping algorithm (see section 3.11)
long-term treatment discontinuation rates because of lack of response or adverse events are the same for all treatments and based on TONES 5 data (see section 3.13).Compared with pitolisant, solriamfetol was associated with a high south-west incremental cost-effectiveness ratio (ICER) of £886,555 (with a positive net monetary benefit at both £20,000 and £30,000 per QALY gained). This meant that solriamfetol was less expensive and only marginally less effective than pitolisant, which leads to high cost savings in relation to the loss of QALYs. Solriamfetol dominated sodium oxybate (it was less expensive and marginally more effective). Solriamfetol also dominated sodium oxybate when a confidential discount for sodium oxybate was considered. The committee recalled that access to pitolisant and sodium oxybate varied and, if available, they were usually offered after modafinil and either dexamfetamine or methylphenidate (see section 3.3). The committee considered that quality of life changes were not appropriately captured in the analysis (see section 3.11) and that treatment response is not exclusively based on ESS score in NHS clinical practice (see section 3.9). Despite these uncertainties, the committee concluded that solriamfetol is a cost-effective use of NHS resources after treatment with modafinil and either dexamfetamine or methylphenidate. It therefore recommended solriamfetol as a treatment option at this part of the treatment pathway. The committee was also aware of a potential equalities issue related to the MHRA warning that modafinil use is linked to birth defects and reduced oral contraception efficacy (see section 3.17). It therefore thought it was reasonable to also recommend solriamfetol without prior modafinil and after treatment with either dexamfetamine or methylphenidate if people cannot take modafinil.
## Solriamfetol is not a cost-effective use of NHS resources after treatment with only modafinil
The company's and ERG's scenario analysis showed that solriamfetol was associated with ICERs consistently above £30,000 per QALY gained compared with dexamfetamine or methylphenidate across a range of sensitivity analyses. The scenario and sensitivity analysis included the following changes to the base case:
Adverse event costs for dexamfetamine and methylphenidate estimated based on SmPC and MHRA yellow card data and a scenario in which these treatments were assumed to increase mortality rates (see section 3.14). The ERG also did a scenario analysis in which discontinuation rates due to adverse events were assumed to be higher for dexamfetamine and methylphenidate (see section 3.14).
Dexamfetamine and methylphenidate assumed to be equal to 4.5 g sodium oxybate in terms of ESS reduction as estimated by the company's NMA. This was because of a lack of trial data and a sensitivity analysis that varied ESS reduction relative to 150 mg solriamfetol for these treatments (see section 3.6).
Threshold analysis assuming a proportion of people remain on treatment with dexamfetamine or methylphenidate despite not having an ESS reduction (see section 3.11).The committee agreed that after first-line modafinil the most relevant second-line comparators are dexamfetamine and methylphenidate (see section 3.2 and section 3.3). The committee also agreed that the company's scenario analysis comparing solriamfetol against dexamfetamine and methylphenidate was highly uncertain because of a lack of trial data (see section 3.6). The committee considered that the cost-effectiveness scenario analyses presented were highly uncertain and sensitive to various modelling assumptions. It concluded that the most plausible range of ICER estimates was likely to be above what NICE considers a cost-effective use of NHS resources. Therefore, it did not recommend solriamfetol as a treatment option when modafinil is the only previous treatment.
# Other factors
A patient organisation raised a potential equality issue in that the MHRA has issued a warning that modafinil use is linked to birth defects and reduced oral contraception efficacy. It said anyone with narcolepsy affected by this warning needs alternative treatment options. The committee was also aware that treatment with dexamfetamine or methylphenidate may not be suitable for some people. This includes people with certain mental health conditions. The committee concluded that its recommendations would not affect these groups any differently than other groups because they allow solriamfetol treatment when modafinil, methylphenidate or dexamfetamine cannot be used.
The QALY may not have captured changes in health-related quality of life in the model and the committee took this into account in its decision-making (see section 3.1 and section 3.11).
# Conclusion
## Solriamfetol is recommended for treating excessive daytime sleepiness caused by narcolepsy after modafinil and either dexamfetamine or methylphenidate
The committee concluded that solriamfetol was cost effective compared with pitolisant or sodium oxybate. It also concluded that the most plausible ICERs for solriamfetol compared with dexamfetamine or methylphenidate were substantially above the range that NICE usually considers an acceptable use of NHS resources. Therefore, it recommended solriamfetol for routine commissioning in the NHS only when modafinil and either dexamfetamine or methylphenidate have not worked well enough or are not suitable to control excessive daytime sleepiness caused by narcolepsy.
|
{'Recommendations': "Solriamfetol is recommended as an option for treating excessive daytime sleepiness in adults with narcolepsy with or without cataplexy. This is only if modafinil and either dexamfetamine or methylphenidate have not worked well enough or are not suitable.\n\nThis recommendation is not intended to affect treatment with solriamfetol that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nExcessive daytime sleepiness caused by narcolepsy is usually first treated with modafinil, then dexamfetamine or methylphenidate. Availability of other treatments such as sodium oxybate and pitolisant varies in clinics across England. If available, they're normally used after modafinil and dexamfetamine or methylphenidate.\n\nClinical trial evidence shows that solriamfetol reduces excessive daytime sleepiness compared with placebo. It does not show a difference in quality of life but this is not certain because of the way that quality of life was assessed in the trial. There is no data comparing solriamfetol with dexamfetamine or methylphenidate. And there is no direct data comparing it with sodium oxybate or pitolisant. There is some indirect data but it is from only a small number of short trials. So solriamfetol's clinical effectiveness compared with these treatments is uncertain.\n\nThe cost-effectiveness estimates for solriamfetol compared with dexamfetamine or methylphenidate are highly uncertain, because they were based only on assumptions. And they're likely to be higher than what NICE normally considers acceptable. But solriamfetol is cost effective compared with pitolisant and sodium oxybate. So solriamfetol is recommended if modafinil and dexamfetamine or methylphenidate have not worked well enough or are not suitable to control excessive daytime sleepiness caused by narcolepsy.", 'Information about solriamfetol': "# Marketing authorisation indication\n\nSolriamfetol (Sunosi, Jazz Pharmaceuticals) has a marketing authorisation 'to improve wakefulness and reduce excessive daytime sleepiness in adult patients with narcolepsy (with or without cataplexy)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for solriamfetol is £177.52 for a 75\xa0mg 28‑day pack and £248.64 for a 150\xa0mg 28‑day pack (BNF online accessed October\xa02021). Costs may vary in different settings because of negotiated procurement discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Jazz Pharmaceuticals, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented and took these into account in its decision-making. It discussed the following issues: treatment pathway, comparators, generalisability of clinical trial evidence, indirect treatment comparison, subgroup analysis, dosing splits, treatment discontinuation and healthcare resource use (see the technical report issues\xa01 to\xa09), which were outstanding after the technical engagement stage.\n\n# The condition\n\n## Narcolepsy substantially affects many aspects of daily life and people with narcolepsy would welcome a new treatment option\n\nExcessive daytime sleepiness and other symptoms of narcolepsy can significantly affect the quality of life of people with the condition. According to the patient experts, as well as excessive daytime sleepiness, symptoms include cataplexy, sleep paralysis and poor sleep quality. As a result people with the condition often feel extremely tired throughout the day. The patient experts said their narcolepsy affects their physical and mental wellbeing and every aspect of daily life, including education, employment, maintaining a social life, carrying out everyday activities and the ability to drive. They said it can also affect family members. The patient experts said that narcolepsy can be unpredictable, because symptoms and treatment effectiveness can differ significantly from person to person. They also said that the condition was difficult to manage with current treatments and that a new treatment option would be welcomed. The clinical and patient experts pointed out that diagnosis can be delayed in clinical practice because it is not always easy to identify. The committee concluded that narcolepsy is a debilitating disease that significantly affects many aspects of daily life and that people with narcolepsy would welcome a new treatment option.\n\n# Treatment pathway and comparators\n\n## Dexamfetamine and methylphenidate are standard treatments after modafinil; access to pitolisant and sodium oxybate varies\n\nThe clinical experts said that narcolepsy symptoms vary widely, and the characteristics and comorbidities of each person need to be considered when making treatment decisions (see section\xa03.1). This means that treatments for narcolepsy vary depending on the person. They explained that modafinil is currently the established first-line treatment for excessive daytime sleepiness caused by narcolepsy in NHS clinical practice in England. The clinical experts explained that treatment options after modafinil vary because of different access to some treatments in different centres. Options include dexamfetamine, methylphenidate, sodium oxybate and pitolisant. Only sodium oxybate, pitolisant and dexamfetamine have marketing authorisations in the UK for narcolepsy. The clinical experts said that sodium oxybate is used primarily when cataplexy symptoms are severe in people with narcolepsy. However, they also explained that sodium oxybate and pitolisant are not always available in clinics across England, and access can be restricted. The committee was aware that sodium oxybate and pitolisant had not been appraised by NICE for treating narcolepsy. The clinical experts said that sodium oxybate is available for children who have narcolepsy with cataplexy through NHS England's national commissioning policy, but this policy does not include adults. They explained that treatment with pitolisant or sodium oxybate can require an individual funding request, which is often rejected. This meant that if someone's condition did not respond to dexamfetamine or methylphenidate, which are widely available treatments after modafinil, no more treatments may be available. At consultation the company provided further information on pitolisant and sodium oxybate's availability, saying that clinical experts had advised them that they are widely used in the NHS. The company also provided NHS formulary data to show that both treatments were used across various regions of England. The ERG agreed that pitolisant and sodium oxybate are used but noted that they are usually subject to restrictions such as the number of prior treatments. Some regions require individual funding requests. At consultation, the company and other consultees highlighted that a Regional Medicines Optimisation Committee had published a commissioning statement for sodium oxybate and another was planned for pitolisant. The committee noted that the commissioning statement recommended considering sodium oxybate as a third or later line treatment. The committee acknowledged that modafinil is the standard first-line treatment and that there is considerable variation in the use and availability of treatments after modafinil. The committee concluded that dexamfetamine and methylphenidate were the established treatments for narcolepsy in NHS practice after modafinil, and that access to pitolisant and sodium oxybate varies.\n\n## The comparators for solriamfetol depend on the treatment pathway\n\nThe NICE scope listed modafinil, dexamfetamine, methylphenidate, pitolisant and sodium oxybate as comparators to solriamfetol. Although the marketing authorisation for solriamfetol does not require previous treatments, the company positioned solriamfetol as a second-line treatment after modafinil. The clinical experts agreed that this was appropriate given that modafinil is the established first-line treatment for excessive daytime sleepiness caused by narcolepsy. They said solriamfetol may also be used third or fourth line depending on baseline characteristics and comorbidities. The committee agreed with the company that modafinil was not an appropriate comparator. The company considered dexamfetamine, methylphenidate, pitolisant and sodium oxybate to be appropriate comparators to solriamfetol. Because of the limited data available for dexamfetamine and methylphenidate, the company focused its clinical and cost effectiveness submission on a comparison with pitolisant and sodium oxybate, and only provided a comparison with dexamfetamine and methylphenidate as scenario analyses. The committee acknowledged that there is limited data for dexamfetamine and methylphenidate, but concluded that they were the most relevant second-line comparators. It also noted that pitolisant and sodium oxybate are usually given third line or later if available (see section\xa03.2). The committee agreed that pitolisant and sodium oxybate could be considered relevant third-line comparators, despite some variability in access. The committee concluded that the relevant comparators for solriamfetol depend on their position in the treatment pathway.\n\n# Clinical evidence\n\n## TONES\xa02 results are generalisable to people with excessive daytime sleepiness caused by narcolepsy seen in the NHS\n\nTONES\xa02 was a randomised 12‑week trial comparing solriamfetol against placebo in people with narcolepsy. Results from this trial inform the efficacy of solriamfetol in the network meta-analysis (NMA; see section\xa03.6) and therefore its cost effectiveness. They showed that solriamfetol significantly reduced excessive daytime sleepiness as measured by the Epworth Sleepiness Scale (ESS) compared with placebo after 12\xa0weeks (ESS changes of -2.2 and -3.8 compared with placebo for solriamfetol 75\xa0mg and 150\xa0mg doses respectively). However, there was no significant change between trial arms in terms of EQ‑5D utilities, functional outcomes of sleep questionnaire score (FOSQ‑10; disease-specific measure) or the physical or mental health component scales of the SF‑36 (see section\xa03.11). The trial was primarily carried out in the US and Canada. The proportion of patients in the trial with cataplexy and the proportion of patients whose condition had previously been treated with modafinil were lower than in NHS clinical practice. In addition, small numbers of patients were randomised to each solriamfetol dose (59\xa0patients had 75\xa0mg and 59 had 150\xa0mg). The ERG and clinical experts explained that, although there were some differences between TONES\xa02 and the narcolepsy population in NHS practice in England, they considered that the results were generalisable. The committee concluded that the results from TONES\xa02 were generalisable to the population seen in NHS clinical practice.\n\n## Subgroup analysis by prior modafinil and cataplexy status is informative but limited by the data available\n\nThe company provided a TONES\xa02 analysis that was stratified by 2\xa0subgroups: prior modafinil and cataplexy status. The ERG said that the prior modafinil subgroup reflected the company's positioning of solriamfetol as a post-modafinil treatment. But it was based on small numbers of patients (exact numbers are academic in confidence and cannot be reported here) and therefore the subgroups may be underpowered. The clinical experts said that the lower proportion of modafinil use in TONES\xa02 may be because the trial was primarily done in the US and Canada. The company pointed out that the results showed solriamfetol effectiveness did not differ significantly depending on whether modafinil had been taken previously. But the trial was not powered to detect differences in effectiveness by this subgroup. The clinical experts said that there were fewer people in TONES\xa02 with cataplexy than in NHS practice. The company explained that this was likely to be because of the small numbers in the trial or because the trial excluded people who did not stop their anticataplexy treatment. It also explained that solriamfetol was not thought to affect cataplexy symptoms, and the main aim was to improve wakefulness and reduce excessive daytime sleepiness. The committee recalled that the patient experts explained that narcolepsy can involve other symptoms, for example cataplexy, which can also substantially affect quality of life (see section\xa03.1). The ERG said that the subgroup analysis from TONES\xa02 showed no clear difference in outcomes between people with narcolepsy with cataplexy and without it in terms of ESS reduction. It noted however that effectiveness could still differ between these groups. The company said that it was not possible to include subgroups in the indirect comparison because the comparator treatment trials did not report results by these groups (see section\xa03.6) and pointed out that neither of the subgroup analyses changed the cost-effectiveness conclusions. The committee agreed that the subgroup analysis by prior modafinil use and cataplexy status was informative because it added some certainty to solriamfetol's clinical effectiveness after modafinil and for narcolepsy with cataplexy. But it concluded that it was limited by the data available.\n\n# Indirect treatment comparison\n\n## The indirect treatment comparison between solriamfetol, pitolisant and sodium oxybate is limited by the data available and adds uncertainty to the analysis\n\nBecause TONES\xa02 only included a placebo comparator, the company used an NMA to indirectly compare solriamfetol with pitolisant and sodium oxybate. Only one NMA (which estimated mean change in the ESS) was used in the cost-effectiveness analysis to compare solriamfetol with comparators through a common placebo comparator. The results from the random effects model showed that the mean ESS change 95% credible intervals had a wide range and crossed 0 for comparisons between solriamfetol 150\xa0mg and pitolisant (at a dose of less than 40\xa0mg), sodium oxybate (4.5\xa0g, 6\xa0g and 9\xa0g doses), solriamfetol 75\xa0mg and placebo. This meant that ESS change comparisons between solriamfetol 150\xa0mg and comparators were not considered to be statistically different using the random effects model. The ERG noted that the NMA was limited to a small number of trials and that there were high levels of heterogeneity between the included trials, which meant there was substantial uncertainty in its results. The clinical experts said that it was difficult to say if any treatment in the NMA was more effective than another in treating excessive daytime sleepiness caused by narcolepsy. The indirect treatment comparison was also limited by the inability to compare potentially important subgroups, such as previous modafinil use or cataplexy status (see section\xa03.5). The NMA was further limited to an 8‑week timepoint because of the maximum length of comparator trials. The ERG's clinical experts explained that this may underestimate the effectiveness of sodium oxybate, which can take up to 12\xa0weeks to show a response. The committee concluded that the indirect treatment comparison between solriamfetol, pitolisant and sodium oxybate is limited by the data available and adds uncertainty to the analysis.\n\n## Comparisons with dexamfetamine or methylphenidate are highly uncertain because there is no clinical trial data for them\n\nThe company explained that it found no clinical trial evidence to estimate the effectiveness of dexamfetamine or methylphenidate and therefore these treatments could not be included in the indirect treatment comparison. The committee considered that the lack of trial evidence to inform comparisons between dexamfetamine and methylphenidate was a key uncertainty in the analysis. This is because these treatments are commonly used after modafinil as second-line options and therefore are the most relevant comparators at this part of the pathway (see section\xa03.2 and section\xa03.3). At consultation, the company said that the clinical experts they interviewed could not provide estimates for the efficacy of dexamfetamine or methylphenidate. The company therefore presented a cost-effectiveness scenario analysis for solriamfetol compared with dexamfetamine and methylphenidate using a range of assumed ESS reductions. It assumed dexamfetamine and methylphenidate reduced ESS scores by the same amount as 4.5\xa0g sodium oxybate did in the company's NMA (see section\xa03.6). The ERG noted that 4.5\xa0g sodium oxybate had the lowest ESS reduction in the NMA. The committee also noted that this assumed dexamfetamine and methylphenidate were only marginally more effective than placebo. The company also provided a sensitivity analysis that varied the assumed ESS reductions for dexamfetamine and methylphenidate. The committee noted that this limited any comparison between solriamfetol and dexamfetamine and methylphenidate to one based on assumed differences in ESS reduction between these treatments, which made results highly uncertain. The committee concluded that the analysis comparing solriamfetol with dexamfetamine and methylphenidate is limited by the data available and adds a high level of uncertainty to the analysis.\n\n# Treatment discontinuation due to adverse events\n\n## Discontinuation due to adverse events for solriamfetol, pitolisant and sodium oxybate is similar but uncertain for dexamfetamine and methylphenidate\n\nInformation on adverse events leading to discontinuation of treatment for solriamfetol comes from the TONES\xa02 and TONES\xa05 (long-term follow up) trials. In TONES\xa02 the incidence of adverse events that led to discontinuation was low at 12\xa0weeks (1.7%, 1.7% and 5.1% for placebo, solriamfetol 75\xa0mg, and solriamfetol 150\xa0mg, respectively). In TONES\xa05, discontinuation due to adverse events was 10.2% for people with narcolepsy; however, 56.8% of these events were in the first 4\xa0weeks of treatment. The company did an NMA estimating the rate of adverse events of solriamfetol, pitolisant and sodium oxybate at 8\xa0weeks using TONES\xa02 data for solriamfetol (see section\xa03.6). This showed that these rates were similar across all treatments except for the higher dose of solriamfetol (150\xa0mg). The company said that the rates of discontinuation due to adverse events were low with no significant differences between treatments. The company noted that there was no clinical trial evidence to allow dexamfetamine or methylphenidate to be included in this NMA. The committee accepted that adverse events resulting in discontinuation in the NMA were similar for solriamfetol, pitolisant and sodium oxybate, but the rates for dexamfetamine and methylphenidate were uncertain because of a lack of data.\n\n# The economic model\n\n## Response to treatment is not based only on the Epworth Sleepiness Scale in clinical practice but there may not be appropriate alternatives\n\nImprovements in excessive daytime sleepiness and response to treatment were estimated in the company's analysis by the reduction in ESS from baseline. The company explained that it only used the ESS because there was no appropriate alternative measure. The clinical experts explained that a response to treatment is normally defined by consulting with the person having treatment, not just by ESS reduction. The company assumed that a reduction in the ESS by 3\xa0points or more would equal a response to treatment in the model, and this determined if people remained on treatment beyond 8\xa0weeks. The clinical experts said that, although an ESS reduction of 3 may be appropriate, there is no consensus on what a clinically relevant ESS reduction is, and it varies from person to person. The ESS reduction threshold was tested in a scenario analysis by the ERG, which noted that the choice of ESS reduction threshold did not significantly affect cost-effectiveness results. The committee concluded that using the ESS alone to determine response to treatment is unlikely to reflect clinical practice but there may not be appropriate alternative measures.\n\n## The treatment pathway after modafinil is not fully captured in the company's model\n\nThe company model included a decision tree, which estimated the proportion of people who have a treatment response at 8\xa0weeks (see section\xa03.6). After this timepoint, the company used a Markov model in which people who have a treatment response were assumed to continue treatment until they stop because of a loss of response or an adverse event (see section\xa03.13). People continuing treatment were assumed to have the same level of reduction in mean ESS as measured at 8\xa0weeks. The company positioned solriamfetol as second-line treatment and did not model any later lines of treatment after treatment stops. The company explained that the modelling approach was limited by the available evidence base. The committee agreed that the lack of evidence made it difficult to model the complexity of the narcolepsy treatment pathway. But it also noted that the model did not include people having treatment after second line, which was a limitation in the analysis. The clinical experts said that if treatment with second-line dexamfetamine or methylphenidate was not effective, people with excessive daytime sleepiness caused by narcolepsy may not have access to pitolisant or sodium oxybate (see section\xa03.2 and section\xa03.3). These people may remain on dexamfetamine or methylphenidate, potentially trying a higher dose or a combination of treatments, which could provide a small benefit. At consultation, the company provided a scenario analysis that assumed some people continue these treatments without seeing any ESS reduction. The ERG noted that people may remain on treatment with solriamfetol despite a lack of response if there were no other treatments, so provided a scenario analysis for this. The committee noted that the company's base case only included comparisons against pitolisant and sodium oxybate, which were usually given third line or later in the treatment pathway if available (see sections\xa03.2 and 3.3). The committee concluded that the treatment pathway after modafinil was not fully captured in the company's model.\n\n## Changes in quality of life may not be adequately captured by mapping the Epworth Sleepiness Scale to the EQ-5D\n\nTONES\xa02 collected data on a range of quality-of-life measures including the EQ‑5D‑5L. After 12\xa0weeks there was no significant change in EQ‑5D utility values between patients who had solriamfetol (75\xa0mg or 150\xa0mg) or placebo. The committee also recalled that there was no statistical difference between TONES\xa02 arms in terms of the FOSQ‑10 (disease-specific measure) or the physical or mental health component scales of the SF‑36 (see section\xa03.4). The company explained that the EQ‑5D was not sensitive to changes in quality of life in people with excessive daytime sleepiness caused by narcolepsy because the measure does not include a sleep domain. It also noted that the trial was not long enough to capture changes in quality of life. The company therefore developed a mapping algorithm that estimated EQ‑5D values based on ESS scores using data from the National Health and Wellness Survey (NHWS). The company also provided an analysis that used the alternative mapping approach published by McDaid et al. (2007). The ERG considered that the company's approach was appropriate given the lack of alternative data. But it noted that mapping from the ESS may underestimate the impact of treatments on quality of life in this condition. At the second meeting the company updated its mapping approach to include only UK EQ‑5D tariff values, which the ERG agreed with. The committee noted that the results estimated from both the NHWS and the McDaid mapping were associated with uncertainty. It also acknowledged that the estimated relative differences in quality-adjusted life years (QALYs) between treatments were very similar for each mapping approach. The committee concluded that mapping from the ESS to the EQ‑5D may not adequately capture changes in quality of life but the mapping analysis was acceptable for decision-making.\n\n## A range of dosing assumptions in the analysis is appropriate to account for the variability in clinical practice\n\nAll treatments for narcolepsy are available in different doses, which vary in cost and effectiveness. These different dose options were weighted, based on assumptions, to inform cost-effectiveness comparisons between solriamfetol and other treatments. The company's original base case assumed the proportions of people taking 75\xa0mg and 150\xa0mg doses of solriamfetol were the same as reported in French prescribing data. After consultation the company updated these proportions based on more recent German sales data. (These figures are commercial in confidence and cannot be reported here.) The ERG noted that the cost-effectiveness conclusions were not sensitive to solriamfetol dose split assumptions. The clinical experts explained that it is also difficult to estimate the most likely dose split in NHS clinical practice for the comparator treatments. At consultation the company presented a scenario analysis using doses of 40\xa0mg for dexamfetamine (instant release tablet) and methylphenidate (modified release capsule). The company explained that it was difficult to determine which dose was the most appropriate, and that its estimate was conservative. The committee considered that the scenario analysis may have overestimated the cost of methylphenidate and dexamfetamine and noted that other formulations and doses with lower costs were available. The committee considered that the most appropriate dose splits were uncertain, particularly for dexamfetamine and methylphenidate, but a range of dosing assumptions in the analysis is appropriate to account for the variability in clinical practice.\n\n## The treatment discontinuation due to adverse events assumptions are uncertain for analysis involving dexamfetamine and methylphenidate\n\nThe company assumed that discontinuation due to adverse events at 8\xa0weeks was the same for each treatment, based on the NMA, which did not show a statistical difference in rates between solriamfetol, pitolisant and sodium oxybate (see section\xa03.8). There was no long-term clinical trial evidence to inform treatment discontinuation due to adverse events for any comparator treatment in the analysis after 8\xa0weeks. So, the company assumed in its economic model that all treatments were discontinued because of an adverse event at the same rate from 8\xa0weeks onwards (an annual rate of 4.4%, which assumes the rate at week\xa04 in TONES\xa05 is similar to the rate at week\xa08; see section\xa03.8). The ERG agreed that this simplifying assumption was appropriate because there was no robust evidence to inform long-term discontinuation rates due to adverse events. The clinical experts said that dexamfetamine and methylphenidate were associated with higher rates of adverse events, for example cardiovascular adverse events, than other treatments in the analysis. After consultation the company said that clinical experts advised them that adverse event rates were likely to be higher for dexamfetamine and methylphenidate than solriamfetol, but there was no robust evidence to inform this. The company also provided a scenario analysis in which dexamfetamine and methylphenidate were assumed to increase mortality. The ERG noted that the sources the company provided to support excess mortality with these treatments did not refer to mortality rates. Therefore, it did not consider this scenario to be robust. The ERG did a scenario analysis that assumed higher treatment discontinuation rates for dexamfetamine and methylphenidate. The committee agreed that they may be associated with higher rates of discontinuation due to adverse events. But it noted that it was difficult to determine the appropriate rate to use. The committee concluded that assumptions about treatment discontinuation due to adverse events were uncertain for dexamfetamine and methylphenidate.\n\n## It is appropriate to include the costs of healthcare resource use because of adverse events in the analysis for dexamfetamine and methylphenidate\n\nThe company only included the costs of drug acquisition in its original cost-effectiveness analysis. The company pointed out that the number of serious adverse events in the clinical evidence was low and that adverse events from solriamfetol treatment tended to occur early, be mild in nature and resolve quickly (see section\xa03.8). The clinical and patient experts explained that treatment with dexamfetamine or methylphenidate would be associated with higher healthcare resource use costs because they are associated with more adverse events (see section\xa03.13). The committee acknowledged that it was difficult to estimate healthcare resource use because of the lack of available data. But it agreed that the economic modelling did not account fully for the likely increased healthcare resource use from adverse events from dexamfetamine and methylphenidate and likely underestimated the costs of these treatments. After consultation the company updated its scenario analysis to include adverse event costs for dexamfetamine and methylphenidate based on analysis of their summary of product characteristics (SmPC) and the Medicines and Healthcare products Regulatory Agency (MHRA) yellow card scheme data. The ERG agreed with including these costs and noted that, although the analysis was uncertain, it did not believe the company had overestimated these costs. The committee concluded that including the costs of adverse events for dexamfetamine and methylphenidate was appropriate.\n\n# Cost-effectiveness estimates\n\n## Solriamfetol is a cost-effective use of NHS resources after modafinil and either dexamfetamine or methylphenidate\n\nThe company's and ERG's base case compared solriamfetol with pitolisant and sodium oxybate. Comparisons with dexamfetamine and methylphenidate were included in a scenario analysis. The company's and ERG's base case assumptions included:\n\nresponse defined as an ESS reduction of 3 or more (see section\xa03.9)\n\nEQ-5D utility values estimated from using the ESS score using a novel mapping algorithm (see section\xa03.11)\n\nlong-term treatment discontinuation rates because of lack of response or adverse events are the same for all treatments and based on TONES\xa05 data (see section\xa03.13).Compared with pitolisant, solriamfetol was associated with a high south-west incremental cost-effectiveness ratio (ICER) of £886,555 (with a positive net monetary benefit at both £20,000 and £30,000 per QALY gained). This meant that solriamfetol was less expensive and only marginally less effective than pitolisant, which leads to high cost savings in relation to the loss of QALYs. Solriamfetol dominated sodium oxybate (it was less expensive and marginally more effective). Solriamfetol also dominated sodium oxybate when a confidential discount for sodium oxybate was considered. The committee recalled that access to pitolisant and sodium oxybate varied and, if available, they were usually offered after modafinil and either dexamfetamine or methylphenidate (see section\xa03.3). The committee considered that quality of life changes were not appropriately captured in the analysis (see section\xa03.11) and that treatment response is not exclusively based on ESS score in NHS clinical practice (see section\xa03.9). Despite these uncertainties, the committee concluded that solriamfetol is a cost-effective use of NHS resources after treatment with modafinil and either dexamfetamine or methylphenidate. It therefore recommended solriamfetol as a treatment option at this part of the treatment pathway. The committee was also aware of a potential equalities issue related to the MHRA warning that modafinil use is linked to birth defects and reduced oral contraception efficacy (see section\xa03.17). It therefore thought it was reasonable to also recommend solriamfetol without prior modafinil and after treatment with either dexamfetamine or methylphenidate if people cannot take modafinil.\n\n## Solriamfetol is not a cost-effective use of NHS resources after treatment with only modafinil\n\nThe company's and ERG's scenario analysis showed that solriamfetol was associated with ICERs consistently above £30,000 per QALY gained compared with dexamfetamine or methylphenidate across a range of sensitivity analyses. The scenario and sensitivity analysis included the following changes to the base case:\n\nAdverse event costs for dexamfetamine and methylphenidate estimated based on SmPC and MHRA yellow card data and a scenario in which these treatments were assumed to increase mortality rates (see section\xa03.14). The ERG also did a scenario analysis in which discontinuation rates due to adverse events were assumed to be higher for dexamfetamine and methylphenidate (see section\xa03.14).\n\nDexamfetamine and methylphenidate assumed to be equal to 4.5\xa0g sodium oxybate in terms of ESS reduction as estimated by the company's NMA. This was because of a lack of trial data and a sensitivity analysis that varied ESS reduction relative to 150\xa0mg solriamfetol for these treatments (see section\xa03.6).\n\nThreshold analysis assuming a proportion of people remain on treatment with dexamfetamine or methylphenidate despite not having an ESS reduction (see section\xa03.11).The committee agreed that after first-line modafinil the most relevant second-line comparators are dexamfetamine and methylphenidate (see section\xa03.2 and section\xa03.3). The committee also agreed that the company's scenario analysis comparing solriamfetol against dexamfetamine and methylphenidate was highly uncertain because of a lack of trial data (see section\xa03.6). The committee considered that the cost-effectiveness scenario analyses presented were highly uncertain and sensitive to various modelling assumptions. It concluded that the most plausible range of ICER estimates was likely to be above what NICE considers a cost-effective use of NHS resources. Therefore, it did not recommend solriamfetol as a treatment option when modafinil is the only previous treatment.\n\n# Other factors\n\nA patient organisation raised a potential equality issue in that the MHRA has issued a warning that modafinil use is linked to birth defects and reduced oral contraception efficacy. It said anyone with narcolepsy affected by this warning needs alternative treatment options. The committee was also aware that treatment with dexamfetamine or methylphenidate may not be suitable for some people. This includes people with certain mental health conditions. The committee concluded that its recommendations would not affect these groups any differently than other groups because they allow solriamfetol treatment when modafinil, methylphenidate or dexamfetamine cannot be used.\n\nThe QALY may not have captured changes in health-related quality of life in the model and the committee took this into account in its decision-making (see section\xa03.1 and section\xa03.11).\n\n# Conclusion\n\n## Solriamfetol is recommended for treating excessive daytime sleepiness caused by narcolepsy after modafinil and either dexamfetamine or methylphenidate\n\nThe committee concluded that solriamfetol was cost effective compared with pitolisant or sodium oxybate. It also concluded that the most plausible ICERs for solriamfetol compared with dexamfetamine or methylphenidate were substantially above the range that NICE usually considers an acceptable use of NHS resources. Therefore, it recommended solriamfetol for routine commissioning in the NHS only when modafinil and either dexamfetamine or methylphenidate have not worked well enough or are not suitable to control excessive daytime sleepiness caused by narcolepsy."}
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https://www.nice.org.uk/guidance/ta758
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Evidence-based recommendations on solriamfetol (Sunosi) for treating excessive daytime sleepiness caused by narcolepsy in adults.
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d53e96d7f5c24354419bf38c69f90ebbd3447cda
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nice
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Headaches in over 12s: diagnosis and management
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Headaches in over 12s: diagnosis and management
This guideline covers advice on the diagnosis and management of tension-type headache, migraine (including migraine with aura and menstrual-related migraine), cluster headache and medication overuse headache in young people (aged 12 years and older) and adults. It aims to improve the recognition and management of headaches, with more targeted treatment to improve the quality of life for people with headaches, and to reduce unnecessary investigations.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Assessment
Evaluate people who present with headache and any of the following features, and consider the need for further investigations and/or referral:
worsening headache with fever
sudden‑onset headache reaching maximum intensity within 5 minutes
new‑onset neurological deficit
new‑onset cognitive dysfunction
change in personality
impaired level of consciousness
recent (typically within the past 3 months) head trauma
headache triggered by cough, valsalva (trying to breathe out with nose and mouth blocked) or sneeze
headache triggered by exercise
-rthostatic headache (headache that changes with posture)
symptoms suggestive of giant cell arteritis
symptoms and signs of acute narrow angle glaucoma
a substantial change in the characteristics of their headache. For information on referral for suspected tumours of the brain or central nervous system, see the NICE guideline on suspected cancer.
Consider further investigations and/or referral for people who present with new‑onset headache and any of the following:
compromised immunity, caused, for example, by HIV or immunosuppressive drugs
age under 20 years and a history of malignancy
a history of malignancy known to metastasise to the brain
vomiting without other obvious cause.
Consider using a headache diary to aid the diagnosis of primary headaches.
If a headache diary is used, ask the person to record the following for a minimum of 8 weeks:
frequency, duration and severity of headaches
any associated symptoms
all prescribed and over the counter medications taken to relieve headaches
possible precipitants
relationship of headaches to menstruation.
# Diagnosis
## Tension‑type headache, migraine (with or without aura) and cluster headache
Diagnose tension‑type headache, migraine or cluster headache according to the headache features in table 1. Chronic migraine and chronic tension‑type headache commonly overlap. If there are any features of migraine, diagnose chronic migraine.See recommendations 1.2.2, 1.2.3 and 1.2.4 for more information on diagnosis of migraine with aura.
Headache feature
Tension‑type headache
Migraine (with or without aura)
Cluster headache
Pain location (can be in the head, face or neck)
Bilateral
Unilateral or bilateral
Unilateral (around the eye, above the eye and along the side of the head/face)
Pain quality
Pressing/tightening (non‑pulsating)
Pulsating (throbbing or banging in young people aged 12 to 17 years)
Variable (can be sharp, boring, burning, throbbing or tightening)
Pain intensity
Mild or moderate
Moderate or severe
Severe or very severe
Effect on activities
Not aggravated by routine activities of daily living
Aggravated by, or causes avoidance of, routine activities of daily living
Restlessness or agitation
Other symptoms
None
Unusual sensitivity to light and/or sound or nausea and/or vomiting
Symptoms of aura can occur with or without headache and:
are fully reversible
develop over at least 5 minutes
last 5 to 60 minutes
Typical aura symptoms include visual symptoms such as flickering lights, spots or lines and/or partial loss of vision; sensory symptoms such as numbness and/or pins and needles; and/or speech disturbance
On the same side as the headache:
red and/or watery eye
nasal congestion and/or runny nose
swollen eyelid
forehead and facial sweating
constricted pupil and/or drooping eyelid
Duration of headache
minutes to continuous
to 72 hours in adults
to 72 hours in young people aged 12 to 17 years
to 180 minutes
Episodic tension-type headaches occur on fewer than 15 days per month. Chronic tension-type headaches occur on 15 or more days per month for more than 3 months.
Episodic migraines (with or without aura) occur on fewer than 15 days per month. Chronic migraines (with or without aura) occur on 15 or more days per month for more than 3 months.
Episodic cluster headaches occur from once every other day to 8 times a day with a pain-free period of more than 1 month. Chronic cluster headaches occur from once every other day to 8 times a day with a continuous pain-free period of less than 1 month in a 12-month period.
NICE has developed technology appraisal guidance on botulinum toxin type A for the prevention of headaches in adults with chronic migraine (headaches on at least 15 days per month of which at least 8 days are with migraine).
## Migraine with aura
Suspect aura in people who present with or without headache and with neurological symptoms that:
are fully reversible and
develop gradually, either alone or in succession, over at least 5 minutes and
last for 5 to 60 minutes.
Diagnose migraine with aura in people who present with or without headache and with one or more of the following typical aura symptoms that meet the criteria in recommendation 1.2.2:
visual symptoms that may be positive (for example, flickering lights, spots or lines) and/or negative (for example, partial loss of vision)
sensory symptoms that may be positive (for example, pins and needles) and/or negative (for example, numbness)
speech disturbance.
Consider further investigations and/or referral for people who present with or without migraine headache and with any of the following atypical aura symptoms that meet the criteria in recommendation 1.2.2:
motor weakness or
double vision or
visual symptoms affecting only one eye or
poor balance or
decreased level of consciousness.
## Menstrual‑related migraine
Suspect menstrual‑related migraine in women and girls whose migraine occurs predominantly between 2 days before and 3 days after the start of menstruation in at least 2 out of 3 consecutive menstrual cycles.
Diagnose menstrual‑related migraine using a headache diary (see recommendation 1.1.4) for at least 2 menstrual cycles.
## Medication overuse headache
Be alert to the possibility of medication overuse headache in people whose headache developed or worsened while they were taking the following drugs for 3 months or more:
triptans, opioids, ergots or combination analgesic medications on 10 days per month or more or
paracetamol, aspirin or an NSAID, either alone or in any combination, on 15 days per month or more. For guidance on safe prescribing of opioids and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
# Management
## All headache disorders
Consider using a headache diary:
to record the frequency, duration and severity of headaches
to monitor the effectiveness of headache interventions
as a basis for discussion with the person about their headache disorder and its impact.
Consider further investigations and/or referral if a person diagnosed with a headache disorder develops any of the features listed in recommendation 1.1.1.
Do not refer people diagnosed with tension‑type headache, migraine, cluster headache or medication overuse headache for neuroimaging solely for reassurance.
Include the following in discussions with the person with a headache disorder:
a positive diagnosis, including an explanation of the diagnosis and reassurance that other pathology has been excluded and
the options for management and
recognition that headache is a valid medical disorder that can have a significant impact on the person and their family or carers.
Give the person written and oral information about headache disorders, including information about support organisations.
Explain the risk of medication overuse headache to people who are using acute treatments for their headache disorder.
## Tension‑type headache
Consider aspirin, paracetamol or an NSAID for the acute treatment of tension‑type headache, taking into account the person's preference, comorbidities and risk of adverse events.Because of the association with Reye's syndrome, preparations containing aspirin should not be offered to under 16s.
Do not offer opioids for the acute treatment of tension‑type headache.
Consider a course of up to 10 sessions of acupuncture over 5 to 8 weeks for the prophylactic treatment of chronic tension‑type headache.
## Migraine with or without aura
Offer combination therapy with an oral triptan and an NSAID, or an oral triptan and paracetamol, for the acute treatment of migraine, taking into account the person's preference, comorbidities and risk of adverse events. For young people aged 12 to 17 years consider a nasal triptan in preference to an oral triptan. In November 2015, this was an off-label use of triptans (except nasal sumatriptan) in under 18s. See NICE's information on prescribing medicines.
For people who prefer to take only one drug, consider monotherapy with an oral triptan, NSAID, aspirin (900 mg) or paracetamol for the acute treatment of migraine, taking into account the person's preference, comorbidities and risk of adverse events. In November 2015, this was an off-label use of triptans in under 18s. See NICE's information on prescribing medicines. Because of the association with Reye's syndrome, preparations containing aspirin should not be offered to under 16s.
When prescribing a triptan start with the one that has the lowest acquisition cost; if this is consistently ineffective, try one or more alternative triptans. In November 2015, this was an off-label use of triptans in under 18s. See NICE's information on prescribing medicines.
Consider an anti‑emetic in addition to other acute treatment for migraine even in the absence of nausea and vomiting.
Do not offer ergots or opioids for the acute treatment of migraine.
For people in whom oral preparations (or nasal preparations in young people aged 12 to 17 years) for the acute treatment of migraine are ineffective or not tolerated:
consider a non‑oral preparation of metoclopramide or prochlorperazine and
if non-oral metoclopramide or prochlorperazine is used, consider adding a non‑oral NSAID or triptan if they have not been tried. Note the special warnings and precautions for use in the summaries of product characteristics for metoclopramide and prochlorperazine, and discuss the benefits and risks with the person (or their parents or carers, as appropriate).In November 2015, only a buccal preparation of prochlorperazine was licensed for this indication (prochlorperazine was licensed for the relief of nausea and vomiting); nasal sumatriptan was the only triptan licensed for this indication in under 18s. This was an off‑label use of metoclopramide in children and young people. See NICE's information on prescribing medicines.
Discuss the benefits and risks of prophylactic treatment for migraine with the person, taking into account the person's preference, comorbidities, risk of adverse events and the impact of the headache on their quality of life.
For the prophylaxis of migraine, offer topiramate or propranolol after a full discussion of the benefits and risks of each option. Include in the discussion:
the potential benefit in reducing migraine recurrence and severity
the risk of fetal malformations with topiramate
the risk of reduced effectiveness of hormonal contraceptives with topiramate
the importance of effective contraception for women and girls of childbearing potential who are taking topiramate (for example, by using medroxyprogesterone acetate depot injection, an intrauterine method or combined hormonal contraception with a barrier method).Follow the MHRA safety advice on antiepileptic drugs in pregnancy. In November 2015, this was an off-label use of topiramate in children and young people. See NICE's information on prescribing medicines. People with depression and migraine could be at an increased risk of using propranolol for self-harm. Use caution when prescribing propranolol, in line with the Healthcare Safety Investigation Branch's report on the under-recognised risk of harm from propranolol.
Consider amitriptyline for the prophylactic treatment of migraine according to the person's preference, comorbidities and risk of adverse events. In November 2015, this was an off-label use of amitriptyline. See NICE's information on prescribing medicines. For guidance on safe prescribing of antidepressants (such as amitriptyline) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
Do not offer gabapentin for the prophylactic treatment of migraine.
If both topiramate and propranolol are unsuitable or ineffective, consider a course of up to 10 sessions of acupuncture over 5 to 8 weeks according to the person's preference, comorbidities and risk of adverse events.
For people who are already having treatment with another form of prophylaxis and whose migraine is well controlled, continue the current treatment as required.
Review the need for continuing migraine prophylaxis 6 months after the start of prophylactic treatment.
Advise people with migraine that riboflavin (400 mg once a day) may be effective in reducing migraine frequency and intensity for some people. In November 2015, this was an off-label use of riboflavin, but this is available as a food supplement.
Do not routinely offer combined hormonal contraceptives for contraception to women and girls who have migraine with aura.
For women and girls with predictable menstrual‑related migraine that does not respond adequately to standard acute treatment, consider treatment with frovatriptan (2.5 mg twice a day) or zolmitriptan (2.5 mg twice or three times a day) on the days migraine is expected. In November 2015, this was an off-label use of frovatriptan and zolmitriptan. See NICE's information on prescribing medicines.
Offer pregnant women paracetamol for the acute treatment of migraine. Consider the use of a triptan or an NSAID after discussing the woman's need for treatment and the risks associated with the use of each medication during pregnancy. In November 2015, this was an off-label use of triptans (except nasal sumatriptan) in under 18s. See NICE's information on prescribing medicines.
Seek specialist advice if prophylactic treatment for migraine is needed during pregnancy.
## Cluster headache
Discuss the need for neuroimaging for people with a first bout of cluster headache with a GP with a special interest in headache or a neurologist.
Offer oxygen and/or a subcutaneous or nasal triptan for the acute treatment of cluster headache. In November 2015, this was an off-label use of subcutaneous triptans in under 18s. Nasal triptans did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.
When using oxygen for the acute treatment of cluster headache:
use 100% oxygen at a flow rate of at least 12 litres per minute with a non‑rebreathing mask and a reservoir bag and
arrange provision of home and ambulatory oxygen.
When using a subcutaneous or nasal triptan, ensure the person is offered an adequate supply of triptans calculated according to their history of cluster bouts, based on the manufacturer's maximum daily dose. In November 2015, this was an off-label use of subcutaneous triptans in under 18s. Nasal triptans did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.
Do not offer paracetamol, NSAIDS, opioids, ergots or oral triptans for the acute treatment of cluster headache.
Consider verapamil for prophylactic treatment during a bout of cluster headache. If unfamiliar with its use for cluster headache, seek specialist advice before starting verapamil, including advice on electrocardiogram monitoring. In November 2015, this was an off-label use of verapamil. See NICE's information on prescribing medicines.
Seek specialist advice for cluster headache that does not respond to verapamil. In November 2015, this was an off-label use of verapamil. See NICE's information on prescribing medicines.
Seek specialist advice if treatment for cluster headache is needed during pregnancy.
## Medication overuse headache
For guidance on managing withdrawal of opioids, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.
Explain to people with medication overuse headache that it is treated by withdrawing overused medication.
Advise people to stop taking all overused acute headache medications for at least 1 month and to stop abruptly rather than gradually.
Advise people that headache symptoms are likely to get worse in the short term before they improve and that there may be associated withdrawal symptoms, and provide them with close follow‑up and support according to their needs.
Consider prophylactic treatment for the underlying primary headache disorder in addition to withdrawal of overused medication for people with medication overuse headache.
Do not routinely offer inpatient withdrawal for medication overuse headache.
Consider specialist referral and/or inpatient withdrawal of overused medication for people who are using strong opioids, or have relevant comorbidities, or in whom previous repeated attempts at withdrawal of overused medication have been unsuccessful.
Review the diagnosis of medication overuse headache and further management 4 to 8 weeks after the start of withdrawal of overused medication.
# Terms used in this guideline
## Acute narrow‑angle glaucoma
An uncommon eye condition that results from blockage of the drainage of fluid from the eye. Symptoms of acute glaucoma may include headache with a painful red eye and misty vision or haloes, and in some cases nausea. Acute glaucoma may be differentiated from cluster headache by the presence of a semi‑dilated pupil compared with the presence of a constricted pupil in cluster headache.
## Cluster headache bout
The duration over which recurrent cluster headaches occur, usually lasting weeks or months. Headaches occur from 1 every other day to 8 times per day.
## Giant cell arteritis
Also known as temporal arteritis, giant cell arteritis is characterised by the inflammation of the walls of medium and large arteries. Branches of the carotid artery and the ophthalmic artery are preferentially involved, giving rise to symptoms of headache, visual disturbances and jaw claudication.
## NSAID
Non‑steroidal anti‑inflammatory drug.
## Positive diagnosis
A diagnosis based on the typical clinical picture that does not require any further investigations to exclude alternative explanations for a patient's symptoms.# Context
Headaches are one of the most common neurological problems presented to GPs and neurologists. They are painful and debilitating for individuals, an important cause of absence from work or school and a substantial burden on society.
Headache disorders are classified as primary or secondary. The aetiology of primary headaches is not well understood and they are classified according to their clinical pattern. The most common primary headache disorders are tension‑type headache, migraine and cluster headache. Secondary headaches are attributed to underlying disorders and include, for example, headaches associated with medication overuse, giant cell arteritis, raised intracranial pressure and infection. Medication overuse headache most commonly occurs in those taking medication for a primary headache disorder. The major health and social burden of headaches is caused by primary headache disorders and medication overuse headache.
This guideline makes recommendations on the diagnosis and management of the most common primary headache disorders in young people (aged 12 years and older) and adults. Many people with headache do not have an accurate diagnosis of headache type. Healthcare professionals can find the diagnosis of headache difficult, and both people with headache and their healthcare professionals can be concerned about possible underlying causes. Improved recognition of primary headaches will help the generalist clinician to manage headaches more effectively, allow better targeting of treatment and potentially improve quality of life and reduce unnecessary investigations for people with headache.
In 2015, we reviewed the evidence on the prophylactic treatment of headaches and updated or added new recommendations.# Recommendations for research
In 2012, the guideline committee made the following recommendations for research.
# Amitriptyline to prevent recurrent migraine
Is amitriptyline a clinically and cost effective prophylactic treatment for recurrent migraine?
## Why this is important
Effective prevention has the potential to make a major impact on the burden of disability caused by recurrent migraine. There are few pharmacological agents that have been proven to prevent recurrent migraine.
Amitriptyline is widely used, off‑label, to treat chronic painful disorders, including migraine. The updated evidence review (2015) found evidence comparing amitriptyline with topiramate, but not with placebo, and there was uncertainty about the effectiveness of amitriptyline as a prophylactic treatment. A double‑blind randomised controlled trial (RCT) is needed to assess the clinical and cost effectiveness of amitriptyline compared with placebo. The definition of migraine used should be that in the International classification of headache disorders 2 or this guideline. Outcomes should include change in patient‑reported headache days, responder rate and incidence of serious adverse events.
# Pizotifen to prevent recurrent migraine
Is pizotifen a clinically and cost effective prophylactic treatment for recurrent migraine?
## Why this is important
There are few data to inform guidance on the prevention of migraine in children and young people.
Pizotifen is a popular treatment for migraine prevention in the UK, especially in children and young people. It has been in use since the 1970s and appears to be well tolerated. Inadequate evidence was found in the review for this guideline for the effectiveness of pizotifen in the prophylaxis of migraine. A double‑blind RCT either head‑to‑head with best available treatment, or placebo controlled, is needed to assess the clinical and cost effectiveness of pizotifen in young people aged under 18 and adults. The trial should enrol people aged under 18 and adults. The definition of migraine used should be that in the International classification of headache disorders 2 or this guideline. Outcomes should include change in patient‑reported migraine days, responder rate and incidence of serious adverse events. If pizotifen is shown to be effective, it will widen the range of therapeutic options, in particular for young people in whom recommended medications are ineffective or not tolerated.
# Topiramate to prevent recurrent cluster headache
Is topiramate a clinically and cost effective prophylactic treatment for recurrent cluster headache?
## Why this is important
Cluster headache is an excruciatingly painful and highly disabling disorder. The management of cluster headache includes the use of preventive treatments to stop the attacks as quickly and safely as possible. There is a significant unmet clinical need for effective preventive treatments in cluster headache and few data to inform guidance on prophylaxis of cluster headache. Although numerous agents including verapamil, topiramate, lithium, methysergide and gabapentin are used in routine clinical practice, this is largely based on clinical experience as very few RCTs have been performed.
Several open‑label studies have reported on the efficacy of topiramate in the preventive treatment of cluster headache. There is therefore a need for a high‑quality RCT of topiramate in the prevention of cluster headaches.
# Psychological interventions to manage chronic headache disorders
Does a psychological intervention such as cognitive behavioural therapy (CBT) improve headache outcomes and quality of life for people with chronic headache disorders?
## Why this is important
Psychological interventions such as CBT are widely recommended for people with chronic painful disorders. An effective psychological intervention based on cognitive behavioural principles for people with chronic headache disorders has the potential to substantially improve their quality of life. There are few data to support the use of these interventions to manage chronic headache disorders.
A pragmatic RCT is needed to assess the impact of a psychological intervention compared with an active control. Mood disorders are commonly comorbid with headache disorders, but the trial needs to address the impact of a psychological intervention on headache alone, using appropriate headache outcomes such as change in patient‑reported headache days and headache‑specific quality of life.
# Pharmacological treatments for headache prophylaxis to aid withdrawal treatment in medication overuse headache
Does a course of steroid treatment or pharmacological treatments used for headache prophylaxis help people with medication overuse headaches withdraw from medication?
## Why this is important
Medication overuse headache is a common disorder. Current best advice is for abrupt withdrawal without any supportive pharmacological treatment. Many people with medication overuse headache find it difficult to withdraw abruptly because in the short term their headaches can become much worse. The use of steroids may aid withdrawal and for those who have an underlying headache disorder such as migraine or tension‑type headache, appropriate prophylaxis may assist in treating the headache.
Double‑blind RCTs are needed in people with suspected medication overuse headache who have an identifiable primary headache disorder. There should be two separate trials, one to investigate withdrawal of medication with placebo versus withdrawal of medication with steroid treatment, and the other to investigate withdrawal of medication with placebo versus withdrawal of medication with appropriate pharmacological prophylaxis. Outcomes should include change in acute medication use, proportion of patients who no longer have suspected medication overuse headache, change in patient‑reported headache days and headache‑specific quality of life.
|
{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Assessment\n\nEvaluate people who present with headache and any of the following features, and consider the need for further investigations and/or referral:\n\nworsening headache with fever\n\nsudden‑onset headache reaching maximum intensity within 5\xa0minutes\n\nnew‑onset neurological deficit\n\nnew‑onset cognitive dysfunction\n\nchange in personality\n\nimpaired level of consciousness\n\nrecent (typically within the past 3\xa0months) head trauma\n\nheadache triggered by cough, valsalva (trying to breathe out with nose and mouth blocked) or sneeze\n\nheadache triggered by exercise\n\northostatic headache (headache that changes with posture)\n\nsymptoms suggestive of giant cell arteritis\n\nsymptoms and signs of acute narrow angle glaucoma\n\na substantial change in the characteristics of their headache. For information on referral for suspected tumours of the brain or central nervous system, see the NICE guideline on suspected cancer.\n\nConsider further investigations and/or referral for people who present with new‑onset headache and any of the following:\n\ncompromised immunity, caused, for example, by HIV or immunosuppressive drugs\n\nage under 20\xa0years and a history of malignancy\n\na history of malignancy known to metastasise to the brain\n\nvomiting without other obvious cause. \n\nConsider using a headache diary to aid the diagnosis of primary headaches. \n\nIf a headache diary is used, ask the person to record the following for a minimum of 8\xa0weeks:\n\nfrequency, duration and severity of headaches\n\nany associated symptoms\n\nall prescribed and over the counter medications taken to relieve headaches\n\npossible precipitants\n\nrelationship of headaches to menstruation. \n\n# Diagnosis\n\n## Tension‑type headache, migraine (with or without aura) and cluster headache\n\nDiagnose tension‑type headache, migraine or cluster headache according to the headache features in table\xa01. Chronic migraine and chronic tension‑type headache commonly overlap. If there are any features of migraine, diagnose chronic migraine.See recommendations 1.2.2, 1.2.3 and 1.2.4 for more information on diagnosis of migraine with aura. \n\nHeadache feature\n\nTension‑type headache\n\nMigraine (with or without aura)\n\nCluster headache\n\nPain location (can be in the head, face or neck)\n\nBilateral\n\nUnilateral or bilateral\n\nUnilateral (around the eye, above the eye and along the side of the head/face)\n\nPain quality\n\nPressing/tightening (non‑pulsating)\n\nPulsating (throbbing or banging in young people aged 12 to 17\xa0years)\n\nVariable (can be sharp, boring, burning, throbbing or tightening)\n\nPain intensity\n\nMild or moderate\n\nModerate or severe\n\nSevere or very severe\n\nEffect on activities\n\nNot aggravated by routine activities of daily living\n\nAggravated by, or causes avoidance of, routine activities of daily living\n\nRestlessness or agitation\n\nOther symptoms\n\nNone\n\nUnusual sensitivity to light and/or sound or nausea and/or vomiting\n\nSymptoms of aura can occur with or without headache and:\n\nare fully reversible\n\ndevelop over at least 5\xa0minutes\n\nlast 5 to 60\xa0minutes\n\nTypical aura symptoms include visual symptoms such as flickering lights, spots or lines and/or partial loss of vision; sensory symptoms such as numbness and/or pins and needles; and/or speech disturbance\n\nOn the same side as the headache:\n\nred and/or watery eye\n\nnasal congestion and/or runny nose\n\nswollen eyelid\n\nforehead and facial sweating\n\nconstricted pupil and/or drooping eyelid\n\nDuration of headache\n\nminutes to continuous\n\nto 72\xa0hours in adults\n\nto 72\xa0hours in young people aged 12 to 17\xa0years\n\nto 180\xa0minutes\n\nEpisodic tension-type headaches occur on fewer than 15\xa0days per month. Chronic tension-type headaches occur on 15\xa0or more days per month for more than 3\xa0months.\n\nEpisodic migraines (with or without aura) occur on fewer than 15\xa0days per month. Chronic migraines (with or without aura) occur on 15\xa0or more days per month for more than 3\xa0months.\n\nEpisodic cluster headaches occur from once every other day to 8\xa0times a day with a pain-free period of more than 1\xa0month. Chronic cluster headaches occur from once every other day to 8\xa0times a day with a continuous pain-free period of less than 1\xa0month in a 12-month period.\n\nNICE has developed technology appraisal guidance on botulinum toxin type\xa0A for the prevention of headaches in adults with chronic migraine (headaches on at least 15\xa0days per month of which at least 8\xa0days are with migraine).\n\n## Migraine with aura\n\nSuspect aura in people who present with or without headache and with neurological symptoms that:\n\nare fully reversible and\n\ndevelop gradually, either alone or in succession, over at least 5\xa0minutes and\n\nlast for 5\xa0to 60\xa0minutes. \n\nDiagnose migraine with aura in people who present with or without headache and with one or more of the following typical aura symptoms that meet the criteria in recommendation\xa01.2.2:\n\nvisual symptoms that may be positive (for example, flickering lights, spots or lines) and/or negative (for example, partial loss of vision)\n\nsensory symptoms that may be positive (for example, pins and needles) and/or negative (for example, numbness)\n\nspeech disturbance. \n\nConsider further investigations and/or referral for people who present with or without migraine headache and with any of the following atypical aura symptoms that meet the criteria in recommendation\xa01.2.2:\n\nmotor weakness or\n\ndouble vision or\n\nvisual symptoms affecting only one eye or\n\npoor balance or\n\ndecreased level of consciousness. \n\n## Menstrual‑related migraine\n\nSuspect menstrual‑related migraine in women and girls whose migraine occurs predominantly between 2\xa0days before and 3\xa0days after the start of menstruation in at least 2\xa0out of 3\xa0consecutive menstrual cycles. \n\nDiagnose menstrual‑related migraine using a headache diary (see recommendation\xa01.1.4) for at least 2\xa0menstrual cycles. \n\n## Medication overuse headache\n\nBe alert to the possibility of medication overuse headache in people whose headache developed or worsened while they were taking the following drugs for 3\xa0months or more:\n\ntriptans, opioids, ergots or combination analgesic medications on 10\xa0days per month or more or\n\nparacetamol, aspirin or an NSAID, either alone or in any combination, on 15\xa0days per month or more. For guidance on safe prescribing of opioids and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\n# Management\n\n## All headache disorders\n\nConsider using a headache diary:\n\nto record the frequency, duration and severity of headaches\n\nto monitor the effectiveness of headache interventions\n\nas a basis for discussion with the person about their headache disorder and its impact. \n\nConsider further investigations and/or referral if a person diagnosed with a headache disorder develops any of the features listed in recommendation\xa01.1.1. \n\nDo not refer people diagnosed with tension‑type headache, migraine, cluster headache or medication overuse headache for neuroimaging solely for reassurance. \n\nInclude the following in discussions with the person with a headache disorder:\n\na positive diagnosis, including an explanation of the diagnosis and reassurance that other pathology has been excluded and\n\nthe options for management and\n\nrecognition that headache is a valid medical disorder that can have a significant impact on the person and their family or carers. \n\nGive the person written and oral information about headache disorders, including information about support organisations. \n\nExplain the risk of medication overuse headache to people who are using acute treatments for their headache disorder. \n\n## Tension‑type headache\n\nConsider aspirin, paracetamol or an NSAID for the acute treatment of tension‑type headache, taking into account the person's preference, comorbidities and risk of adverse events.Because of the association with Reye's syndrome, preparations containing aspirin should not be offered to under\xa016s. \n\nDo not offer opioids for the acute treatment of tension‑type headache. \n\nConsider a course of up to 10\xa0sessions of acupuncture over 5\xa0to 8\xa0weeks for the prophylactic treatment of chronic tension‑type headache. \n\n## Migraine with or without aura\n\nOffer combination therapy with an oral triptan and an NSAID, or an oral triptan and paracetamol, for the acute treatment of migraine, taking into account the person's preference, comorbidities and risk of adverse events. For young people aged 12\xa0to 17\xa0years consider a nasal triptan in preference to an oral triptan. In November 2015, this was an off-label use of triptans (except nasal sumatriptan) in under\xa018s. See NICE's information on prescribing medicines.\n\nFor people who prefer to take only one drug, consider monotherapy with an oral triptan, NSAID, aspirin (900\xa0mg) or paracetamol for the acute treatment of migraine, taking into account the person's preference, comorbidities and risk of adverse events. In November 2015, this was an off-label use of triptans in under\xa018s. See NICE's information on prescribing medicines. Because of the association with Reye's syndrome, preparations containing aspirin should not be offered to under\xa016s.\n\nWhen prescribing a triptan start with the one that has the lowest acquisition cost; if this is consistently ineffective, try one or more alternative triptans. In November 2015, this was an off-label use of triptans in under\xa018s. See NICE's information on prescribing medicines.\n\nConsider an anti‑emetic in addition to other acute treatment for migraine even in the absence of nausea and vomiting. \n\nDo not offer ergots or opioids for the acute treatment of migraine. \n\nFor people in whom oral preparations (or nasal preparations in young people aged 12\xa0to 17\xa0years) for the acute treatment of migraine are ineffective or not tolerated:\n\nconsider a non‑oral preparation of metoclopramide or prochlorperazine and\n\nif non-oral metoclopramide or prochlorperazine is used, consider adding a non‑oral NSAID or triptan if they have not been tried. [2012, amended 2021]Note the special warnings and precautions for use in the summaries of product characteristics for metoclopramide and prochlorperazine, and discuss the benefits and risks with the person (or their parents or carers, as appropriate).In November 2015, only a buccal preparation of prochlorperazine was licensed for this indication (prochlorperazine was licensed for the relief of nausea and vomiting); nasal sumatriptan was the only triptan licensed for this indication in under\xa018s. This was an off‑label use of metoclopramide in children and young people. See NICE's information on prescribing medicines.\n\nDiscuss the benefits and risks of prophylactic treatment for migraine with the person, taking into account the person's preference, comorbidities, risk of adverse events and the impact of the headache on their quality of life. \n\nFor the prophylaxis of migraine, offer topiramate or propranolol after a full discussion of the benefits and risks of each option. Include in the discussion:\n\nthe potential benefit in reducing migraine recurrence and severity\n\nthe risk of fetal malformations with topiramate\n\nthe risk of reduced effectiveness of hormonal contraceptives with topiramate\n\nthe importance of effective contraception for women and girls of childbearing potential who are taking topiramate (for example, by using medroxyprogesterone acetate depot injection, an intrauterine method or combined hormonal contraception with a barrier method).Follow the MHRA safety advice on antiepileptic drugs in pregnancy. [2015, amended 2021]In November 2015, this was an off-label use of topiramate in children and young people. See NICE's information on prescribing medicines. People with depression and migraine could be at an increased risk of using propranolol for self-harm. Use caution when prescribing propranolol, in line with the Healthcare Safety Investigation Branch's report on the under-recognised risk of harm from propranolol.\n\nConsider amitriptyline for the prophylactic treatment of migraine according to the person's preference, comorbidities and risk of adverse events. In November 2015, this was an off-label use of amitriptyline. See NICE's information on prescribing medicines. For guidance on safe prescribing of antidepressants (such as amitriptyline) and managing withdrawal, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nDo not offer gabapentin for the prophylactic treatment of migraine. \n\nIf both topiramate and propranolol are unsuitable or ineffective, consider a course of up to 10\xa0sessions of acupuncture over 5\xa0to\xa08\xa0weeks according to the person's preference, comorbidities and risk of adverse events. [2012, amended 2015]\n\nFor people who are already having treatment with another form of prophylaxis and whose migraine is well controlled, continue the current treatment as required. [2012, amended 2015]\n\nReview the need for continuing migraine prophylaxis 6\xa0months after the start of prophylactic treatment. \n\nAdvise people with migraine that riboflavin (400\xa0mg once a day) may be effective in reducing migraine frequency and intensity for some people. In November 2015, this was an off-label use of riboflavin, but this is available as a food supplement.\n\nDo not routinely offer combined hormonal contraceptives for contraception to women and girls who have migraine with aura. \n\nFor women and girls with predictable menstrual‑related migraine that does not respond adequately to standard acute treatment, consider treatment with frovatriptan (2.5\xa0mg twice a day) or zolmitriptan (2.5\xa0mg twice or three times a day) on the days migraine is expected. In November 2015, this was an off-label use of frovatriptan and zolmitriptan. See NICE's information on prescribing medicines.\n\nOffer pregnant women paracetamol for the acute treatment of migraine. Consider the use of a triptan or an NSAID after discussing the woman's need for treatment and the risks associated with the use of each medication during pregnancy. In November 2015, this was an off-label use of triptans (except nasal sumatriptan) in under\xa018s. See NICE's information on prescribing medicines.\n\nSeek specialist advice if prophylactic treatment for migraine is needed during pregnancy. \n\n## Cluster headache\n\nDiscuss the need for neuroimaging for people with a first bout of cluster headache with a GP with a special interest in headache or a neurologist. \n\nOffer oxygen and/or a subcutaneous or nasal triptan for the acute treatment of cluster headache. In November 2015, this was an off-label use of subcutaneous triptans in under\xa018s. Nasal triptans did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.\n\nWhen using oxygen for the acute treatment of cluster headache:\n\nuse 100% oxygen at a flow rate of at least 12\xa0litres per minute with a non‑rebreathing mask and a reservoir bag and\n\narrange provision of home and ambulatory oxygen. \n\nWhen using a subcutaneous or nasal triptan, ensure the person is offered an adequate supply of triptans calculated according to their history of cluster bouts, based on the manufacturer's maximum daily dose. In November 2015, this was an off-label use of subcutaneous triptans in under\xa018s. Nasal triptans did not have a UK marketing authorisation for this indication. See NICE's information on prescribing medicines.\n\nDo not offer paracetamol, NSAIDS, opioids, ergots or oral triptans for the acute treatment of cluster headache. \n\nConsider verapamil for prophylactic treatment during a bout of cluster headache. If unfamiliar with its use for cluster headache, seek specialist advice before starting verapamil, including advice on electrocardiogram monitoring. In November 2015, this was an off-label use of verapamil. See NICE's information on prescribing medicines.\n\nSeek specialist advice for cluster headache that does not respond to verapamil. In November 2015, this was an off-label use of verapamil. See NICE's information on prescribing medicines.\n\nSeek specialist advice if treatment for cluster headache is needed during pregnancy. \n\n## Medication overuse headache\n\nFor guidance on managing withdrawal of opioids, see NICE's guideline on medicines associated with dependence or withdrawal symptoms.\n\nExplain to people with medication overuse headache that it is treated by withdrawing overused medication. \n\nAdvise people to stop taking all overused acute headache medications for at least 1\xa0month and to stop abruptly rather than gradually. \n\nAdvise people that headache symptoms are likely to get worse in the short term before they improve and that there may be associated withdrawal symptoms, and provide them with close follow‑up and support according to their needs. \n\nConsider prophylactic treatment for the underlying primary headache disorder in addition to withdrawal of overused medication for people with medication overuse headache. \n\nDo not routinely offer inpatient withdrawal for medication overuse headache. \n\nConsider specialist referral and/or inpatient withdrawal of overused medication for people who are using strong opioids, or have relevant comorbidities, or in whom previous repeated attempts at withdrawal of overused medication have been unsuccessful. \n\nReview the diagnosis of medication overuse headache and further management 4\xa0to 8\xa0weeks after the start of withdrawal of overused medication. \n\n# Terms used in this guideline\n\n## Acute narrow‑angle glaucoma\n\nAn uncommon eye condition that results from blockage of the drainage of fluid from the eye. Symptoms of acute glaucoma may include headache with a painful red eye and misty vision or haloes, and in some cases nausea. Acute glaucoma may be differentiated from cluster headache by the presence of a semi‑dilated pupil compared with the presence of a constricted pupil in cluster headache.\n\n## Cluster headache bout\n\nThe duration over which recurrent cluster headaches occur, usually lasting weeks or months. Headaches occur from 1\xa0every other day to 8\xa0times per day.\n\n## Giant cell arteritis\n\nAlso known as temporal arteritis, giant cell arteritis is characterised by the inflammation of the walls of medium and large arteries. Branches of the carotid artery and the ophthalmic artery are preferentially involved, giving rise to symptoms of headache, visual disturbances and jaw claudication.\n\n## NSAID\n\nNon‑steroidal anti‑inflammatory drug.\n\n## Positive diagnosis\n\nA diagnosis based on the typical clinical picture that does not require any further investigations to exclude alternative explanations for a patient's symptoms.", 'Context': 'Headaches are one of the most common neurological problems presented to GPs and neurologists. They are painful and debilitating for individuals, an important cause of absence from work or school and a substantial burden on society.\n\nHeadache disorders are classified as primary or secondary. The aetiology of primary headaches is not well understood and they are classified according to their clinical pattern. The most common primary headache disorders are tension‑type headache, migraine and cluster headache. Secondary headaches are attributed to underlying disorders and include, for example, headaches associated with medication overuse, giant cell arteritis, raised intracranial pressure and infection. Medication overuse headache most commonly occurs in those taking medication for a primary headache disorder. The major health and social burden of headaches is caused by primary headache disorders and medication overuse headache.\n\nThis guideline makes recommendations on the diagnosis and management of the most common primary headache disorders in young people (aged 12\xa0years and older) and adults. Many people with headache do not have an accurate diagnosis of headache type. Healthcare professionals can find the diagnosis of headache difficult, and both people with headache and their healthcare professionals can be concerned about possible underlying causes. Improved recognition of primary headaches will help the generalist clinician to manage headaches more effectively, allow better targeting of treatment and potentially improve quality of life and reduce unnecessary investigations for people with headache.\n\nIn 2015, we reviewed the evidence on the prophylactic treatment of headaches and updated or added new recommendations.', 'Recommendations for research': 'In 2012, the guideline committee made the following recommendations for research.\n\n# Amitriptyline to prevent recurrent migraine\n\nIs amitriptyline a clinically and cost effective prophylactic treatment for recurrent migraine?\n\n## Why this is important\n\nEffective prevention has the potential to make a major impact on the burden of disability caused by recurrent migraine. There are few pharmacological agents that have been proven to prevent recurrent migraine.\n\nAmitriptyline is widely used, off‑label, to treat chronic painful disorders, including migraine. The updated evidence review (2015) found evidence comparing amitriptyline with topiramate, but not with placebo, and there was uncertainty about the effectiveness of amitriptyline as a prophylactic treatment. A double‑blind randomised controlled trial (RCT) is needed to assess the clinical and cost effectiveness of amitriptyline compared with placebo. The definition of migraine used should be that in the International classification of headache disorders\xa02 or this guideline. Outcomes should include change in patient‑reported headache days, responder rate and incidence of serious adverse events.\n\n# Pizotifen to prevent recurrent migraine\n\nIs pizotifen a clinically and cost effective prophylactic treatment for recurrent migraine?\n\n## Why this is important\n\nThere are few data to inform guidance on the prevention of migraine in children and young people.\n\nPizotifen is a popular treatment for migraine prevention in the UK, especially in children and young people. It has been in use since the 1970s and appears to be well tolerated. Inadequate evidence was found in the review for this guideline for the effectiveness of pizotifen in the prophylaxis of migraine. A double‑blind RCT either head‑to‑head with best available treatment, or placebo controlled, is needed to assess the clinical and cost effectiveness of pizotifen in young people aged under\xa018 and adults. The trial should enrol people aged under\xa018 and adults. The definition of migraine used should be that in the International classification of headache disorders\xa02 or this guideline. Outcomes should include change in patient‑reported migraine days, responder rate and incidence of serious adverse events. If pizotifen is shown to be effective, it will widen the range of therapeutic options, in particular for young people in whom recommended medications are ineffective or not tolerated.\n\n# Topiramate to prevent recurrent cluster headache\n\nIs topiramate a clinically and cost effective prophylactic treatment for recurrent cluster headache?\n\n## Why this is important\n\nCluster headache is an excruciatingly painful and highly disabling disorder. The management of cluster headache includes the use of preventive treatments to stop the attacks as quickly and safely as possible. There is a significant unmet clinical need for effective preventive treatments in cluster headache and few data to inform guidance on prophylaxis of cluster headache. Although numerous agents including verapamil, topiramate, lithium, methysergide and gabapentin are used in routine clinical practice, this is largely based on clinical experience as very few RCTs have been performed.\n\nSeveral open‑label studies have reported on the efficacy of topiramate in the preventive treatment of cluster headache. There is therefore a need for a high‑quality RCT of topiramate in the prevention of cluster headaches.\n\n# Psychological interventions to manage chronic headache disorders\n\nDoes a psychological intervention such as cognitive behavioural therapy (CBT) improve headache outcomes and quality of life for people with chronic headache disorders?\n\n## Why this is important\n\nPsychological interventions such as CBT are widely recommended for people with chronic painful disorders. An effective psychological intervention based on cognitive behavioural principles for people with chronic headache disorders has the potential to substantially improve their quality of life. There are few data to support the use of these interventions to manage chronic headache disorders.\n\nA pragmatic RCT is needed to assess the impact of a psychological intervention compared with an active control. Mood disorders are commonly comorbid with headache disorders, but the trial needs to address the impact of a psychological intervention on headache alone, using appropriate headache outcomes such as change in patient‑reported headache days and headache‑specific quality of life.\n\n# Pharmacological treatments for headache prophylaxis to aid withdrawal treatment in medication overuse headache\n\nDoes a course of steroid treatment or pharmacological treatments used for headache prophylaxis help people with medication overuse headaches withdraw from medication?\n\n## Why this is important\n\nMedication overuse headache is a common disorder. Current best advice is for abrupt withdrawal without any supportive pharmacological treatment. Many people with medication overuse headache find it difficult to withdraw abruptly because in the short term their headaches can become much worse. The use of steroids may aid withdrawal and for those who have an underlying headache disorder such as migraine or tension‑type headache, appropriate prophylaxis may assist in treating the headache.\n\nDouble‑blind RCTs are needed in people with suspected medication overuse headache who have an identifiable primary headache disorder. There should be two separate trials, one to investigate withdrawal of medication with placebo versus withdrawal of medication with steroid treatment, and the other to investigate withdrawal of medication with placebo versus withdrawal of medication with appropriate pharmacological prophylaxis. Outcomes should include change in acute medication use, proportion of patients who no longer have suspected medication overuse headache, change in patient‑reported headache days and headache‑specific quality of life.'}
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https://www.nice.org.uk/guidance/cg150
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This guideline covers advice on the diagnosis and management of tension-type headache, migraine (including migraine with aura and menstrual-related migraine), cluster headache and medication overuse headache in young people (aged 12 years and older) and adults. It aims to improve the recognition and management of headaches, with more targeted treatment to improve the quality of life for people with headaches, and to reduce unnecessary investigations.
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b753a83dbdde611098db1dbdd6bb4f1119a6c976
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nice
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Endo-SPONGE for treating low rectal anastomotic leak
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Endo-SPONGE for treating low rectal anastomotic leak
Evidence-based recommendations on Endo-SPONGE for treating low rectal anastomotic leak.
# Recommendations
Endo-SPONGE shows promise for treating low rectal anastomotic leaks. However, there is not enough good-quality evidence to support the case for routine adoption in the NHS.
Further evidence in the form of real-world data collection is recommended to address uncertainties about selection criteria, patient-reported outcome measures, stoma reversal and bowel function recovery compared with other treatments. Find out more in the section on further research in this guidance.
Why the committee made these recommendations
Anastomotic leak is a serious complication after colorectal surgery. Endo‑SPONGE is designed to treat leaks after a low rectal anastomosis.
There's not enough evidence assessing the clinical effectiveness of Endo‑SPONGE compared with other non-surgical or surgical treatments in the NHS. Observational studies suggest that Endo‑SPONGE may stop anastomotic leakage and reduce the chance of a permanent stoma, but this evidence is weak.
There are also uncertainties about the cost impact of using Endo-SPONGE in the NHS because of the weak clinical evidence.# The technology
# Technology
Endo-SPONGE is a minimally invasive surgical treatment for anastomotic leak in the low rectal area. It consists of an open-pore sponge with a drain tube, a sponge pusher, silicon overtube guides and a drainage set and system. The system is designed to improve the clearance of leaking discharge in the anastomotic cavity and to promote granulation tissue formation and healing. Risks associated with Endo‑SPONGE include residual sponge particles left in the cavity, erosion of structures next to the sponge, injury to the intestinal wall and bleeding.
The sponge needs to be replaced every 2 to 3 days. The replacement sponge is cut to the size of the leaking cavity as it gets smaller and the drainage tube exits the body through the anus. The first insertion procedure is usually done in an operating theatre under general anaesthesia. The replacement procedures can be done in a day-case theatre or endoscopy suite under light sedation.
# Innovative aspects
Endo‑SPONGE is an endoluminal vacuum therapy device. The sponge is inserted into the leaking cavity using a flexible endoscope or open access through the anus. A drainage tube is connected to the sponge at one end with a drainage bottle at the other end. The bottle has a low-vacuum drainage container that uses suction to put continuous negative pressure on the sponge.
# Intended use
Endo‑SPONGE is intended for people with an extraperitoneal rectal anastomotic leak. It is inserted by colorectal surgeons, endoscopists and gastroenterologists in hospital. The Endo‑SPONGE system is not suitable for the following conditions: malignant tumour wound, necrotic tissue or gangrene, untreated osteomyelitis, anastomotic leak directly adjacent to vessels, bladder or small bowel obstruction, non-drainable septic focus, systemic sepsis and clotting disorders.
# Relevant pathway
NICE has not published guidelines on rectal anastomotic leak and the clinical experts said that there is no standard care pathway. The Association of Coloproctology of Great Britain and Ireland's (ACPGBI) guidance on the prevention, diagnosis and management of colorectal anastomotic leakage (March 2016) says that people with anastomotic leaks who are clinically stable may have conservative treatment using fluids, antibiotics and oxygen, with close clinical observation. But if people show signs of sepsis, the source of the leak must be removed within 3 to 18 hours, depending on the underlying condition and severity of infection. In less severe cases of sepsis associated with extraperitoneal rectal anastomotic leak, proximal defunctioning of the anastomosis with trans-anal or trans-peritoneal drainage may be considered. If there is radiological evidence that the anastomotic cavity is separate from the bowel, or if there are multiple sites of anastomotic leak, surgical intervention is needed.
# Costs
The Endo‑SPONGE kit costs £250.20 (excluding VAT) for a single sponge. The company estimates that complete treatment with Endo‑SPONGE needs about 7 or 8 sponges. The drain bottle is bought separately, costing £20.90 per bottle (excluding VAT). Any glycerol-based hydrogel can be used and costs between £1 and £1.50 per tube.For more details, see the website for Endo-SPONGE.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## Relevant evidence comes from 20 observational studies, including 2 comparative studies
Twenty studies were relevant to the decision problem in the scope:
comparative studies (Schiffmann et al. 2019, Wasmann et al. 2019)
prospective studies (Jiménez Rodríguez et al. 2018, Milito et al. 2017, Rottoli et al. 2018, Strangio et al. 2015)
retrospective studies (Arezzo et al. 2015, Boschetti et al. 2018, Huisman et al. 2019, Katz et al. 2018, Keskin et al. 2015, Kuehn et al. 2016, Manta et al. 2016, Mussetto et al. 2017, Nerup et al. 2013, Riss et al. 2010, Riss et al. 2009, Srinivasamurthy et al. 2013, van Koperen et al. 2009, Weidenhagen et al. 2008).Three abstracts of non-comparative studies were also included (DiMitri et al. 2010, Martel et al. 2013, and McAuley et al. 2013). Three studies were in the UK.
## The evidence is limited because of a heterogeneous population and inconsistent reported outcomes
The EAC considered the quality of the evidence for Endo-SPONGE to be very low. It found a high risk of bias because of the retrospective study design and small sample sizes (ranging from 3 to 34 people). It noted the clinical heterogeneity related to population characteristics and the definition of surgical site infections and success. It also found inconsistencies in how long Endo‑SPONGE was in place and how many times it was changed, the length and frequency of follow up and concurrent or additional treatments. This might reflect the clinical uncertainty and variation in practice when treating anastomotic leaks. The clinical experts suggested that there is no clearly defined care pathway, and treatment is based on several factors. These include the patient's overall condition, the anastomotic defect size and location, the indication for primary resection and the presence of a proximal stoma.
## The evidence suggests that Endo-SPONGE could be an option to treat anastomotic leak
The available evidence suggests that Endo‑SPONGE could be a treatment option for anastomotic leak. The success rate of cavity closure for Endo‑SPONGE was about 85% and ranged from 40% to 100%, but the definition of success varied across studies. The stoma reversal rate after successful Endo‑SPONGE treatment was about 77%, ranging from 38.5% to 92.3%. One study reported that 6 out of 8 patients would be willing to have Endo‑SPONGE treatment again if needed.
# Cost evidence
## The company estimates that using Endo-SPONGE saves £2,419.50 per person in the first year
The company presented a de novo cost analysis with an Endo‑SPONGE decision tree and a comparator decision tree. Each decision tree had 4 branches for different grades of anastomotic leak that may result in non-surgical or surgical treatment. The company noted that its cost model structure was based on the grades referred to in The Association of Coloproctology of Great Britain and Ireland's (ACPGBI) guidance on the prevention, diagnosis and management of colorectal anastomotic leakage. The results from the company model estimated that Endo‑SPONGE was cost saving by £2,419.50 per person in the first year.
## There are 3 possible scenarios proposed by the EAC to reflect clinical practice in the NHS
The EAC noted that there was no standard treatment pathway for managing anastomotic leak. The procedure cost varied by care setting (inpatient or outpatient), types of sedation (general or local anaesthetic) and whether or not it was combined with other interventions. The EAC proposed 3 scenarios based on available evidence and expert advice to explore the cost impact in clinical practice.
## The EAC has revised key clinical parameters based on published data but also uses clinical parameters from the company submission
The EAC considered the company model structure, a 1‑year cycle and a 10‑year time horizon to be appropriate. It changed some of the clinical and cost parameters based on published studies and expert advice and focused on percutaneous drainage as a comparator. However, it acknowledged that there was uncertainty about the most appropriate clinical inputs to the model because there was no clearly defined care pathway. Because of the uncertainty in the clinical parameters, the EAC also used the company clinical values in the scenario analyses.
## The cost impact of Endo-SPONGE varies depending on the scenarios and clinical parameters considered
The EAC noted that the cost impact of Endo‑SPONGE compared with percutaneous drainage varied depending on the scenarios and clinical parameters considered. One scenario was based on Endo‑SPONGE insertion under general anaesthesia in theatre, with subsequent sponge changes in an outpatient setting such as an endoscopy suite. Using the company's clinical parameters in the model, this scenario estimated that Endo‑SPONGE would save £726 per person in the first year. Using the EAC's alternative clinical inputs in the model, Endo‑SPONGE was estimated to have an additional cost of £1,141 per person in the first year. If both the insertion and replacement procedures were done in an operating theatre under general anaesthesia, then Endo‑SPONGE was cost incurring in the first year.
## Endo-SPONGE may be cost saving in the long term
The EAC model estimated that Endo‑SPONGE was cost saving over a 10‑year time horizon. This was when the insertion procedure was done in an operating theatre and sponge changes were done in an endoscopy suite or day-case theatre under light sedation. Using the company's or EAC's clinical parameters, this results in cost savings of £2,829.30 and £68.20 per person at 10 years, respectively, compared with percutaneous drainage.
## Additional analysis suggests Endo-SPONGE is cost saving compared with non-surgical treatments
In response to the committee discussion and consultation comments about the draft recommendations, the EAC did additional scenario analyses with alternative comparators. It acknowledged that the treatment pathway is complex and covers a heterogeneous patient population. Also, there is little data available on all the treatment options. The new analyses therefore included comparisons of Endo‑SPONGE with non-surgical interventions including percutaneous drain, trans-anal drain and others that were not specified in the company submission. The results showed that Endo‑SPONGE is cost saving by £298 per person over 1 year compared with a general non-surgical comparator.# Committee discussion
# Clinical-effectiveness overview
## Endo-SPONGE could treat anastomotic leak in a relatively small number of carefully selected patients
The clinical experts advised the committee that Endo‑SPONGE is a 'niche' technology that is only suitable for treating anastomotic leak in a small selection of people. They explained that several key factors decided how anastomotic leak was treated. These included the anatomy of the anastomosis, the location and accessibility of the leak, and the patient's clinical condition (specifically sepsis severity and their general health status). The clinical experts explained that, in their clinical experience, Endo‑SPONGE would be considered if:
the anastomotic leak was in the low colorectal area
the leak cavity was accessible through the anus
the leak remained localised with no abdomen or peritoneum contamination
the patient was clinically stable enough to have the procedure.These anatomical and patient-related factors are likely to inform clinicians' decision making for treating anastomotic leaks in general. But, they do not give any insight about who will benefit most from the procedure. The committee noted that there is no evidence that clearly defines the criteria for patient selection but it was aware of The Association of Coloproctology of Great Britain and Ireland's (ACPGBI) guidance on the prevention, diagnosis and management of colorectal anastomotic leakage, which describes the treatment options. It concluded that it is important to understand which patient population might benefit from Endo‑SPONGE. Collecting real-world evidence from its use in the NHS would help to develop this understanding.
## The benefits of Endo-SPONGE are not consistently defined and reported in the included studies
The definition of treatment success after Endo‑SPONGE varied between studies. It was most frequently defined as closure of the leakage cavity to less than 1 cm, or complete granulation and resolution of the cavity. Also, the reported stoma reversal rates varied widely between studies. Experts advised this was an important outcome to measure the clinical effectiveness of Endo-SPONGE relative to other treatments. The committee agreed that there is some evidence that Endo‑SPONGE may improve healing of an anastomotic leakage cavity and increase stoma reversal. However, the evidence is low quality with considerable variation in important clinical endpoints between studies.
## More evidence is needed to assess how acceptable Endo-SPONGE is to patients
The clinical experts advised that Endo‑SPONGE is likely to improve patients' quality of life. This is because it offers the possibility of stoma reversal and restoration of bowel function. However, only 2 studies reported patient outcomes that included patient acceptability (Riss et al. 2009) and functional bowel recovery (Huismann et al. 2019). In the clinical experts' experience, pain and discomfort are the 2 most reported adverse symptoms. Endo‑SPONGE treatment is stopped because of pain in a small number of their patients. The committee concluded that there is uncertainty about the tolerability of Endo‑SPONGE in the wider population. More real-world evidence is needed to understand the effect of Endo‑SPONGE on health-related quality of life and residual bowel function.
## National databases could improve the evidence for Endo-SPONGE
The committee concluded that the overall quality of the current evidence is low with a high risk of bias. This is because of the retrospective design of most studies, limited comparators and small sample sizes. The clinical experts explained that the patient groups for whom Endo‑SPONGE might be suitable are small and need to be carefully selected. So, it is unlikely that it would be practical to do a randomised controlled trial. They suggested that using a national database or clinical registry could help evaluate the clinical benefits of Endo‑SPONGE and define the most appropriate patient population. The committee agreed that further research with observational and real-world data would strengthen the evidence.
# NHS considerations overview
## Managing anastomotic leak is challenging without a clearly defined care pathway
The clinical experts noted that the rate of anastomotic leak after colorectal surgery in the UK is relatively low (reported to be between 4% and 12%). The clinical experts recognised that there have been improvements in techniques for colorectal surgery, such as stapling and robotics. This could help reduce the incidence of anastomotic leak. However, it remains a serious complication after colorectal surgery in some people. The clinical experts explained that the treatment care pathway for people with anastomotic leak varies across the NHS. It depends on local clinicians' experience and the facilities and resources available. The committee concluded that managing anastomotic leak is made more challenging because there is not a clearly defined care pathway.
# Training
## The Endo-SPONGE procedure is easy to learn but specific training is needed
The clinical experts advised that specific training is needed for the Endo‑SPONGE procedure but it is easy to learn. The company provides free on-site training. The main challenge of getting clinical experience for this technology is the small number of patients for whom it can be used. A clinical expert explained that, in their organisation, Endo‑SPONGE may only be suitable for about 4 to 5 people per year. Support from the company in the form of training such as simulation training may help to resolve this issue. The committee concluded that training is needed to do the Endo-SPONGE procedure.
# Cost modelling overview
## Comparing Endo-SPONGE and percutaneous drainage may not be appropriate because they are likely to be used in different clinical scenarios
The cost modelling done by the external assessment centre (EAC) compared Endo‑SPONGE with percutaneous drainage for treating anastomotic leak. However, the clinical experts advised that this comparison may not be appropriate. They explained that alternative comparators such as the placement of a trans‑rectal or trans-anal drain may also be used for leaks after a low rectal anastomosis. People having these different treatments are likely to have different clinical and anatomical characteristics. The committee concluded from the consultation comments and expert advice that comparators for Endo‑SPONGE in the care pathway may vary depending on patient selection, and percutaneous drainage is likely to be used in a different clinical scenario.
## The cost consequences of Endo-SPONGE are uncertain but it is likely to be cost saving.
There were 3 clinical scenarios modelled by the EAC. Of these, the clinical experts agreed on a scenario that best reflected current clinical practice. This was the one in which the first assessment and Endo‑SPONGE insertion was done in an operating theatre under general anaesthesia, with subsequent sponge changes done in an outpatient setting under local anaesthesia or light sedation. The clinical experts also added that, in their experience, endoscopy is not necessarily needed to insert Endo‑SPONGE, because of how close the leakage cavities are to the anal verge. The committee noted the EAC's additional cost modelling used other non-surgical comparators. This showed a cost saving of £298 per person over 1 year and £2,230 per person over 10 years. The committee noted that the main cost drivers were reoperation rates and rates of avoiding costs associated with a permanent stoma. However, the studies reported a wide range of values for these important clinical parameters. The committee noted that comparative cost modelling is therefore difficult with the available evidence. It concluded that there are significant uncertainties about the cost consequences of using Endo‑SPONGE. Collecting real-world data would be helpful to inform uncertainties around patient selection, Endo‑SPONGE's place in the care pathway, and clinical and cost outcomes.
# Further research
## Endo-SPONGE shows promise and data is needed on using Endo-SPONGE in clinical practice
The committee concluded that Endo‑SPONGE shows promise for treating anastomotic leak and further studies will help define the clinical and cost benefits. However, doing comparative research is likely to be challenging because of the small number of people with low colorectal anastomotic leak in the NHS each year, and the lack of a clearly defined care pathway. The committee was advised that real-world data, such as from a national registry, would be useful. It could help resolve uncertainties around the optimal use of this technology in clinical practice, including:
the selection criteria for people who could benefit from Endo‑SPONGE
the comparative rate of stoma reversal and bowel function recovery using Endo‑SPONGE compared with other treatments
patient-reported outcome measures such as health-related quality of life
the cost of Endo‑SPONGE compared with other treatments for anastomotic leak.
## A feasibility study shows that the best approach would be to establish a new national anastomotic leak registry
NICE commissioned an independent feasibility assessment to consider the potential for further data collection to address the uncertainties in the clinical evidence identified by the committee. The feasibility assessment highlighted that the best approach would be to establish a new national anastomotic leak registry to collect data on all patients with the condition, not just those having Endo‑SPONGE treatment. There are significant cost and resource implications to establish such an NHS-wide register, to collect patient data and produce the required analyses.
|
{'Recommendations': "Endo-SPONGE shows promise for treating low rectal anastomotic leaks. However, there is not enough good-quality evidence to support the case for routine adoption in the NHS.\n\nFurther evidence in the form of real-world data collection is recommended to address uncertainties about selection criteria, patient-reported outcome measures, stoma reversal and bowel function recovery compared with other treatments. Find out more in the section on further research in this guidance.\n\nWhy the committee made these recommendations\n\nAnastomotic leak is a serious complication after colorectal surgery. Endo‑SPONGE is designed to treat leaks after a low rectal anastomosis.\n\nThere's not enough evidence assessing the clinical effectiveness of Endo‑SPONGE compared with other non-surgical or surgical treatments in the NHS. Observational studies suggest that Endo‑SPONGE may stop anastomotic leakage and reduce the chance of a permanent stoma, but this evidence is weak.\n\nThere are also uncertainties about the cost impact of using Endo-SPONGE in the NHS because of the weak clinical evidence.", 'The technology': "# Technology\n\nEndo-SPONGE is a minimally invasive surgical treatment for anastomotic leak in the low rectal area. It consists of an open-pore sponge with a drain tube, a sponge pusher, silicon overtube guides and a drainage set and system. The system is designed to improve the clearance of leaking discharge in the anastomotic cavity and to promote granulation tissue formation and healing. Risks associated with Endo‑SPONGE include residual sponge particles left in the cavity, erosion of structures next to the sponge, injury to the intestinal wall and bleeding.\n\nThe sponge needs to be replaced every 2\xa0to 3\xa0days. The replacement sponge is cut to the size of the leaking cavity as it gets smaller and the drainage tube exits the body through the anus. The first insertion procedure is usually done in an operating theatre under general anaesthesia. The replacement procedures can be done in a day-case theatre or endoscopy suite under light sedation.\n\n# Innovative aspects\n\nEndo‑SPONGE is an endoluminal vacuum therapy device. The sponge is inserted into the leaking cavity using a flexible endoscope or open access through the anus. A drainage tube is connected to the sponge at one end with a drainage bottle at the other end. The bottle has a low-vacuum drainage container that uses suction to put continuous negative pressure on the sponge.\n\n# Intended use\n\nEndo‑SPONGE is intended for people with an extraperitoneal rectal anastomotic leak. It is inserted by colorectal surgeons, endoscopists and gastroenterologists in hospital. The Endo‑SPONGE system is not suitable for the following conditions: malignant tumour wound, necrotic tissue or gangrene, untreated osteomyelitis, anastomotic leak directly adjacent to vessels, bladder or small bowel obstruction, non-drainable septic focus, systemic sepsis and clotting disorders.\n\n# Relevant pathway\n\nNICE has not published guidelines on rectal anastomotic leak and the clinical experts said that there is no standard care pathway. The Association of Coloproctology of Great Britain and Ireland's (ACPGBI) guidance on the prevention, diagnosis and management of colorectal anastomotic leakage (March\xa02016) says that people with anastomotic leaks who are clinically stable may have conservative treatment using fluids, antibiotics and oxygen, with close clinical observation. But if people show signs of sepsis, the source of the leak must be removed within 3\xa0to\xa018\xa0hours, depending on the underlying condition and severity of infection. In less severe cases of sepsis associated with extraperitoneal rectal anastomotic leak, proximal defunctioning of the anastomosis with trans-anal or trans-peritoneal drainage may be considered. If there is radiological evidence that the anastomotic cavity is separate from the bowel, or if there are multiple sites of anastomotic leak, surgical intervention is needed.\n\n# Costs\n\nThe Endo‑SPONGE kit costs £250.20 (excluding VAT) for a single sponge. The company estimates that complete treatment with Endo‑SPONGE needs about 7\xa0or 8\xa0sponges. The drain bottle is bought separately, costing £20.90 per bottle (excluding VAT). Any glycerol-based hydrogel can be used and costs between £1 and £1.50 per tube.For more details, see the website for Endo-SPONGE.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## Relevant evidence comes from 20\xa0observational studies, including 2\xa0comparative studies\n\nTwenty studies were relevant to the decision problem in the scope:\n\ncomparative studies (Schiffmann et al. 2019, Wasmann et al. 2019)\n\nprospective studies (Jiménez Rodríguez et al. 2018, Milito et al. 2017, Rottoli et al. 2018, Strangio et al. 2015)\n\nretrospective studies (Arezzo et al. 2015, Boschetti et al. 2018, Huisman et al. 2019, Katz et al. 2018, Keskin et al. 2015, Kuehn et al. 2016, Manta et al. 2016, Mussetto et al. 2017, Nerup et al. 2013, Riss et al. 2010, Riss et al. 2009, Srinivasamurthy et al. 2013, van Koperen et al. 2009, Weidenhagen et al. 2008).Three abstracts of non-comparative studies were also included (DiMitri et al. 2010, Martel et al. 2013, and McAuley et al. 2013). Three studies were in the UK.\n\n## The evidence is limited because of a heterogeneous population and inconsistent reported outcomes\n\nThe EAC considered the quality of the evidence for Endo-SPONGE to be very low. It found a high risk of bias because of the retrospective study design and small sample sizes (ranging from 3\xa0to\xa034\xa0people). It noted the clinical heterogeneity related to population characteristics and the definition of surgical site infections and success. It also found inconsistencies in how long Endo‑SPONGE was in place and how many times it was changed, the length and frequency of follow up and concurrent or additional treatments. This might reflect the clinical uncertainty and variation in practice when treating anastomotic leaks. The clinical experts suggested that there is no clearly defined care pathway, and treatment is based on several factors. These include the patient's overall condition, the anastomotic defect size and location, the indication for primary resection and the presence of a proximal stoma.\n\n## The evidence suggests that Endo-SPONGE could be an option to treat anastomotic leak\n\nThe available evidence suggests that Endo‑SPONGE could be a treatment option for anastomotic leak. The success rate of cavity closure for Endo‑SPONGE was about 85% and ranged from 40% to 100%, but the definition of success varied across studies. The stoma reversal rate after successful Endo‑SPONGE treatment was about 77%, ranging from 38.5% to 92.3%. One study reported that 6\xa0out of 8\xa0patients would be willing to have Endo‑SPONGE treatment again if needed.\n\n# Cost evidence\n\n## The company estimates that using Endo-SPONGE saves £2,419.50 per person in the first year\n\nThe company presented a de novo cost analysis with an Endo‑SPONGE decision tree and a comparator decision tree. Each decision tree had 4\xa0branches for different grades of anastomotic leak that may result in non-surgical or surgical treatment. The company noted that its cost model structure was based on the grades referred to in The Association of Coloproctology of Great Britain and Ireland's (ACPGBI) guidance on the prevention, diagnosis and management of colorectal anastomotic leakage. The results from the company model estimated that Endo‑SPONGE was cost saving by £2,419.50 per person in the first year.\n\n## There are 3 possible scenarios proposed by the EAC to reflect clinical practice in the NHS\n\nThe EAC noted that there was no standard treatment pathway for managing anastomotic leak. The procedure cost varied by care setting (inpatient or outpatient), types of sedation (general or local anaesthetic) and whether or not it was combined with other interventions. The EAC proposed 3\xa0scenarios based on available evidence and expert advice to explore the cost impact in clinical practice.\n\n## The EAC has revised key clinical parameters based on published data but also uses clinical parameters from the company submission\n\nThe EAC considered the company model structure, a 1‑year cycle and a 10‑year time horizon to be appropriate. It changed some of the clinical and cost parameters based on published studies and expert advice and focused on percutaneous drainage as a comparator. However, it acknowledged that there was uncertainty about the most appropriate clinical inputs to the model because there was no clearly defined care pathway. Because of the uncertainty in the clinical parameters, the EAC also used the company clinical values in the scenario analyses.\n\n## The cost impact of Endo-SPONGE varies depending on the scenarios and clinical parameters considered\n\nThe EAC noted that the cost impact of Endo‑SPONGE compared with percutaneous drainage varied depending on the scenarios and clinical parameters considered. One scenario was based on Endo‑SPONGE insertion under general anaesthesia in theatre, with subsequent sponge changes in an outpatient setting such as an endoscopy suite. Using the company's clinical parameters in the model, this scenario estimated that Endo‑SPONGE would save £726 per person in the first year. Using the EAC's alternative clinical inputs in the model, Endo‑SPONGE was estimated to have an additional cost of £1,141 per person in the first year. If both the insertion and replacement procedures were done in an operating theatre under general anaesthesia, then Endo‑SPONGE was cost incurring in the first year.\n\n## Endo-SPONGE may be cost saving in the long term\n\nThe EAC model estimated that Endo‑SPONGE was cost saving over a 10‑year time horizon. This was when the insertion procedure was done in an operating theatre and sponge changes were done in an endoscopy suite or day-case theatre under light sedation. Using the company's or EAC's clinical parameters, this results in cost savings of £2,829.30 and £68.20 per person at 10\xa0years, respectively, compared with percutaneous drainage.\n\n## Additional analysis suggests Endo-SPONGE is cost saving compared with non-surgical treatments\n\nIn response to the committee discussion and consultation comments about the draft recommendations, the EAC did additional scenario analyses with alternative comparators. It acknowledged that the treatment pathway is complex and covers a heterogeneous patient population. Also, there is little data available on all the treatment options. The new analyses therefore included comparisons of Endo‑SPONGE with non-surgical interventions including percutaneous drain, trans-anal drain and others that were not specified in the company submission. The results showed that Endo‑SPONGE is cost saving by £298 per person over 1\xa0year compared with a general non-surgical comparator.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## Endo-SPONGE could treat anastomotic leak in a relatively small number of carefully selected patients\n\nThe clinical experts advised the committee that Endo‑SPONGE is a 'niche' technology that is only suitable for treating anastomotic leak in a small selection of people. They explained that several key factors decided how anastomotic leak was treated. These included the anatomy of the anastomosis, the location and accessibility of the leak, and the patient's clinical condition (specifically sepsis severity and their general health status). The clinical experts explained that, in their clinical experience, Endo‑SPONGE would be considered if:\n\nthe anastomotic leak was in the low colorectal area\n\nthe leak cavity was accessible through the anus\n\nthe leak remained localised with no abdomen or peritoneum contamination\n\nthe patient was clinically stable enough to have the procedure.These anatomical and patient-related factors are likely to inform clinicians' decision making for treating anastomotic leaks in general. But, they do not give any insight about who will benefit most from the procedure. The committee noted that there is no evidence that clearly defines the criteria for patient selection but it was aware of The Association of Coloproctology of Great Britain and Ireland's (ACPGBI) guidance on the prevention, diagnosis and management of colorectal anastomotic leakage, which describes the treatment options. It concluded that it is important to understand which patient population might benefit from Endo‑SPONGE. Collecting real-world evidence from its use in the NHS would help to develop this understanding.\n\n## The benefits of Endo-SPONGE are not consistently defined and reported in the included studies\n\nThe definition of treatment success after Endo‑SPONGE varied between studies. It was most frequently defined as closure of the leakage cavity to less than 1\xa0cm, or complete granulation and resolution of the cavity. Also, the reported stoma reversal rates varied widely between studies. Experts advised this was an important outcome to measure the clinical effectiveness of Endo-SPONGE relative to other treatments. The committee agreed that there is some evidence that Endo‑SPONGE may improve healing of an anastomotic leakage cavity and increase stoma reversal. However, the evidence is low quality with considerable variation in important clinical endpoints between studies.\n\n## More evidence is needed to assess how acceptable Endo-SPONGE is to patients\n\nThe clinical experts advised that Endo‑SPONGE is likely to improve patients' quality of life. This is because it offers the possibility of stoma reversal and restoration of bowel function. However, only 2\xa0studies reported patient outcomes that included patient acceptability (Riss et al. 2009) and functional bowel recovery (Huismann et al. 2019). In the clinical experts' experience, pain and discomfort are the 2 most reported adverse symptoms. Endo‑SPONGE treatment is stopped because of pain in a small number of their patients. The committee concluded that there is uncertainty about the tolerability of Endo‑SPONGE in the wider population. More real-world evidence is needed to understand the effect of Endo‑SPONGE on health-related quality of life and residual bowel function.\n\n## National databases could improve the evidence for Endo-SPONGE\n\nThe committee concluded that the overall quality of the current evidence is low with a high risk of bias. This is because of the retrospective design of most studies, limited comparators and small sample sizes. The clinical experts explained that the patient groups for whom Endo‑SPONGE might be suitable are small and need to be carefully selected. So, it is unlikely that it would be practical to do a randomised controlled trial. They suggested that using a national database or clinical registry could help evaluate the clinical benefits of Endo‑SPONGE and define the most appropriate patient population. The committee agreed that further research with observational and real-world data would strengthen the evidence.\n\n# NHS considerations overview\n\n## Managing anastomotic leak is challenging without a clearly defined care pathway\n\nThe clinical experts noted that the rate of anastomotic leak after colorectal surgery in the UK is relatively low (reported to be between 4% and 12%). The clinical experts recognised that there have been improvements in techniques for colorectal surgery, such as stapling and robotics. This could help reduce the incidence of anastomotic leak. However, it remains a serious complication after colorectal surgery in some people. The clinical experts explained that the treatment care pathway for people with anastomotic leak varies across the NHS. It depends on local clinicians' experience and the facilities and resources available. The committee concluded that managing anastomotic leak is made more challenging because there is not a clearly defined care pathway.\n\n# Training\n\n## The Endo-SPONGE procedure is easy to learn but specific training is needed\n\nThe clinical experts advised that specific training is needed for the Endo‑SPONGE procedure but it is easy to learn. The company provides free on-site training. The main challenge of getting clinical experience for this technology is the small number of patients for whom it can be used. A clinical expert explained that, in their organisation, Endo‑SPONGE may only be suitable for about 4\xa0to 5\xa0people per year. Support from the company in the form of training such as simulation training may help to resolve this issue. The committee concluded that training is needed to do the Endo-SPONGE procedure.\n\n# Cost modelling overview\n\n## Comparing Endo-SPONGE and percutaneous drainage may not be appropriate because they are likely to be used in different clinical scenarios\n\nThe cost modelling done by the external assessment centre (EAC) compared Endo‑SPONGE with percutaneous drainage for treating anastomotic leak. However, the clinical experts advised that this comparison may not be appropriate. They explained that alternative comparators such as the placement of a trans‑rectal or trans-anal drain may also be used for leaks after a low rectal anastomosis. People having these different treatments are likely to have different clinical and anatomical characteristics. The committee concluded from the consultation comments and expert advice that comparators for Endo‑SPONGE in the care pathway may vary depending on patient selection, and percutaneous drainage is likely to be used in a different clinical scenario.\n\n## The cost consequences of Endo-SPONGE are uncertain but it is likely to be cost saving.\n\nThere were 3\xa0clinical scenarios modelled by the EAC. Of these, the clinical experts agreed on a scenario that best reflected current clinical practice. This was the one in which the first assessment and Endo‑SPONGE insertion was done in an operating theatre under general anaesthesia, with subsequent sponge changes done in an outpatient setting under local anaesthesia or light sedation. The clinical experts also added that, in their experience, endoscopy is not necessarily needed to insert Endo‑SPONGE, because of how close the leakage cavities are to the anal verge. The committee noted the EAC's additional cost modelling used other non-surgical comparators. This showed a cost saving of £298 per person over 1\xa0year and £2,230 per person over 10\xa0years. The committee noted that the main cost drivers were reoperation rates and rates of avoiding costs associated with a permanent stoma. However, the studies reported a wide range of values for these important clinical parameters. The committee noted that comparative cost modelling is therefore difficult with the available evidence. It concluded that there are significant uncertainties about the cost consequences of using Endo‑SPONGE. Collecting real-world data would be helpful to inform uncertainties around patient selection, Endo‑SPONGE's place in the care pathway, and clinical and cost outcomes.\n\n# Further research\n\n## Endo-SPONGE shows promise and data is needed on using Endo-SPONGE in clinical practice\n\nThe committee concluded that Endo‑SPONGE shows promise for treating anastomotic leak and further studies will help define the clinical and cost benefits. However, doing comparative research is likely to be challenging because of the small number of people with low colorectal anastomotic leak in the NHS each year, and the lack of a clearly defined care pathway. The committee was advised that real-world data, such as from a national registry, would be useful. It could help resolve uncertainties around the optimal use of this technology in clinical practice, including:\n\nthe selection criteria for people who could benefit from Endo‑SPONGE\n\nthe comparative rate of stoma reversal and bowel function recovery using Endo‑SPONGE compared with other treatments\n\npatient-reported outcome measures such as health-related quality of life\n\nthe cost of Endo‑SPONGE compared with other treatments for anastomotic leak.\n\n## A feasibility study shows that the best approach would be to establish a new national anastomotic leak registry\n\nNICE commissioned an independent feasibility assessment to consider the potential for further data collection to address the uncertainties in the clinical evidence identified by the committee. The feasibility assessment highlighted that the best approach would be to establish a new national anastomotic leak registry to collect data on all patients with the condition, not just those having Endo‑SPONGE treatment. There are significant cost and resource implications to establish such an NHS-wide register, to collect patient data and produce the required analyses."}
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https://www.nice.org.uk/guidance/mtg63
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Evidence-based recommendations on Endo-SPONGE for treating low rectal anastomotic leak.
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0efdea6c8bc1357bed6df5de3b9c1cdfcd6cb5d7
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nice
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Risdiplam for treating spinal muscular atrophy
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Risdiplam for treating spinal muscular atrophy
Evidence-based recommendations on risdiplam (Evrysdi) for 5q spinal muscular atrophy (SMA) in adults and children aged 2 months and over.
# Recommendations
Risdiplam is recommended as an option for treating 5q spinal muscular atrophy (SMA) in people 2 months and older with a clinical diagnosis of SMA types 1, 2 or 3 or with pre-symptomatic SMA and 1 to 4 SMN2 copies. It is recommended only if the conditions of the managed access agreement are followed.
Why the committee made these recommendations
SMA is a rare genetic condition and there is an unmet need for effective treatments that can slow disease progression.
Clinical evidence shows that risdiplam improves motor function in SMA types 1 to 3. There is some evidence suggesting that people with type 1 SMA who have risdiplam live for longer. There is also some evidence suggesting risdiplam may be effective for people with pre-symptomatic SMA. But there is no direct evidence comparing risdiplam with usual care for type 1 SMA. And although it's likely that risdiplam has long-term benefits, there is no long-term evidence, so this is uncertain.
The cost-effectiveness estimates are higher than what NICE usually considers an acceptable use of NHS resources. So risdiplam cannot be recommended for routine use in the NHS. But because of the unmet need for effective treatments for SMA, risdiplam is recommended through a managed access agreement while more data is collected to address the uncertainties in the evidence.# Information about risdiplam
# Marketing authorisation indication
Risdiplam (Evrysdi, Roche) is indicated for 'the treatment of 5q spinal muscular atrophy (SMA) in patients 2 months of age and older, with a clinical diagnosis of SMA Type 1, Type 2 or Type 3 or with one to four SMN2 copies'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £7,900 per 60‑mg (80‑ml) vial. The company has a commercial arrangement. This makes risdiplam available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that the company's treatment-effect plateau (which assumes people who have had risdiplam will not reach additional motor milestones after 66 months of treatment for type 1 SMA and 26 months for SMA types 2 or 3) is acceptable and consistent with NICE's technology appraisal guidance on nusinersen for treating spinal muscular atrophy (from now, TA588; see key issues 3, 6 and 7 in the ERG critique of the company's technical engagement response, page 12).
It discussed the following issues (issues 1, 2, 4, 5 and 8 to 10), which were outstanding after the technical engagement stage.
# Clinical need
## Spinal muscular atrophy is a rare, progressive neuromuscular disorder
Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease caused by a genetic mutation in the SMN1 gene on chromosome 5q. People with the condition have a range of symptoms, including muscle weakness, and have worsening physical disability, mobility loss and respiratory dysfunction. SMA can be grouped into 5 main types (0 to 4), based on the age of onset and the maximum motor function reached. SMA type 0, the most severe, affects babies before birth. The babies do not develop any motor skills and often survive for only a few weeks after birth. Babies with type 1 SMA are unable to sit or roll because of severe muscle weakness, which gets worse over time. The muscle weakness also affects swallowing and breathing, and typically results in death within 2 years if respiratory support is not used. In type 2 SMA, the onset of symptoms is between 7 months and 18 months. People with this condition can sit independently at diagnosis. However, progressive loss of motor function means they have a reduced life expectancy compared with the general population. In type 3 SMA there are varying degrees of muscle weakness, which appear between 18 months and 18 years. People with this condition can have a normal lifespan and walk or sit unaided, but many lose mobility and other functions over time. Type 4 SMA is the least severe and affects adults, who may have milder motor impairment and live a normal lifespan. The clinical experts explained that type 0 and type 4 SMA are rarely diagnosed in clinical practice in the NHS in England. The patient experts explained that SMA is a progressive disorder, so all patients experience more severe symptoms over time. The committee concluded that SMA is a rare, progressive neuromuscular disorder that affects all aspects of daily life.
## The current SMA classification system has limitations but has been used in the marketing authorisation and clinical evidence for risdiplam
The patient experts commented that the SMA classification system does not always reflect the full extent of the disease. The boundaries between the different SMA types are blurred and can be subjective. They also explained that the classification system was not originally intended to define populations who were eligible for treatment. One patient expert with a child with type 3 SMA described how progressive loss of motor function has affected all daily activities. They noted that being unable to access treatments such as nusinersen has a big effect on physical and mental health. The committee understood that risdiplam's marketing authorisation includes types 1 to 3 SMA as currently defined by the SMA classification system, and these definitions were also used in the clinical evidence (see section 3.5). The committee acknowledged the limitations of the current SMA classification system but concluded that it had been used in the marketing authorisation and clinical evidence for risdiplam.
## SMA severely affects the quality of life of patients, carers and their families
The clinical and patient experts explained that most people with SMA need constant support. This can include full-time care and attention, needing physical effort (such as lifting and carrying) and causing loss of sleep for patients and carers, stress, and fear about loss of abilities. One patient expert with a child with type 2 SMA described how living with the condition can put considerable strain on relationships with other family members and friends. Siblings have a restricted social circle because of the fear of respiratory infections, and often act as young carers. As well as dealing with the physical and mental stress as the condition progresses, the financial burden also increases as more supportive equipment is needed. Another patient expert with type 2 SMA described the fear of losing fine motor skills and how being unable to work would affect the whole family. All these factors have a large effect on family members' health-related quality of life. The patient experts emphasised how caring for people with SMA affects the whole family and can cause physical, mental and financial issues. The committee concluded that SMA has a substantial effect on the quality of life of patients, caregivers and their families.
# Comparator
## Best supportive care is the most appropriate comparator for risdiplam
Nusinersen was the only disease-modifying treatment available for SMA at the start of this appraisal. The clinical and patient experts explained that many people with SMA have spinal fusion (that is, spinal surgery to treat scoliosis) so cannot have nusinersen because it is delivered by intrathecal injection and requires access to the lower spine. They commented that an oral treatment option would be welcome. It would also address several issues related to the delivery of nusinersen including the use of sedation, radiographic imaging and anxiety associated with lumbar puncture. Nusinersen is recommended in TA588 through a managed access agreement. This makes nusinersen available while more data is collected. However, nusinersen is not routinely commissioned in the NHS in England. So, for many people, current treatment is best supportive care. The aim is to control symptoms, maintain movement and function for as long as possible, and improve quality of life. This involves a multidisciplinary approach including respiratory, gastroenterology and orthopaedic care, as well as nutritional support, physiotherapy, assistive technologies, occupational therapy and social care. However, the clinical and patient experts emphasised that these supportive treatments do not affect disease progression, so people with SMA will ultimately become dependent on their families and carers. The committee was aware of the recently published NICE highly specialised technologies guidance on onasemnogene abeparvovec for treating spinal muscular atrophy type 1. It noted that this treatment is recommended for routine commissioning for some babies 12 months or younger with SMA type 1. However, it understood that the guidance was not published at the start of this appraisal so onasemnogene abeparvovec could not be included as a comparator. The NHS England commissioning expert described the potential treatment pathway, if risdiplam were to be recommended, as a treatment option alongside nusinersen and onasemnogene abeparvovec. They explained that repeated treatment switching would only be expected in exceptional circumstances, related to issues such as fertility or side effects. The committee recognised that treatment options used routinely in the NHS in England are currently limited and there is an unmet need for people with SMA. It recalled that best supportive care is routinely used in clinical practice in the NHS in England. It concluded that best supportive care was the most appropriate comparator for risdiplam.
# Clinical evidence
## Evidence from SUNFISH and FIREFISH is appropriate for decision making for SMA types 1 to 3
The main clinical-effectiveness evidence for risdiplam came from 2 clinical studies:
SUNFISH, which is a randomised, double-blind, multicentre (excluding UK sites), phase 2, placebo-controlled trial for the first 12 months of treatment. After 12 months, people in the placebo arm could switch to the risdiplam arm. It included 180 people aged 2 to 25 years with types 2 or 3 SMA. Part 2 of SUNFISH excluded patients who had any previous treatment, and also those with type 3 SMA who were able to walk.
FIREFISH, which is a single-arm study of 41 patients aged 1 month to 7 months with type 1 SMA and two SMN2 copies. It excluded patients who had previous treatment and those having chronic ventilation.There are also 2 ongoing studies. RAINBOWFISH is a phase 2, single-arm study of babies 6 weeks or younger who had been genetically diagnosed with SMA but did not have symptoms. JEWELFISH is an open-label, single-arm study for SMA types 1, 2 and 3 in people of 6 months to 60 years who had previously enrolled in the MOONFISH study or who had previously had nusinersen, onasemnogene abeparvovec or olesoxime. The ERG considered that although SUNFISH excluded patients with type 3 SMA who could walk, this group accounts for a small proportion of SMA cases. It also noted that SUNFISH and FIREFISH excluded patients who had previous treatment. The committee noted the age restrictions used in both studies. It was aware that some babies may be diagnosed with type 1 SMA when they are older than 7 months. The clinical experts explained that the study populations were generally representative of patients with SMA in the NHS in England. The committee concluded that the evidence presented for SMA types 1 to 3 was suitable for decision making.
## Risdiplam may be effective for patients who have had nusinersen
After consultation the company reported interim results from JEWELFISH for 174 patients, of whom 76 had previously had nusinersen (see section 3.5). The primary outcomes for JEWELFISH were safety and pharmacokinetics, but motor function was assessed as an exploratory outcome using the 32‑item Motor Function Measure (MFM‑32). The 12‑month interim data showed low rates of discontinuation of risdiplam for patients who previously had nusinersen, with rapid, sustained increase in SMN protein levels and stable motor function. The company stated that there is no plausible biological rationale to expect the treatment effect to differ based on prior treatment, because nusinersen and risdiplam have similar mechanisms of action (they are both SMN2 RNA splicing modifiers). The committee recalled that some people who had nusinersen may have preferred not to have had it, but it was the only option available (see section 3.4). The company did not present any cost-effectiveness evidence for people who have had nusinersen. The committee concluded that risdiplam may be effective after previous treatments such as nusinersen and agreed to take this into account when making its recommendations.
## Risdiplam may be effective for pre-symptomatic SMA
After consultation, the company reported interim results from RAINBOWFISH for 5 patients with pre-symptomatic SMA who had risdiplam for at least 12 months (see section 3.5). This 12‑month interim data showed 80% of patients reached the maximum score on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‑INTEND) and Hammersmith Infant Neurological Examination Module 2 (HINE‑2) scales, which measure motor function. The company considered these results to be promising compared with natural history studies. For example, the ANCHOVY chart review of 60 patients, 30 of whom had confirmed SMN2 copies, suggested that no HINE‑2 milestones were reached at 12‑month follow up. The company highlighted that subgroup analyses from both SUNFISH and FIREFISH showed that earlier treatment improved outcomes (the company considers the data to be confidential so it cannot be reported here). The company did not present cost-effectiveness evidence for people with pre-symptomatic SMA. The committee was encouraged by early results for the pre-symptomatic SMA population and agreed to take this into account when making its recommendations.
## Risdiplam improves motor function for people with SMA types 1, 2 or 3
The 12‑month results from SUNFISH, adjusted for multiple testing, showed risdiplam improved motor function scores (measured by the MFM‑32) in patients with type 2 or 3 SMA, compared with placebo (1.55; 95% confidence interval 0.30 to 2.81). The results from FIREFISH were compared against pre-defined performance criteria based on natural history data for patients with type 1 SMA. The 12‑month results suggest that more patients who had risdiplam (29%) were able to sit without support for at least 5 seconds than would be expected for patients with type 1 SMA (5%). After consultation, the company submitted 24‑month follow-up data from both SUNFISH and FIREFISH (see table 1 and table 2). The committee noted that this longer-term data generally showed improvements or stable disease but recognised that the data was not comparative (see section 3.5). The company and the ERG agreed that improvements seen in both SUNFISH and FIREFISH were clinically important. The patient experts described their experiences of using risdiplam and noted improvements in motor function, lung capacity, energy levels and stamina. They explained that even very small improvements in fine motor skills and upper limb function were very important because they allow patients to maintain independence. They emphasised that although the studies showed improvements in motor function, patients would also highly value a treatment that keeps the disease stable and stops it getting worse. The committee agreed that the clinical evidence showed improved motor function with risdiplam but noted that overall-survival data was only available for type 1 SMA.
Outcome
‑month follow up (standard deviation)
‑month follow up (standard deviation)
‑item Motor Function Measure total score
Hammersmith Functional Motor Scale Expanded total score
Revised Upper Limb Module total score
Caregiver-reported SMA independence scale score
Patient-reported SMA independence scale total score
Outcome
‑month follow up (percentage)
‑month follow up (percentage)
Performance criterion
Sitting without support for at least 5 seconds assessed by the Bayley Scales of Infant and Toddler Development 3
Able to support weight or stand with support as assessed by the Hammersmith Infant Neurological Examination Module 2
Not applicable
Able to bounce while assessing the walking item of the Hammersmith Infant Neurological Examination Module 2
Not applicable
Alive without permanent ventilation
Alive
## The company's matched adjusted indirect comparison for type 1 SMA is acceptable
After technical engagement, both the company and the ERG used the company's matched adjusted indirect comparison to model the treatment effect of risdiplam compared with best supportive care for type 1 SMA. This analysis matched data from the risdiplam arm of FIREFISH and the best supportive care arm of the ENDEAR trial, which compared nusinersen with placebo. The indirect comparison showed improvements in motor function such as sitting with and without support, ventilation-free survival and overall survival (the company considers the data to be confidential so it cannot be reported here). The committee concluded that the company's matched adjusted indirect comparison for type 1 SMA was acceptable.
## Long-term benefits with risdiplam are uncertain
After consultation, the company presented 24‑month follow-up data from SUNFISH and FIREFISH but noted that these studies were ongoing. The ERG noted that the 24‑month data for SUNFISH was not comparative because the placebo-controlled period ended after 12 months of treatment. The clinical experts explained that there was considerable uncertainty about the long-term benefits of risdiplam but in their clinical experience the results were promising. The committee concluded that risdiplam would likely provide long-term benefits, but these are uncertain because the size and nature of the benefits are not known.
# The company's economic model
## The company's model structure was broadly similar to the model used in the appraisal of nusinersen
The company presented 2 separate models after consultation. The model for types 2 and 3 SMA used clinical data from SUNFISH. The model for type 1 SMA used clinical data from the matched adjusted indirect treatment comparison. Both models compared risdiplam with best supportive care. Health-state transitions were based on assessments of motor milestones using the HINE‑2 for type 1 SMA, and the MFM‑32 and the Hammersmith Functional Motor Scale Expanded criteria for SMA types 2 and 3. After technical engagement, the company added a treatment-effect plateau similar to that used in TA588. The plateau assumed patients who have had risdiplam will not reach additional motor milestones after 66 months of treatment for SMA type 1 and 26 months for SMA type 2 or 3. The ERG explained that the company's models could be split into 3 sections:
The first 2 years of treatment, which used data from SUNFISH and FIREFISH to determine the transition probabilities (that is, the rate that patients will move between the different health states). In the type 1 model, the company applied the inverse hazard ratio from the matched adjusted indirect treatment comparison to the risdiplam arm because FIREFISH was a single-arm study.
After 2 years of treatment, when the transition probabilities were adjusted so disease in the best supportive care arm could not improve (it could only remain stable or worsen). The type 1 model assumed that no patients having risdiplam moved to the worse health states. The type 2 or 3 model assumed this probability was much lower for patients having risdiplam compared with best supportive care (the company considers this proportion to be commercial in confidence so it cannot be reported).
After the treatment plateau, when the company assumed patients having risdiplam stopped treatment. After stopping risdiplam, the models assumed a gradual loss of motor milestones but there was no effect on overall survival or utility values.The committee concluded that the company's model was broadly similar to the model used in the appraisal of nusinersen.
## The company's model structure will need to be updated at the end of the managed access period
The committee discussed several limitations of the company's models after consultation:
The type 1 model overestimated overall survival in the best supportive care arm because it relied on using the inverse of the hazard ratio from the matched adjusted indirect treatment comparison. This overestimation increased when the updated clinical data was applied after consultation (see section 3.13).
The model structures could not reflect the company's preferred stopping rules from NICE's updated review of TA588 because it did not allow for consecutive worsening of motor function (see section 3.17).
The company's approach to including additional benefit from risdiplam to account for improvements in fine motor skills and fewer complications led to changes in the best supportive care arm. The committee did not consider this to be appropriate (see section 3.16).
The model was not structured in a way that included pairs of data for patients who did and did not have risdiplam. So, it was not possible to separate out the additional overall-survival gain from risdiplam. The committee understood this affected the way that caregiver utility values were included in the model (see section 3.15).The committee carefully considered the limitations of the models and the new elements proposed by the company after consultation (updated data for the type 1 model, the proposed stopping rule, utility benefits from risdiplam and a new way to model caregiver utilities). It concluded that changes to the model structure were needed to calculate plausible cost-effectiveness results. The committee noted that the company committed to engaging with NHS England and the wider SMA community to propose a managed access agreement. It concluded that an updated model structure would be needed by the time the guidance is reviewed as part of the agreed managed access agreement.
# Overall survival for best supportive care
## The company's modelled survival for best supportive care in type 1 SMA is not appropriate
Overall-survival predictions in the type 1 model relied on the matched adjusted indirect treatment comparison because FIREFISH was a single-arm study (see section 3.5). After technical engagement, the company's model predicted a mean overall survival of 4.9 years in the best supportive care arm. The ERG noted that the company's approach overestimated overall survival in the best supportive care arm. It stated that the company should have applied the hazard ratio to the best supportive care group instead of applying the inverse of the hazard ratio to the risdiplam group. After consultation, the company updated the model with the 24‑month data from FIREFISH but this led to even higher survival predictions in the best supportive care arm (10.2 years). The committee did not consider the company's approach to be appropriate because new data for risdiplam should not affect survival for patients having best supportive care. It also questioned the clinical plausibility of these assumptions. The clinical experts confirmed that the company's model prediction did not reflect clinical practice. The committee noted that this was not an issue in the type 2 or 3 model because the best supportive care arm was modelled separately and was not changed by the updated study data. The committee concluded that the company's modelled survival for best supportive care in the type 1 model was not appropriate.
# Utility values
## Caregiver utility is considered in decision making but is difficult to quantify
In its original base case, the company used an additive approach and assumed that caregiver health-related quality of life increased linearly with each motor milestone that was met. The ERG explained that the company's additive approach assumed that after a patient died the caregiver health-related quality of life was zero. This increased the quality-adjusted life year (QALY) gains for risdiplam because patients live longer. The ERG did not think this was appropriate because it assumed society places value on caregivers of patients with SMA but not on bereaved caregivers after a patient dies. Submissions at technical engagement from patient and professional organisations emphasised that bereavement would have a significant and sustained effect on a caregiver's health-related quality of life. After technical engagement, the ERG presented its preferred analysis and 2 scenario analyses that explored the effects of bereavement. It preferred to apply a disutility (reduction in health-related quality of life) that was linked to the health state of the patient with SMA. But in the base case, after the patient died, the caregiver utility value was assumed to return to that of the general population. In the first scenario, the ERG applied a disutility of -0.04 from Song et al. (2010) for 20 years after a patient with SMA died. In the second scenario the same disutility was applied for the maximum time horizon (90 years). The ERG cautioned that the analyses were limited because they used arbitrary assumptions and the company's model did not include caregiver ageing or survival. The committee considered that the ERG's disutility approach:
was consistent with TA588, and it was not aware of any previous technology appraisals that used the company's preferred additive approach to model caregiver utility values
did not fully account for the effect of bereavement on caregiver quality of life. It noted that NICE's guide to the methods of technology evaluation states that direct health effects for carers can be included in analyses, but it is unclear whether this extends to valuing caregiver bereavement
substantially increased the cost-effectiveness estimates, particularly for type 1 SMA. This was because the substantial caregiver disutilities were subtracted from the patient utility values, which themselves reflect a poor quality of life. So increased survival results in a low number of QALYs, but at a high extra cost. This was less of an issue for type 2 and type 3 SMA because the additional survival is associated with higher patient utility and lower carer disutility than in the type 1 model, meaning a higher number of QALYs can be accrued. The company noted that this was counterintuitive because it made a life-extending treatment appear to be less cost effective. It also noted that using the ERG's approach meant that risdiplam was not cost effective, even when there was no cost for risdiplam. The ERG explained that the cost effectiveness of risdiplam was related to other factors including extended overall survival and high disease management costs. Also, the committee understood that the company preferred to assume each patient with SMA would have 2.2 caregivers. However, the ERG preferred to assume 3 caregivers for patients with type 2 or 3 SMA who cannot sit because this is consistent with TA588.The committee did not accept the company's approach to caregiver utility but recognised the difficulties in valuing caregiver utility values. It noted that the ERG approach also had limitations and resulted in particularly high incremental cost-effectiveness ratios (ICERs) for type 1 SMA. Despite accepting the logic of the ERG's modelling, it did not agree that including carer quality of life would result in fewer QALYs being accrued by carers when risdiplam extends survival. The committee concluded that the ERG's approach to including caregiver utility values is consistent with TA588 but neither the company's nor the ERG approach was ideal. The committee concluded that it should consider carer utility in its decision making but that quantifying caregiver utility was extremely difficult.
## The company's amended approach to modelling caregiver utilities for type 1 SMA is not appropriate
After consultation, the company used the ERG's disutility approach to include caregiver utility values for patients with type 2 or 3 SMA. For patients with type 1 SMA, the company used an amended disutility approach in which:
a disutility was applied to both treatment groups until 10.2 years (the mean overall survival for the best supportive care arm)
there were no QALY losses applied after this time, and
an additional bereavement disutility was applied to both arms until mean overall survival was reached (about 31 years for risdiplam).The company explained that this approach addressed the committee's concerns at the first meeting because it did not include caregiver QALY losses for risdiplam from extending survival. The ERG noted that in the company's approach, the total caregiver QALY losses over time were similar for each treatment group although the reasons differed. In the risdiplam group, QALY losses were driven by patients being in better health states and more patients surviving. In the best supportive care group, QALY losses were driven by patients being in worse health states and fewer patients surviving. The ERG recognised that including caregiver utility values in the economic model was challenging, particularly for type 1 SMA, because risdiplam extended overall survival and this led to increased caregiver burden over this extended period. But it did not consider the company's approach to be appropriate because:
it is inconsistent to assume SMA affects caregivers up to a specific timepoint but not beyond it
the company's cohort-level model did not include data for pairs of patients having risdiplam and those who were having best supportive care, so it was not possible to determine the additional extension to life from risdiplam, and
QALY losses in the best supportive care arm were also affected and this was counterintuitive.The committee discussed the challenges of including caregiver utility values in the economic model. It noted that the company's approach for type 1 SMA was limited by the model structure and its predictions may not be clinically plausible. It would have liked to have seen caregiver utility values fully captured in the model, a consideration of the impact of bereavement and the same approach used for both models. It concluded that the company's amended approach for including caregiver utility values for type 1 SMA was not appropriate.
## The company's approach to account for risdiplam's additional benefits is not appropriate
After technical engagement, the company included in its base case an additional utility gain to reflect risdiplam's potential benefits in fine motor skills. The company applied a utility gain of 0.05 and 0.10 for patients who had risdiplam in the non-sitting and sitting health states respectively, based on Thokala et al. (2020). The ERG preferred to exclude these additional utility gains for fine motor skills because:
the values were based on assumptions rather than evidence
there was uncertainty about how many patients who had risdiplam would have these utility gains, and
there was uncertainty about the duration of any utility gains.The patient experts described the importance of maintaining upper limb function because it allows independence. They explained that some benefits were not captured in the available motor function scales because even small improvements were highly valued by patients and made a large difference to health-related quality of life. The committee was sympathetic to these arguments and noted that 24‑month follow-up data from SUNFISH showed improvements in upper limb function and SMA independence scale scores (see table 1). After consultation, the company increased the size of the additional benefit for fine motor skills. It explained that clinical and patient advice suggested that quality of life could improve by about 50%. So, it increased utility values by 0.2 for patients in all sitting and non-sitting health states and by 0.05 for caregivers. The company also amended the utility values to try and account for benefits of risdiplam that may not be captured in the modelling. It did this by applying additional disutility values and costs for scoliosis and decline in respiratory and bulbar function (including swallowing, vocalising and communication). The ERG highlighted several limitations of the company's approach, which applied costs and disutility values to all patients in the best supportive care arm and 50% of patients in the risdiplam arm:
The company's assumptions may not be clinically plausible because additional utility gains were maintained even after risdiplam was stopped.
Double counting may be an issue because the original utility estimates from TA588 came from an elicitation study of clinical experts. The ERG considered that these factors could already be accounted for in the estimated patient utility values for the best supportive care group.
The company's net utility values may not be plausible after accounting for additional benefits from fine motor skills and fewer complications. Also, the changes should not have impacted net values for the best supportive care arm.The committee considered that an elicitation approach, similar to that used in TA588, may provide more robust estimates of net utility values. It would have liked to have seen:
plausible utility values elicited from clinical and patient experts for each health state for both treatment groups
consideration of which patients might accrue these benefits and for how long after stopping treatment. The committee concluded that the company's approach to account for risdiplam's additional benefits was not appropriate, because it resulted in health-state values in each arm that were not plausible.
# Stopping rule for risdiplam
## Analyses based on the company's modelled stopping rules are not appropriate
After consultation, the company amended its time-based stopping rule for risdiplam, which restricted its use to a maximum of 50 years for type 1 SMA and 30 years for types 2 and 3 SMA. It applied criteria to stop risdiplam in the worst health states after the treatment plateau (see section 3.11). The company explained that if the committee conclude it is appropriate to include stopping rules in its recommendations, it would prefer that these align with the stopping rules from NICE's updated review of TA588. However, these rules cannot be included within the current model structures. So, it used the treatment plateau as a proxy instead but acknowledged that the rules that were applied in the economic models would not be used in clinical practice. The committee understood that the updated stopping criteria in TA588 were based on clinical outcomes including repeated loss of motor function, the need for ventilation and scoliosis. The patient and clinical experts advised that the updated criteria were developed in collaboration with the wider SMA community. The new criteria allowed greater flexibility on the scales used to measure motor function and had generally been accepted by the clinical and patient community. The ERG explained that the stopping rule used in the models assumed lower costs for risdiplam but there was no change to predicted overall survival and predicted additional benefits from fine motor skills and lower rates of complications. The committee did not consider it appropriate to assume that the benefits of risdiplam would continue after treatment stopped. It was also concerned that the stopping rule modelled by the company did not reflect clinical practice. The clinical and patient experts reiterated that a treatment plateau is considered a positive outcome because it suggests disease is stable and would not be a reason to stop treatment. The committee would have liked to have seen the company's intended stopping rule applied to the models. It noted that an amended model structure that allowed consecutive worsening of motor function would be needed as well as consideration of the plausibility of sustained benefits after treatment is stopped. The committee concluded that analyses based on the company's modelled stopping rules were not appropriate for decision-making.
# End of life
## It is reasonable to accept that risdiplam meets the short life-expectancy criterion for type 1 SMA
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that risdiplam met NICE's criteria for a life-extending treatment at the end of life for type 1 SMA, but did not make a case for meeting the criteria for SMA types 2 and 3. The committee accepted that risdiplam did not meet the end-of-life criteria for people with type 2 or 3 because, although risdiplam may provide a survival benefit, life expectancy is likely to be over 2 years. For people with type 1 SMA the company noted that survival depends on the nature and extent of supportive care. The median age of death or permanent respiratory support in published natural history studies was 9 months to 13 months. The ERG commented that mean survival in the company's model for people with type 1 SMA having best supportive care was 4.88 years, but this was likely to be overestimated because of the way the company had applied the hazard ratios in the model (see section 3.13). The committee recalled that, after consultation, the company's model for type 1 SMA predicted mean overall survival of 10.2 years in the best supportive care arm. The committee did not consider this to be clinically plausible (see section 3.13). It noted that it usually assesses whether this criterion is met by referring to the mean survival predicted by the model. However, it accepted the limitations of the model in this case mean that estimates from the literature are more robust. The committee recognised that the life expectancy is uncertain but considered it reasonable to accept that risdiplam could meet the short life-expectancy criterion for type 1 SMA.
## It is likely that risdiplam extends life by more than 3 months for type 1 SMA
Having concluded that the short life-expectancy criterion was met for type 1 SMA, the committee recalled that the long-term survival estimates for these patients are very uncertain (see section 3.10). However, the modelling suggests that risdiplam is likely to extend life by at least 3 months for type 1 SMA. The committee noted that nusinersen (TA588) was considered to have met the criteria for a life-extending treatment at the end of life for type 1 SMA, but not for types 2 or 3. The committee concluded this also applied for risdiplam.
# Cost-effectiveness results
## The ICERs for risdiplam are above £50,000 per QALY gained
After consultation, the company's base-case ICERs for risdiplam compared with best supportive care were below £30,000 per QALY gained for SMA types 2 and 3 but were above £50,000 per QALY gained for SMA type 1 (the company considers the exact ICERs to be confidential so they cannot be reported here). The committee noted that the company's analyses did not include all of its preferred assumptions, and concluded that:
The company's modelled stopping rules are not appropriate (see section 3.17).
The company's approach to account for risdiplam's additional benefits is not appropriate (see section 3.16).
The ERG's approach for including caregiver utility values is accepted because it is consistent with TA588 but there is substantial uncertainty (see section 3.14).
For type 1 SMA, the company's amended disutility approach to include caregiver utility values is not appropriate (see section 3.15).The committee noted that, using its preferred assumptions, the most plausible ICER for type 1 SMA is likely to be much higher than £50,000 per QALY gained. For types 2 and 3, the ICER was much higher than £30,000 per QALY gained. The committee also recalled that after consultation the company's model structure led to implausible predictions for the best supportive care arm and did not allow clinically appropriate stopping rules based on consecutive worsening to be implemented (see section 3.11 and section 3.17). Also, it affected how caregiver utility values were included (see section 3.15). The committee concluded that the ICERs for risdiplam are likely to be above £50,000 per QALY gained but that changes to the model structure are needed to robustly capture all the costs and benefits associated with risdiplam.
# Other factors
## A managed access agreement has the potential to address uncertainties
The committee noted that the company engaged with NHS England and Improvement, the patient and clinical community and NICE to develop a managed access agreement for risdiplam. The agreement includes defined criteria for starting and stopping risdiplam, and for monitoring and data collection requirements. The proposed managed access agreement includes people with SMA types 1 to 3 as well as pre-symptomatic SMA. The committee recalled that it was encouraged by the early results from RAINBOWFISH (see section 3.7) and agreed that it was appropriate that pre-symptomatic SMA should be included within a managed access agreement and further data collected. It also acknowledged the need to manage risks associated with the identified uncertainties. It considered the details of the proposed eligibility criteria in the managed access agreement and concluded that they were clinically achievable. It considered that the proposed commercial agreement would reduce the risk to the NHS while the data was being collected. The committee concluded that the uncertainties in risdiplam's clinical evidence could be addressed by collecting data through a managed access agreement.
## Risdiplam is innovative and there may be some benefits not captured in the models
The company suggested that risdiplam is innovative because it is taken orally, so people can have treatment at home. The clinical and patient experts explained that nusinersen is given by lumbar puncture. Many people with SMA have spinal fusion, which means they cannot have a lumbar puncture so are unable to have nusinersen. The clinical and patient experts agreed that an alternative treatment option is needed. The company suggested that the models do not adequately reflect all potential benefits of risdiplam. This is because the benefits of improvements in respiratory and bulbar function (such as swallowing, vocalising and the ability to communicate) may not have been adequately captured in the models. The committee noted that even small improvements in motor skills are highly valued by patients and make a large difference to health-related quality of life, which may not be captured in the available motor function measures (see section 3.16). After consultation, the company attempted to include the uncaptured benefits of risdiplam in its modelling. The committee did not consider the company's approach to be plausible (see section 3.16) so preferred not to base its decision making on these analyses. It agreed that risdiplam was innovative and that there may be some benefits not captured in the models.
## No equality issues were identified
The patient and professional submissions suggested that the use of arbitrary disease categories means some people with type 3 SMA cannot access other treatments. The committee discussed this and recognised the limitations but noted that these classifications are used in the marketing authorisation and the clinical evidence. A clinical expert commented that the evidence did not fully capture the diverse ethnic demographic of people with SMA. The committee considered these potential issues but noted that recommendations would apply to all patients, regardless of ethnicity. It concluded that no equality issues had been identified.
## The nature of the eligible population and the disease was considered in the decision making
The committee noted that the population for which risdiplam is indicated includes children and young people. It noted that the clinical evidence and the models included children affected by the condition. It discussed whether adjustments to its normal considerations were needed. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages. It noted NICE's principles for the development of guidance and standards, which emphasise the importance of considering the distribution of health resources fairly within society as a whole, as well as factors other than relative costs and benefits. The committee acknowledged that the population eligible for risdiplam has serious disabilities. It acknowledged and considered the nature of the eligible population as part of its decision making.
## The decision making takes into account the rarity and severity of the disease
Risdiplam has features that are commonly seen in treatments assessed by NICE's highly specialised technologies programme, but it was considered as a single technology appraisal. This is because the population covered by the marketing authorisation is larger than what can be considered in highly specialised technologies evaluations. Also, the management of SMA is not commissioned through a highly specialised service. The committee acknowledged the difficulty of appraising drugs for very rare conditions. The committee was aware that SMA is a rare and very serious condition. It reflected on the benefits associated with risdiplam, and how they are highly valued by patients and families. It acknowledged and considered whether adjustments to its normal considerations were needed to take into account the rarity and severity of the disease. Its decision making took into account the rarity and severity of the disease.
# Conclusion
## Risdiplam is recommended for treating SMA with a managed access agreement
The committee acknowledged that the cost-effectiveness estimates were above the range NICE normally considers cost effective. However, it was mindful of many other important factors to account for in its decision making. It recalled that there were benefits associated with risdiplam that may not have been captured in the economic analyses. It also recognised that there is evidence of benefit for those who have had previous treatment and pre-symptomatic SMA (see section 3.6 and section 3.7). It also acknowledged the difficulty in distinguishing between SMA types (see section 3.2). However, the committee acknowledged that all the clinical- and cost-effectiveness evidence presented was uncertain, because of the lack of data. It accepted that more data was needed, and considered that the commercial agreement sufficiently manages the financial risk to the NHS. The committee considered the consultation responses, views of parents, carers and clinical experts, and the available evidence. It concluded that risdiplam should be recommended as an option for treating pre-symptomatic SMA and SMA types 1, 2 and 3, for the duration of and within the conditions set out in the managed access agreement. This is only if the company provides risdiplam with the confidential commercial terms agreed with NHS England. It reiterated that an updated model structure should be provided when the guidance is reviewed as part of the agreed managed access agreement.
|
{'Recommendations': "Risdiplam is recommended as an option for treating 5q spinal muscular atrophy (SMA) in people 2 months and older with a clinical diagnosis of SMA types 1,\xa02 or\xa03 or with pre-symptomatic SMA and 1\xa0to\xa04 SMN2 copies. It is recommended only if the conditions of the managed access agreement are followed.\n\nWhy the committee made these recommendations\n\nSMA is a rare genetic condition and there is an unmet need for effective treatments that can slow disease progression.\n\nClinical evidence shows that risdiplam improves motor function in SMA types\xa01\xa0to 3. There is some evidence suggesting that people with type\xa01 SMA who have risdiplam live for longer. There is also some evidence suggesting risdiplam may be effective for people with pre-symptomatic SMA. But there is no direct evidence comparing risdiplam with usual care for type\xa01 SMA. And although it's likely that risdiplam has long-term benefits, there is no long-term evidence, so this is uncertain.\n\nThe cost-effectiveness estimates are higher than what NICE usually considers an acceptable use of NHS resources. So risdiplam cannot be recommended for routine use in the NHS. But because of the unmet need for effective treatments for SMA, risdiplam is recommended through a managed access agreement while more data is collected to address the uncertainties in the evidence.", 'Information about risdiplam': "# Marketing authorisation indication\n\nRisdiplam (Evrysdi, Roche) is indicated for 'the treatment of 5q spinal muscular atrophy (SMA) in patients 2\xa0months of age and older, with a clinical diagnosis of SMA Type\xa01, Type\xa02 or Type\xa03 or with one to four SMN2 copies'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £7,900\xa0per 60‑mg (80‑ml) vial. The company has a commercial arrangement. This makes risdiplam available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that the company's treatment-effect plateau (which assumes people who have had risdiplam will not reach additional motor milestones after 66\xa0months of treatment for type\xa01 SMA and 26\xa0months for SMA types\xa02 or\xa03) is acceptable and consistent with NICE's technology appraisal guidance on nusinersen for treating spinal muscular atrophy (from now, TA588; see key issues\xa03, 6\xa0and 7 in the ERG critique of the company's technical engagement response, page\xa012).\n\nIt discussed the following issues (issues\xa01, 2, 4, 5 and 8\xa0to 10), which were outstanding after the technical engagement stage.\n\n# Clinical need\n\n## Spinal muscular atrophy is a rare, progressive neuromuscular disorder\n\nSpinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease caused by a genetic mutation in the SMN1 gene on chromosome\xa05q. People with the condition have a range of symptoms, including muscle weakness, and have worsening physical disability, mobility loss and respiratory dysfunction. SMA can be grouped into 5\xa0main types (0\xa0to\xa04), based on the age of onset and the maximum motor function reached. SMA type\xa00, the most severe, affects babies before birth. The babies do not develop any motor skills and often survive for only a few weeks after birth. Babies with type\xa01 SMA are unable to sit or roll because of severe muscle weakness, which gets worse over time. The muscle weakness also affects swallowing and breathing, and typically results in death within 2\xa0years if respiratory support is not used. In type\xa02 SMA, the onset of symptoms is between 7\xa0months and 18\xa0months. People with this condition can sit independently at diagnosis. However, progressive loss of motor function means they have a reduced life expectancy compared with the general population. In type\xa03 SMA there are varying degrees of muscle weakness, which appear between 18\xa0months and 18\xa0years. People with this condition can have a normal lifespan and walk or sit unaided, but many lose mobility and other functions over time. Type\xa04 SMA is the least severe and affects adults, who may have milder motor impairment and live a normal lifespan. The clinical experts explained that type\xa00 and type\xa04 SMA are rarely diagnosed in clinical practice in the NHS in England. The patient experts explained that SMA is a progressive disorder, so all patients experience more severe symptoms over time. The committee concluded that SMA is a rare, progressive neuromuscular disorder that affects all aspects of daily life.\n\n## The current SMA classification system has limitations but has been used in the marketing authorisation and clinical evidence for risdiplam\n\nThe patient experts commented that the SMA classification system does not always reflect the full extent of the disease. The boundaries between the different SMA types are blurred and can be subjective. They also explained that the classification system was not originally intended to define populations who were eligible for treatment. One patient expert with a child with type\xa03 SMA described how progressive loss of motor function has affected all daily activities. They noted that being unable to access treatments such as nusinersen has a big effect on physical and mental health. The committee understood that risdiplam's marketing authorisation includes types\xa01 to\xa03 SMA as currently defined by the SMA classification system, and these definitions were also used in the clinical evidence (see section 3.5). The committee acknowledged the limitations of the current SMA classification system but concluded that it had been used in the marketing authorisation and clinical evidence for risdiplam.\n\n## SMA severely affects the quality of life of patients, carers and their families\n\nThe clinical and patient experts explained that most people with SMA need constant support. This can include full-time care and attention, needing physical effort (such as lifting and carrying) and causing loss of sleep for patients and carers, stress, and fear about loss of abilities. One patient expert with a child with type\xa02 SMA described how living with the condition can put considerable strain on relationships with other family members and friends. Siblings have a restricted social circle because of the fear of respiratory infections, and often act as young carers. As well as dealing with the physical and mental stress as the condition progresses, the financial burden also increases as more supportive equipment is needed. Another patient expert with type\xa02 SMA described the fear of losing fine motor skills and how being unable to work would affect the whole family. All these factors have a large effect on family members' health-related quality of life. The patient experts emphasised how caring for people with SMA affects the whole family and can cause physical, mental and financial issues. The committee concluded that SMA has a substantial effect on the quality of life of patients, caregivers and their families.\n\n# Comparator\n\n## Best supportive care is the most appropriate comparator for risdiplam\n\nNusinersen was the only disease-modifying treatment available for SMA at the start of this appraisal. The clinical and patient experts explained that many people with SMA have spinal fusion (that is, spinal surgery to treat scoliosis) so cannot have nusinersen because it is delivered by intrathecal injection and requires access to the lower spine. They commented that an oral treatment option would be welcome. It would also address several issues related to the delivery of nusinersen including the use of sedation, radiographic imaging and anxiety associated with lumbar puncture. Nusinersen is recommended in TA588 through a managed access agreement. This makes nusinersen available while more data is collected. However, nusinersen is not routinely commissioned in the NHS in England. So, for many people, current treatment is best supportive care. The aim is to control symptoms, maintain movement and function for as long as possible, and improve quality of life. This involves a multidisciplinary approach including respiratory, gastroenterology and orthopaedic care, as well as nutritional support, physiotherapy, assistive technologies, occupational therapy and social care. However, the clinical and patient experts emphasised that these supportive treatments do not affect disease progression, so people with SMA will ultimately become dependent on their families and carers. The committee was aware of the recently published NICE highly specialised technologies guidance on onasemnogene abeparvovec for treating spinal muscular atrophy type\xa01. It noted that this treatment is recommended for routine commissioning for some babies 12\xa0months or younger with SMA type\xa01. However, it understood that the guidance was not published at the start of this appraisal so onasemnogene abeparvovec could not be included as a comparator. The NHS England commissioning expert described the potential treatment pathway, if risdiplam were to be recommended, as a treatment option alongside nusinersen and onasemnogene abeparvovec. They explained that repeated treatment switching would only be expected in exceptional circumstances, related to issues such as fertility or side effects. The committee recognised that treatment options used routinely in the NHS in England are currently limited and there is an unmet need for people with SMA. It recalled that best supportive care is routinely used in clinical practice in the NHS in England. It concluded that best supportive care was the most appropriate comparator for risdiplam.\n\n# Clinical evidence\n\n## Evidence from SUNFISH and FIREFISH is appropriate for decision making for SMA types\xa01\xa0to 3\n\nThe main clinical-effectiveness evidence for risdiplam came from 2\xa0clinical studies:\n\nSUNFISH, which is a randomised, double-blind, multicentre (excluding UK sites), phase\xa02, placebo-controlled trial for the first 12\xa0months of treatment. After 12\xa0months, people in the placebo arm could switch to the risdiplam arm. It included 180\xa0people aged 2\xa0to 25\xa0years with types\xa02 or\xa03 SMA. Part\xa02 of SUNFISH excluded patients who had any previous treatment, and also those with type\xa03 SMA who were able to walk.\n\nFIREFISH, which is a single-arm study of 41\xa0patients aged 1\xa0month\xa0to 7\xa0months with type\xa01 SMA and two SMN2 copies. It excluded patients who had previous treatment and those having chronic ventilation.There are also 2\xa0ongoing studies. RAINBOWFISH is a phase\xa02, single-arm study of babies 6\xa0weeks or younger who had been genetically diagnosed with SMA but did not have symptoms. JEWELFISH is an open-label, single-arm study for SMA types\xa01, 2 and 3 in people of 6\xa0months to 60\xa0years who had previously enrolled in the MOONFISH study or who had previously had nusinersen, onasemnogene abeparvovec or olesoxime. The ERG considered that although SUNFISH excluded patients with type\xa03 SMA who could walk, this group accounts for a small proportion of SMA cases. It also noted that SUNFISH and FIREFISH excluded patients who had previous treatment. The committee noted the age restrictions used in both studies. It was aware that some babies may be diagnosed with type\xa01 SMA when they are older than 7\xa0months. The clinical experts explained that the study populations were generally representative of patients with SMA in the NHS in England. The committee concluded that the evidence presented for SMA types\xa01 to 3 was suitable for decision making.\n\n## Risdiplam may be effective for patients who have had nusinersen\n\nAfter consultation the company reported interim results from JEWELFISH for 174\xa0patients, of whom 76 had previously had nusinersen (see section 3.5). The primary outcomes for JEWELFISH were safety and pharmacokinetics, but motor function was assessed as an exploratory outcome using the 32‑item Motor Function Measure (MFM‑32). The 12‑month interim data showed low rates of discontinuation of risdiplam for patients who previously had nusinersen, with rapid, sustained increase in SMN protein levels and stable motor function. The company stated that there is no plausible biological rationale to expect the treatment effect to differ based on prior treatment, because nusinersen and risdiplam have similar mechanisms of action (they are both SMN2 RNA splicing modifiers). The committee recalled that some people who had nusinersen may have preferred not to have had it, but it was the only option available (see section 3.4). The company did not present any cost-effectiveness evidence for people who have had nusinersen. The committee concluded that risdiplam may be effective after previous treatments such as nusinersen and agreed to take this into account when making its recommendations.\n\n## Risdiplam may be effective for pre-symptomatic SMA\n\nAfter consultation, the company reported interim results from RAINBOWFISH for 5\xa0patients with pre-symptomatic SMA who had risdiplam for at least 12\xa0months (see section 3.5). This 12‑month interim data showed 80% of patients reached the maximum score on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‑INTEND) and Hammersmith Infant Neurological Examination Module 2 (HINE‑2) scales, which measure motor function. The company considered these results to be promising compared with natural history studies. For example, the ANCHOVY chart review of 60\xa0patients, 30 of whom had confirmed SMN2 copies, suggested that no HINE‑2 milestones were reached at 12‑month follow up. The company highlighted that subgroup analyses from both SUNFISH and FIREFISH showed that earlier treatment improved outcomes (the company considers the data to be confidential so it cannot be reported here). The company did not present cost-effectiveness evidence for people with pre-symptomatic SMA. The committee was encouraged by early results for the pre-symptomatic SMA population and agreed to take this into account when making its recommendations.\n\n## Risdiplam improves motor function for people with SMA types\xa01, 2 or 3\n\nThe 12‑month results from SUNFISH, adjusted for multiple testing, showed risdiplam improved motor function scores (measured by the MFM‑32) in patients with type\xa02 or\xa03 SMA, compared with placebo (1.55; 95% confidence interval [CI] 0.30\xa0to\xa02.81). The results from FIREFISH were compared against pre-defined performance criteria based on natural history data for patients with type\xa01 SMA. The 12‑month results suggest that more patients who had risdiplam (29%) were able to sit without support for at least 5\xa0seconds than would be expected for patients with type\xa01 SMA (5%). After consultation, the company submitted 24‑month follow-up data from both SUNFISH and FIREFISH (see table\xa01\xa0and table\xa02). The committee noted that this longer-term data generally showed improvements or stable disease but recognised that the data was not comparative (see section 3.5). The company and the ERG agreed that improvements seen in both SUNFISH and FIREFISH were clinically important. The patient experts described their experiences of using risdiplam and noted improvements in motor function, lung capacity, energy levels and stamina. They explained that even very small improvements in fine motor skills and upper limb function were very important because they allow patients to maintain independence. They emphasised that although the studies showed improvements in motor function, patients would also highly value a treatment that keeps the disease stable and stops it getting worse. The committee agreed that the clinical evidence showed improved motor function with risdiplam but noted that overall-survival data was only available for type\xa01 SMA.\n\nOutcome\n\n‑month follow up (standard deviation)\n\n‑month follow up (standard deviation)\n\n‑item Motor Function Measure total score\n\n(4.70)\n\n(5.59)\n\nHammersmith Functional Motor Scale Expanded total score\n\n(3.68)\n\n(5.28)\n\nRevised Upper Limb Module total score\n\n(3.87)\n\n(4.38)\n\nCaregiver-reported SMA independence scale score\n\n(4.95)\n\n(5.16)\n\nPatient-reported SMA independence scale total score\n\n(3.78)\n\n(4.83)\n\nOutcome\n\n‑month follow up (percentage)\n\n‑month follow up (percentage)\n\nPerformance criterion\n\nSitting without support for at least 5\xa0seconds assessed by the Bayley Scales of Infant and Toddler Development\xa03\n\n(29%)\n\n(61%)\n\n%\n\nAble to support weight or stand with support as assessed by the Hammersmith Infant Neurological Examination Module\xa02\n\n(22%)\n\n(27%)\n\nNot applicable\n\nAble to bounce while assessing the walking item of the Hammersmith Infant Neurological Examination Module\xa02\n\n(2%)\n\n(4%)\n\nNot applicable\n\nAlive without permanent ventilation\n\n(85%)\n\n(83%)\n\n%\n\nAlive\n\n(93%)\n\n(93%)\n\n%\n\n## The company's matched adjusted indirect comparison for type\xa01 SMA is acceptable\n\nAfter technical engagement, both the company and the ERG used the company's matched adjusted indirect comparison to model the treatment effect of risdiplam compared with best supportive care for type\xa01 SMA. This analysis matched data from the risdiplam arm of FIREFISH and the best supportive care arm of the ENDEAR trial, which compared nusinersen with placebo. The indirect comparison showed improvements in motor function such as sitting with and without support, ventilation-free survival and overall survival (the company considers the data to be confidential so it cannot be reported here). The committee concluded that the company's matched adjusted indirect comparison for type\xa01 SMA was acceptable.\n\n## Long-term benefits with risdiplam are uncertain\n\nAfter consultation, the company presented 24‑month follow-up data from SUNFISH and FIREFISH but noted that these studies were ongoing. The ERG noted that the 24‑month data for SUNFISH was not comparative because the placebo-controlled period ended after 12\xa0months of treatment. The clinical experts explained that there was considerable uncertainty about the long-term benefits of risdiplam but in their clinical experience the results were promising. The committee concluded that risdiplam would likely provide long-term benefits, but these are uncertain because the size and nature of the benefits are not known.\n\n# The company's economic model\n\n## The company's model structure was broadly similar to the model used in the appraisal of nusinersen\n\nThe company presented 2\xa0separate models after consultation. The model for types\xa02 and 3 SMA used clinical data from SUNFISH. The model for type\xa01 SMA used clinical data from the matched adjusted indirect treatment comparison. Both models compared risdiplam with best supportive care. Health-state transitions were based on assessments of motor milestones using the HINE‑2 for type\xa01 SMA, and the MFM‑32 and the Hammersmith Functional Motor Scale Expanded criteria for SMA types\xa02\xa0and 3. After technical engagement, the company added a treatment-effect plateau similar to that used in TA588. The plateau assumed patients who have had risdiplam will not reach additional motor milestones after 66\xa0months of treatment for SMA type\xa01 and 26\xa0months for SMA type\xa02\xa0or 3. The ERG explained that the company's models could be split into 3\xa0sections:\n\nThe first 2\xa0years of treatment, which used data from SUNFISH and FIREFISH to determine the transition probabilities (that is, the rate that patients will move between the different health states). In the type\xa01 model, the company applied the inverse hazard ratio from the matched adjusted indirect treatment comparison to the risdiplam arm because FIREFISH was a single-arm study.\n\nAfter 2\xa0years of treatment, when the transition probabilities were adjusted so disease in the best supportive care arm could not improve (it could only remain stable or worsen). The type\xa01 model assumed that no patients having risdiplam moved to the worse health states. The type\xa02\xa0or 3 model assumed this probability was much lower for patients having risdiplam compared with best supportive care (the company considers this proportion to be commercial in confidence so it cannot be reported).\n\nAfter the treatment plateau, when the company assumed patients having risdiplam stopped treatment. After stopping risdiplam, the models assumed a gradual loss of motor milestones but there was no effect on overall survival or utility values.The committee concluded that the company's model was broadly similar to the model used in the appraisal of nusinersen.\n\n## The company's model structure will need to be updated at the end of the managed access period\n\nThe committee discussed several limitations of the company's models after consultation:\n\nThe type\xa01 model overestimated overall survival in the best supportive care arm because it relied on using the inverse of the hazard ratio from the matched adjusted indirect treatment comparison. This overestimation increased when the updated clinical data was applied after consultation (see section 3.13).\n\nThe model structures could not reflect the company's preferred stopping rules from NICE's updated review of TA588 because it did not allow for consecutive worsening of motor function (see section 3.17).\n\nThe company's approach to including additional benefit from risdiplam to account for improvements in fine motor skills and fewer complications led to changes in the best supportive care arm. The committee did not consider this to be appropriate (see section 3.16).\n\nThe model was not structured in a way that included pairs of data for patients who did and did not have risdiplam. So, it was not possible to separate out the additional overall-survival gain from risdiplam. The committee understood this affected the way that caregiver utility values were included in the model (see section 3.15).The committee carefully considered the limitations of the models and the new elements proposed by the company after consultation (updated data for the type\xa01 model, the proposed stopping rule, utility benefits from risdiplam and a new way to model caregiver utilities). It concluded that changes to the model structure were needed to calculate plausible cost-effectiveness results. The committee noted that the company committed to engaging with NHS England and the wider SMA community to propose a managed access agreement. It concluded that an updated model structure would be needed by the time the guidance is reviewed as part of the agreed managed access agreement.\n\n# Overall survival for best supportive care\n\n## The company's modelled survival for best supportive care in type\xa01 SMA is not appropriate\n\nOverall-survival predictions in the type\xa01 model relied on the matched adjusted indirect treatment comparison because FIREFISH was a single-arm study (see section 3.5). After technical engagement, the company's model predicted a mean overall survival of 4.9\xa0years in the best supportive care arm. The ERG noted that the company's approach overestimated overall survival in the best supportive care arm. It stated that the company should have applied the hazard ratio to the best supportive care group instead of applying the inverse of the hazard ratio to the risdiplam group. After consultation, the company updated the model with the 24‑month data from FIREFISH but this led to even higher survival predictions in the best supportive care arm (10.2\xa0years). The committee did not consider the company's approach to be appropriate because new data for risdiplam should not affect survival for patients having best supportive care. It also questioned the clinical plausibility of these assumptions. The clinical experts confirmed that the company's model prediction did not reflect clinical practice. The committee noted that this was not an issue in the type\xa02\xa0or 3 model because the best supportive care arm was modelled separately and was not changed by the updated study data. The committee concluded that the company's modelled survival for best supportive care in the type\xa01 model was not appropriate.\n\n# Utility values\n\n## Caregiver utility is considered in decision making but is difficult to quantify\n\nIn its original base case, the company used an additive approach and assumed that caregiver health-related quality of life increased linearly with each motor milestone that was met. The ERG explained that the company's additive approach assumed that after a patient died the caregiver health-related quality of life was zero. This increased the quality-adjusted life year (QALY) gains for risdiplam because patients live longer. The ERG did not think this was appropriate because it assumed society places value on caregivers of patients with SMA but not on bereaved caregivers after a patient dies. Submissions at technical engagement from patient and professional organisations emphasised that bereavement would have a significant and sustained effect on a caregiver's health-related quality of life. After technical engagement, the ERG presented its preferred analysis and 2\xa0scenario analyses that explored the effects of bereavement. It preferred to apply a disutility (reduction in health-related quality of life) that was linked to the health state of the patient with SMA. But in the base case, after the patient died, the caregiver utility value was assumed to return to that of the general population. In the first scenario, the ERG applied a disutility of -0.04 from Song et al. (2010) for 20\xa0years after a patient with SMA died. In the second scenario the same disutility was applied for the maximum time horizon (90\xa0years). The ERG cautioned that the analyses were limited because they used arbitrary assumptions and the company's model did not include caregiver ageing or survival. The committee considered that the ERG's disutility approach:\n\nwas consistent with TA588, and it was not aware of any previous technology appraisals that used the company's preferred additive approach to model caregiver utility values\n\ndid not fully account for the effect of bereavement on caregiver quality of life. It noted that NICE's guide to the methods of technology evaluation states that direct health effects for carers can be included in analyses, but it is unclear whether this extends to valuing caregiver bereavement\n\nsubstantially increased the cost-effectiveness estimates, particularly for type\xa01 SMA. This was because the substantial caregiver disutilities were subtracted from the patient utility values, which themselves reflect a poor quality of life. So increased survival results in a low number of QALYs, but at a high extra cost. This was less of an issue for type\xa02 and type\xa03 SMA because the additional survival is associated with higher patient utility and lower carer disutility than in the type\xa01 model, meaning a higher number of QALYs can be accrued. The company noted that this was counterintuitive because it made a life-extending treatment appear to be less cost effective. It also noted that using the ERG's approach meant that risdiplam was not cost effective, even when there was no cost for risdiplam. The ERG explained that the cost effectiveness of risdiplam was related to other factors including extended overall survival and high disease management costs. Also, the committee understood that the company preferred to assume each patient with SMA would have 2.2\xa0caregivers. However, the ERG preferred to assume 3\xa0caregivers for patients with type\xa02\xa0or 3 SMA who cannot sit because this is consistent with TA588.The committee did not accept the company's approach to caregiver utility but recognised the difficulties in valuing caregiver utility values. It noted that the ERG approach also had limitations and resulted in particularly high incremental cost-effectiveness ratios (ICERs) for type\xa01 SMA. Despite accepting the logic of the ERG's modelling, it did not agree that including carer quality of life would result in fewer QALYs being accrued by carers when risdiplam extends survival. The committee concluded that the ERG's approach to including caregiver utility values is consistent with TA588 but neither the company's nor the ERG approach was ideal. The committee concluded that it should consider carer utility in its decision making but that quantifying caregiver utility was extremely difficult.\n\n## The company's amended approach to modelling caregiver utilities for type\xa01 SMA is not appropriate\n\nAfter consultation, the company used the ERG's disutility approach to include caregiver utility values for patients with type\xa02\xa0or 3 SMA. For patients with type\xa01 SMA, the company used an amended disutility approach in which:\n\na disutility was applied to both treatment groups until 10.2\xa0years (the mean overall survival for the best supportive care arm)\n\nthere were no QALY losses applied after this time, and\n\nan additional bereavement disutility was applied to both arms until mean overall survival was reached (about 31\xa0years for risdiplam).The company explained that this approach addressed the committee's concerns at the first meeting because it did not include caregiver QALY losses for risdiplam from extending survival. The ERG noted that in the company's approach, the total caregiver QALY losses over time were similar for each treatment group although the reasons differed. In the risdiplam group, QALY losses were driven by patients being in better health states and more patients surviving. In the best supportive care group, QALY losses were driven by patients being in worse health states and fewer patients surviving. The ERG recognised that including caregiver utility values in the economic model was challenging, particularly for type\xa01 SMA, because risdiplam extended overall survival and this led to increased caregiver burden over this extended period. But it did not consider the company's approach to be appropriate because:\n\nit is inconsistent to assume SMA affects caregivers up to a specific timepoint but not beyond it\n\nthe company's cohort-level model did not include data for pairs of patients having risdiplam and those who were having best supportive care, so it was not possible to determine the additional extension to life from risdiplam, and\n\nQALY losses in the best supportive care arm were also affected and this was counterintuitive.The committee discussed the challenges of including caregiver utility values in the economic model. It noted that the company's approach for type\xa01 SMA was limited by the model structure and its predictions may not be clinically plausible. It would have liked to have seen caregiver utility values fully captured in the model, a consideration of the impact of bereavement and the same approach used for both models. It concluded that the company's amended approach for including caregiver utility values for type\xa01 SMA was not appropriate.\n\n## The company's approach to account for risdiplam's additional benefits is not appropriate\n\nAfter technical engagement, the company included in its base case an additional utility gain to reflect risdiplam's potential benefits in fine motor skills. The company applied a utility gain of 0.05 and 0.10 for patients who had risdiplam in the non-sitting and sitting health states respectively, based on Thokala et al. (2020). The ERG preferred to exclude these additional utility gains for fine motor skills because:\n\nthe values were based on assumptions rather than evidence\n\nthere was uncertainty about how many patients who had risdiplam would have these utility gains, and\n\nthere was uncertainty about the duration of any utility gains.The patient experts described the importance of maintaining upper limb function because it allows independence. They explained that some benefits were not captured in the available motor function scales because even small improvements were highly valued by patients and made a large difference to health-related quality of life. The committee was sympathetic to these arguments and noted that 24‑month follow-up data from SUNFISH showed improvements in upper limb function and SMA independence scale scores (see table 1). After consultation, the company increased the size of the additional benefit for fine motor skills. It explained that clinical and patient advice suggested that quality of life could improve by about 50%. So, it increased utility values by 0.2 for patients in all sitting and non-sitting health states and by 0.05 for caregivers. The company also amended the utility values to try and account for benefits of risdiplam that may not be captured in the modelling. It did this by applying additional disutility values and costs for scoliosis and decline in respiratory and bulbar function (including swallowing, vocalising and communication). The ERG highlighted several limitations of the company's approach, which applied costs and disutility values to all patients in the best supportive care arm and 50% of patients in the risdiplam arm:\n\nThe company's assumptions may not be clinically plausible because additional utility gains were maintained even after risdiplam was stopped.\n\nDouble counting may be an issue because the original utility estimates from TA588 came from an elicitation study of clinical experts. The ERG considered that these factors could already be accounted for in the estimated patient utility values for the best supportive care group.\n\nThe company's net utility values may not be plausible after accounting for additional benefits from fine motor skills and fewer complications. Also, the changes should not have impacted net values for the best supportive care arm.The committee considered that an elicitation approach, similar to that used in TA588, may provide more robust estimates of net utility values. It would have liked to have seen:\n\nplausible utility values elicited from clinical and patient experts for each health state for both treatment groups\n\nconsideration of which patients might accrue these benefits and for how long after stopping treatment. The committee concluded that the company's approach to account for risdiplam's additional benefits was not appropriate, because it resulted in health-state values in each arm that were not plausible.\n\n# Stopping rule for risdiplam\n\n## Analyses based on the company's modelled stopping rules are not appropriate\n\nAfter consultation, the company amended its time-based stopping rule for risdiplam, which restricted its use to a maximum of 50\xa0years for type\xa01 SMA and 30\xa0years for types\xa02\xa0and 3 SMA. It applied criteria to stop risdiplam in the worst health states after the treatment plateau (see section 3.11). The company explained that if the committee conclude it is appropriate to include stopping rules in its recommendations, it would prefer that these align with the stopping rules from NICE's updated review of TA588. However, these rules cannot be included within the current model structures. So, it used the treatment plateau as a proxy instead but acknowledged that the rules that were applied in the economic models would not be used in clinical practice. The committee understood that the updated stopping criteria in TA588 were based on clinical outcomes including repeated loss of motor function, the need for ventilation and scoliosis. The patient and clinical experts advised that the updated criteria were developed in collaboration with the wider SMA community. The new criteria allowed greater flexibility on the scales used to measure motor function and had generally been accepted by the clinical and patient community. The ERG explained that the stopping rule used in the models assumed lower costs for risdiplam but there was no change to predicted overall survival and predicted additional benefits from fine motor skills and lower rates of complications. The committee did not consider it appropriate to assume that the benefits of risdiplam would continue after treatment stopped. It was also concerned that the stopping rule modelled by the company did not reflect clinical practice. The clinical and patient experts reiterated that a treatment plateau is considered a positive outcome because it suggests disease is stable and would not be a reason to stop treatment. The committee would have liked to have seen the company's intended stopping rule applied to the models. It noted that an amended model structure that allowed consecutive worsening of motor function would be needed as well as consideration of the plausibility of sustained benefits after treatment is stopped. The committee concluded that analyses based on the company's modelled stopping rules were not appropriate for decision-making.\n\n# End of life\n\n## It is reasonable to accept that risdiplam meets the short life-expectancy criterion for type\xa01 SMA\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company proposed that risdiplam met NICE's criteria for a life-extending treatment at the end of life for type\xa01 SMA, but did not make a case for meeting the criteria for SMA types\xa02\xa0and 3. The committee accepted that risdiplam did not meet the end-of-life criteria for people with type\xa02\xa0or 3 because, although risdiplam may provide a survival benefit, life expectancy is likely to be over 2\xa0years. For people with type\xa01 SMA the company noted that survival depends on the nature and extent of supportive care. The median age of death or permanent respiratory support in published natural history studies was 9\xa0months\xa0to 13\xa0months. The ERG commented that mean survival in the company's model for people with type\xa01 SMA having best supportive care was 4.88\xa0years, but this was likely to be overestimated because of the way the company had applied the hazard ratios in the model (see section 3.13). The committee recalled that, after consultation, the company's model for type\xa01 SMA predicted mean overall survival of 10.2\xa0years in the best supportive care arm. The committee did not consider this to be clinically plausible (see section 3.13). It noted that it usually assesses whether this criterion is met by referring to the mean survival predicted by the model. However, it accepted the limitations of the model in this case mean that estimates from the literature are more robust. The committee recognised that the life expectancy is uncertain but considered it reasonable to accept that risdiplam could meet the short life-expectancy criterion for type\xa01 SMA.\n\n## It is likely that risdiplam extends life by more than 3\xa0months for type\xa01 SMA\n\nHaving concluded that the short life-expectancy criterion was met for type\xa01 SMA, the committee recalled that the long-term survival estimates for these patients are very uncertain (see section\xa03.10). However, the modelling suggests that risdiplam is likely to extend life by at least 3\xa0months for type\xa01 SMA. The committee noted that nusinersen (TA588) was considered to have met the criteria for a life-extending treatment at the end of life for type\xa01 SMA, but not for types\xa02\xa0or 3. The committee concluded this also applied for risdiplam.\n\n# Cost-effectiveness results\n\n## The ICERs for risdiplam are above £50,000 per QALY gained\n\nAfter consultation, the company's base-case ICERs for risdiplam compared with best supportive care were below £30,000 per QALY gained for SMA types\xa02\xa0and 3 but were above £50,000 per QALY gained for SMA type\xa01 (the company considers the exact ICERs to be confidential so they cannot be reported here). The committee noted that the company's analyses did not include all of its preferred assumptions, and concluded that:\n\nThe company's modelled stopping rules are not appropriate (see section 3.17).\n\nThe company's approach to account for risdiplam's additional benefits is not appropriate (see section 3.16).\n\nThe ERG's approach for including caregiver utility values is accepted because it is consistent with TA588 but there is substantial uncertainty (see section 3.14).\n\nFor type\xa01 SMA, the company's amended disutility approach to include caregiver utility values is not appropriate (see section 3.15).The committee noted that, using its preferred assumptions, the most plausible ICER for type\xa01 SMA is likely to be much higher than £50,000 per QALY gained. For types\xa02\xa0and 3, the ICER was much higher than £30,000 per QALY gained. The committee also recalled that after consultation the company's model structure led to implausible predictions for the best supportive care arm and did not allow clinically appropriate stopping rules based on consecutive worsening to be implemented (see section 3.11 and section 3.17). Also, it affected how caregiver utility values were included (see section 3.15). The committee concluded that the ICERs for risdiplam are likely to be above £50,000 per QALY gained but that changes to the model structure are needed to robustly capture all the costs and benefits associated with risdiplam.\n\n# Other factors\n\n## A managed access agreement has the potential to address uncertainties\n\nThe committee noted that the company engaged with NHS England and Improvement, the patient and clinical community and NICE to develop a managed access agreement for risdiplam. The agreement includes defined criteria for starting and stopping risdiplam, and for monitoring and data collection requirements. The proposed managed access agreement includes people with SMA types\xa01\xa0to 3 as well as pre-symptomatic SMA. The committee recalled that it was encouraged by the early results from RAINBOWFISH (see section 3.7) and agreed that it was appropriate that pre-symptomatic SMA should be included within a managed access agreement and further data collected. It also acknowledged the need to manage risks associated with the identified uncertainties. It considered the details of the proposed eligibility criteria in the managed access agreement and concluded that they were clinically achievable. It considered that the proposed commercial agreement would reduce the risk to the NHS while the data was being collected. The committee concluded that the uncertainties in risdiplam's clinical evidence could be addressed by collecting data through a managed access agreement.\n\n## Risdiplam is innovative and there may be some benefits not captured in the models\n\nThe company suggested that risdiplam is innovative because it is taken orally, so people can have treatment at home. The clinical and patient experts explained that nusinersen is given by lumbar puncture. Many people with SMA have spinal fusion, which means they cannot have a lumbar puncture so are unable to have nusinersen. The clinical and patient experts agreed that an alternative treatment option is needed. The company suggested that the models do not adequately reflect all potential benefits of risdiplam. This is because the benefits of improvements in respiratory and bulbar function (such as swallowing, vocalising and the ability to communicate) may not have been adequately captured in the models. The committee noted that even small improvements in motor skills are highly valued by patients and make a large difference to health-related quality of life, which may not be captured in the available motor function measures (see section 3.16). After consultation, the company attempted to include the uncaptured benefits of risdiplam in its modelling. The committee did not consider the company's approach to be plausible (see section 3.16) so preferred not to base its decision making on these analyses. It agreed that risdiplam was innovative and that there may be some benefits not captured in the models.\n\n## No equality issues were identified\n\nThe patient and professional submissions suggested that the use of arbitrary disease categories means some people with type\xa03 SMA cannot access other treatments. The committee discussed this and recognised the limitations but noted that these classifications are used in the marketing authorisation and the clinical evidence. A clinical expert commented that the evidence did not fully capture the diverse ethnic demographic of people with SMA. The committee considered these potential issues but noted that recommendations would apply to all patients, regardless of ethnicity. It concluded that no equality issues had been identified.\n\n## The nature of the eligible population and the disease was considered in the decision making\n\nThe committee noted that the population for which risdiplam is indicated includes children and young people. It noted that the clinical evidence and the models included children affected by the condition. It discussed whether adjustments to its normal considerations were needed. It discussed the need to balance the importance of improving the lives of children and their families with fairness to people of all ages. It noted NICE's principles for the development of guidance and standards, which emphasise the importance of considering the distribution of health resources fairly within society as a whole, as well as factors other than relative costs and benefits. The committee acknowledged that the population eligible for risdiplam has serious disabilities. It acknowledged and considered the nature of the eligible population as part of its decision making.\n\n## The decision making takes into account the rarity and severity of the disease\n\nRisdiplam has features that are commonly seen in treatments assessed by NICE's highly specialised technologies programme, but it was considered as a single technology appraisal. This is because the population covered by the marketing authorisation is larger than what can be considered in highly specialised technologies evaluations. Also, the management of SMA is not commissioned through a highly specialised service. The committee acknowledged the difficulty of appraising drugs for very rare conditions. The committee was aware that SMA is a rare and very serious condition. It reflected on the benefits associated with risdiplam, and how they are highly valued by patients and families. It acknowledged and considered whether adjustments to its normal considerations were needed to take into account the rarity and severity of the disease. Its decision making took into account the rarity and severity of the disease.\n\n# Conclusion\n\n## Risdiplam is recommended for treating SMA with a managed access agreement\n\nThe committee acknowledged that the cost-effectiveness estimates were above the range NICE normally considers cost effective. However, it was mindful of many other important factors to account for in its decision making. It recalled that there were benefits associated with risdiplam that may not have been captured in the economic analyses. It also recognised that there is evidence of benefit for those who have had previous treatment and pre-symptomatic SMA (see section 3.6 and section 3.7). It also acknowledged the difficulty in distinguishing between SMA types (see section 3.2). However, the committee acknowledged that all the clinical- and cost-effectiveness evidence presented was uncertain, because of the lack of data. It accepted that more data was needed, and considered that the commercial agreement sufficiently manages the financial risk to the NHS. The committee considered the consultation responses, views of parents, carers and clinical experts, and the available evidence. It concluded that risdiplam should be recommended as an option for treating pre-symptomatic SMA and SMA types\xa01, 2\xa0and 3, for the duration of and within the conditions set out in the managed access agreement. This is only if the company provides risdiplam with the confidential commercial terms agreed with NHS England. It reiterated that an updated model structure should be provided when the guidance is reviewed as part of the agreed managed access agreement."}
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https://www.nice.org.uk/guidance/ta755
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Evidence-based recommendations on risdiplam (Evrysdi) for 5q spinal muscular atrophy (SMA) in adults and children aged 2 months and over.
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11352cc0057d439b988e515df43d09f5ed7d2bff
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nice
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Fedratinib for treating disease-related splenomegaly or symptoms in myelofibrosis
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Fedratinib for treating disease-related splenomegaly or symptoms in myelofibrosis
Evidence-based recommendations on fedratinib (Inrebic) for treating disease-related splenomegaly or symptoms in myelofibrosis in adults.
# Recommendations
Fedratinib is recommended for use within the Cancer Drugs Fund as an option for treating disease-related splenomegaly or symptoms of primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis in adults. It is recommended only if:
they have previously had ruxolitinib and
the conditions in the managed access agreement for fedratinib are followed.
This recommendation is not intended to affect treatment with fedratinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Most people with higher-risk myelofibrosis have ruxolitinib, and continue having it even if their disease does not fully respond, or stops responding. After ruxolitinib is stopped, people can have best available therapy, which includes chemotherapy, radiation therapy, splenectomy or red blood cell transfusion. The company proposes that fedratinib would only be used after ruxolitinib, which is more restrictive than its marketing authorisation.
Clinical trial evidence for people who have stopped ruxolitinib suggests that fedratinib improves myelofibrosis symptoms and reduces spleen size. However, this evidence is uncertain because fedratinib was not compared with best available therapy and some people did not finish the trial. Fedratinib has been compared indirectly with best available therapy using evidence from other studies. There is further uncertainty because of some differences between the trial populations in the indirect comparison.
Also, it is unclear how much longer people having fedratinib live compared with best available therapy, and this has a large effect on the cost-effectiveness results. There is also uncertainty around how many people would continue having fedratinib if their disease does not fully respond, or stops responding.
Fedratinib does not meet NICE's criteria to be considered a life-extending treatment at the end of life based on the evidence currently available. The cost-effectiveness estimates for fedratinib compared with best available therapy are uncertain because of limitations in the data. Because some of these estimates are higher than what NICE normally considers an acceptable use of NHS resources, fedratinib cannot be recommended for routine use in the NHS. Collecting more data on overall survival and treatment duration will reduce the uncertainty in the evidence. Therefore, fedratinib is recommended for use in the Cancer Drugs Fund.# Information about fedratinib
# Marketing authorisation indication
Fedratinib (Inrebic, Celgene) has a marketing authorisation for 'the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naive or have been treated with ruxolitinib'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of fedratinib is £6,120 for a 120‑capsule pack of 100 mg capsules (excluding VAT; BNF online accessed September 2021). The company has a commercial arrangement. This makes fedratinib available to the NHS with a discount. The size of the discount is commercial in confidence. It's the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented, and took these into account in its decision making. It discussed the following key issues, which were outstanding after the technical engagement stage:
Whether there was an overall survival benefit for fedratinib over best available therapy (see ERG critique of company technical engagement response, issue 7, page 16).
Which was the most appropriate model of time to treatment discontinuation for fedratinib (see ERG critique of company addendum submission, page 6).
Whether the company's subsequent treatment assumption for people having fedratinib was appropriate (see ERG critique of company technical engagement response, issue 6, page 15).
Whether the company's approach to estimating ruxolitinib costs was appropriate (see ERG critique of company technical engagement response, issue 9, page 20).
How the transformation rate to acute myeloid leukaemia (AML) should be modelled for people having fedratinib (see ERG critique of company addendum submission, page 9).
Whether fedratinib meets the criteria for end of life treatments (see ERG critique of company technical engagement response, issue 11, page 22).
# Treatment pathway, population and comparator
## People with myelofibrosis often experience severe symptoms
Myelofibrosis is a rare haematological disorder that often causes an enlarged spleen (splenomegaly) and constitutional symptoms, and shortens life. The patient experts explained that people with myelofibrosis experience debilitating fatigue, pain from splenomegaly, severe itching, night sweats, bone pain, and mental health problems including depression. Many people with myelofibrosis must reduce working hours or stop working completely because of fatigue. The patient experts added that the combined symptom burden can be very intense, and people can become dependent on carers. They also noted that people with myelofibrosis may be unable to exercise and that lack of exercise could contribute to other health issues. Around 75% of people with myelofibrosis reported experiencing depression or low mood. The patient experts explained the fear of living with a disease that is incurable for most people. They explained that knowing there are limited treatment options adds to their worry. They would like a new treatment option to increase life expectancy and improve quality of life. The committee concluded that people with myelofibrosis often have a high symptom burden. Improving survival and the symptoms associated with myelofibrosis, particularly fatigue and itching, would greatly benefit the wellbeing of people with myelofibrosis and their families.
## People with myelofibrosis would welcome a new treatment option, particularly when ruxolitinib is no longer suitable
Myelofibrosis has 4 different risk categories according to the Dynamic International Prognostic Scoring System (DIPSS): low, intermediate‑1, intermediate‑2 and high risk. Clinicians can use these risk scores to guide treatment. People without symptoms or who have low-risk disease may have their myelofibrosis observed without active treatment. Most people with intermediate‑2 or high-risk disease have ruxolitinib, which was recommended in NICE's technology appraisal guidance on ruxolitinib for treating disease-related splenomegaly or symptoms in adults with primary or secondary myelofibrosis (from now, TA386). The rest have best available therapy, which comprises several treatment options including hydroxycarbamide, androgens, radiation therapy, and red blood cell transfusion. The clinical experts explained that peoples' experiences with ruxolitinib varied. Ruxolitinib may work well at first, but many people experience disease relapse. People having ruxolitinib often have side effects which can mean they have to stop treatment. The clinical and patient experts also explained that best available therapy has limited effectiveness. This means that many people continue having suboptimal ruxolitinib treatment even if the disease does not respond or subsequently loses response, because there are no other effective treatment options. However, disease symptoms will usually return for people having suboptimal ruxolitinib. When ruxolitinib is no longer suitable there are no other options other than best available therapy. The committee agreed that patients and clinicians would welcome a new treatment option for myelofibrosis, particularly when ruxolitinib is no longer suitable.
## The company's positioning of fedratinib for people with intermediate-2 or high-risk myelofibrosis who have had ruxolitinib is appropriate
Fedratinib's marketing authorisation covers people with primary or secondary myelofibrosis (regardless of risk category) who have either not had a Janus kinase (JAK) inhibitor, or had ruxolitinib. However, the company positioned fedratinib in people with intermediate‑2 or high‑risk disease who have had ruxolitinib. The company considered this positioning reflected an area of unmet need and was how clinicians would use fedratinib in clinical practice. People who have had ruxolitinib have few treatment options (see section 3.2). So, the committee concluded that it was appropriate to appraise fedratinib for intermediate‑2 or high‑risk myelofibrosis after ruxolitinib.
## The company's mixed comparator is acceptable, but the evidence for best available therapy in the model should reflect the proportion of people assumed to have ruxolitinib
The comparator in the NICE scope for people who had previous treatment with ruxolitinib, or when ruxolitinib was not appropriate, was established clinical practice, also called best available therapy. This included hydroxycarbamide, other chemotherapies, androgens, splenectomy, radiation therapy, erythropoietin and red blood cell transfusion. In the company's economic model (see section 3.9), around 89% of people having best available therapy were assumed to have ruxolitinib. The ERG considered that the company should have split the population in its model into 2 subgroups: people who would have continued having suboptimal ruxolitinib, and people who would have stopped having ruxolitinib altogether. This was supported by the feedback from clinical experts. The clinical experts commented that most people whose disease is relapsed or refractory to ruxolitinib would keep having it, but people for whom ruxolitinib is poorly tolerated would usually stop having it. The ERG noted that the 2 subgroups would have different comparators. The comparator for the first group would be ruxolitinib, and the comparator for the second group would be best available therapy without ruxolitinib. The ERG considered that separating the population in this way would have helped to interpret the results. However, the company stated that it was not possible to split the trial population into the groups suggested by the ERG. The company also noted that there were no internationally recognised criteria for defining these groups, and they could therefore overlap. The comparator included a mix of people having ruxolitinib and people having best available therapy without ruxolitinib. The committee agreed that this mixed comparator was acceptable, but noted that the evidence used for best available therapy in the model should reflect the proportion of people assumed to have ruxolitinib (see section 3.10).
# Clinical evidence
## JAKARTA-2 is generalisable to people in the NHS with myelofibrosis who would have fedratinib
The evidence for fedratinib came from JAKARTA‑2, a single-arm, open-label, phase 2 study. The study included 97 adults with intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis that was deemed resistant to ruxolitinib after at least 14 days of treatment, or who were intolerant to ruxolitinib after any duration of treatment. Of these people, 81 had intermediate‑2 or high-risk disease, corresponding to where the company positioned fedratinib (see section 3.3). The dose of fedratinib used in the study was 400 mg per day for 6 consecutive 28‑day cycles (24 weeks). The daily dose could be increased to up to 600 mg within the first 6 cycles if there was a reduction in spleen size by palpation of less than 50% at the end of cycles 2 and 4. The primary outcome was spleen response, defined as the proportion of people with a spleen volume reduction of 35% or more from baseline at the end of cycle 6. Secondary outcomes included: symptom response (the proportion of people with a reduction in total symptom score of 50% or more from baseline to the end of cycle 6), the proportion of people with a reduction in palpable spleen length of 50% or more from baseline to the end of cycle 6, spleen response at the end of cycle 3 (12 weeks), percentage change in spleen volume from baseline to the end of cycles 3 and 6, and safety. The clinical experts noted that the inclusion criteria for JAKARTA‑2 were quite unrestricted, and that the study would be generalisable to the NHS in England. The committee concluded that JAKARTA‑2 was generalisable to people in the NHS with myelofibrosis who would have fedratinib.
## Fedratinib is clinically effective, but the lack of comparator data makes assessing comparative effectiveness challenging
In November 2013, the Food and Drug Administration (FDA) in the US put a clinical hold on fedratinib because of 8 suspected cases of Wernicke's encephalopathy. During the clinical hold, people stopped having fedratinib while the suspected cases of Wernicke's encephalopathy were investigated. The clinical hold meant that 13 people in JAKARTA‑2 stopped having fedratinib before they reached cycle 6 because of the study being stopped early. Also, during the marketing authorisation process, the Committee for Medicinal Products for Human Use (CHMP) requested additional analyses of JAKARTA‑2 because of uncertainty around the additional benefits from increasing the fedratinib daily dose above 400 mg. The company therefore submitted analyses that counted disease response with a daily dose of more than 400 mg as not responding. This CHMP definition of response was used in the company and ERG analyses in the model. In the JAKARTA‑2 intention-to-treat population, 23% of people had a spleen response while having a maximum daily dose of 400 mg. The proportion of people who had a symptom response in the intention-to-treat population while having a maximum daily dose of 400 mg was 21%. The ERG noted that the absence of a control arm in JAKARTA‑2 meant that it was possible that there was regression to the mean effects. This is when extreme values return to average over time. The committee acknowledged the difficulty of collecting data for rare diseases. It concluded that fedratinib is clinically effective, but that the disruption to the trial and lack of comparative data made the assessment of comparative effectiveness challenging.
## Fedratinib has manageable adverse events
The company noted that the adverse event rates from JAKARTA‑2 were generally low. The most common non-haematological adverse events for people having fedratinib were gastrointestinal disorders including diarrhoea (62%), nausea (56%), and vomiting (41%). The most common grade 3 or 4 adverse events were haematological and included anaemia (38%) and thrombocytopenia (22%). Treatment-emergent adverse events that meant fedratinib was stopped were seen in 20% of people. Across all fedratinib studies there were 8 suspected cases of Wernicke's encephalopathy, 1 of which had a clear diagnosis. It was found to be a consequence of gastrointestinal adverse events in people who were undernourished. Wernicke's encephalopathy can be managed by monitoring thiamine levels and supplementing as needed. The clinical experts noted that they follow the summary of product characteristics for monitoring thiamine levels and making dose adjustments. The company confirmed that there have been no additional instances of Wernicke's encephalopathy since the end of the FDA's clinical hold. The committee concluded that fedratinib has a manageable adverse event profile.
# Indirect treatment comparison
## The indirect treatment comparison suggests fedratinib improves response compared with best available therapy, but there are uncertainties
In the absence of direct head-to-head evidence comparing the efficacy of fedratinib with best available therapy, the company did a matching-adjusted indirect comparison (MAIC) for spleen or symptom response (see section 3.5 for definitions of these outcomes). The company used evidence from the intermediate‑2 or high-risk group from JAKARTA‑2 (n=81) for fedratinib and evidence from the SIMPLIFY‑2 trial (n=52) for best available therapy. SIMPLIFY‑2 was a randomised trial comparing momelotinib with best available therapy in people whose myelofibrosis had a suboptimal response to ruxolitinib, or who had haematological toxic effects with ruxolitinib. The company's base-case MAIC was adjusted for DIPSS risk category (see section 3.2) and Eastern Cooperative Oncology Group (ECOG) performance status. The company chose these variables based on clinical input that they were prognostic, and that there was a meaningful imbalance between JAKARTA‑2 and the best available therapy arm from SIMPLIFY‑2. The results of the MAIC suggested that fedratinib improves response compared with best available therapy, but the exact values are confidential and cannot be reported here. The ERG commented that ignoring variables because they were balanced individually may not achieve balance between the study populations overall. It noted that people in SIMPLIFY‑2 could be currently having ruxolitinib (which was not the case in JAKARTA‑2), and that this difference could not be adjusted for in the MAIC. Differences in how symptom response was assessed between JAKARTA‑2 and SIMPLIFY‑2 and the absence of a washout period in SIMPLIFY‑2 may also have favoured fedratinib. The committee agreed that the MAIC suggests fedratinib improves response compared with best available therapy, but there was considerable uncertainty around these results.
# The company's cost-effectiveness model
## The company's model is similar to that from TA386, but a simpler model structure may have been more robust for decision making
The company submitted an individual patient discrete event simulation model comparing fedratinib with best available therapy. This was similar to the approach used in TA386. The company considered this design to be more flexible and transparent compared with a Markov cohort approach. The model had 5 health states (on fedratinib, on best available therapy, on best available therapy after fedratinib, supportive care, and death). People entered the model having either fedratinib or best available therapy. They were then categorised into response or non-response groups at 24 weeks based on the outputs of the company's MAIC (see section 3.8). People having fedratinib stopped treatment according to models of time to treatment discontinuation fitted to the data from JAKARTA‑2. The company modelled time to treatment discontinuation from the start of the model, using separate extrapolations according to whether there was a response at week 24. For people having fedratinib, the company estimated survival from the point of stopping fedratinib, using models fitted to the survival data after stopping treatment from JAKARTA‑2. Like time to treatment discontinuation, this was split by response at week 24. People having best available therapy at the start of the model stopped treatment according to a model of time to treatment discontinuation fitted to data from the Haematological Malignancy Research Network (HMRN; see section 3.10). Unlike the fedratinib arm, the company used a single extrapolation of time to treatment discontinuation from the start of the model regardless of response at week 24. The company estimated overall survival for people having best available therapy using data from Schain et al. 2019 (see section 3.10). Like time to treatment discontinuation for best available therapy, the company fitted a single overall survival curve from the start of the model regardless of response at week 24. The ERG had several concerns with the company's model. It questioned the value of separating the population by response at week 24, given the small sample size of JAKARTA‑2. It also noted that the company had used several different evidence sources for people having best available therapy (see section 3.10), and that there were important differences between these sources in terms of the patient populations and treatments. The ERG was also concerned that the company had used a different modelling approach for the fedratinib arm compared with the best available therapy arm. The committee shared the ERG's reservations with the model, noting that it was overly complex given the limitations of the clinical evidence for fedratinib (see section 3.6). In response to consultation, the company provided additional justification for the model structure. It noted that the issues identified with the model structure could only be overcome by additional data collection. Also, the different modelling approaches for the 2 treatment arms reflected that the treatment pathways would be different. The company acknowledged that some complexity arose from splitting people in the model into those whose disease did or did not respond to fedratinib for the survival and time to treatment discontinuation models. But it stated that survival and time to treatment discontinuation models could also be applied to the overall population having fedratinib in the model (not split by disease response). This gave similar results to the company's base case. The company further noted that a simpler model could have created separate issues. The ERG's view of the model remained unchanged after consultation. At its second meeting, the committee noted that the company had made few changes to the model presented at the first committee meeting. It reiterated its conclusion from the first committee meeting that a simpler model structure may have been more robust for decision making.
## Using different sources of evidence to model best available therapy increases uncertainty
The company used a range of evidence sources for best available therapy in its model. For its base case, the company used the data from SIMPLIFY‑2 for the spleen or symptom response MAIC (see section 3.8), for the adverse event frequency for best available therapy as a comparator, and for the composition of best available therapy. Although overall survival data for people having best available therapy was available from SIMPLIFY‑2, the company did not use that in its base case. Instead, it used evidence from people who had stopped having ruxolitinib from Schain et al. 2019 (n=71). This was a retrospective observational study of people with myelofibrosis in Sweden and Norway, which the company considered best represented the people likely to have fedratinib in the NHS. The ERG noted that Schain included more people with primary myelofibrosis than JAKARTA‑2, and the population was also older on average. Therefore, the ERG expected people in Schain to have a worse prognosis than those in JAKARTA‑2. The ERG had additional concerns with comparing survival data from an observational study (Schain) with a clinical trial (JAKARTA‑2). It also considered that SIMPLIFY‑2 was a more appropriate source of evidence for best available therapy to align costs and outcomes in the model. This was because nobody in Schain had ruxolitinib, and so it did not reflect the composition of best available therapy from SIMPLIFY‑2 (in which around 89% of people had ruxolitinib). The company used evidence from people who stopped having ruxolitinib (n=39) in COMFORT‑2 for the adverse event frequency for people having best available therapy after fedratinib. COMFORT‑2 was a randomised phase 3 trial comparing ruxolitinib with best available therapy in people with myelofibrosis. The company also used the data from the best available therapy arm of COMFORT‑2 (n=73) to model the rate of transformation to AML for people having fedratinib and for people having best available therapy (see section 3.14). Finally, the company used evidence from the HMRN to inform the model of time to treatment discontinuation for people having best available therapy. The HMRN measured treatment outcomes in people with primary or secondary myelofibrosis in the Yorkshire and the Humber and Yorkshire Coast Cancer Networks between September 2004 and August 2017. The ERG was concerned that the populations in SIMPLIFY‑2, COMFORT‑2, Schain, and the HMRN were different in terms of age, risk score, and the types of best available therapy options that people were having. It was also concerned that the company did not use evidence sources consistently in its model. The committee agreed that using different sources of evidence to model best available therapy was inappropriate and increased uncertainty. The comparator in the company's model was comprised mainly of people having ruxolitinib (see section 3.4), and the evidence used for best available therapy should reflect this.
## Fedratinib is likely to extend survival, but the extent of the survival benefit is highly uncertain
To model survival after stopping treatment for people having fedratinib, the company fitted parametric models to the JAKARTA‑2 intermediate‑2 or high-risk subgroup survival data after stopping treatment, split by response status at week 24. Based on clinical expert advice, the company considered a Weibull distribution to be the most plausible distribution for people whose disease did respond and those whose disease did not respond. The company also noted that the Weibull distribution provided a conservative survival estimate for fedratinib. For best available therapy, the company fitted a Weibull distribution to the overall survival data from Schain for people who stopped having ruxolitinib. The company's base-case model predicted a mean overall survival benefit for fedratinib of 6.2 months based on the naive comparison of overall survival from JAKARTA‑2 and Schain. However, the ERG had concerns with using the overall survival data from Schain (see section 3.10). It considered that the observed survival benefit could be because the company had used different modelling approaches for the 2 treatment arms. The ERG requested that the company do an exploratory MAIC for overall survival using evidence from JAKARTA‑2 and SIMPLIFY‑2. It noted that after matching based on DIPSS risk category, the overall survival for people having fedratinib was similar to that for people having best available therapy. The ERG also noted that after adjusting for other prognostic factors such as platelet count and transfusion dependence in the MAIC, people having fedratinib had a shorter overall survival than those having best available therapy. The company considered that the overall survival data from SIMPLIFY‑2 was not reliable because of discrepancies in the data reported. It also noted that overall survival was not a pre-specified outcome in SIMPLIFY‑2, and that people could switch from best available therapy to momelotinib after 24 weeks. The company highlighted that there was evidence to suggest that spleen response is linked to overall survival. As such, fedratinib could be expected to have an overall survival benefit based on the results of the company's MAIC for spleen or symptom response (see section 3.8). The clinical experts agreed, stating that there is real-world and clinical trial evidence linking spleen response to overall survival. They considered that it was implausible that fedratinib would have no overall survival benefit over best available therapy. At its first meeting, the committee considered that fedratinib was likely to extend overall survival, but the extent of this overall survival benefit was highly uncertain. In response to consultation, the company highlighted 4 studies that quantified the association between spleen response and improved survival. The ERG noted that the company did not use spleen response as a surrogate for survival in its base-case model. The ERG reiterated that when survival was compared with the same evidence source the company used in its response MAIC (SIMPLIFY‑2, see section 3.8), there did not appear to be a survival benefit for fedratinib. The committee was concerned that the population in Schain, where people had stopped ruxolitinib treatment, did not reflect the modelled best available therapy arm, where most people continued ruxolitinib treatment. It considered that it had not seen sufficient evidence to change its conclusion from the first meeting. It felt that fedratinib was likely to extend overall survival compared with best available therapy. However, it concluded that based on the evidence presented, the extent of this overall survival benefit was highly uncertain.
## The fedratinib extrapolations for time to treatment discontinuation are uncertain, but are not a main driver of the cost-effectiveness results
The company fitted several parametric models to the time to treatment discontinuation data from JAKARTA‑2 and identified the exponential curve for disease response and the log-normal curve for disease non-response as the most appropriate. The ERG noted that the choice of distribution was very uncertain because of the small sample size and short follow up, and was confounded by the clinical hold and CHMP response definition for JAKARTA‑2 (see section 3.6). The ERG added that other distributions were also equally plausible, and provided a scenario analysis assuming a Gompertz distribution for both disease response and non-response. The committee understood the limitations with the JAKARTA‑2 evidence, but noted that the models for time to fedratinib discontinuation were not among the main drivers of the cost-effectiveness results.
## The proportion of people staying on ruxolitinib in the model after their disease stops responding (89%) should also apply to fedratinib, for consistency
In its model presented at the first committee meeting, the company assumed that people having fedratinib would stop having it after their disease stops responding. They would then have best available therapy (without ruxolitinib) or supportive care, or both, until death. In contrast, the company assumed that most people (89%) starting best available therapy in the model were having ruxolitinib, in a population that had already had ruxolitinib (see section 3.4). The ERG considered that in NHS clinical practice, most people whose disease was relapsed or refractory to fedratinib would keep having it, or would switch back to ruxolitinib. It presented scenarios assuming the same proportion of people (89%) would keep having fedratinib or switch back to ruxolitinib as were having ruxolitinib in the best available therapy arm. The clinical experts noted that the treatment assumptions after fedratinib were hard to comment on because fedratinib is not used in current clinical practice. They agreed that most people were likely to continue having fedratinib even if their disease had not responded adequately, consistent with how ruxolitinib is used in practice. The clinical lead for the Cancer Drugs Fund noted that it was unlikely that NHS England would commission ruxolitinib after fedratinib, given that people switched to fedratinib because of insufficient disease response or intolerance to ruxolitinib. At its first meeting, the committee considered that most people with relapsed or refractory disease would continue having fedratinib, similar to how people currently keep having ruxolitinib because there are no other treatment options. In response to consultation, the company updated its model base case with the assumption that 65% of people whose disease responded to fedratinib would continue having fedratinib after their disease stops responding. This was calculated based on the discontinuation rate in JAKARTA‑2 up to the end of cycle 6. The ERG noted that the company's updated assumption for fedratinib was inconsistent with the best available therapy arm, in which 89% of people continued ruxolitinib treatment until supportive care or death. The company commented on the proportion of time spent on a JAK inhibitor in each arm, but the values are confidential and cannot be reported here. The ERG presented 2 further scenarios. The scenarios assumed that 65% or 89%, respectively, of all people starting fedratinib would keep having it after their disease stops responding. This was regardless of whether their disease initially responded at 24 weeks. The committee understood that in practice clinicians would likely be reluctant to stop fedratinib even if the disease does not fully respond, or stops responding. This was because there would be no other treatment options. The committee concluded that it was appropriate to assume that 89% of all people starting fedratinib would continue fedratinib after their disease stops responding. This was consistent with the proportion who were assumed to continue ruxolitinib in the best available therapy arm.
## People having fedratinib should be assumed to have the same AML transformation rate as people having best available therapy
Myelofibrosis can transform into AML. The company modelled AML as an adverse event, with an associated cost and quality-of-life impact. In its model presented at the first committee meeting, the company used evidence from the JAKARTA‑2 intermediate‑2 or high-risk subgroup to inform the AML transformation for people having fedratinib. For people having best available therapy, the company used evidence from COMFORT‑2 (see section 3.10). The ERG commented that the same AML transformation rate should be used for fedratinib and best available therapy, because it is unclear whether fedratinib treatment affects AML transformation. The ERG added that it was more appropriate to use evidence from COMFORT‑2 to inform the AML transformation rate for both fedratinib and best available therapy arms. This was because COMFORT‑2 had a longer follow up than JAKARTA‑2. The committee considered that there was insufficient evidence to tell whether fedratinib affects the rate of AML transformation. It concluded that it was appropriate to assume the same AML transformation rate for fedratinib as for people having best available therapy. In response to consultation, the company updated its base case to assume the same AML transformation rate for both arms, consistent with the committee preference.
# Ruxolitinib costs
## It is appropriate to use the platelet count distribution from JAKARTA-2 to estimate the cost of ruxolitinib
Ruxolitinib dose depends on platelet count. People with a platelet count of less than 100×109/litre have a lower dose of ruxolitinib, which costs less. In its model, the company based the proportion of people having the lower ruxolitinib dose in the best available therapy arm on the platelet count distribution from JAKARTA‑2. The ERG noted that mean platelet count in JAKARTA‑2 was higher than that reported in SIMPLIFY‑2, from which the company used the data for best available therapy in the indirect treatment comparison for response (see section 3.8). The ERG considered that the cost of ruxolitinib had therefore been overestimated by the company. The company noted that although the proportion of people with a platelet count of less than 100×109/litre was not reported from SIMPLIFY‑2, around 27% of patients were having a 5 mg dose 2 times per day or less. This was lower than the proportion based on the platelet count distribution from JAKARTA‑2, suggesting that the cost of ruxolitinib had been underestimated in the model rather than overestimated. In response to consultation, the company provided baseline characteristics from a global chart review to support its argument that people having best available therapy have poor survival outcomes (see section 3.17). These baseline characteristics included the proportion of people with a platelet count of less than 100×109/litre. The ERG noted that this proportion was higher than in JAKARTA‑2, and considered that it was more likely to resemble the distribution in SIMPLIFY‑2 than JAKARTA‑2 did. So, the ERG used the figure from the global chart review in its updated base case for the second committee meeting. The company reiterated that it considered that the cost of ruxolitinib had been underestimated in the model, and that basing the platelet count distribution on the global chart review would further underestimate its cost. The company also noted that using the global chart review to inform the proportion of people having the lower ruxolitinib dose would mean that costs and outcomes in the model would not be aligned, because this data was available from SIMPLIFY‑2. The committee understood that there was uncertainty as to which platelet count distribution should be used in the model. It noted the company's concerns with using the global chart review to inform ruxolitinib costs. It concluded that, on balance, the platelet count distribution from JAKARTA‑2 was appropriate to use to estimate the cost of ruxolitinib.
## It is appropriate to consider scenarios with and without drug wastage for ruxolitinib
The company base-case model included an additional 5% drug wastage for ruxolitinib, in line with the ERG preference in TA386. The ERG considered this inappropriate because in TA386 the clinical experts advised that assuming no drug wastage for ruxolitinib reflected its use in clinical practice. As such, the ERG preferred to exclude ruxolitinib wastage from the model. In response to consultation, the company did not update its base case. The company indicated that informal discussions with clinicians supported that drug wastage would happen for ruxolitinib in clinical practice. The ERG speculated that there could be less ruxolitinib wastage in the second-line setting because more people would have the 5 mg dose. It also reiterated that the cost of ruxolitinib could already be overestimated in the model (see section 3.15). The committee was aware that including drug wastage for ruxolitinib had a large effect on the cost-effectiveness results in some scenarios. It acknowledged the uncertainty, and concluded that it was appropriate to consider scenarios with and without drug wastage for ruxolitinib.
# End of life
## Fedratinib does not meet the end of life criteria based on the evidence currently available
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The clinical experts explained that life expectancy for people who stop ruxolitinib is around 12 to 18 months. They noted that most people in JAKARTA‑2 had died within 2 to 3 years of stopping fedratinib, even though most had retreatment with ruxolitinib. The committee was aware that median overall survival after stopping ruxolitinib was 16 months or less in COMFORT‑2, Schain and based on the HMRN data. However, it noted that the company base-case model predicted that people having best available therapy had a mean life expectancy of 28.7 months. The company explained that the Weibull distribution it had used to extrapolate overall survival for people having best available therapy (see section 3.11) gave an optimistic survival prediction. Selecting a more conservative exponential model resulted in a mean life expectancy of less than 24 months. The ERG base case assumed no survival difference (see section 3.11), so people having best available therapy had the same life expectancy as people having fedratinib (34.9 months). At its first meeting, the committee concluded that there was considerable uncertainty about whether people having best available therapy would have a life expectancy of less than 24 months. There was also uncertainty about the extent of fedratinib's survival benefit over best available therapy (see section 3.11). In response to consultation, the company noted that the high-risk disease group in TA386 met the end of life criteria. Because 42% of the modelled population were high risk, the company indicated that these people should therefore meet the end of life criteria for consistency with TA386. The company added that because the Kaplan–Meier data from Schain was immature, the median survival was more appropriate than the mean survival to inform the life expectancy criterion. The company also provided baseline characteristics for a global chart review that it considered showed poor survival outcomes for people having best available therapy (including ruxolitinib). The company believed that these baseline characteristics were similar to JAKARTA‑2. The ERG noted that the survival estimates discussed at the first committee meeting (from COMFORT‑2, Schain and the HMRN data) were from people who had stopped ruxolitinib treatment, but in the best available therapy arm in the model 89% of people were having ruxolitinib. The ERG also considered that there was a lack of detail on the global chart review, and that it was unclear how similar the population was to JAKARTA‑2. At its second meeting, the committee discussed the survival estimates from clinicians that the company had used to select its survival model for people having best available therapy. It understood that the company had originally asked clinicians for their estimates of survival for when people had stopped having ruxolitinib, rather than for when most people were having suboptimal ruxolitinib. There was also some variability around the clinician responses. The committee noted that the 2 distributions selected as clinically plausible by the company (Weibull and exponential) lay on either side of the clinician estimates, and it would have preferred to see a scenario with a survival model fitted directly through these estimates. Because this would lie above the exponential distribution (which gave a mean survival of 23.3 months), the committee considered that it was likely that this scenario would give a mean survival of more than 24 months. The committee also noted that because the cost-effectiveness results are calculated based on mean (rather than median) values, it is important to consider the mean survival results when assessing if the end of life criteria were met. The committee considered that it had not seen robust enough evidence to conclude that fedratinib met either of the criteria to be considered a life-extending treatment at the end of life based on the evidence currently available.
# Cost-effectiveness estimates
## The most likely cost-effectiveness estimates are higher than those normally considered an acceptable use of NHS resources
The committee considered the deterministic incremental cost-effectiveness ratios (ICERs) for fedratinib compared with best available therapy. Because of a confidential commercial arrangement for ruxolitinib, the exact cost-effectiveness results cannot be reported here. The committee noted that the 2 main drivers of the cost-effectiveness results were whether or not fedratinib was assumed to extend overall survival (see section 3.11) and what proportion of people would continue having fedratinib after their disease stops responding (see section 3.13). In the company's base case, fedratinib was assumed to extend overall survival by 6.2 months, and 65% of people whose disease initially responded to fedratinib continued having it. The ERG presented 2 base cases in which it assumed that fedratinib had no overall survival benefit compared with best available therapy and 89% of all people starting fedratinib continue having fedratinib after their disease stops responding. Ruxolitinib wastage was included in ERG base case 1, and excluded in ERG base case 2. The ERG base cases also included several other of the ERG's preferred assumptions, that is:
excluding gender from the utility regression model
using the same dose intensity for all people having fedratinib (suboptimal or not)
basing the fedratinib adverse event rates in the model on the intention-to-treat population from JAKARTA‑2, rather than the intermediate‑2 or high‑risk subgroup.The committee considered analyses including the following assumptions:
with and without a survival benefit (see section 3.11)
the cost of ruxolitinib based on the platelet count distribution from JAKARTA‑2 (see section 3.15)
both with and without drug wastage for ruxolitinib (see section 3.16)
% of all people starting fedratinib would keep having it after their disease does not fully respond or stops responding (see section 3.13)
including the other ERG-preferred assumptions, outlined above.The analyses accounting for a survival benefit for fedratinib resulted in ICERs less than £30,000 per quality-adjusted life year (QALY) gained, but the analyses without a survival benefit resulted in ICERs greater than this. The committee considered that the most plausible ICER was likely to be between the scenarios with and without a survival benefit for fedratinib applied. However, this ICER would likely be above £30,000 per QALY gained, the upper end of the range normally considered a cost-effective use of NHS resources when the end of life criteria are not met. The committee concluded that fedratinib could not be recommended for routine use in the NHS.
# Other factors
The company considered fedratinib to be an innovative treatment but did not provide evidence of significant and substantial health-related benefits that were not included in the QALY calculations. The committee concluded that there were no additional gains in health-related quality of life associated with fedratinib over those already included in the QALY calculations.
An equalities issue was raised that myelofibrosis often affects older people. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal.
# Cancer Drugs Fund
## Fedratinib is recommended in the Cancer Drugs Fund
Having concluded that fedratinib could not be recommended for routine use, the committee then considered if it could be recommended within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee considered whether the remaining uncertainties in the company's modelling could be addressed through collecting more data. It was aware that FREEDOM‑2, a randomised controlled trial directly comparing fedratinib with best available therapy in people with myelofibrosis previously treated with ruxolitinib, is currently ongoing. The company expressed an interest in fedratinib being considered for funding through the Cancer Drugs Fund. The committee considered that FREEDOM‑2 would likely resolve some of the modelling uncertainties. These included the extent of a fedratinib survival benefit compared with best available therapy and the ruxolitinib treatment costs (how many people have the lower dose of ruxolitinib in the setting of best available therapy). Using fedratinib in the NHS would also allow data to be collected using the Systemic Anti-Cancer (SACT) dataset. This would provide data on overall survival and treatment duration for people having fedratinib in clinical practice. The committee recalled that fedratinib had shown plausible potential to be cost effective when assuming the size of survival benefit from the company's base case (see section 3.18). The committee concluded that fedratinib met the criteria for inclusion in the Cancer Drugs Fund for treating disease-related splenomegaly or symptoms of primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis in adults who have previously had ruxolitinib.
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{'Recommendations': "Fedratinib is recommended for use within the Cancer Drugs Fund as an option for treating disease-related splenomegaly or symptoms of primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis in adults. It is recommended only if:\n\nthey have previously had ruxolitinib and\n\nthe conditions in the managed access agreement for fedratinib are followed.\n\nThis recommendation is not intended to affect treatment with fedratinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nMost people with higher-risk myelofibrosis have ruxolitinib, and continue having it even if their disease does not fully respond, or stops responding. After ruxolitinib is stopped, people can have best available therapy, which includes chemotherapy, radiation therapy, splenectomy or red blood cell transfusion. The company proposes that fedratinib would only be used after ruxolitinib, which is more restrictive than its marketing authorisation.\n\nClinical trial evidence for people who have stopped ruxolitinib suggests that fedratinib improves myelofibrosis symptoms and reduces spleen size. However, this evidence is uncertain because fedratinib was not compared with best available therapy and some people did not finish the trial. Fedratinib has been compared indirectly with best available therapy using evidence from other studies. There is further uncertainty because of some differences between the trial populations in the indirect comparison.\n\nAlso, it is unclear how much longer people having fedratinib live compared with best available therapy, and this has a large effect on the cost-effectiveness results. There is also uncertainty around how many people would continue having fedratinib if their disease does not fully respond, or stops responding.\n\nFedratinib does not meet NICE's criteria to be considered a life-extending treatment at the end of life based on the evidence currently available. The cost-effectiveness estimates for fedratinib compared with best available therapy are uncertain because of limitations in the data. Because some of these estimates are higher than what NICE normally considers an acceptable use of NHS resources, fedratinib cannot be recommended for routine use in the NHS. Collecting more data on overall survival and treatment duration will reduce the uncertainty in the evidence. Therefore, fedratinib is recommended for use in the Cancer Drugs Fund.", 'Information about fedratinib': "# Marketing authorisation indication\n\nFedratinib (Inrebic, Celgene) has a marketing authorisation for 'the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naive or have been treated with ruxolitinib'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of fedratinib is £6,120\xa0for a 120‑capsule pack of 100\xa0mg capsules (excluding VAT; BNF online accessed September\xa02021). The company has a commercial arrangement. This makes fedratinib available to the NHS with a discount. The size of the discount is commercial in confidence. It's the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Celgene, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee recognised that there were remaining areas of uncertainty associated with the analyses presented, and took these into account in its decision making. It discussed the following key issues, which were outstanding after the technical engagement stage:\n\nWhether there was an overall survival benefit for fedratinib over best available therapy (see ERG critique of company technical engagement response, issue\xa07, page\xa016).\n\nWhich was the most appropriate model of time to treatment discontinuation for fedratinib (see ERG critique of company addendum submission, page\xa06).\n\nWhether the company's subsequent treatment assumption for people having fedratinib was appropriate (see ERG critique of company technical engagement response, issue\xa06, page\xa015).\n\nWhether the company's approach to estimating ruxolitinib costs was appropriate (see ERG critique of company technical engagement response, issue\xa09, page\xa020).\n\nHow the transformation rate to acute myeloid leukaemia (AML) should be modelled for people having fedratinib (see ERG critique of company addendum submission, page\xa09).\n\nWhether fedratinib meets the criteria for end of life treatments (see ERG critique of company technical engagement response, issue\xa011, page\xa022).\n\n# Treatment pathway, population and comparator\n\n## People with myelofibrosis often experience severe symptoms\n\nMyelofibrosis is a rare haematological disorder that often causes an enlarged spleen (splenomegaly) and constitutional symptoms, and shortens life. The patient experts explained that people with myelofibrosis experience debilitating fatigue, pain from splenomegaly, severe itching, night sweats, bone pain, and mental health problems including depression. Many people with myelofibrosis must reduce working hours or stop working completely because of fatigue. The patient experts added that the combined symptom burden can be very intense, and people can become dependent on carers. They also noted that people with myelofibrosis may be unable to exercise and that lack of exercise could contribute to other health issues. Around 75% of people with myelofibrosis reported experiencing depression or low mood. The patient experts explained the fear of living with a disease that is incurable for most people. They explained that knowing there are limited treatment options adds to their worry. They would like a new treatment option to increase life expectancy and improve quality of life. The committee concluded that people with myelofibrosis often have a high symptom burden. Improving survival and the symptoms associated with myelofibrosis, particularly fatigue and itching, would greatly benefit the wellbeing of people with myelofibrosis and their families.\n\n## People with myelofibrosis would welcome a new treatment option, particularly when ruxolitinib is no longer suitable\n\nMyelofibrosis has 4\xa0different risk categories according to the Dynamic International Prognostic Scoring System (DIPSS): low, intermediate‑1, intermediate‑2 and high risk. Clinicians can use these risk scores to guide treatment. People without symptoms or who have low-risk disease may have their myelofibrosis observed without active treatment. Most people with intermediate‑2 or high-risk disease have ruxolitinib, which was recommended in NICE's technology appraisal guidance on ruxolitinib for treating disease-related splenomegaly or symptoms in adults with primary or secondary myelofibrosis (from now, TA386). The rest have best available therapy, which comprises several treatment options including hydroxycarbamide, androgens, radiation therapy, and red blood cell transfusion. The clinical experts explained that peoples' experiences with ruxolitinib varied. Ruxolitinib may work well at first, but many people experience disease relapse. People having ruxolitinib often have side effects which can mean they have to stop treatment. The clinical and patient experts also explained that best available therapy has limited effectiveness. This means that many people continue having suboptimal ruxolitinib treatment even if the disease does not respond or subsequently loses response, because there are no other effective treatment options. However, disease symptoms will usually return for people having suboptimal ruxolitinib. When ruxolitinib is no longer suitable there are no other options other than best available therapy. The committee agreed that patients and clinicians would welcome a new treatment option for myelofibrosis, particularly when ruxolitinib is no longer suitable.\n\n## The company's positioning of fedratinib for people with intermediate-2 or high-risk myelofibrosis who have had ruxolitinib is appropriate\n\nFedratinib's marketing authorisation covers people with primary or secondary myelofibrosis (regardless of risk category) who have either not had a Janus kinase (JAK) inhibitor, or had ruxolitinib. However, the company positioned fedratinib in people with intermediate‑2 or high‑risk disease who have had ruxolitinib. The company considered this positioning reflected an area of unmet need and was how clinicians would use fedratinib in clinical practice. People who have had ruxolitinib have few treatment options (see section\xa03.2). So, the committee concluded that it was appropriate to appraise fedratinib for intermediate‑2 or high‑risk myelofibrosis after ruxolitinib.\n\n## The company's mixed comparator is acceptable, but the evidence for best available therapy in the model should reflect the proportion of people assumed to have ruxolitinib\n\nThe comparator in the NICE scope for people who had previous treatment with ruxolitinib, or when ruxolitinib was not appropriate, was established clinical practice, also called best available therapy. This included hydroxycarbamide, other chemotherapies, androgens, splenectomy, radiation therapy, erythropoietin and red blood cell transfusion. In the company's economic model (see section\xa03.9), around 89% of people having best available therapy were assumed to have ruxolitinib. The ERG considered that the company should have split the population in its model into 2\xa0subgroups: people who would have continued having suboptimal ruxolitinib, and people who would have stopped having ruxolitinib altogether. This was supported by the feedback from clinical experts. The clinical experts commented that most people whose disease is relapsed or refractory to ruxolitinib would keep having it, but people for whom ruxolitinib is poorly tolerated would usually stop having it. The ERG noted that the 2\xa0subgroups would have different comparators. The comparator for the first group would be ruxolitinib, and the comparator for the second group would be best available therapy without ruxolitinib. The ERG considered that separating the population in this way would have helped to interpret the results. However, the company stated that it was not possible to split the trial population into the groups suggested by the ERG. The company also noted that there were no internationally recognised criteria for defining these groups, and they could therefore overlap. The comparator included a mix of people having ruxolitinib and people having best available therapy without ruxolitinib. The committee agreed that this mixed comparator was acceptable, but noted that the evidence used for best available therapy in the model should reflect the proportion of people assumed to have ruxolitinib (see section\xa03.10).\n\n# Clinical evidence\n\n## JAKARTA-2 is generalisable to people in the NHS with myelofibrosis who would have fedratinib\n\nThe evidence for fedratinib came from JAKARTA‑2, a single-arm, open-label, phase\xa02 study. The study included 97\xa0adults with intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis that was deemed resistant to ruxolitinib after at least 14\xa0days of treatment, or who were intolerant to ruxolitinib after any duration of treatment. Of these people, 81 had intermediate‑2 or high-risk disease, corresponding to where the company positioned fedratinib (see section\xa03.3). The dose of fedratinib used in the study was 400\xa0mg per day for 6\xa0consecutive 28‑day cycles (24\xa0weeks). The daily dose could be increased to up to 600\xa0mg within the first 6\xa0cycles if there was a reduction in spleen size by palpation of less than 50% at the end of cycles\xa02 and\xa04. The primary outcome was spleen response, defined as the proportion of people with a spleen volume reduction of 35% or more from baseline at the end of cycle\xa06. Secondary outcomes included: symptom response (the proportion of people with a reduction in total symptom score of 50% or more from baseline to the end of cycle\xa06), the proportion of people with a reduction in palpable spleen length of 50% or more from baseline to the end of cycle\xa06, spleen response at the end of cycle\xa03 (12\xa0weeks), percentage change in spleen volume from baseline to the end of cycles\xa03 and\xa06, and safety. The clinical experts noted that the inclusion criteria for JAKARTA‑2 were quite unrestricted, and that the study would be generalisable to the NHS in England. The committee concluded that JAKARTA‑2 was generalisable to people in the NHS with myelofibrosis who would have fedratinib.\n\n## Fedratinib is clinically effective, but the lack of comparator data makes assessing comparative effectiveness challenging\n\nIn November\xa02013, the Food and Drug Administration (FDA) in the US put a clinical hold on fedratinib because of 8\xa0suspected cases of Wernicke's encephalopathy. During the clinical hold, people stopped having fedratinib while the suspected cases of Wernicke's encephalopathy were investigated. The clinical hold meant that 13\xa0people in JAKARTA‑2 stopped having fedratinib before they reached cycle\xa06 because of the study being stopped early. Also, during the marketing authorisation process, the Committee for Medicinal Products for Human Use (CHMP) requested additional analyses of JAKARTA‑2 because of uncertainty around the additional benefits from increasing the fedratinib daily dose above 400\xa0mg. The company therefore submitted analyses that counted disease response with a daily dose of more than 400\xa0mg as not responding. This CHMP definition of response was used in the company and ERG analyses in the model. In the JAKARTA‑2 intention-to-treat population, 23% of people had a spleen response while having a maximum daily dose of 400\xa0mg. The proportion of people who had a symptom response in the intention-to-treat population while having a maximum daily dose of 400\xa0mg was 21%. The ERG noted that the absence of a control arm in JAKARTA‑2 meant that it was possible that there was regression to the mean effects. This is when extreme values return to average over time. The committee acknowledged the difficulty of collecting data for rare diseases. It concluded that fedratinib is clinically effective, but that the disruption to the trial and lack of comparative data made the assessment of comparative effectiveness challenging.\n\n## Fedratinib has manageable adverse events\n\nThe company noted that the adverse event rates from JAKARTA‑2 were generally low. The most common non-haematological adverse events for people having fedratinib were gastrointestinal disorders including diarrhoea (62%), nausea (56%), and vomiting (41%). The most common grade\xa03 or\xa04 adverse events were haematological and included anaemia (38%) and thrombocytopenia (22%). Treatment-emergent adverse events that meant fedratinib was stopped were seen in 20% of people. Across all fedratinib studies there were 8\xa0suspected cases of Wernicke's encephalopathy, 1 of which had a clear diagnosis. It was found to be a consequence of gastrointestinal adverse events in people who were undernourished. Wernicke's encephalopathy can be managed by monitoring thiamine levels and supplementing as needed. The clinical experts noted that they follow the summary of product characteristics for monitoring thiamine levels and making dose adjustments. The company confirmed that there have been no additional instances of Wernicke's encephalopathy since the end of the FDA's clinical hold. The committee concluded that fedratinib has a manageable adverse event profile.\n\n# Indirect treatment comparison\n\n## The indirect treatment comparison suggests fedratinib improves response compared with best available therapy, but there are uncertainties\n\nIn the absence of direct head-to-head evidence comparing the efficacy of fedratinib with best available therapy, the company did a matching-adjusted indirect comparison (MAIC) for spleen or symptom response (see section\xa03.5 for definitions of these outcomes). The company used evidence from the intermediate‑2 or high-risk group from JAKARTA‑2 (n=81) for fedratinib and evidence from the SIMPLIFY‑2 trial (n=52) for best available therapy. SIMPLIFY‑2 was a randomised trial comparing momelotinib with best available therapy in people whose myelofibrosis had a suboptimal response to ruxolitinib, or who had haematological toxic effects with ruxolitinib. The company's base-case MAIC was adjusted for DIPSS risk category (see section\xa03.2) and Eastern Cooperative Oncology Group (ECOG) performance status. The company chose these variables based on clinical input that they were prognostic, and that there was a meaningful imbalance between JAKARTA‑2 and the best available therapy arm from SIMPLIFY‑2. The results of the MAIC suggested that fedratinib improves response compared with best available therapy, but the exact values are confidential and cannot be reported here. The ERG commented that ignoring variables because they were balanced individually may not achieve balance between the study populations overall. It noted that people in SIMPLIFY‑2 could be currently having ruxolitinib (which was not the case in JAKARTA‑2), and that this difference could not be adjusted for in the MAIC. Differences in how symptom response was assessed between JAKARTA‑2 and SIMPLIFY‑2 and the absence of a washout period in SIMPLIFY‑2 may also have favoured fedratinib. The committee agreed that the MAIC suggests fedratinib improves response compared with best available therapy, but there was considerable uncertainty around these results.\n\n# The company's cost-effectiveness model\n\n## The company's model is similar to that from TA386, but a simpler model structure may have been more robust for decision making\n\nThe company submitted an individual patient discrete event simulation model comparing fedratinib with best available therapy. This was similar to the approach used in TA386. The company considered this design to be more flexible and transparent compared with a Markov cohort approach. The model had 5\xa0health states (on fedratinib, on best available therapy, on best available therapy after fedratinib, supportive care, and death). People entered the model having either fedratinib or best available therapy. They were then categorised into response or non-response groups at 24\xa0weeks based on the outputs of the company's MAIC (see section\xa03.8). People having fedratinib stopped treatment according to models of time to treatment discontinuation fitted to the data from JAKARTA‑2. The company modelled time to treatment discontinuation from the start of the model, using separate extrapolations according to whether there was a response at week\xa024. For people having fedratinib, the company estimated survival from the point of stopping fedratinib, using models fitted to the survival data after stopping treatment from JAKARTA‑2. Like time to treatment discontinuation, this was split by response at week\xa024. People having best available therapy at the start of the model stopped treatment according to a model of time to treatment discontinuation fitted to data from the Haematological Malignancy Research Network (HMRN; see section\xa03.10). Unlike the fedratinib arm, the company used a single extrapolation of time to treatment discontinuation from the start of the model regardless of response at week\xa024. The company estimated overall survival for people having best available therapy using data from Schain et al. 2019 (see section\xa03.10). Like time to treatment discontinuation for best available therapy, the company fitted a single overall survival curve from the start of the model regardless of response at week\xa024. The ERG had several concerns with the company's model. It questioned the value of separating the population by response at week\xa024, given the small sample size of JAKARTA‑2. It also noted that the company had used several different evidence sources for people having best available therapy (see section\xa03.10), and that there were important differences between these sources in terms of the patient populations and treatments. The ERG was also concerned that the company had used a different modelling approach for the fedratinib arm compared with the best available therapy arm. The committee shared the ERG's reservations with the model, noting that it was overly complex given the limitations of the clinical evidence for fedratinib (see section 3.6). In response to consultation, the company provided additional justification for the model structure. It noted that the issues identified with the model structure could only be overcome by additional data collection. Also, the different modelling approaches for the 2\xa0treatment arms reflected that the treatment pathways would be different. The company acknowledged that some complexity arose from splitting people in the model into those whose disease did or did not respond to fedratinib for the survival and time to treatment discontinuation models. But it stated that survival and time to treatment discontinuation models could also be applied to the overall population having fedratinib in the model (not split by disease response). This gave similar results to the company's base case. The company further noted that a simpler model could have created separate issues. The ERG's view of the model remained unchanged after consultation. At its second meeting, the committee noted that the company had made few changes to the model presented at the first committee meeting. It reiterated its conclusion from the first committee meeting that a simpler model structure may have been more robust for decision making.\n\n## Using different sources of evidence to model best available therapy increases uncertainty\n\nThe company used a range of evidence sources for best available therapy in its model. For its base case, the company used the data from SIMPLIFY‑2 for the spleen or symptom response MAIC (see section\xa03.8), for the adverse event frequency for best available therapy as a comparator, and for the composition of best available therapy. Although overall survival data for people having best available therapy was available from SIMPLIFY‑2, the company did not use that in its base case. Instead, it used evidence from people who had stopped having ruxolitinib from Schain et al. 2019 (n=71). This was a retrospective observational study of people with myelofibrosis in Sweden and Norway, which the company considered best represented the people likely to have fedratinib in the NHS. The ERG noted that Schain included more people with primary myelofibrosis than JAKARTA‑2, and the population was also older on average. Therefore, the ERG expected people in Schain to have a worse prognosis than those in JAKARTA‑2. The ERG had additional concerns with comparing survival data from an observational study (Schain) with a clinical trial (JAKARTA‑2). It also considered that SIMPLIFY‑2 was a more appropriate source of evidence for best available therapy to align costs and outcomes in the model. This was because nobody in Schain had ruxolitinib, and so it did not reflect the composition of best available therapy from SIMPLIFY‑2 (in which around 89% of people had ruxolitinib). The company used evidence from people who stopped having ruxolitinib (n=39) in COMFORT‑2 for the adverse event frequency for people having best available therapy after fedratinib. COMFORT‑2 was a randomised phase\xa03 trial comparing ruxolitinib with best available therapy in people with myelofibrosis. The company also used the data from the best available therapy arm of COMFORT‑2 (n=73) to model the rate of transformation to AML for people having fedratinib and for people having best available therapy (see section 3.14). Finally, the company used evidence from the HMRN to inform the model of time to treatment discontinuation for people having best available therapy. The HMRN measured treatment outcomes in people with primary or secondary myelofibrosis in the Yorkshire and the Humber and Yorkshire Coast Cancer Networks between September\xa02004 and August\xa02017. The ERG was concerned that the populations in SIMPLIFY‑2, COMFORT‑2, Schain, and the HMRN were different in terms of age, risk score, and the types of best available therapy options that people were having. It was also concerned that the company did not use evidence sources consistently in its model. The committee agreed that using different sources of evidence to model best available therapy was inappropriate and increased uncertainty. The comparator in the company's model was comprised mainly of people having ruxolitinib (see section\xa03.4), and the evidence used for best available therapy should reflect this.\n\n## Fedratinib is likely to extend survival, but the extent of the survival benefit is highly uncertain\n\nTo model survival after stopping treatment for people having fedratinib, the company fitted parametric models to the JAKARTA‑2 intermediate‑2 or high-risk subgroup survival data after stopping treatment, split by response status at week\xa024. Based on clinical expert advice, the company considered a Weibull distribution to be the most plausible distribution for people whose disease did respond and those whose disease did not respond. The company also noted that the Weibull distribution provided a conservative survival estimate for fedratinib. For best available therapy, the company fitted a Weibull distribution to the overall survival data from Schain for people who stopped having ruxolitinib. The company's base-case model predicted a mean overall survival benefit for fedratinib of 6.2\xa0months based on the naive comparison of overall survival from JAKARTA‑2 and Schain. However, the ERG had concerns with using the overall survival data from Schain (see section\xa03.10). It considered that the observed survival benefit could be because the company had used different modelling approaches for the 2\xa0treatment arms. The ERG requested that the company do an exploratory MAIC for overall survival using evidence from JAKARTA‑2 and SIMPLIFY‑2. It noted that after matching based on DIPSS risk category, the overall survival for people having fedratinib was similar to that for people having best available therapy. The ERG also noted that after adjusting for other prognostic factors such as platelet count and transfusion dependence in the MAIC, people having fedratinib had a shorter overall survival than those having best available therapy. The company considered that the overall survival data from SIMPLIFY‑2 was not reliable because of discrepancies in the data reported. It also noted that overall survival was not a pre-specified outcome in SIMPLIFY‑2, and that people could switch from best available therapy to momelotinib after 24\xa0weeks. The company highlighted that there was evidence to suggest that spleen response is linked to overall survival. As such, fedratinib could be expected to have an overall survival benefit based on the results of the company's MAIC for spleen or symptom response (see section\xa03.8). The clinical experts agreed, stating that there is real-world and clinical trial evidence linking spleen response to overall survival. They considered that it was implausible that fedratinib would have no overall survival benefit over best available therapy. At its first meeting, the committee considered that fedratinib was likely to extend overall survival, but the extent of this overall survival benefit was highly uncertain. In response to consultation, the company highlighted 4\xa0studies that quantified the association between spleen response and improved survival. The ERG noted that the company did not use spleen response as a surrogate for survival in its base-case model. The ERG reiterated that when survival was compared with the same evidence source the company used in its response MAIC (SIMPLIFY‑2, see section 3.8), there did not appear to be a survival benefit for fedratinib. The committee was concerned that the population in Schain, where people had stopped ruxolitinib treatment, did not reflect the modelled best available therapy arm, where most people continued ruxolitinib treatment. It considered that it had not seen sufficient evidence to change its conclusion from the first meeting. It felt that fedratinib was likely to extend overall survival compared with best available therapy. However, it concluded that based on the evidence presented, the extent of this overall survival benefit was highly uncertain.\n\n## The fedratinib extrapolations for time to treatment discontinuation are uncertain, but are not a main driver of the cost-effectiveness results\n\nThe company fitted several parametric models to the time to treatment discontinuation data from JAKARTA‑2 and identified the exponential curve for disease response and the log-normal curve for disease non-response as the most appropriate. The ERG noted that the choice of distribution was very uncertain because of the small sample size and short follow up, and was confounded by the clinical hold and CHMP response definition for JAKARTA‑2 (see section\xa03.6). The ERG added that other distributions were also equally plausible, and provided a scenario analysis assuming a Gompertz distribution for both disease response and non-response. The committee understood the limitations with the JAKARTA‑2 evidence, but noted that the models for time to fedratinib discontinuation were not among the main drivers of the cost-effectiveness results.\n\n## The proportion of people staying on ruxolitinib in the model after their disease stops responding (89%) should also apply to fedratinib, for consistency\n\nIn its model presented at the first committee meeting, the company assumed that people having fedratinib would stop having it after their disease stops responding. They would then have best available therapy (without ruxolitinib) or supportive care, or both, until death. In contrast, the company assumed that most people (89%) starting best available therapy in the model were having ruxolitinib, in a population that had already had ruxolitinib (see section\xa03.4). The ERG considered that in NHS clinical practice, most people whose disease was relapsed or refractory to fedratinib would keep having it, or would switch back to ruxolitinib. It presented scenarios assuming the same proportion of people (89%) would keep having fedratinib or switch back to ruxolitinib as were having ruxolitinib in the best available therapy arm. The clinical experts noted that the treatment assumptions after fedratinib were hard to comment on because fedratinib is not used in current clinical practice. They agreed that most people were likely to continue having fedratinib even if their disease had not responded adequately, consistent with how ruxolitinib is used in practice. The clinical lead for the Cancer Drugs Fund noted that it was unlikely that NHS England would commission ruxolitinib after fedratinib, given that people switched to fedratinib because of insufficient disease response or intolerance to ruxolitinib. At its first meeting, the committee considered that most people with relapsed or refractory disease would continue having fedratinib, similar to how people currently keep having ruxolitinib because there are no other treatment options. In response to consultation, the company updated its model base case with the assumption that 65% of people whose disease responded to fedratinib would continue having fedratinib after their disease stops responding. This was calculated based on the discontinuation rate in JAKARTA‑2 up to the end of cycle\xa06. The ERG noted that the company's updated assumption for fedratinib was inconsistent with the best available therapy arm, in which 89% of people continued ruxolitinib treatment until supportive care or death. The company commented on the proportion of time spent on a JAK inhibitor in each arm, but the values are confidential and cannot be reported here. The ERG presented 2\xa0further scenarios. The scenarios assumed that 65% or 89%, respectively, of all people starting fedratinib would keep having it after their disease stops responding. This was regardless of whether their disease initially responded at 24\xa0weeks. The committee understood that in practice clinicians would likely be reluctant to stop fedratinib even if the disease does not fully respond, or stops responding. This was because there would be no other treatment options. The committee concluded that it was appropriate to assume that 89% of all people starting fedratinib would continue fedratinib after their disease stops responding. This was consistent with the proportion who were assumed to continue ruxolitinib in the best available therapy arm.\n\n## People having fedratinib should be assumed to have the same AML transformation rate as people having best available therapy\n\nMyelofibrosis can transform into AML. The company modelled AML as an adverse event, with an associated cost and quality-of-life impact. In its model presented at the first committee meeting, the company used evidence from the JAKARTA‑2 intermediate‑2 or high-risk subgroup to inform the AML transformation for people having fedratinib. For people having best available therapy, the company used evidence from COMFORT‑2 (see section\xa03.10). The ERG commented that the same AML transformation rate should be used for fedratinib and best available therapy, because it is unclear whether fedratinib treatment affects AML transformation. The ERG added that it was more appropriate to use evidence from COMFORT‑2 to inform the AML transformation rate for both fedratinib and best available therapy arms. This was because COMFORT‑2 had a longer follow up than JAKARTA‑2. The committee considered that there was insufficient evidence to tell whether fedratinib affects the rate of AML transformation. It concluded that it was appropriate to assume the same AML transformation rate for fedratinib as for people having best available therapy. In response to consultation, the company updated its base case to assume the same AML transformation rate for both arms, consistent with the committee preference.\n\n# Ruxolitinib costs\n\n## It is appropriate to use the platelet count distribution from JAKARTA-2 to estimate the cost of ruxolitinib\n\nRuxolitinib dose depends on platelet count. People with a platelet count of less than 100×109/litre have a lower dose of ruxolitinib, which costs less. In its model, the company based the proportion of people having the lower ruxolitinib dose in the best available therapy arm on the platelet count distribution from JAKARTA‑2. The ERG noted that mean platelet count in JAKARTA‑2 was higher than that reported in SIMPLIFY‑2, from which the company used the data for best available therapy in the indirect treatment comparison for response (see section 3.8). The ERG considered that the cost of ruxolitinib had therefore been overestimated by the company. The company noted that although the proportion of people with a platelet count of less than 100×109/litre was not reported from SIMPLIFY‑2, around 27% of patients were having a 5\xa0mg dose 2\xa0times per day or less. This was lower than the proportion based on the platelet count distribution from JAKARTA‑2, suggesting that the cost of ruxolitinib had been underestimated in the model rather than overestimated. In response to consultation, the company provided baseline characteristics from a global chart review to support its argument that people having best available therapy have poor survival outcomes (see section 3.17). These baseline characteristics included the proportion of people with a platelet count of less than 100×109/litre. The ERG noted that this proportion was higher than in JAKARTA‑2, and considered that it was more likely to resemble the distribution in SIMPLIFY‑2 than JAKARTA‑2 did. So, the ERG used the figure from the global chart review in its updated base case for the second committee meeting. The company reiterated that it considered that the cost of ruxolitinib had been underestimated in the model, and that basing the platelet count distribution on the global chart review would further underestimate its cost. The company also noted that using the global chart review to inform the proportion of people having the lower ruxolitinib dose would mean that costs and outcomes in the model would not be aligned, because this data was available from SIMPLIFY‑2. The committee understood that there was uncertainty as to which platelet count distribution should be used in the model. It noted the company's concerns with using the global chart review to inform ruxolitinib costs. It concluded that, on balance, the platelet count distribution from JAKARTA‑2 was appropriate to use to estimate the cost of ruxolitinib.\n\n## It is appropriate to consider scenarios with and without drug wastage for ruxolitinib\n\nThe company base-case model included an additional 5% drug wastage for ruxolitinib, in line with the ERG preference in TA386. The ERG considered this inappropriate because in TA386 the clinical experts advised that assuming no drug wastage for ruxolitinib reflected its use in clinical practice. As such, the ERG preferred to exclude ruxolitinib wastage from the model. In response to consultation, the company did not update its base case. The company indicated that informal discussions with clinicians supported that drug wastage would happen for ruxolitinib in clinical practice. The ERG speculated that there could be less ruxolitinib wastage in the second-line setting because more people would have the 5\xa0mg dose. It also reiterated that the cost of ruxolitinib could already be overestimated in the model (see section 3.15). The committee was aware that including drug wastage for ruxolitinib had a large effect on the cost-effectiveness results in some scenarios. It acknowledged the uncertainty, and concluded that it was appropriate to consider scenarios with and without drug wastage for ruxolitinib.\n\n# End of life\n\n## Fedratinib does not meet the end of life criteria based on the evidence currently available\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The clinical experts explained that life expectancy for people who stop ruxolitinib is around 12\xa0to 18\xa0months. They noted that most people in JAKARTA‑2 had died within 2\xa0to 3\xa0years of stopping fedratinib, even though most had retreatment with ruxolitinib. The committee was aware that median overall survival after stopping ruxolitinib was 16\xa0months or less in COMFORT‑2, Schain and based on the HMRN data. However, it noted that the company base-case model predicted that people having best available therapy had a mean life expectancy of 28.7\xa0months. The company explained that the Weibull distribution it had used to extrapolate overall survival for people having best available therapy (see section\xa03.11) gave an optimistic survival prediction. Selecting a more conservative exponential model resulted in a mean life expectancy of less than 24\xa0months. The ERG base case assumed no survival difference (see section\xa03.11), so people having best available therapy had the same life expectancy as people having fedratinib (34.9\xa0months). At its first meeting, the committee concluded that there was considerable uncertainty about whether people having best available therapy would have a life expectancy of less than 24\xa0months. There was also uncertainty about the extent of fedratinib's survival benefit over best available therapy (see section\xa03.11). In response to consultation, the company noted that the high-risk disease group in TA386 met the end of life criteria. Because 42% of the modelled population were high risk, the company indicated that these people should therefore meet the end of life criteria for consistency with TA386. The company added that because the Kaplan–Meier data from Schain was immature, the median survival was more appropriate than the mean survival to inform the life expectancy criterion. The company also provided baseline characteristics for a global chart review that it considered showed poor survival outcomes for people having best available therapy (including ruxolitinib). The company believed that these baseline characteristics were similar to JAKARTA‑2. The ERG noted that the survival estimates discussed at the first committee meeting (from COMFORT‑2, Schain and the HMRN data) were from people who had stopped ruxolitinib treatment, but in the best available therapy arm in the model 89% of people were having ruxolitinib. The ERG also considered that there was a lack of detail on the global chart review, and that it was unclear how similar the population was to JAKARTA‑2. At its second meeting, the committee discussed the survival estimates from clinicians that the company had used to select its survival model for people having best available therapy. It understood that the company had originally asked clinicians for their estimates of survival for when people had stopped having ruxolitinib, rather than for when most people were having suboptimal ruxolitinib. There was also some variability around the clinician responses. The committee noted that the 2\xa0distributions selected as clinically plausible by the company (Weibull and exponential) lay on either side of the clinician estimates, and it would have preferred to see a scenario with a survival model fitted directly through these estimates. Because this would lie above the exponential distribution (which gave a mean survival of 23.3\xa0months), the committee considered that it was likely that this scenario would give a mean survival of more than 24\xa0months. The committee also noted that because the cost-effectiveness results are calculated based on mean (rather than median) values, it is important to consider the mean survival results when assessing if the end of life criteria were met. The committee considered that it had not seen robust enough evidence to conclude that fedratinib met either of the criteria to be considered a life-extending treatment at the end of life based on the evidence currently available.\n\n# Cost-effectiveness estimates\n\n## The most likely cost-effectiveness estimates are higher than those normally considered an acceptable use of NHS resources\n\nThe committee considered the deterministic incremental cost-effectiveness ratios (ICERs) for fedratinib compared with best available therapy. Because of a confidential commercial arrangement for ruxolitinib, the exact cost-effectiveness results cannot be reported here. The committee noted that the 2\xa0main drivers of the cost-effectiveness results were whether or not fedratinib was assumed to extend overall survival (see section\xa03.11) and what proportion of people would continue having fedratinib after their disease stops responding (see section\xa03.13). In the company's base case, fedratinib was assumed to extend overall survival by 6.2\xa0months, and 65% of people whose disease initially responded to fedratinib continued having it. The ERG presented 2\xa0base cases in which it assumed that fedratinib had no overall survival benefit compared with best available therapy and 89% of all people starting fedratinib continue having fedratinib after their disease stops responding. Ruxolitinib wastage was included in ERG base case\xa01, and excluded in ERG base case\xa02. The ERG base cases also included several other of the ERG's preferred assumptions, that is:\n\nexcluding gender from the utility regression model\n\nusing the same dose intensity for all people having fedratinib (suboptimal or not)\n\nbasing the fedratinib adverse event rates in the model on the intention-to-treat population from JAKARTA‑2, rather than the intermediate‑2 or high‑risk subgroup.The committee considered analyses including the following assumptions:\n\nwith and without a survival benefit (see section 3.11)\n\nthe cost of ruxolitinib based on the platelet count distribution from JAKARTA‑2 (see section 3.15)\n\nboth with and without drug wastage for ruxolitinib (see section 3.16)\n\n% of all people starting fedratinib would keep having it after their disease does not fully respond or stops responding (see section 3.13)\n\nincluding the other ERG-preferred assumptions, outlined above.The analyses accounting for a survival benefit for fedratinib resulted in ICERs less than £30,000 per quality-adjusted life year (QALY) gained, but the analyses without a survival benefit resulted in ICERs greater than this. The committee considered that the most plausible ICER was likely to be between the scenarios with and without a survival benefit for fedratinib applied. However, this ICER would likely be above £30,000 per QALY gained, the upper end of the range normally considered a cost-effective use of NHS resources when the end of life criteria are not met. The committee concluded that fedratinib could not be recommended for routine use in the NHS.\n\n# Other factors\n\nThe company considered fedratinib to be an innovative treatment but did not provide evidence of significant and substantial health-related benefits that were not included in the QALY calculations. The committee concluded that there were no additional gains in health-related quality of life associated with fedratinib over those already included in the QALY calculations.\n\nAn equalities issue was raised that myelofibrosis often affects older people. However, issues related to differences in prevalence or incidence of a disease cannot be addressed in a technology appraisal.\n\n# Cancer Drugs Fund\n\n## Fedratinib is recommended in the Cancer Drugs Fund\n\nHaving concluded that fedratinib could not be recommended for routine use, the committee then considered if it could be recommended within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum). The committee considered whether the remaining uncertainties in the company's modelling could be addressed through collecting more data. It was aware that FREEDOM‑2, a randomised controlled trial directly comparing fedratinib with best available therapy in people with myelofibrosis previously treated with ruxolitinib, is currently ongoing. The company expressed an interest in fedratinib being considered for funding through the Cancer Drugs Fund. The committee considered that FREEDOM‑2 would likely resolve some of the modelling uncertainties. These included the extent of a fedratinib survival benefit compared with best available therapy and the ruxolitinib treatment costs (how many people have the lower dose of ruxolitinib in the setting of best available therapy). Using fedratinib in the NHS would also allow data to be collected using the Systemic Anti-Cancer (SACT) dataset. This would provide data on overall survival and treatment duration for people having fedratinib in clinical practice. The committee recalled that fedratinib had shown plausible potential to be cost effective when assuming the size of survival benefit from the company's base case (see section 3.18). The committee concluded that fedratinib met the criteria for inclusion in the Cancer Drugs Fund for treating disease-related splenomegaly or symptoms of primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythaemia myelofibrosis in adults who have previously had ruxolitinib."}
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https://www.nice.org.uk/guidance/ta756
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Evidence-based recommendations on fedratinib (Inrebic) for treating disease-related splenomegaly or symptoms in myelofibrosis in adults.
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6fdde24ca8c5063754046883f98ff82c87a54e27
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nice
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Colorectal cancer
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Colorectal cancer
This guideline covers managing colorectal (bowel) cancer in people aged 18 and over. It aims to improve quality of life and survival for adults with colorectal cancer through management of local disease and secondary tumours (metastatic disease).
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Reduction in risk of colorectal cancer in people with Lynch syndrome
Consider daily aspirin, to be taken for more than 2 years, to reduce the risk of colorectal cancer in people with Lynch syndrome. In January 2020 this was an off-label use of aspirin. See NICE's information on prescribing medicines.NICE has produced a patient decision aid to support discussions about taking aspirin.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prevention of colorectal cancer in people with Lynch syndrome .
Full details of the evidence and the committee's discussion are in evidence review A1: effectiveness of aspirin in the prevention of colorectal cancer in people with Lynch syndrome.
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# Information for people with colorectal cancer
Provide people with colorectal cancer information about their treatment (both written and spoken) in a sensitive and timely manner throughout their care, tailored to their needs and circumstances. Make sure the information is relevant to them, based on the treatment they might have and the possible side effects. Also see the NICE guidelines on patient experience in adult NHS services and decision-making and mental capacity.
Give people information on all treatment options for colorectal cancer available to them, including:
surgery, radiotherapy, systemic anti-cancer therapy or palliative care
the potential benefits, risks, side effects and implications of treatments, for example, possible effects on bowel and sexual function (see also recommendation 1.6.2), quality of life and independence.
Advise people with colorectal cancer of possible reasons why their treatment plan might need to change during their care, including:
changes from laparoscopic to open surgery or curative to non-curative treatment, and why this change may be the most suitable option for them
the likelihood of having a stoma, why it might be necessary and for how long it might be needed.
If recovery protocols (such as 'enhanced recovery after surgery', ERAS) are used, explain to people with colorectal cancer what these involve and their value in improving their recovery after surgery.
Ensure that appropriate specialists discuss possible side effects with people who have had surgery for colorectal cancer, including:
altered bowel, urinary and sexual function
physical changes, including anal discharge or bleeding.If relevant, have a trained stoma professional provide information on the care and management of stomas and on learning to live with a stoma.
Emphasise to people the importance of monitoring and managing side effects during non-surgical treatment to try to prevent permanent damage (for example, monitoring prolonged sensory symptoms after platinum-based chemotherapy treatment, which can be a sign that the dose needs to be reduced to minimise future permanent peripheral neuropathy).
Give people who have had treatments for colorectal cancer information about possible short-term, long-term, permanent and late side effects which can affect quality of life, including:
pain
altered bowel, urinary or sexual function
nerve damage and neuropathy
mental and emotional changes, including anxiety, depression, chemotherapy-related cognitive impairment, and changes to self-perception and social identity.
Prepare people for discharge after treatment for colorectal cancer by giving them advice on:
adapting physical activity to maintain their quality of life
diet, including advice on foods that can cause or contribute to bowel problems such as diarrhoea, flatulence, incontinence and difficulty in emptying the bowels
weight management, physical activity and healthy lifestyle choices (for example stopping smoking and reducing alcohol use)
how long their recovery might take
how, when and where to seek help if side effects become problematic.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information for people with colorectal cancer .
Full details of the evidence and the committee's discussion are in evidence review E3: information needs of people prior, during and after treatment for colorectal cancer.
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# Management of local disease
## People with rectal cancer
Offer one of the treatments shown in table 1 to people with early rectal cancer (cT1-T2, cN0, M0) after discussing the implications of each treatment and reaching a shared decision with the person about the best option.
Transanal excision (TAE), including transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery (TEMS)
Endoscopic submucosal dissection (ESD)
Total mesorectal excision (TME)
Type of procedure
Endoscopic/Surgery
Endoscopic
Surgery
Minimally invasive procedure
Yes
Yes
Possible
Resection of bowel (may have more impact on sexual and bowel function)
No
No
Yes
Stoma needed (a permanent or temporary opening in the abdomen for waste to pass through)
No
No
Possible
General anaesthetic needed (and the possibility of associated complications)
Yes
No, conscious sedation
Yes
Able to do a full thickness excision (better chance of removing cancerous cells and more accurate prediction of lymph node involvement)
Yes
No
Yes
Removal of lymph nodes (more accurate staging of the cancer so better chance of cure)
No
No
Yes
Conversion to more invasive surgery needed if complication
Possible
Possible
Possible
Further surgery needed depending on histology
Possible
Possible
Usually no
Usual hospital stay
to 2 days
to 2 days
to 7 days
External scarring
No
No
Yes
Possible complications include (in alphabetical order)
Abdominal pain
Bleeding
Mild anal incontinence
Perirectal abscess/sepsis and stricture (narrowing)
Perforation
Suture line dehiscence (wound reopening)
Urinary retention
Abdominal pain
Bleeding
Bloating
Perforation
Adhesions
Anastomotic leak (leaking of bowel contents into the abdomen)
Anastomotic stricture (narrowing at internal operation site)
Bleeding
Incisional hernia (hernia where the surgical incision was made)
Injury to neighbouring structures
Pelvic abscess
Urinary retention
Some of the potential complications shown in the table were identified from the evidence review, others based on committee's expertise.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment for people with early rectal cancer .
Full details of the evidence and the committee's discussion are in evidence review C1: treatment for early rectal cancer.
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Do not offer preoperative radiotherapy to people with early rectal cancer (cT1-T2 cN0, M0), unless as part of a clinical trial.
Offer preoperative radiotherapy or chemoradiotherapy to people with rectal cancer that is cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preoperative treatment for people with rectal cancer .
Full details of the evidence and the committee's discussion are in evidence review C1: treatment for early rectal cancer and evidence review C2: preoperative radiotherapy and chemoradiotherapy for rectal cancer.
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Offer surgery to people with rectal cancer (cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0) who have a resectable tumour.
Inform people with a complete clinical and radiological response to neoadjuvant treatment who wish to defer surgery that there is a risk of recurrence, and there are no prognostic factors to guide selection for deferral of surgery. For those who choose to defer, encourage their participation in a clinical trial and ensure that data is collected via a national registry.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery for people with rectal cancer .
Full details of the evidence and the committee's discussion are in evidence review C4: deferral of surgery in people having neoadjuvant therapy for rectal cancer.
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Offer laparoscopic surgery for rectal cancer, in line with NICE's technology appraisal guidance on laparoscopic surgery for colorectal cancer.
Consider open surgery if clinically indicated, for example by locally advanced tumours, multiple previous abdominal operations or previous pelvic surgery.
Only consider robotic surgery within established programmes that have appropriate audited outcomes.
Only consider transanal total mesorectal excision (TME) surgery in the context of research in line with the NICE interventional procedures guidance on transanal total mesorectal excision for rectal cancer.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgical technique for people with rectal cancer .
Full details of the evidence and the committee's discussion are in evidence review C3: optimal surgical technique for rectal cancer.
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Consider referring people with locally advanced primary or recurrent rectal cancer that might potentially need multi-visceral or beyond-TME surgery to a specialist centre to discuss exenterative surgery.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on locally advanced or recurrent rectal cancer .
Full details of the evidence and the committee's discussion are in evidence review C5: effectiveness of exenterative surgery for locally advanced or recurrent rectal cancer.
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Hospitals performing major resection for rectal cancer should perform at least 10 of these operations each year.
Individual surgeons performing major resection for rectal cancer should perform at least 5 of these operations each year.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgical volumes for rectal cancer operations .
Full details of the evidence and the committee's discussion are in evidence review C7: preoperative chemotherapy for non-metastatic colon cancer.
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## People with colon cancer
Consider preoperative systemic anti-cancer therapy for people with cT4 colon cancer.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preoperative treatment for people with colon cancer .
Full details of the evidence and the committee's discussion are in evidence review C7: preoperative chemotherapy for non-metastatic colon cancer.
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For advice on laparoscopic surgery see NICE's technology appraisal guidance on laparoscopic surgery for colorectal cancer.
## People with either colon or rectal cancer
Patients with rectal cancer treated with long-course chemoradiotherapy are not covered by this recommendation.
For people with stage III colon cancer (pT1-4, pN1-2, M0), or stage III rectal cancer (pT1-4, pN1-2, M0) treated with short-course radiotherapy or no preoperative treatment, offer:
capecitabine in combination with oxaliplatin (CAPOX) for 3 months, or if this is not suitable
-xaliplatin in combination with 5-fluorouracil and folinic acid (FOLFOX) for 3 to 6 months, or
single-agent fluoropyrimidine (for example, capecitabine) for 6 months, in line with NICE technology appraisal guidance (see the NICE technology appraisal guidance on our topic page on colorectal cancer).Base the choice on the person's histopathology (for example pT1-T3 and pN1, and pT4 and/or pN2), performance status, any comorbidities, age and personal preferences. In January 2020, the use of some treatments was off label:
-xaliplatin in combination with capecitabine (though CAPOX is common in UK clinical practice)
capecitabine for 3 months duration of adjuvant treatment in people with colon cancer
CAPOX and FOLFOX in stage III rectal cancer.See NICE's information on prescribing medicines.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on duration of adjuvant chemotherapy for people with colorectal cancer .
Full details of the evidence and the committee's discussion are in evidence review C8: optimal duration of adjuvant chemotherapy for colorectal cancer.
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Consider stenting for people presenting with acute left-sided large bowel obstruction who are to be treated with palliative intent.
Offer either stenting or emergency surgery for people presenting with acute left-sided large bowel obstruction if potentially curative treatment is suitable for them.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on colonic stents in acute large bowel obstruction .
Full details of the evidence and the committee's discussion are in evidence review C9: effectiveness of stenting for acute large bowel obstruction.
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# Molecular biomarkers to guide systemic anti-cancer therapy
Also see the NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer.
Test for RAS and BRAF V600E mutations in all people with metastatic colorectal cancer suitable for systemic anti-cancer treatment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on molecular biomarkers to guide systemic anti-cancer therapy .
Full details of the evidence and the committee's discussion are in evidence review B1: use of molecular biomarkers to guide systemic therapy.
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# Management of metastatic disease
## People with asymptomatic primary tumour
Consider surgical resection of the primary tumour for people with incurable metastatic colorectal cancer who are receiving systemic anti-cancer therapy and have an asymptomatic primary tumour. Discuss the implications of the treatment options with the person before making a shared decision. See table 2.
Advantages
Disadvantages
Resection of the asymptomatic primary tumour
Possible improvement in overall survival rate (based on low quality evidence from research)
Avoidance of primary tumour-related symptoms such as obstruction, perforation, bleeding and pain
Around 5 in 100 people will have severe postoperative complications (based on moderate quality evidence from research)
Systemic therapy still needed, and may be delayed if surgical complications occur
No resection (systemic anti-cancer therapy only)
Avoids surgery and the potential for postoperative complications
Around 20 in 100 people will develop primary tumour-related symptoms such as obstruction, perforation, bleeding and pain that need surgery (based on low quality evidence from research)
Advantages and disadvantages in table 2 are based on committee expertise unless otherwise indicated.
Quality of evidence (based on grading of recommendations, assessment, development and evaluations ):
Moderate: true effect is probably close to the estimated effect.
Low: true effect might be markedly different from the estimated effect.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on asymptomatic primary tumour .
Full details of the evidence and the committee's discussion are in evidence review D1: surgery for asymptomatic primary tumour.
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## Systemic anti-cancer therapy for people with metastatic colorectal cancer
For advice on systemic anti-cancer therapy for people with metastatic cancer, see NICE technology appraisal guidance on our topic page on colorectal cancer.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on systemic anti-cancer therapy for people with metastatic colorectal cancer .
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## Genomic biomarker-based treatment
The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments for guidance on specific treatments.
## People with metastatic colorectal cancer in the liver
Consider resection, either simultaneous or sequential, after discussion by a multidisciplinary team with expertise in resection of disease in all involved sites.
Consider perioperative systemic anti-cancer therapy if liver resection is a suitable treatment.
Consider chemotherapy with local ablative techniques for people with colorectal liver metastases that are unsuitable for liver resection after discussion by a specialist multidisciplinary team.
Do not offer selective internal radiation therapy (SIRT) as first-line treatment for people with colorectal liver metastases that are unsuitable for local treatment. See the NICE interventional procedures guidance on selective internal radiation therapy for unresectable colorectal metastases in the liver, which recommends that SIRT should only be offered:
with special arrangements for clinical governance, consent, and audit or research to people who are chemotherapy intolerant or who have liver metastases that are refractory to chemotherapy
in the context of research to people who can have chemotherapy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metastatic colorectal cancer in the liver .
Full details of the evidence and the committee's discussion are in evidence review D2a: treatment for metastatic colorectal cancer in the liver amenable to treatment with curative intent and evidence review D2b: optimal combination and sequence of treatments in patients presenting with metastatic colorectal cancer in the liver not amenable to treatment with curative intent.
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## People with metastatic colorectal cancer in the lung
Consider metastasectomy, ablation or stereotactic body radiation therapy for people with lung metastases that are suitable for local treatment, after discussion by a multidisciplinary team that includes a thoracic surgeon and a specialist in non-surgical ablation.
Consider biopsy for people with a single lung lesion to exclude primary lung cancer.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metastatic colorectal cancer in the lung .
Full details of the evidence and the committee's discussion are in evidence review D3: treatment for metastatic colorectal cancer in the lung amenable to local treatment.
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## People with metastatic colorectal cancer in the peritoneum
For people with colorectal cancer metastases limited to the peritoneum:
-ffer systemic anti-cancer therapy and
within a multidisciplinary team, discuss referral to a nationally commissioned specialist centre to consider cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metastatic colorectal cancer in the peritoneum .
Full details of the evidence and the committee's discussion are in evidence review D4: local and systemic treatments for metastatic colorectal cancer isolated in the peritoneum.
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# Ongoing care and support
## Follow-up for detection of local recurrence and distant metastases
For people who have had potentially curative surgical treatment for non-metastatic colorectal cancer, offer follow-up for detection of local recurrence and distant metastases for the first 3 years. Follow-up should include serum carcinoembryonic antigen (CEA) and CT scan of the chest, abdomen and pelvis.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for detection of local recurrence and distant metastases .
Full details of the evidence and the committee's discussion are in evidence review E1: follow-up to detect recurrence after treatment for non-metastatic colorectal cancer.
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## Management of low anterior resection syndrome
Give information on low anterior resection syndrome (LARS) to people who will potentially have sphincter-preserving surgery. Advise them to seek help from primary care if they think they have symptoms of LARS, such as:
increased frequency of stool
urgency with or without incontinence of stool
feeling of incomplete emptying
fragmentation of stool (passing small amounts little and often)
difficulty in differentiating between gas and stool.
Assess people with symptoms of LARS using a validated patient-administered questionnaire (for example, the Low Anterior Resection Syndrome score (LARS score), at the European Society of Coloproctology).
Offer people with bowel dysfunction treatment for associated symptoms in primary care (such as dietary management, laxatives, anti-bulking agents, anti-diarrhoeal agents, or anti-spasmodic agents). Seek advice from secondary care if the treatment is not successful.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of low anterior resection syndrome .
Full details of the evidence and the committee's discussion are in evidence review E2: optimal management of low anterior resection syndrome.
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# Terms used in this guideline
This section defines terms that have been used in a specific way for this guideline. For general definitions, please see the NICE glossary.
## Beyond-TME surgery
Beyond total mesorectal excision (TME) surgery is when the tumour extends beyond what is achievable to resect by TME and needs more extensive surgery to achieve clear margins.
## Major resection for rectal cancer
Major resection for rectal cancer means a surgical operation when part or all of the rectum is removed, including anterior resection and abdominoperineal resection.
## Recovery protocols
Recovery protocols, such as 'enhanced recovery after surgery' (ERAS), are perioperative care pathways designed to promote early recovery for patients undergoing major surgery by optimising the person's health before surgery and maintaining health and functioning after surgery.
## Social identity
Social identity is about changes to people's concept of themselves as a result of either their cancer, or the long-term side effects from treatment. For example, it could cover changes from being a previously fit person to someone who has physical or mental health problems, from being someone with the expectation of years to live to someone with a limited life expectancy, or the change from being a carer to becoming cared for.
## TNM classification
This guideline uses the tumour, node, metastasis (TNM) classification developed by the Union for Interventional Cancer Control (UICC) to describe the stage of the cancer. Please refer to The TNM Classification of Malignant Tumours, 8th Edition for further information. In this guideline early rectal cancer is defined as cT1-2, cN0, M0. cTNM refers to clinical classification based on evidence acquired before treatment, for example imaging, physical examination and endoscopy. pTNM refers to pathological classification based on histopathology.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Treatment for metastatic colorectal cancer in the lung
What is the cost effectiveness and safety of non-surgical ablation and stereotactic body radiotherapy compared to resection for people with metastatic colorectal cancer in the lung amenable to local treatment?
For a short explanation of why the committee made the recommendation for research, see the rationale on people with metastatic colorectal cancer in the lung .
Full details of the evidence and the committee's discussion are in evidence review D3: treatment for metastatic colorectal cancer in the lung amenable to local treatment.
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# Management of low anterior resection syndrome
What is the effectiveness and safety of sacral nerve stimulation and transanal irrigation compared to symptomatic treatment for people with major low anterior resection syndrome?
For a short explanation of why the committee made the recommendation for research, see the rationale on management of low anterior resection syndrome .
Full details of the evidence and the committee's discussion are in evidence review E2: optimal management of low anterior resection syndrome.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Prevention of colorectal cancer in people with Lynch syndrome
Recommendation 1.1.1
## Why the committee made the recommendation
Evidence from a multi-country randomised controlled trial showed that taking 600 mg of aspirin daily for more than 2 years reduces the risk of colorectal cancer in people with Lynch syndrome, although this was only evident when restricting the analysis to those who actually took aspirin as planned, increasing the uncertainty around the evidence. An observational study among people with Lynch syndrome also showed a reduced risk of colorectal cancer in people who had taken aspirin (varying self-reported doses) in the long term compared to those who had not.
Long-term use of aspirin may slightly increase the risk of bleeding. However, no increased risk of peptic ulcer, gastrointestinal bleeding or cerebral haemorrhage was observed in the randomised controlled trial, although this might be because of the relatively short follow-up time. Given that the potential benefits are likely to outweigh the potential harms for most people with Lynch syndrome, the committee agreed taking aspirin long term will be appropriate in most, but not all, cases (for example in people with history of peptic ulcers).
The optimal dose of aspirin that balances the benefits of aspirin in preventing colorectal cancer and the potential increased bleeding risk (especially with higher doses) remains unclear. Because of this the committee was not able to recommend a dose, though an ongoing trial is currently studying this. Commonly used doses in current practice are 150 mg or 300 mg.
In July 2020, NICE carried out a surveillance review on a follow-up study to the randomised controlled trial that was used to inform development of the recommendation. The decision was that no change to the recommended advice was needed at this time.
## How the recommendation might affect practice
Aspirin is already widely used for this indication and so the recommendation is not expected to have a significant impact on practice.
Full details of the evidence and the committee's discussion are in evidence review A1: effectiveness of aspirin in the prevention of colorectal cancer in people with Lynch syndrome.
Return to recommendation
# Information for people with colorectal cancer
Recommendations 1.2.1 to 1.2.8
## Why the committee made the recommendations
There was evidence that people having treatment for colorectal cancer need different information at different stages of their care, and this was supported by the committee's own clinical experience as well as NICE's guideline on patient experience in adult NHS services.
The committee based their recommendations on qualitative evidence and their clinical experience, which enabled the committee to identify areas where people lacked understanding and issues that people would value information on. This included explaining colorectal cancer and its treatments in depth, including non-surgical treatment options and palliative care, as well as explaining how people can alter their diet to reduce bowel problems and manage their weight.
The committee also agreed it was important to prepare people for the fact that changes to the agreed plan are sometimes needed during treatment, and to explain what these could be so that people feel ready for this possibility.
## How the recommendations might affect practice
Current practice varies between hospitals, so these recommendations aim to reduce variation and encourage best practice. There may be a cost to providing training to professionals but this is expected to be small.
Full details of the evidence and the committee's discussion are in evidence review E3: information needs of people prior, during and after treatment for colorectal cancer.
Return to recommendations
# Treatment for people with early rectal cancer
Recommendation 1.3.1
## Why the committee made the recommendation
The committee agreed that it was not possible to recommend one treatment over another because of the low quality of the evidence and the limited amount of evidence available. The available evidence showed no clinically important differences between treatments and, in addition, for many of the outcomes specified in the protocol and a number of the comparisons no evidence was identified at all. However, based on their knowledge and experience, the committee noted that there are risks and benefits associated with each treatment option. They highlighted that while total mesorectal excision (TME) is a radical intervention and has more risks than the others, it is the only way to accurately stage lymph nodes and, by doing so, allow better treatment planning. Therefore, the committee recommended discussing the implications of each intervention with the person before making a choice.
## How the recommendation might affect practice
Currently, endoscopic submucosal dissection (ESD) is not widely available in the UK. In centres where ESD is not already available, resources and time would be needed to provide this service, including purchasing equipment and training staff (although this would be a short-term cost). After this initial investment there will be minimal cost difference between ESD and alternatives. Transanal excision (TAE; including transanal minimally invasive surgery and transanal endoscopic microsurgery) and TME are current practice in the UK, so the recommendations will have a minimal effect for these interventions. However, the recommendations will allow for an informed discussion with patients so they are fully aware of the risks and benefits of each procedure.
Full details of the evidence and the committee's discussion are in evidence review C1: treatment for early rectal cancer.
Return to recommendation
# Preoperative treatment for people with rectal cancer
Recommendations 1.3.2 and 1.3.3
## Why the committee made the recommendations
There was no evidence for the effectiveness of preoperative radiotherapy for people with early rectal cancer, and based on their experience the committee would not recommend preoperative radiotherapy. However, the ongoing STAR-TREC trial, which is a multicentre randomised controlled trial, compares radiotherapy to TME for early rectal cancer. Because of this, the committee recommended that preoperative radiotherapy for early rectal cancer could be offered, but only in the context of a clinical trial.
For rectal cancer cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0, the evidence from several randomised controlled trials (RCTs) shows that people who have preoperative radiotherapy or chemoradiotherapy have less local recurrence and have better overall and disease-free survival compared to people who did not have preoperative therapy. Although preoperative therapy can potentially have adverse effects, from the evidence the committee did not find a difference in quality of life or treatment-related mortality between those who did or did not receive preoperative therapy.
The committee was not able to make a recommendation on the duration and type of radiotherapy or chemoradiotherapy because the available evidence did not show a difference between short-course and long-course radiotherapy, chemoradiotherapy with or without induction chemotherapy, or internal radiotherapy with or without external radiotherapy and external radiotherapy alone.
## How the recommendations might affect practice
There is some variation in current practice among different multidisciplinary teams as to who is offered preoperative therapy. The aim of the recommendation is to standardise treatment across the country, so this might have a resource impact in areas where preoperative therapy is not currently offered and where more clinical oncologists and radiotherapy equipment and staff will be needed. The committee was aware that in some areas, therapeutic radiographers are taking on roles at advanced and consultant level to support specialist oncologists. There may be savings downstream through reduced recurrence and increased disease-free survival avoiding or delaying expensive further treatment.
The recommendation might increase the number of people offered preoperative radiotherapy or chemoradiotherapy for lower-risk tumours (mainly cancers in the upper and mid rectum). In current practice, people with cancer in the upper and mid rectum might not have preoperative therapy because there is a lower risk of recurrence in cancers in these locations compared to cancer in the low rectum.
Full details of the evidence and the committee's discussion are in:
evidence review C1: treatment for early rectal cancer
evidence review C2: preoperative radiotherapy and chemoradiotherapy for rectal cancer.
Return to recommendations
# Surgery for people with rectal cancer
Recommendations 1.3.4 and 1.3.5
## Why the committee made the recommendations
Surgery is the gold standard treatment for people with rectal cancer (cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0) if the tumour is resectable. The committee acknowledged that some people whose rectal cancer shows a complete clinical response to neoadjuvant therapy choose to defer surgery and opt for an organ preserving 'watch-and-wait' strategy instead. However, no evidence was identified on which prognostic factors could predict recurrence and survival to better select people for deferral of surgery. The committee were uncertain about how different definitions of complete clinical response and different watch-and-wait surveillance protocols would impact risk of recurrence. Because of the lack of evidence, they agreed that people wishing to defer surgery after a complete clinical and radiological response to neoadjuvant treatment should be made aware of the uncertainty about their outcome. Around one third of these people will experience local regrowth of their tumour and need salvage surgery.
The committee noted that there is no agreed definition of complete clinical and radiological response and no evidence on factors that predict recurrence, therefore, those who choose to defer surgery should be encouraged to enter a clinical trial or entered into a national registry. These could gather evidence to help define groups for whom deferral of surgery may be safe and appropriate.
## How the recommendations might affect practice
The watch-and-wait approach requires repeated surveillance examinations and endoscopies to monitor for tumour regrowth. In some cases, people choosing to defer surgery will need to be referred to another centre that can provide the necessary watch-and-wait surveillance programme. The recommendations are not expected to have a significant impact on practice.
Full details of the evidence and the committee's discussion are in evidence review C4: deferral of surgery in people having neoadjuvant therapy for rectal cancer.
Return to recommendations
# Surgical technique for people with rectal cancer
Recommendations 1.3.6 to 1.3.9
## Why the committee made the recommendations
The clinical evidence on the different surgical techniques for rectal cancer showed that the short- and long‑term outcomes of laparoscopic technique were similar or better than of the open technique and that there seemed to be no difference in effectiveness between laparoscopic and robotic techniques. The committee agreed that in addition to the clinical effectiveness it was important to consider the costs of these different techniques in order to assess which technique is the most cost-effective approach in rectal cancer surgery, therefore, a health economic analysis was done.
The evidence showed that laparoscopic surgery is cost effective compared to open surgery or robotic surgery. However, in some cases open surgery might be clinically more appropriate and laparoscopic surgery might be less feasible, for example because of scarring from previous operations or technically demanding resection of adjacent organs or structures in locally advanced tumours.
Robotic surgery was not found to be cost effective; however, this technique could be considered in centres that have already invested in a robot and have an established programme. These programmes should collect outcome data in order to benchmark the effectiveness and safety of this technique in clinical practice against other centres and techniques. The techniques and equipment of robotic surgery develop rapidly and more evidence on its cost effectiveness will be available in the future.
There is evidence that transanal TME is effective, but evidence about its safety is inconsistent. However, transanal TME could be considered as part of a formal research study. Outcome data should be submitted to a national registry in order to assess the safety and effectiveness of this technique in clinical practice. This is in line with NICE interventional procedures guidance on transanal total mesorectal excision for rectal cancer.
## How the recommendations might affect practice
There will be more laparoscopic surgery, while recognising that there is a role for open surgery in appropriately selected cases. Current robotic techniques were found not to be cost effective, so there may be less investment in robotic techniques for this indication. However, the recommendation will not affect the use of robotic surgery within established programmes. The recommendations are not expected to have an impact on the use of transanal TME as these are largely done within structured and supervised programmes in current practice.
Full details of the evidence and the committee's discussion are in evidence review C3: optimal surgical technique for rectal cancer.
Return to recommendations
# People with locally advanced or recurrent rectal cancer
Recommendation 1.3.10
## Why the committee made the recommendation
Based on their clinical experience, the committee acknowledged that many patients are not currently referred to specialist centres and are only offered palliative care instead of potentially curative surgery. The committee also noted that pelvic exenteration is a complex and invasive procedure.
However, there was some very low-quality evidence that showed people who had pelvic exenteration had similar quality of life scores to those who did not, and that the procedure improved survival over 12 months. The committee agreed that evidence from long-term follow-up of quality of life would help to inform the recommendation, but there was no quality-of-life data available beyond 12 months. Therefore, the committee could not recommend referring everyone with locally advanced or recurrent rectal cancer to have pelvic exenteration, but agreed that people should have the opportunity to discuss pelvic exenteration as an option in a specialist centre. Despite the lack of long-term quality of life evidence, a research recommendation was not made because the low number of eligible participants meant a prospective comparative study would not be feasible. Additionally, an international collaborative study of outcomes after pelvic exenteration (PelvEx) is already underway.
## How the recommendation might affect practice
The recommendation could increase the number of referrals to specialist centres in hospitals where this is not current practice. This would, in turn, increase demand for specialist time and mean that more people may go on to have surgery. However, this may improve quality of life and survival.
Full details of the evidence and the committee's discussion are in evidence review C5: effectiveness of exenterative surgery for locally advanced or recurrent rectal cancer.
Return to recommendation
# Surgical volumes for rectal cancer operations
Recommendations 1.3.11 and 1.3.12
## Why the committee made the recommendations
Currently, there is uncertainty in the clinical community about optimal hospital and surgeon volumes for rectal cancer outcomes, with some clinicians advocating for the centralisation of services. There was evidence that when the threshold is set between 10 and 20 rectal cancer surgery patients per year, higher volume hospitals have better outcomes than lower volume hospitals in terms of overall survival, local recurrence, permanent stoma rates and perioperative mortality. Similarly, there was evidence of benefit with a surgeon case volume threshold of between 5 and 10 cases per year in terms of resection margins, local recurrence and permanent stoma rates.
The committee were cautious in their interpretation of the evidence: individual studies had used different case volume thresholds and had not treated case volume as a continuous outcome, and there were additional complexities with surgeon-level data (that is, consultants may do more complex operations, but fewer of them, and a consultant might be involved with other operations but not be the named surgeon) as well as with hospital-level data (that is, some studies were old and from outside the UK, with inconsistent staging across studies).
Given the uncertainties in the data, the committee agreed that the evidence was not strong enough to recommend a minimum cut-off of 20 cases and instead decided to recommend a more conservative cut-off of 10 cases a year.
## How the recommendations might affect services
An audit of operations for rectal cancer in the UK has indicated that most hospitals in the UK perform at least 20 cases of rectal cancer surgery per year. Therefore, the recommendation for a minimum threshold of 10 cases per year at hospital level will not have a large impact on current practice. Based on their clinical knowledge, the committee were aware that some surgeons in the UK currently perform fewer than 5 operations per year, so the recommendation could have an impact on these surgeons. Fewer surgeons performing more cases could have an impact on staffing, although as the overall number of operations will be the same the overall cost impact should be neutral. There may be an increase in the distance patients need to travel for surgery and this will have a cost impact on the NHS where this is reimbursed. This cost will be offset by better surgical outcomes reducing care-related costs later on and increasing quality of life.
Full details of the evidence and the committee's discussion are in evidence review F1: surgical volumes and outcomes for rectal cancer.
Return to recommendations
# Preoperative treatment for people with colon cancer
Recommendation 1.3.13
## Why the committee made the recommendation
The committee made the recommendation to consider chemotherapy preoperatively for people with cT4 colonic cancer based on evidence that it improved survival and rates of clear resection margins in these patients. The committee was only able to recommend preoperative chemotherapy as an option to consider because the evidence was of low quality, despite the large sample size. There was no evidence on the effectiveness of preoperative chemotherapy for people with colonic cancers at other stages.
The committee also considered non-peer-reviewed results from FOxTROT: a large international trial comparing preoperative plus postoperative chemotherapy (with or without panitumumab) to standard postoperative chemotherapy in people with cT3 or cT4a resectable tumours. The results showed that complete clinical response and tumour downstaging are more likely in those who receive preoperative chemotherapy, however at the time of publication of this guideline there was insufficient duration of follow‑up to assess long‑term outcomes.
## How the recommendation might affect practice
The current standard of care is surgical resection with postoperative chemotherapy, dependent on the organs or structures involved and the degree of involvement. The committee was aware that some centres already give preoperative chemotherapy, but noted that this recommendation will affect practice and have a resource impact in hospitals where this is not standard practice.
Full details of the evidence and the committee's discussion are in evidence review C7: preoperative chemotherapy for non-metastatic colon cancer.
Return to recommendation
# Duration of adjuvant chemotherapy for people with colorectal cancer
Recommendation 1.3.14
## Why the committee made the recommendation
The benefits and risks of adjuvant chemotherapy can depend on several factors, including the stage and characteristics of the cancer, and the person's performance status, comorbidities and age.
Peripheral neuropathy is recognised as a major long-term side effect of oxaliplatin chemotherapy, and the risk of developing persistent neuropathy increases by cumulative dose of treatment. The standard duration of chemotherapy has been 6 months, but a shorter 3‑month course has been investigated.
There was good evidence that showed 3 months of CAPOX chemotherapy was at least as beneficial for people with colon cancer as a 6‑month course but caused considerably less severe neuropathy and was cost saving. However, with FOLFOX chemotherapy, disease-free survival was worse after a 3‑month course compared with the standard 6‑month course, although the rate of severe neuropathy was again considerably lower in the 3‑month group.
A high‑quality health economic study found a 3‑month course of FOLFOX to be cost effective compared to a 6‑month course, despite lower disease-free survival, as a result of a decrease in costs. Although this economic evidence was directly applicable to the clinical question, and the study was included in the consideration of the clinical evidence, the committee was concerned that basing recommendations solely in line with the economic evaluation (that is, CAPOX for 3 months or FOLFOX for 3 months) might lead to people who would otherwise have received 6‑month FOLFOX to opt for 3‑month CAPOX instead.
In the SCOT trial CAPOX was associated with a higher rate of severe diarrhoea than FOLFOX. This was not looked at by the economic evaluation and the 'switching' group would likely to be at higher risk of toxicity‑related complications with worse outcomes, increased treatment-related mortality and increased costs from the treatment of severe adverse events than the trial population for 3‑month CAPOX. This would decrease the certainty of the conclusions of the economic evaluation.
Based on the balance of benefits and lower risk of long-term adverse effects, the committee agreed CAPOX for 3 months should be the first choice of adjuvant treatment. If CAPOX is not suitable, for example because of the person's higher risk of and lower tolerance for severe diarrhoea, FOLFOX should be offered. Having considered the economic evaluation given the clinical concerns, it was decided that there should be an individualised consideration of the duration of FOLFOX for people if 3‑month CAPOX chemotherapy is not suitable for them, taking into account the benefits and short- and long-term harms of both options, the person's comorbidities, performance status and preference.
Single-agent capecitabine chemotherapy is also an effective adjuvant treatment and can be more suitable for people who are older (for example over 70) or less fit, as it is associated with fewer side effects than chemotherapy treatments that contain oxaliplatin.
The available evidence is mainly for people with colon cancer. However, people with rectal cancer who had received either short-course preoperative radiotherapy or no preoperative therapy were also included in a large randomised trial and their outcomes were similar to people with colon cancer, and therefore the committee agreed the recommendation could also apply to this population.
No recommendations were made for people with rectal cancer who have been treated with long-course chemotherapy or chemoradiotherapy because no evidence was identified in the available trials.
## How the recommendation might affect practice
Halving the standard care from 6 months to 3 months (for people who can have CAPOX) will reduce treatment time and costs, meaning people have chemotherapy side effects for a shorter time, and will lower the incidence of long-term toxicity (neuropathy) and its consequences.
Full details of the evidence and the committee's discussion are in evidence review C8: optimal duration of adjuvant chemotherapy for colorectal cancer.
Return to recommendation
# Colonic stents in acute large bowel obstruction
Recommendations 1.3.15 and 1.3.16
## Why the committee made the recommendations
In patients presenting with acute left-sided large bowel obstruction, evidence showed that stoma rates were reduced in the stenting group compared to the emergency surgery group. There was no evidence of a difference in overall or disease-free survival. Stenting also allows time to fully assess the patient and stabilise any comorbidities before proceeding with potentially curative surgery. The committee considered the yet to be published results of the CREST trial shared with the committee in confidence which were consistent with the published evidence.
The committee noted the evidence that stenting sometimes causes perforation and is not always technically successful and so may not be appropriate in all cases for the curative intent treatment group. For this reason they also recommended emergency surgery as an option.
## How the recommendations might affect practice
Stenting is established practice for patients presenting with acute left-sided large bowel obstruction who are to be treated with palliative intent. Stenting is not established practice in those to be treated with curative intent. Therefore, the recommendation could lead to an increase in the provision of stenting and associated costs. However, stenting allows patients to be assessed and become stable before surgery, in turn reducing operative morbidity, the need for stoma and preventing expensive surgery in those people when it would not be appropriate, thus reducing downstream costs. Some patients might need to be transferred to another unit in order to receive a stent.
Full details of the evidence and the committee's discussion are in evidence review C9: effectiveness of stenting for acute large bowel obstruction.
Return to recommendations
# Molecular biomarkers to guide systemic anti-cancer therapy
Recommendation 1.4.1
## Why the committee made the recommendation
The evidence showed that RAS and BRAF V600E mutations were predictive of response to anti-epidermal growth factor receptor (EGFR) targeted therapy in people with metastatic colorectal cancer. People with RAS or BRAF V600E mutant metastatic colorectal cancer also had poorer progression-free and overall survival than those without such mutations. While RAS testing is already used to select those people with metastatic colorectal cancer most likely to benefit from anti-EGFR targeted therapy, BRAF V600E testing has the potential to further refine this group.
The committee noted evidence that testing for deficient DNA mismatch repair may inform systemic therapy choices for those with non-metastatic colorectal cancer, but the NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer already recommends such testing for all people with colorectal cancer when first diagnosed. For this reason no further recommendations were made about testing for deficient DNA mismatch repair.
## How the recommendation might affect practice
RAS testing (KRAS and NRAS) is current practice. BRAF V600E testing is not done routinely in current practice. BRAF V600E test can be done from the extended colorectal cancer molecular test panel which is part of the recommendations in the NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer, so the recommendation should not have a large impact on practice or costs.
Full details of the evidence and the committee's discussion are in evidence review B1: use of molecular biomarkers to guide systemic therapy.
Return to recommendation
# People with asymptomatic primary tumour
Recommendation 1.5.1
## Why the committee made the recommendation
For people with incurable metastatic colorectal cancer whose primary tumour is asymptomatic, there was some low-quality evidence of better overall survival in those who had resection of their primary tumour and chemotherapy compared with chemotherapy alone.
Around a quarter of this group had postoperative complications and a small proportion (around 5%) had severe postoperative complications which needed intervention or were life-threatening. However, resecting the tumour at this stage can prevent symptoms from developing later: almost a fifth of people who did not have the asymptomatic primary tumour resected went on to develop primary tumour-related symptoms that needed surgical treatment which could often mean an emergency operation that can have higher risks of complications and stoma. Because of this, the committee agreed the implications should be discussed with the person so they can make an informed decision.
## How the recommendation might affect practice
There could be an increase in resections of asymptomatic primary tumours, however, the population with metastatic colorectal cancer and asymptomatic primary tumour is small so no major cost impact is expected.
Full details of the evidence and the committee's discussion are in evidence review D1: surgery for asymptomatic primary tumour.
Return to recommendation
# Systemic anti-cancer therapy for people with metastatic colorectal cancer
Recommendation 1.5.2
## Why the committee made the recommendation
Guidance on systemic anti-cancer therapy for people with metastatic colorectal cancer is covered by NICE technology appraisals, which were not updated by this guideline. The committee did not review the technology appraisals. The technology appraisals should be used when appropriate to guide the choice of systemic anti-cancer therapy.
## How the recommendation might affect practice
The recommendation reflects current practice and no change in practice is expected.
Return to recommendation
# People with metastatic colorectal cancer in the liver
Recommendations 1.5.3 to 1.5.6
## Why the committee made the recommendations
There was not enough evidence to show if simultaneous or sequential resection is better. There was some poor‑quality evidence from retrospective cohort studies showing that people who underwent sequential resection had better liver progression-free survival. However, these results might be influenced by baseline differences between the groups, and there was no difference in recurrence in other parts of the body or in overall survival in several studies. There was no difference in short-term adverse events and no evidence on quality of life was available. Based on these findings and their experience, the committee agreed that a multidisciplinary team with expertise in both colorectal and liver disease should consider if a simultaneous or a sequential resection is appropriate, taking into account the person's preference.
Evidence from randomised trials suggested that chemotherapy in addition to liver resection improves disease-free survival and may improve overall survival. The potential benefit on survival should be balanced with a higher rate of treatment-related adverse events because of added chemotherapy. No quality of life evidence was available.
The evidence on chemotherapy combined with radiofrequency ablation showed better overall survival and progression-free survival compared to chemotherapy alone. No difference was observed in treatment‑related mortality and morbidity. The evidence on quality of life was too limited for the committee to draw any conclusions. The evidence on survival came from a single small study and the committee had doubts about its relevance to current practice. Because of the uncertainties in the evidence, the committee recommended considering chemotherapy with local ablative techniques as an option for people whose liver metastases are determined by the multidisciplinary team to be unresectable but potentially curable. The evidence was on radiofrequency ablation, which is still used but in many centres has been largely replaced by newer local ablative techniques such as microwave ablation (see the NICE interventional procedures guidance on microwave ablation for treating liver metastases). Therefore, the committee agreed that it is more appropriate that local ablative techniques, not only radiofrequency ablation, are considered.
Evidence from several RCTs did not show any benefit on overall survival from selective internal radiation therapy (SIRT) as a first-line treatment for people with colorectal liver metastases. NICE interventional procedures guidance on selective internal radiation therapy for non-resectable colorectal metastases in the liver gives further guidance in which circumstances SIRT could be used. Only limited evidence from one small RCT was available on the effectiveness of SIRT for people refractory or intolerant to standard chemotherapy. The committee were aware of an NHS England commissioning policy on SIRT as third-line treatment, which used observational data in addition to the small RCT as their evidence base. However, because of limited RCT evidence the committee was not able to make a recommendation.
## How the recommendations might affect practice
The recommendations largely reflect current practice and no substantial change in practice is expected.
Full details of the evidence and the committee's discussion are in:
evidence review D2a: treatment for metastatic colorectal cancer in the liver amenable to treatment with curative intent
evidence review D2b: optimal combination and sequence of treatments in patients presenting with metastatic colorectal cancer in the liver not amenable to treatment with curative intent.
Return to recommendations
# People with metastatic colorectal cancer in the lung
Recommendations 1.5.7 and 1.5.8
## Why the committee made the recommendations
As there was limited evidence, the committee made recommendations based on their clinical knowledge. There was not enough evidence to recommend one treatment over another even though the current first choice is to perform surgery over stereotactic body radiation therapy or ablation. Referring people to multidisciplinary teams that specialise in primary lung disease may not be appropriate as they do not specialise in the management of lung metastases from colorectal cancer. Therefore, the committee agreed that the multidisciplinary team should include a thoracic surgeon and a specialist in non-surgical ablation to ensure that the appropriate specialist knowledge is available.
Based on their clinical knowledge, the committee recommended that biopsies should be considered for patients with a single lung lesion to rule out primary lung cancer and guide treatment options even if surgical excision is not planned.
Because of the lack of clinical evidence, a randomised trial comparing surgical to non-surgical treatment is needed to provide more high quality, comparative data, so the committee made a research recommendation on this topic.
## How the recommendations might affect practice
The recommendations are expected to increase the involvement of thoracic surgeons in the management of metastatic colorectal cancer, however this additional expertise would result in expensive treatments being more appropriately targeted. While assessing fitness for surgery is common practice, the advice to also discuss factors including disease-free interval, carcinoembryonic antigen (CEA) level, number, size and site of metastases and other sites of disease should improve best practice across the NHS.
Full details of the evidence, the committee's discussion and the recommended approach to research are in evidence review D3: treatment for metastatic colorectal cancer in the lung amenable to local treatment.
Return to recommendations
# People with metastatic colorectal cancer in the peritoneum
Recommendation 1.5.9
## Why the committee made the recommendation
The committee made the recommendation based on both the evidence and their clinical knowledge. The advice to offer systemic anti-cancer therapy and to discuss referral to a specialist cytoreductive surgery centre is in the same recommendation because these interventions should happen at the same time. That is, making a referral should not wait until chemotherapy has been given, and chemotherapy could be started before the person is reviewed in the specialist centre.
It is standard practice to start all patients on a course of systemic anti-cancer therapy and the evidence supported this, showing greater overall survival compared to supportive care. The evidence on the effectiveness of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) was mixed but, based on their clinical knowledge, the committee decided they should be considered.
The committee agreed it was important to recommend referral to a nationally commissioned specialist centre after discussion within a multidisciplinary team for consideration of cytoreductive surgery and HIPEC so that more patients can have potentially curative treatment and to avoid centres offering the treatment without having the necessary training and resources. This advice is in line with the NICE interventional procedures guidance on cytoreductive surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis.
## How the recommendation might affect practice
Stenting is not established practice in those to be treated with curative intent. Therefore, the recommendation could lead to an increase in the provision of stenting and associated costs. However, stenting allows patients to be assessed and become stable before surgery, in turn reducing operative morbidity, the need for stoma and preventing expensive surgery in those people when it would not be appropriate, thus reducing downstream costs. Some patients might need to be transferred to another unit in order to receive a stent.
Full details of the evidence and the committee's discussion are in evidence review D4: local and systemic treatments for metastatic colorectal cancer isolated in the peritoneum.
Return to recommendation
# Follow-up for detection of local recurrence and distant metastases
Recommendation 1.6.1
## Why the committee made the recommendation
Evidence showed that recurrent disease was more likely to be resectable when patients received regular follow-up tests than with minimal or no follow-up. Evidence also showed recurrent disease was more likely to be resectable when follow-up tests included CEA and liver imaging. The 2011 NICE guideline on colorectal cancer (updated and replaced by this guideline) recommended CEA and CT testing in the first 3 years after treatment with curative intent, and the committee did not find evidence to change this. Colonoscopic surveillance to detect metachronous colorectal neoplasia was outside the scope of this guideline (the British Society of Gastroenterology and the Association of Coloproctology for Great Britain and Ireland have guidance on this topic).
## How the recommendation might affect practice
The recommendation reflects current practice so the committee agreed there should be no change in practice.
Full details of the evidence and the committee's discussion are in evidence review E1: follow-up to detect recurrence after treatment for non-metastatic colorectal cancer.
Return to recommendation
# Management of low anterior resection syndrome
Recommendations 1.6.2 to 1.6.4
## Why the committee made the recommendations
Based on their experience, the committee agreed low anterior resection syndrome (LARS) can have a significant impact on a person's quality of life and daily functioning, so it is important to identify and treat it quickly. It is important that people who have had sphincter-preserving surgery are aware of its symptoms so they can seek help. Because LARS may only become apparent after discharge from hospital, it is important that it can be identified in primary care. LARS should be assessed using a validated tool, for example the European Society of Coloproctology's LARS score, which is a validated patient-administered questionnaire.
No comparative evidence on different treatments for LARS was available, so the committee agreed based on their experience that people with LARS should be offered symptomatic treatment in primary care. The committee also agreed that if treatments offered in primary care have not helped, advice should be sought from secondary care to discuss further options and consider specialist input. Timing of this should be based on clinical judgement taking into consideration, for example, severity of symptoms and impact on quality of life.
Because of the lack of evidence on the effectiveness of treatments for LARS, a research recommendation was made to compare sacral nerve stimulation and transanal irrigation in people with LARS for whom conservative treatments have not worked.
## How the recommendations might affect practice
Primary care clinicians are not necessarily aware of LARS or how to assess it, and administering the questionnaire might need extra work and time. However, it is patient-administered and easy to score and no training should be needed. Bowel dysfunction treatment for associated symptoms are commonly delivered in primary care, therefore, the recommendation is not expected to have a large impact on current practice in terms of number of patients and interventions, however, raising awareness of LARS will be needed among primary care professionals.
Full details of the evidence, the committee's discussion and the recommended approach to research are in evidence review E2: optimal management of low anterior resection syndrome.
Return to recommendations# Context
Colorectal cancer (cancer of the colon or rectum, or bowel cancer) is the fourth most common cancer in the UK, with over 41,000 new cases diagnosed each year according to Cancer Research UK's bowel cancer statistics. Risk factors include increasing age, genetics and family history (particularly syndromes such as familial adenomatous polyposis and Lynch syndrome), inflammatory bowel disease and other dietary and lifestyle factors. Survival rates have improved over time, with almost 60% of people diagnosed with colorectal cancer surviving for at least 5 years. Survival is linked to disease stage at presentation, with better survival the earlier the disease is detected and treated.
People with Lynch syndrome have an increased risk of colorectal cancer, with lifetime risk estimated to be between around 50% to 80% (see Lynch Syndrome in Gene Reviews). The main strategy to prevent colorectal cancer in people with Lynch syndrome has been regular screening with colonoscopy and polypectomy. Aspirin has been suggested as another potential prevention strategy for colorectal cancer.
Diagnosis and staging of colorectal cancer are well established with histology and appropriate imaging, and are not covered by this guideline.
Management of colorectal cancer has advanced over time with new treatment methods and strategies being trialled and used. Management of local disease differs depending on the site of the cancer. The standard practice for colon cancer is to offer surgery for those who are fit for it. Recent trials have studied the effectiveness of preoperative systemic anti-cancer therapy for colon cancer to improve survival. Treatment for rectal cancer is more complex. There is variation in current practice in the treatment for early rectal cancer, use of preoperative (chemo)radiotherapy, surgical technique for rectal cancer surgery, and treatment for locally advanced or recurrent rectal cancer. This guideline addresses all these issues. Until now, the standard duration of adjuvant systemic therapy for colorectal cancer has been 6 months, which has been recently challenged by suggestion of a shorter duration in order to lower toxicity caused by the treatment.
Metastatic colorectal cancer commonly affects the liver, lungs or peritoneum. Treatment for metastatic colorectal cancer depends on, for example, the site and number of the metastases and if the metastases are amenable to local treatment. In addition, the role of molecular biomarkers in predicting effectiveness of systemic anti-cancer therapy has been discussed increasingly in recent years.
People who have been treated for colorectal cancer may have long-term side effects of their treatments. For example, low anterior resection syndrome can have major impact on quality of life and daily living, and it affects around 40% of those who have undergone sphincter-preserving surgery for rectal cancer. It is important that the treatment options, their implications and potential consequences are discussed together with the person with colorectal cancer in order to enable shared decision making.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Reduction in risk of colorectal cancer in people with Lynch syndrome\n\nConsider daily aspirin, to be taken for more than 2\xa0years, to reduce the risk of colorectal cancer in people with Lynch syndrome. In January 2020 this was an off-label use of aspirin. See NICE's information on prescribing medicines.NICE has produced a patient decision aid to support discussions about taking aspirin.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on prevention of colorectal cancer in people with Lynch syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A1: effectiveness of aspirin in the prevention of colorectal cancer in people with Lynch syndrome.\n\nLoading. Please wait.\n\n# Information for people with colorectal cancer\n\nProvide people with colorectal cancer information about their treatment (both written and spoken) in a sensitive and timely manner throughout their care, tailored to their needs and circumstances. Make sure the information is relevant to them, based on the treatment they might have and the possible side effects. Also see the NICE guidelines on patient experience in adult NHS services and decision-making and mental capacity.\n\nGive people information on all treatment options for colorectal cancer available to them, including:\n\nsurgery, radiotherapy, systemic anti-cancer therapy or palliative care\n\nthe potential benefits, risks, side effects and implications of treatments, for example, possible effects on bowel and sexual function (see also recommendation 1.6.2), quality of life and independence.\n\nAdvise people with colorectal cancer of possible reasons why their treatment plan might need to change during their care, including:\n\nchanges from laparoscopic to open surgery or curative to non-curative treatment, and why this change may be the most suitable option for them\n\nthe likelihood of having a stoma, why it might be necessary and for how long it might be needed.\n\nIf recovery protocols (such as 'enhanced recovery after surgery', ERAS) are used, explain to people with colorectal cancer what these involve and their value in improving their recovery after surgery.\n\nEnsure that appropriate specialists discuss possible side effects with people who have had surgery for colorectal cancer, including:\n\naltered bowel, urinary and sexual function\n\nphysical changes, including anal discharge or bleeding.If relevant, have a trained stoma professional provide information on the care and management of stomas and on learning to live with a stoma.\n\nEmphasise to people the importance of monitoring and managing side effects during non-surgical treatment to try to prevent permanent damage (for example, monitoring prolonged sensory symptoms after platinum-based chemotherapy treatment, which can be a sign that the dose needs to be reduced to minimise future permanent peripheral neuropathy).\n\nGive people who have had treatments for colorectal cancer information about possible short-term, long-term, permanent and late side effects which can affect quality of life, including:\n\npain\n\naltered bowel, urinary or sexual function\n\nnerve damage and neuropathy\n\nmental and emotional changes, including anxiety, depression, chemotherapy-related cognitive impairment, and changes to self-perception and social identity.\n\nPrepare people for discharge after treatment for colorectal cancer by giving them advice on:\n\nadapting physical activity to maintain their quality of life\n\ndiet, including advice on foods that can cause or contribute to bowel problems such as diarrhoea, flatulence, incontinence and difficulty in emptying the bowels\n\nweight management, physical activity and healthy lifestyle choices (for example stopping smoking and reducing alcohol use)\n\nhow long their recovery might take\n\nhow, when and where to seek help if side effects become problematic.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information for people with colorectal cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E3: information needs of people prior, during and after treatment for colorectal cancer.\n\nLoading. Please wait.\n\n# Management of local disease\n\n## People with rectal cancer\n\nOffer one of the treatments shown in table\xa01 to people with early rectal cancer (cT1-T2, cN0, M0) after discussing the implications of each treatment and reaching a shared decision with the person about the best option.\n\n\n\nTransanal excision (TAE), including transanal minimally invasive surgery (TAMIS) and transanal endoscopic microsurgery (TEMS)\n\nEndoscopic submucosal dissection (ESD)\n\nTotal mesorectal excision (TME)\n\nType of procedure\n\nEndoscopic/Surgery\n\nEndoscopic\n\nSurgery\n\nMinimally invasive procedure\n\nYes\n\nYes\n\nPossible\n\nResection of bowel (may have more impact on sexual and bowel function)\n\nNo\n\nNo\n\nYes\n\nStoma needed (a permanent or temporary opening in the abdomen for waste to pass through)\n\nNo\n\nNo\n\nPossible\n\nGeneral anaesthetic needed (and the possibility of associated complications)\n\nYes\n\nNo, conscious sedation\n\nYes\n\nAble to do a full thickness excision (better chance of removing cancerous cells and more accurate prediction of lymph node involvement)\n\nYes\n\nNo\n\nYes\n\nRemoval of lymph nodes (more accurate staging of the cancer so better chance of cure)\n\nNo\n\nNo\n\nYes\n\nConversion to more invasive surgery needed if complication\n\nPossible\n\nPossible\n\nPossible\n\nFurther surgery needed depending on histology\n\nPossible\n\nPossible\n\nUsually no\n\nUsual hospital stay\n\nto 2 days\n\nto 2 days\n\nto 7 days\n\nExternal scarring\n\nNo\n\nNo\n\nYes\n\nPossible complications include (in alphabetical order)\n\nAbdominal pain\n\nBleeding\n\nMild anal incontinence\n\nPerirectal abscess/sepsis and stricture (narrowing)\n\nPerforation\n\nSuture line dehiscence (wound reopening)\n\nUrinary retention\n\nAbdominal pain\n\nBleeding\n\nBloating\n\nPerforation\n\nAdhesions\n\nAnastomotic leak (leaking of bowel contents into the abdomen)\n\nAnastomotic stricture (narrowing at internal operation site)\n\nBleeding\n\nIncisional hernia (hernia where the surgical incision was made)\n\nInjury to neighbouring structures\n\nPelvic abscess\n\nUrinary retention\n\nSome of the potential complications shown in the table were identified from the evidence review, others based on committee's expertise.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment for people with early rectal cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C1: treatment for early rectal cancer.\n\nLoading. Please wait.\n\nDo not offer preoperative radiotherapy to people with early rectal cancer (cT1-T2 cN0, M0), unless as part of a clinical trial.\n\nOffer preoperative radiotherapy or chemoradiotherapy to people with rectal cancer that is cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preoperative treatment for people with rectal cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C1: treatment for early rectal cancer and evidence review C2: preoperative radiotherapy and chemoradiotherapy for rectal cancer.\n\nLoading. Please wait.\n\nOffer surgery to people with rectal cancer (cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0) who have a resectable tumour.\n\nInform people with a complete clinical and radiological response to neoadjuvant treatment who wish to defer surgery that there is a risk of recurrence, and there are no prognostic factors to guide selection for deferral of surgery. For those who choose to defer, encourage their participation in a clinical trial and ensure that data is collected via a national registry.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgery for people with rectal cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C4: deferral of surgery in people having neoadjuvant therapy for rectal cancer.\n\nLoading. Please wait.\n\nOffer laparoscopic surgery for rectal cancer, in line with NICE's technology appraisal guidance on laparoscopic surgery for colorectal cancer.\n\nConsider open surgery if clinically indicated, for example by locally advanced tumours, multiple previous abdominal operations or previous pelvic surgery.\n\nOnly consider robotic surgery within established programmes that have appropriate audited outcomes.\n\nOnly consider transanal total mesorectal excision (TME) surgery in the context of research in line with the NICE interventional procedures guidance on transanal total mesorectal excision for rectal cancer. [amended 2021]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgical technique for people with rectal cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C3: optimal surgical technique for rectal cancer.\n\nLoading. Please wait.\n\nConsider referring people with locally advanced primary or recurrent rectal cancer that might potentially need multi-visceral or beyond-TME surgery to a specialist centre to discuss exenterative surgery.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on locally advanced or recurrent rectal cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C5: effectiveness of exenterative surgery for locally advanced or recurrent rectal cancer.\n\nLoading. Please wait.\n\nHospitals performing major resection for rectal cancer should perform at least 10\xa0of these operations each year.\n\nIndividual surgeons performing major resection for rectal cancer should perform at least 5\xa0of these operations each year.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on surgical volumes for rectal cancer operations\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C7: preoperative chemotherapy for non-metastatic colon cancer.\n\nLoading. Please wait.\n\n## People with colon cancer\n\nConsider preoperative systemic anti-cancer therapy for people with cT4 colon cancer.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on preoperative treatment for people with colon cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C7: preoperative chemotherapy for non-metastatic colon cancer.\n\nLoading. Please wait.\n\nFor advice on laparoscopic surgery see NICE's technology appraisal guidance on laparoscopic surgery for colorectal cancer.\n\n## People with either colon or rectal cancer\n\nPatients with rectal cancer treated with long-course chemoradiotherapy are not covered by this recommendation.\n\nFor people with stage III colon cancer (pT1-4, pN1-2, M0), or stage III rectal cancer (pT1-4, pN1-2, M0) treated with short-course radiotherapy or no preoperative treatment, offer:\n\ncapecitabine in combination with oxaliplatin (CAPOX) for 3\xa0months, or if this is not suitable\n\noxaliplatin in combination with 5-fluorouracil and folinic acid (FOLFOX) for 3\xa0to\xa06 months, or\n\nsingle-agent fluoropyrimidine (for example, capecitabine) for 6\xa0months, in line with NICE technology appraisal guidance (see the NICE technology appraisal guidance on our topic page on colorectal cancer).Base the choice on the person's histopathology (for example pT1-T3 and pN1, and pT4 and/or pN2), performance status, any comorbidities, age and personal preferences. In January 2020, the use of some treatments was off label:\n\noxaliplatin in combination with capecitabine (though CAPOX is common in UK clinical practice)\n\ncapecitabine for 3\xa0months duration of adjuvant treatment in people with colon cancer\n\nCAPOX and FOLFOX in stage III rectal cancer.See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on duration of adjuvant chemotherapy for people with colorectal cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C8: optimal duration of adjuvant chemotherapy for colorectal cancer.\n\nLoading. Please wait.\n\nConsider stenting for people presenting with acute left-sided large bowel obstruction who are to be treated with palliative intent.\n\nOffer either stenting or emergency surgery for people presenting with acute left-sided large bowel obstruction if potentially curative treatment is suitable for them.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on colonic stents in acute large bowel obstruction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C9: effectiveness of stenting for acute large bowel obstruction.\n\nLoading. Please wait.\n\n# Molecular biomarkers to guide systemic anti-cancer therapy\n\nAlso see the NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer.\n\nTest for RAS and BRAF\xa0V600E mutations in all people with metastatic colorectal cancer suitable for systemic anti-cancer treatment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on molecular biomarkers to guide systemic anti-cancer therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B1: use of molecular biomarkers to guide systemic therapy.\n\nLoading. Please wait.\n\n# Management of metastatic disease\n\n## People with asymptomatic primary tumour\n\nConsider surgical resection of the primary tumour for people with incurable metastatic colorectal cancer who are receiving systemic anti-cancer therapy and have an asymptomatic primary tumour. Discuss the implications of the treatment options with the person before making a shared decision. See table\xa02.\n\n\n\nAdvantages\n\nDisadvantages\n\nResection of the asymptomatic primary tumour\n\nPossible improvement in overall survival rate (based on low quality evidence from research)\n\nAvoidance of primary tumour-related symptoms such as obstruction, perforation, bleeding and pain\n\nAround 5 in 100 people will have severe postoperative complications (based on moderate quality evidence from research)\n\nSystemic therapy still needed, and may be delayed if surgical complications occur\n\nNo resection (systemic anti-cancer therapy only)\n\nAvoids surgery and the potential for postoperative complications\n\nAround 20 in 100 people will develop primary tumour-related symptoms such as obstruction, perforation, bleeding and pain that need surgery (based on low quality evidence from research)\n\nAdvantages and disadvantages in table 2 are based on committee expertise unless otherwise indicated.\n\nQuality of evidence (based on grading of recommendations, assessment, development and evaluations [GRADE]):\n\nModerate: true effect is probably close to the estimated effect.\n\nLow: true effect might be markedly different from the estimated effect.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on asymptomatic primary tumour\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D1: surgery for asymptomatic primary tumour.\n\nLoading. Please wait.\n\n## Systemic anti-cancer therapy for people with metastatic colorectal cancer\n\nFor advice on systemic anti-cancer therapy for people with metastatic cancer, see NICE technology appraisal guidance on our topic page on colorectal cancer.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on systemic anti-cancer therapy for people with metastatic colorectal cancer\xa0.\n\nLoading. Please wait.\n\n## Genomic biomarker-based treatment\n\nThe point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. See the NICE topic page on genomic biomarker-based cancer treatments for guidance on specific treatments.\n\n## People with metastatic colorectal cancer in the liver\n\nConsider resection, either simultaneous or sequential, after discussion by a multidisciplinary team with expertise in resection of disease in all involved sites.\n\nConsider perioperative systemic anti-cancer therapy if liver resection is a suitable treatment.\n\nConsider chemotherapy with local ablative techniques for people with colorectal liver metastases that are unsuitable for liver resection after discussion by a specialist multidisciplinary team.\n\nDo not offer selective internal radiation therapy (SIRT) as first-line treatment for people with colorectal liver metastases that are unsuitable for local treatment. See the NICE interventional procedures guidance on selective internal radiation therapy for unresectable colorectal metastases in the liver, which recommends that SIRT should only be offered:\n\nwith special arrangements for clinical governance, consent, and audit or research to people who are chemotherapy intolerant or who have liver metastases that are refractory to chemotherapy\n\nin the context of research to people who can have chemotherapy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metastatic colorectal cancer in the liver\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D2a: treatment for metastatic colorectal cancer in the liver amenable to treatment with curative intent and evidence review D2b: optimal combination and sequence of treatments in patients presenting with metastatic colorectal cancer in the liver not amenable to treatment with curative intent.\n\nLoading. Please wait.\n\n## People with metastatic colorectal cancer in the lung\n\nConsider metastasectomy, ablation or stereotactic body radiation therapy for people with lung metastases that are suitable for local treatment, after discussion by a multidisciplinary team that includes a thoracic surgeon and a specialist in non-surgical ablation.\n\nConsider biopsy for people with a single lung lesion to exclude primary lung cancer.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metastatic colorectal cancer in the lung\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D3: treatment for metastatic colorectal cancer in the lung amenable to local treatment.\n\nLoading. Please wait.\n\n## People with metastatic colorectal cancer in the peritoneum\n\nFor people with colorectal cancer metastases limited to the peritoneum:\n\noffer systemic anti-cancer therapy and\n\nwithin a multidisciplinary team, discuss referral to a nationally commissioned specialist centre to consider cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on metastatic colorectal cancer in the peritoneum\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D4: local and systemic treatments for metastatic colorectal cancer isolated in the peritoneum.\n\nLoading. Please wait.\n\n# Ongoing care and support\n\n## Follow-up for detection of local recurrence and distant metastases\n\nFor people who have had potentially curative surgical treatment for non-metastatic colorectal cancer, offer follow-up for detection of local recurrence and distant metastases for the first 3\xa0years. Follow-up should include serum carcinoembryonic antigen (CEA) and CT scan of the chest, abdomen and pelvis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow-up for detection of local recurrence and distant metastases\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E1: follow-up to detect recurrence after treatment for non-metastatic colorectal cancer.\n\nLoading. Please wait.\n\n## Management of low anterior resection syndrome\n\nGive information on low anterior resection syndrome (LARS) to people who will potentially have sphincter-preserving surgery. Advise them to seek help from primary care if they think they have symptoms of LARS, such as:\n\nincreased frequency of stool\n\nurgency with or without incontinence of stool\n\nfeeling of incomplete emptying\n\nfragmentation of stool (passing small amounts little and often)\n\ndifficulty in differentiating between gas and stool.\n\nAssess people with symptoms of LARS using a validated patient-administered questionnaire (for example, the Low Anterior Resection Syndrome score (LARS score), at the European Society of Coloproctology).\n\nOffer people with bowel dysfunction treatment for associated symptoms in primary care (such as dietary management, laxatives, anti-bulking agents, anti-diarrhoeal agents, or anti-spasmodic agents). Seek advice from secondary care if the treatment is not successful.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on management of low anterior resection syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E2: optimal management of low anterior resection syndrome.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a specific way for this guideline. For general definitions, please see the NICE glossary.\n\n## Beyond-TME surgery\n\nBeyond total mesorectal excision (TME) surgery is when the tumour extends beyond what is achievable to resect by TME and needs more extensive surgery to achieve clear margins.\n\n## Major resection for rectal cancer\n\nMajor resection for rectal cancer means a surgical operation when part or all of the rectum is removed, including anterior resection and abdominoperineal resection.\n\n## Recovery protocols\n\nRecovery protocols, such as 'enhanced recovery after surgery' (ERAS), are perioperative care pathways designed to promote early recovery for patients undergoing major surgery by optimising the person's health before surgery and maintaining health and functioning after surgery.\n\n## Social identity\n\nSocial identity is about changes to people's concept of themselves as a result of either their cancer, or the long-term side effects from treatment. For example, it could cover changes from being a previously fit person to someone who has physical or mental health problems, from being someone with the expectation of years to live to someone with a limited life expectancy, or the change from being a carer to becoming cared for.\n\n## TNM classification\n\nThis guideline uses the tumour, node, metastasis (TNM) classification developed by the Union for Interventional Cancer Control (UICC) to describe the stage of the cancer. Please refer to The TNM Classification of Malignant Tumours, 8th Edition for further information. In this guideline early rectal cancer is defined as cT1-2, cN0, M0. cTNM refers to clinical classification based on evidence acquired before treatment, for example imaging, physical examination and endoscopy. pTNM refers to pathological classification based on histopathology.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Treatment for metastatic colorectal cancer in the lung\n\nWhat is the cost effectiveness and safety of non-surgical ablation and stereotactic body radiotherapy compared to resection for people with metastatic colorectal cancer in the lung amenable to local treatment?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on people with metastatic colorectal cancer in the lung\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D3: treatment for metastatic colorectal cancer in the lung amenable to local treatment.\n\nLoading. Please wait.\n\n# Management of low anterior resection syndrome\n\nWhat is the effectiveness and safety of sacral nerve stimulation and transanal irrigation compared to symptomatic treatment for people with major low anterior resection syndrome?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on management of low anterior resection syndrome\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E2: optimal management of low anterior resection syndrome.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Prevention of colorectal cancer in people with Lynch syndrome\n\nRecommendation 1.1.1\n\n## Why the committee made the recommendation\n\nEvidence from a multi-country randomised controlled trial showed that taking 600\xa0mg of aspirin daily for more than 2\xa0years reduces the risk of colorectal cancer in people with Lynch syndrome, although this was only evident when restricting the analysis to those who actually took aspirin as planned, increasing the uncertainty around the evidence. An observational study among people with Lynch syndrome also showed a reduced risk of colorectal cancer in people who had taken aspirin (varying self-reported doses) in the long term compared to those who had not.\n\nLong-term use of aspirin may slightly increase the risk of bleeding. However, no increased risk of peptic ulcer, gastrointestinal bleeding or cerebral haemorrhage was observed in the randomised controlled trial, although this might be because of the relatively short follow-up time. Given that the potential benefits are likely to outweigh the potential harms for most people with Lynch syndrome, the committee agreed taking aspirin long term will be appropriate in most, but not all, cases (for example in people with history of peptic ulcers).\n\nThe optimal dose of aspirin that balances the benefits of aspirin in preventing colorectal cancer and the potential increased bleeding risk (especially with higher doses) remains unclear. Because of this the committee was not able to recommend a dose, though an ongoing trial is currently studying this. Commonly used doses in current practice are 150\xa0mg or 300\xa0mg.\n\nIn July 2020, NICE carried out a surveillance review on a follow-up study to the randomised controlled trial that was used to inform development of the recommendation. The decision was that no change to the recommended advice was needed at this time.\n\n## How the recommendation might affect practice\n\nAspirin is already widely used for this indication and so the recommendation is not expected to have a significant impact on practice.\n\nFull details of the evidence and the committee's discussion are in evidence review A1: effectiveness of aspirin in the prevention of colorectal cancer in people with Lynch syndrome.\n\nReturn to recommendation\n\n# Information for people with colorectal cancer\n\nRecommendations 1.2.1 to 1.2.8\n\n## Why the committee made the recommendations\n\nThere was evidence that people having treatment for colorectal cancer need different information at different stages of their care, and this was supported by the committee's own clinical experience as well as NICE's guideline on patient experience in adult NHS services.\n\nThe committee based their recommendations on qualitative evidence and their clinical experience, which enabled the committee to identify areas where people lacked understanding and issues that people would value information on. This included explaining colorectal cancer and its treatments in depth, including non-surgical treatment options and palliative care, as well as explaining how people can alter their diet to reduce bowel problems and manage their weight.\n\nThe committee also agreed it was important to prepare people for the fact that changes to the agreed plan are sometimes needed during treatment, and to explain what these could be so that people feel ready for this possibility.\n\n## How the recommendations might affect practice\n\nCurrent practice varies between hospitals, so these recommendations aim to reduce variation and encourage best practice. There may be a cost to providing training to professionals but this is expected to be small.\n\nFull details of the evidence and the committee's discussion are in evidence review E3: information needs of people prior, during and after treatment for colorectal cancer.\n\nReturn to recommendations\n\n# Treatment for people with early rectal cancer\n\nRecommendation 1.3.1\n\n## Why the committee made the recommendation\n\nThe committee agreed that it was not possible to recommend one treatment over another because of the low quality of the evidence and the limited amount of evidence available. The available evidence showed no clinically important differences between treatments and, in addition, for many of the outcomes specified in the protocol and a number of the comparisons no evidence was identified at all. However, based on their knowledge and experience, the committee noted that there are risks and benefits associated with each treatment option. They highlighted that while total mesorectal excision (TME) is a radical intervention and has more risks than the others, it is the only way to accurately stage lymph nodes and, by doing so, allow better treatment planning. Therefore, the committee recommended discussing the implications of each intervention with the person before making a choice.\n\n## How the recommendation might affect practice\n\nCurrently, endoscopic submucosal dissection (ESD) is not widely available in the UK. In centres where ESD is not already available, resources and time would be needed to provide this service, including purchasing equipment and training staff (although this would be a short-term cost). After this initial investment there will be minimal cost difference between ESD and alternatives. Transanal excision (TAE; including transanal minimally invasive surgery and transanal endoscopic microsurgery) and TME are current practice in the UK, so the recommendations will have a minimal effect for these interventions. However, the recommendations will allow for an informed discussion with patients so they are fully aware of the risks and benefits of each procedure.\n\nFull details of the evidence and the committee's discussion are in evidence review C1: treatment for early rectal cancer.\n\nReturn to recommendation\n\n# Preoperative treatment for people with rectal cancer\n\nRecommendations 1.3.2 and 1.3.3\n\n## Why the committee made the recommendations\n\nThere was no evidence for the effectiveness of preoperative radiotherapy for people with early rectal cancer, and based on their experience the committee would not recommend preoperative radiotherapy. However, the ongoing STAR-TREC trial, which is a multicentre randomised controlled trial, compares radiotherapy to TME for early rectal cancer. Because of this, the committee recommended that preoperative radiotherapy for early rectal cancer could be offered, but only in the context of a clinical trial.\n\nFor rectal cancer cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0, the evidence from several randomised controlled trials (RCTs) shows that people who have preoperative radiotherapy or chemoradiotherapy have less local recurrence and have better overall and disease-free survival compared to people who did not have preoperative therapy. Although preoperative therapy can potentially have adverse effects, from the evidence the committee did not find a difference in quality of life or treatment-related mortality between those who did or did not receive preoperative therapy.\n\nThe committee was not able to make a recommendation on the duration and type of radiotherapy or chemoradiotherapy because the available evidence did not show a difference between short-course and long-course radiotherapy, chemoradiotherapy with or without induction chemotherapy, or internal radiotherapy with or without external radiotherapy and external radiotherapy alone.\n\n## How the recommendations might affect practice\n\nThere is some variation in current practice among different multidisciplinary teams as to who is offered preoperative therapy. The aim of the recommendation is to standardise treatment across the country, so this might have a resource impact in areas where preoperative therapy is not currently offered and where more clinical oncologists and radiotherapy equipment and staff will be needed. The committee was aware that in some areas, therapeutic radiographers are taking on roles at advanced and consultant level to support specialist oncologists. There may be savings downstream through reduced recurrence and increased disease-free survival avoiding or delaying expensive further treatment.\n\nThe recommendation might increase the number of people offered preoperative radiotherapy or chemoradiotherapy for lower-risk tumours (mainly cancers in the upper and mid rectum). In current practice, people with cancer in the upper and mid rectum might not have preoperative therapy because there is a lower risk of recurrence in cancers in these locations compared to cancer in the low rectum.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review C1: treatment for early rectal cancer\n\nevidence review C2: preoperative radiotherapy and chemoradiotherapy for rectal cancer.\n\nReturn to recommendations\n\n# Surgery for people with rectal cancer\n\nRecommendations 1.3.4 and 1.3.5\n\n## Why the committee made the recommendations\n\nSurgery is the gold standard treatment for people with rectal cancer (cT1-T2, cN1-N2, M0, or cT3-T4, any cN, M0) if the tumour is resectable. The committee acknowledged that some people whose rectal cancer shows a complete clinical response to neoadjuvant therapy choose to defer surgery and opt for an organ preserving 'watch-and-wait' strategy instead. However, no evidence was identified on which prognostic factors could predict recurrence and survival to better select people for deferral of surgery. The committee were uncertain about how different definitions of complete clinical response and different watch-and-wait surveillance protocols would impact risk of recurrence. Because of the lack of evidence, they agreed that people wishing to defer surgery after a complete clinical and radiological response to neoadjuvant treatment should be made aware of the uncertainty about their outcome. Around one third of these people will experience local regrowth of their tumour and need salvage surgery.\n\nThe committee noted that there is no agreed definition of complete clinical and radiological response and no evidence on factors that predict recurrence, therefore, those who choose to defer surgery should be encouraged to enter a clinical trial or entered into a national registry. These could gather evidence to help define groups for whom deferral of surgery may be safe and appropriate.\n\n## How the recommendations might affect practice\n\nThe watch-and-wait approach requires repeated surveillance examinations and endoscopies to monitor for tumour regrowth. In some cases, people choosing to defer surgery will need to be referred to another centre that can provide the necessary watch-and-wait surveillance programme. The recommendations are not expected to have a significant impact on practice.\n\nFull details of the evidence and the committee's discussion are in evidence review C4: deferral of surgery in people having neoadjuvant therapy for rectal cancer.\n\nReturn to recommendations\n\n# Surgical technique for people with rectal cancer\n\nRecommendations 1.3.6 to 1.3.9\n\n## Why the committee made the recommendations\n\nThe clinical evidence on the different surgical techniques for rectal cancer showed that the short- and long‑term outcomes of laparoscopic technique were similar or better than of the open technique and that there seemed to be no difference in effectiveness between laparoscopic and robotic techniques. The committee agreed that in addition to the clinical effectiveness it was important to consider the costs of these different techniques in order to assess which technique is the most cost-effective approach in rectal cancer surgery, therefore, a health economic analysis was done.\n\nThe evidence showed that laparoscopic surgery is cost effective compared to open surgery or robotic surgery. However, in some cases open surgery might be clinically more appropriate and laparoscopic surgery might be less feasible, for example because of scarring from previous operations or technically demanding resection of adjacent organs or structures in locally advanced tumours.\n\nRobotic surgery was not found to be cost effective; however, this technique could be considered in centres that have already invested in a robot and have an established programme. These programmes should collect outcome data in order to benchmark the effectiveness and safety of this technique in clinical practice against other centres and techniques. The techniques and equipment of robotic surgery develop rapidly and more evidence on its cost effectiveness will be available in the future.\n\nThere is evidence that transanal TME is effective, but evidence about its safety is inconsistent. However, transanal TME could be considered as part of a formal research study. Outcome data should be submitted to a national registry in order to assess the safety and effectiveness of this technique in clinical practice. This is in line with NICE interventional procedures guidance on transanal total mesorectal excision for rectal cancer.\n\n## How the recommendations might affect practice\n\nThere will be more laparoscopic surgery, while recognising that there is a role for open surgery in appropriately selected cases. Current robotic techniques were found not to be cost effective, so there may be less investment in robotic techniques for this indication. However, the recommendation will not affect the use of robotic surgery within established programmes. The recommendations are not expected to have an impact on the use of transanal TME as these are largely done within structured and supervised programmes in current practice.\n\nFull details of the evidence and the committee's discussion are in evidence review C3: optimal surgical technique for rectal cancer.\n\nReturn to recommendations\n\n# People with locally advanced or recurrent rectal cancer\n\nRecommendation 1.3.10\n\n## Why the committee made the recommendation\n\nBased on their clinical experience, the committee acknowledged that many patients are not currently referred to specialist centres and are only offered palliative care instead of potentially curative surgery. The committee also noted that pelvic exenteration is a complex and invasive procedure.\n\nHowever, there was some very low-quality evidence that showed people who had pelvic exenteration had similar quality of life scores to those who did not, and that the procedure improved survival over 12\xa0months. The committee agreed that evidence from long-term follow-up of quality of life would help to inform the recommendation, but there was no quality-of-life data available beyond 12\xa0months. Therefore, the committee could not recommend referring everyone with locally advanced or recurrent rectal cancer to have pelvic exenteration, but agreed that people should have the opportunity to discuss pelvic exenteration as an option in a specialist centre. Despite the lack of long-term quality of life evidence, a research recommendation was not made because the low number of eligible participants meant a prospective comparative study would not be feasible. Additionally, an international collaborative study of outcomes after pelvic exenteration (PelvEx) is already underway.\n\n## How the recommendation might affect practice\n\nThe recommendation could increase the number of referrals to specialist centres in hospitals where this is not current practice. This would, in turn, increase demand for specialist time and mean that more people may go on to have surgery. However, this may improve quality of life and survival.\n\nFull details of the evidence and the committee's discussion are in evidence review C5: effectiveness of exenterative surgery for locally advanced or recurrent rectal cancer.\n\nReturn to recommendation\n\n# Surgical volumes for rectal cancer operations\n\nRecommendations 1.3.11 and 1.3.12\n\n## Why the committee made the recommendations\n\nCurrently, there is uncertainty in the clinical community about optimal hospital and surgeon volumes for rectal cancer outcomes, with some clinicians advocating for the centralisation of services. There was evidence that when the threshold is set between 10\xa0and\xa020 rectal cancer surgery patients per year, higher volume hospitals have better outcomes than lower volume hospitals in terms of overall survival, local recurrence, permanent stoma rates and perioperative mortality. Similarly, there was evidence of benefit with a surgeon case volume threshold of between 5\xa0and\xa010 cases per year in terms of resection margins, local recurrence and permanent stoma rates.\n\nThe committee were cautious in their interpretation of the evidence: individual studies had used different case volume thresholds and had not treated case volume as a continuous outcome, and there were additional complexities with surgeon-level data (that is, consultants may do more complex operations, but fewer of them, and a consultant might be involved with other operations but not be the named surgeon) as well as with hospital-level data (that is, some studies were old and from outside the UK, with inconsistent staging across studies).\n\nGiven the uncertainties in the data, the committee agreed that the evidence was not strong enough to recommend a minimum cut-off of 20\xa0cases and instead decided to recommend a more conservative cut-off of 10\xa0cases a year.\n\n## How the recommendations might affect services\n\nAn audit of operations for rectal cancer in the UK has indicated that most hospitals in the UK perform at least 20\xa0cases of rectal cancer surgery per year. Therefore, the recommendation for a minimum threshold of 10\xa0cases per year at hospital level will not have a large impact on current practice. Based on their clinical knowledge, the committee were aware that some surgeons in the UK currently perform fewer than 5\xa0operations per year, so the recommendation could have an impact on these surgeons. Fewer surgeons performing more cases could have an impact on staffing, although as the overall number of operations will be the same the overall cost impact should be neutral. There may be an increase in the distance patients need to travel for surgery and this will have a cost impact on the NHS where this is reimbursed. This cost will be offset by better surgical outcomes reducing care-related costs later on and increasing quality of life.\n\nFull details of the evidence and the committee's discussion are in evidence review F1: surgical volumes and outcomes for rectal cancer.\n\nReturn to recommendations\n\n# Preoperative treatment for people with colon cancer\n\nRecommendation 1.3.13\n\n## Why the committee made the recommendation\n\nThe committee made the recommendation to consider chemotherapy preoperatively for people with cT4 colonic cancer based on evidence that it improved survival and rates of clear resection margins in these patients. The committee was only able to recommend preoperative chemotherapy as an option to consider because the evidence was of low quality, despite the large sample size. There was no evidence on the effectiveness of preoperative chemotherapy for people with colonic cancers at other stages.\n\nThe committee also considered non-peer-reviewed results from FOxTROT: a large international trial comparing preoperative plus postoperative chemotherapy (with or without panitumumab) to standard postoperative chemotherapy in people with cT3 or cT4a resectable tumours. The results showed that complete clinical response and tumour downstaging are more likely in those who receive preoperative chemotherapy, however at the time of publication of this guideline there was insufficient duration of follow‑up to assess long‑term outcomes.\n\n## How the recommendation might affect practice\n\nThe current standard of care is surgical resection with postoperative chemotherapy, dependent on the organs or structures involved and the degree of involvement. The committee was aware that some centres already give preoperative chemotherapy, but noted that this recommendation will affect practice and have a resource impact in hospitals where this is not standard practice.\n\nFull details of the evidence and the committee's discussion are in evidence review C7: preoperative chemotherapy for non-metastatic colon cancer.\n\nReturn to recommendation\n\n# Duration of adjuvant chemotherapy for people with colorectal cancer\n\nRecommendation 1.3.14\n\n## Why the committee made the recommendation\n\nThe benefits and risks of adjuvant chemotherapy can depend on several factors, including the stage and characteristics of the cancer, and the person's performance status, comorbidities and age.\n\nPeripheral neuropathy is recognised as a major long-term side effect of oxaliplatin chemotherapy, and the risk of developing persistent neuropathy increases by cumulative dose of treatment. The standard duration of chemotherapy has been 6\xa0months, but a shorter 3‑month course has been investigated.\n\nThere was good evidence that showed 3\xa0months of CAPOX chemotherapy was at least as beneficial for people with colon cancer as a 6‑month course but caused considerably less severe neuropathy and was cost saving. However, with FOLFOX chemotherapy, disease-free survival was worse after a 3‑month course compared with the standard 6‑month course, although the rate of severe neuropathy was again considerably lower in the 3‑month group.\n\nA high‑quality health economic study found a 3‑month course of FOLFOX to be cost effective compared to a 6‑month course, despite lower disease-free survival, as a result of a decrease in costs. Although this economic evidence was directly applicable to the clinical question, and the study was included in the consideration of the clinical evidence, the committee was concerned that basing recommendations solely in line with the economic evaluation (that is, CAPOX for 3\xa0months or FOLFOX for 3\xa0months) might lead to people who would otherwise have received 6‑month FOLFOX to opt for 3‑month CAPOX instead.\n\nIn the SCOT trial CAPOX was associated with a higher rate of severe diarrhoea than FOLFOX. This was not looked at by the economic evaluation and the 'switching' group would likely to be at higher risk of toxicity‑related complications with worse outcomes, increased treatment-related mortality and increased costs from the treatment of severe adverse events than the trial population for 3‑month CAPOX. This would decrease the certainty of the conclusions of the economic evaluation.\n\nBased on the balance of benefits and lower risk of long-term adverse effects, the committee agreed CAPOX for 3\xa0months should be the first choice of adjuvant treatment. If CAPOX is not suitable, for example because of the person's higher risk of and lower tolerance for severe diarrhoea, FOLFOX should be offered. Having considered the economic evaluation given the clinical concerns, it was decided that there should be an individualised consideration of the duration of FOLFOX for people if 3‑month CAPOX chemotherapy is not suitable for them, taking into account the benefits and short- and long-term harms of both options, the person's comorbidities, performance status and preference.\n\nSingle-agent capecitabine chemotherapy is also an effective adjuvant treatment and can be more suitable for people who are older (for example over 70) or less fit, as it is associated with fewer side effects than chemotherapy treatments that contain oxaliplatin.\n\nThe available evidence is mainly for people with colon cancer. However, people with rectal cancer who had received either short-course preoperative radiotherapy or no preoperative therapy were also included in a large randomised trial and their outcomes were similar to people with colon cancer, and therefore the committee agreed the recommendation could also apply to this population.\n\nNo recommendations were made for people with rectal cancer who have been treated with long-course chemotherapy or chemoradiotherapy because no evidence was identified in the available trials.\n\n## How the recommendation might affect practice\n\nHalving the standard care from 6\xa0months to 3\xa0months (for people who can have CAPOX) will reduce treatment time and costs, meaning people have chemotherapy side effects for a shorter time, and will lower the incidence of long-term toxicity (neuropathy) and its consequences.\n\nFull details of the evidence and the committee's discussion are in evidence review C8: optimal duration of adjuvant chemotherapy for colorectal cancer.\n\nReturn to recommendation\n\n# Colonic stents in acute large bowel obstruction\n\nRecommendations 1.3.15 and 1.3.16\n\n## Why the committee made the recommendations\n\nIn patients presenting with acute left-sided large bowel obstruction, evidence showed that stoma rates were reduced in the stenting group compared to the emergency surgery group. There was no evidence of a difference in overall or disease-free survival. Stenting also allows time to fully assess the patient and stabilise any comorbidities before proceeding with potentially curative surgery. The committee considered the yet to be published results of the CREST trial shared with the committee in confidence which were consistent with the published evidence.\n\nThe committee noted the evidence that stenting sometimes causes perforation and is not always technically successful and so may not be appropriate in all cases for the curative intent treatment group. For this reason they also recommended emergency surgery as an option.\n\n## How the recommendations might affect practice\n\nStenting is established practice for patients presenting with acute left-sided large bowel obstruction who are to be treated with palliative intent. Stenting is not established practice in those to be treated with curative intent. Therefore, the recommendation could lead to an increase in the provision of stenting and associated costs. However, stenting allows patients to be assessed and become stable before surgery, in turn reducing operative morbidity, the need for stoma and preventing expensive surgery in those people when it would not be appropriate, thus reducing downstream costs. Some patients might need to be transferred to another unit in order to receive a stent.\n\nFull details of the evidence and the committee's discussion are in evidence review C9: effectiveness of stenting for acute large bowel obstruction.\n\nReturn to recommendations\n\n# Molecular biomarkers to guide systemic anti-cancer therapy\n\nRecommendation 1.4.1\n\n## Why the committee made the recommendation\n\nThe evidence showed that RAS and BRAF\xa0V600E mutations were predictive of response to anti-epidermal growth factor receptor (EGFR) targeted therapy in people with metastatic colorectal cancer. People with RAS or BRAF\xa0V600E mutant metastatic colorectal cancer also had poorer progression-free and overall survival than those without such mutations. While RAS testing is already used to select those people with metastatic colorectal cancer most likely to benefit from anti-EGFR targeted therapy, BRAF\xa0V600E testing has the potential to further refine this group.\n\nThe committee noted evidence that testing for deficient DNA mismatch repair may inform systemic therapy choices for those with non-metastatic colorectal cancer, but the NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer already recommends such testing for all people with colorectal cancer when first diagnosed. For this reason no further recommendations were made about testing for deficient DNA mismatch repair.\n\n## How the recommendation might affect practice\n\nRAS testing (KRAS and NRAS) is current practice. BRAF\xa0V600E testing is not done routinely in current practice. BRAF\xa0V600E test can be done from the extended colorectal cancer molecular test panel which is part of the recommendations in the NICE diagnostics guidance on molecular testing strategies for Lynch syndrome in people with colorectal cancer, so the recommendation should not have a large impact on practice or costs.\n\nFull details of the evidence and the committee's discussion are in evidence review B1: use of molecular biomarkers to guide systemic therapy.\n\nReturn to recommendation\n\n# People with asymptomatic primary tumour\n\nRecommendation 1.5.1\n\n## Why the committee made the recommendation\n\nFor people with incurable metastatic colorectal cancer whose primary tumour is asymptomatic, there was some low-quality evidence of better overall survival in those who had resection of their primary tumour and chemotherapy compared with chemotherapy alone.\n\nAround a quarter of this group had postoperative complications and a small proportion (around 5%) had severe postoperative complications which needed intervention or were life-threatening. However, resecting the tumour at this stage can prevent symptoms from developing later: almost a fifth of people who did not have the asymptomatic primary tumour resected went on to develop primary tumour-related symptoms that needed surgical treatment which could often mean an emergency operation that can have higher risks of complications and stoma. Because of this, the committee agreed the implications should be discussed with the person so they can make an informed decision.\n\n## How the recommendation might affect practice\n\nThere could be an increase in resections of asymptomatic primary tumours, however, the population with metastatic colorectal cancer and asymptomatic primary tumour is small so no major cost impact is expected.\n\nFull details of the evidence and the committee's discussion are in evidence review D1: surgery for asymptomatic primary tumour.\n\nReturn to recommendation\n\n# Systemic anti-cancer therapy for people with metastatic colorectal cancer\n\nRecommendation 1.5.2\n\n## Why the committee made the recommendation\n\nGuidance on systemic anti-cancer therapy for people with metastatic colorectal cancer is covered by NICE technology appraisals, which were not updated by this guideline. The committee did not review the technology appraisals. The technology appraisals should be used when appropriate to guide the choice of systemic anti-cancer therapy.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice and no change in practice is expected.\n\nReturn to recommendation\n\n# People with metastatic colorectal cancer in the liver\n\nRecommendations 1.5.3 to 1.5.6\n\n## Why the committee made the recommendations\n\nThere was not enough evidence to show if simultaneous or sequential resection is better. There was some poor‑quality evidence from retrospective cohort studies showing that people who underwent sequential resection had better liver progression-free survival. However, these results might be influenced by baseline differences between the groups, and there was no difference in recurrence in other parts of the body or in overall survival in several studies. There was no difference in short-term adverse events and no evidence on quality of life was available. Based on these findings and their experience, the committee agreed that a multidisciplinary team with expertise in both colorectal and liver disease should consider if a simultaneous or a sequential resection is appropriate, taking into account the person's preference.\n\nEvidence from randomised trials suggested that chemotherapy in addition to liver resection improves disease-free survival and may improve overall survival. The potential benefit on survival should be balanced with a higher rate of treatment-related adverse events because of added chemotherapy. No quality of life evidence was available.\n\nThe evidence on chemotherapy combined with radiofrequency ablation showed better overall survival and progression-free survival compared to chemotherapy alone. No difference was observed in treatment‑related mortality and morbidity. The evidence on quality of life was too limited for the committee to draw any conclusions. The evidence on survival came from a single small study and the committee had doubts about its relevance to current practice. Because of the uncertainties in the evidence, the committee recommended considering chemotherapy with local ablative techniques as an option for people whose liver metastases are determined by the multidisciplinary team to be unresectable but potentially curable. The evidence was on radiofrequency ablation, which is still used but in many centres has been largely replaced by newer local ablative techniques such as microwave ablation (see the NICE interventional procedures guidance on microwave ablation for treating liver metastases). Therefore, the committee agreed that it is more appropriate that local ablative techniques, not only radiofrequency ablation, are considered.\n\nEvidence from several RCTs did not show any benefit on overall survival from selective internal radiation therapy (SIRT) as a first-line treatment for people with colorectal liver metastases. NICE interventional procedures guidance on selective internal radiation therapy for non-resectable colorectal metastases in the liver gives further guidance in which circumstances SIRT could be used. Only limited evidence from one small RCT was available on the effectiveness of SIRT for people refractory or intolerant to standard chemotherapy. The committee were aware of an NHS England commissioning policy on SIRT as third-line treatment, which used observational data in addition to the small RCT as their evidence base. However, because of limited RCT evidence the committee was not able to make a recommendation.\n\n## How the recommendations might affect practice\n\nThe recommendations largely reflect current practice and no substantial change in practice is expected.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D2a: treatment for metastatic colorectal cancer in the liver amenable to treatment with curative intent\n\nevidence review D2b: optimal combination and sequence of treatments in patients presenting with metastatic colorectal cancer in the liver not amenable to treatment with curative intent.\n\nReturn to recommendations\n\n# People with metastatic colorectal cancer in the lung\n\nRecommendations 1.5.7 and 1.5.8\n\n## Why the committee made the recommendations\n\nAs there was limited evidence, the committee made recommendations based on their clinical knowledge. There was not enough evidence to recommend one treatment over another even though the current first choice is to perform surgery over stereotactic body radiation therapy or ablation. Referring people to multidisciplinary teams that specialise in primary lung disease may not be appropriate as they do not specialise in the management of lung metastases from colorectal cancer. Therefore, the committee agreed that the multidisciplinary team should include a thoracic surgeon and a specialist in non-surgical ablation to ensure that the appropriate specialist knowledge is available.\n\nBased on their clinical knowledge, the committee recommended that biopsies should be considered for patients with a single lung lesion to rule out primary lung cancer and guide treatment options even if surgical excision is not planned.\n\nBecause of the lack of clinical evidence, a randomised trial comparing surgical to non-surgical treatment is needed to provide more high quality, comparative data, so the committee made a research recommendation on this topic.\n\n## How the recommendations might affect practice\n\nThe recommendations are expected to increase the involvement of thoracic surgeons in the management of metastatic colorectal cancer, however this additional expertise would result in expensive treatments being more appropriately targeted. While assessing fitness for surgery is common practice, the advice to also discuss factors including disease-free interval, carcinoembryonic antigen (CEA) level, number, size and site of metastases and other sites of disease should improve best practice across the NHS.\n\nFull details of the evidence, the committee's discussion and the recommended approach to research are in evidence review D3: treatment for metastatic colorectal cancer in the lung amenable to local treatment.\n\nReturn to recommendations\n\n# People with metastatic colorectal cancer in the peritoneum\n\nRecommendation 1.5.9\n\n## Why the committee made the recommendation\n\nThe committee made the recommendation based on both the evidence and their clinical knowledge. The advice to offer systemic anti-cancer therapy and to discuss referral to a specialist cytoreductive surgery centre is in the same recommendation because these interventions should happen at the same time. That is, making a referral should not wait until chemotherapy has been given, and chemotherapy could be started before the person is reviewed in the specialist centre.\n\nIt is standard practice to start all patients on a course of systemic anti-cancer therapy and the evidence supported this, showing greater overall survival compared to supportive care. The evidence on the effectiveness of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) was mixed but, based on their clinical knowledge, the committee decided they should be considered.\n\nThe committee agreed it was important to recommend referral to a nationally commissioned specialist centre after discussion within a multidisciplinary team for consideration of cytoreductive surgery and HIPEC so that more patients can have potentially curative treatment and to avoid centres offering the treatment without having the necessary training and resources. This advice is in line with the NICE interventional procedures guidance on cytoreductive surgery with hyperthermic intraoperative peritoneal chemotherapy for peritoneal carcinomatosis.\n\n## How the recommendation might affect practice\n\nStenting is not established practice in those to be treated with curative intent. Therefore, the recommendation could lead to an increase in the provision of stenting and associated costs. However, stenting allows patients to be assessed and become stable before surgery, in turn reducing operative morbidity, the need for stoma and preventing expensive surgery in those people when it would not be appropriate, thus reducing downstream costs. Some patients might need to be transferred to another unit in order to receive a stent.\n\nFull details of the evidence and the committee's discussion are in evidence review D4: local and systemic treatments for metastatic colorectal cancer isolated in the peritoneum.\n\nReturn to recommendation\n\n# Follow-up for detection of local recurrence and distant metastases\n\nRecommendation 1.6.1\n\n## Why the committee made the recommendation\n\nEvidence showed that recurrent disease was more likely to be resectable when patients received regular follow-up tests than with minimal or no follow-up. Evidence also showed recurrent disease was more likely to be resectable when follow-up tests included CEA and liver imaging. The 2011 NICE guideline on colorectal cancer (updated and replaced by this guideline) recommended CEA and CT testing in the first 3\xa0years after treatment with curative intent, and the committee did not find evidence to change this. Colonoscopic surveillance to detect metachronous colorectal neoplasia was outside the scope of this guideline (the British Society of Gastroenterology and the Association of Coloproctology for Great Britain and Ireland have guidance on this topic).\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice so the committee agreed there should be no change in practice.\n\nFull details of the evidence and the committee's discussion are in evidence review E1: follow-up to detect recurrence after treatment for non-metastatic colorectal cancer.\n\nReturn to recommendation\n\n# Management of low anterior resection syndrome\n\nRecommendations 1.6.2 to 1.6.4\n\n## Why the committee made the recommendations\n\nBased on their experience, the committee agreed low anterior resection syndrome (LARS) can have a significant impact on a person's quality of life and daily functioning, so it is important to identify and treat it quickly. It is important that people who have had sphincter-preserving surgery are aware of its symptoms so they can seek help. Because LARS may only become apparent after discharge from hospital, it is important that it can be identified in primary care. LARS should be assessed using a validated tool, for example the European Society of Coloproctology's LARS score, which is a validated patient-administered questionnaire.\n\nNo comparative evidence on different treatments for LARS was available, so the committee agreed based on their experience that people with LARS should be offered symptomatic treatment in primary care. The committee also agreed that if treatments offered in primary care have not helped, advice should be sought from secondary care to discuss further options and consider specialist input. Timing of this should be based on clinical judgement taking into consideration, for example, severity of symptoms and impact on quality of life.\n\nBecause of the lack of evidence on the effectiveness of treatments for LARS, a research recommendation was made to compare sacral nerve stimulation and transanal irrigation in people with LARS for whom conservative treatments have not worked.\n\n## How the recommendations might affect practice\n\nPrimary care clinicians are not necessarily aware of LARS or how to assess it, and administering the questionnaire might need extra work and time. However, it is patient-administered and easy to score and no training should be needed. Bowel dysfunction treatment for associated symptoms are commonly delivered in primary care, therefore, the recommendation is not expected to have a large impact on current practice in terms of number of patients and interventions, however, raising awareness of LARS will be needed among primary care professionals.\n\nFull details of the evidence, the committee's discussion and the recommended approach to research are in evidence review E2: optimal management of low anterior resection syndrome.\n\nReturn to recommendations", 'Context': "Colorectal cancer (cancer of the colon or rectum, or bowel cancer) is the fourth most common cancer in the UK, with over 41,000 new cases diagnosed each year according to Cancer Research UK's bowel cancer statistics. Risk factors include increasing age, genetics and family history (particularly syndromes such as familial adenomatous polyposis and Lynch syndrome), inflammatory bowel disease and other dietary and lifestyle factors. Survival rates have improved over time, with almost 60% of people diagnosed with colorectal cancer surviving for at least 5\xa0years. Survival is linked to disease stage at presentation, with better survival the earlier the disease is detected and treated.\n\nPeople with Lynch syndrome have an increased risk of colorectal cancer, with lifetime risk estimated to be between around 50% to 80% (see Lynch Syndrome in Gene Reviews). The main strategy to prevent colorectal cancer in people with Lynch syndrome has been regular screening with colonoscopy and polypectomy. Aspirin has been suggested as another potential prevention strategy for colorectal cancer.\n\nDiagnosis and staging of colorectal cancer are well established with histology and appropriate imaging, and are not covered by this guideline.\n\nManagement of colorectal cancer has advanced over time with new treatment methods and strategies being trialled and used. Management of local disease differs depending on the site of the cancer. The standard practice for colon cancer is to offer surgery for those who are fit for it. Recent trials have studied the effectiveness of preoperative systemic anti-cancer therapy for colon cancer to improve survival. Treatment for rectal cancer is more complex. There is variation in current practice in the treatment for early rectal cancer, use of preoperative (chemo)radiotherapy, surgical technique for rectal cancer surgery, and treatment for locally advanced or recurrent rectal cancer. This guideline addresses all these issues. Until now, the standard duration of adjuvant systemic therapy for colorectal cancer has been 6\xa0months, which has been recently challenged by suggestion of a shorter duration in order to lower toxicity caused by the treatment.\n\nMetastatic colorectal cancer commonly affects the liver, lungs or peritoneum. Treatment for metastatic colorectal cancer depends on, for example, the site and number of the metastases and if the metastases are amenable to local treatment. In addition, the role of molecular biomarkers in predicting effectiveness of systemic anti-cancer therapy has been discussed increasingly in recent years.\n\nPeople who have been treated for colorectal cancer may have long-term side effects of their treatments. For example, low anterior resection syndrome can have major impact on quality of life and daily living, and it affects around 40% of those who have undergone sphincter-preserving surgery for rectal cancer. It is important that the treatment options, their implications and potential consequences are discussed together with the person with colorectal cancer in order to enable shared decision making."}
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https://www.nice.org.uk/guidance/ng151
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This guideline covers managing colorectal (bowel) cancer in people aged 18 and over. It aims to improve quality of life and survival for adults with colorectal cancer through management of local disease and secondary tumours (metastatic disease).
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6d65b2f97d0616b72be99122e18b953f865f7c7b
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nice
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Suspected cancer: recognition and referral
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Suspected cancer: recognition and referral
This guideline covers identifying children, young people and adults with symptoms that could be caused by cancer. It outlines appropriate investigations in primary care, and selection of people to refer for a specialist opinion. It aims to help people understand what to expect if they have symptoms that may suggest cancer.
# Introduction
# Safeguarding children
Remember that child maltreatment:
is common
can present anywhere
may co‑exist with other health problems, including suspected cancer.
See NICE's guideline on child maltreatment for clinical features that may be associated with maltreatment.
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations (although this may not apply to recommendations made before 2009; see the section on recommendation wording in guideline updates below). It also has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.
# How the guideline is organised
The recommendations in this guideline have been organised into 3 separate sections to help healthcare professionals find the relevant information easily. The recommendations for investigation and referral organised by site of suspected cancer are also presented in tables of recommendations organised by symptoms and investigation findings. Either section should be used in conjunction with the recommendations on patient support, safety netting and the diagnostic process.
# Recommendation wording in guideline updates
NICE began using standard wording to denote the strength of recommendations in guidelines that started development after January 2009. It does not apply to any recommendations ending (see update information for details about how recommendations are labelled). In particular, for recommendations labelled the word 'consider' may not necessarily be used to denote the strength of the recommendation.# Recommendations organised by site of cancer
Use this guideline to guide referrals. If still uncertain about whether a referral is needed, consider contacting a specialist (see the recommendations on the diagnostic process). Consider a review for people with any symptom associated with increased cancer risk who do not meet the criteria for referral or investigative action (see the recommendations on safety netting).
# Lung and pleural cancers
## Lung cancer
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for lung cancer if they:
have chest X‑ray findings that suggest lung cancer or
are aged 40 and over with unexplained haemoptysis.
Offer an urgent chest X‑ray (to be done within 2 weeks) to assess for lung cancer in people aged 40 and over if they have 2 or more of the following unexplained symptoms, or if they have ever smoked and have 1 or more of the following unexplained symptoms:
cough
fatigue
shortness of breath
chest pain
weight loss
appetite loss.
Consider an urgent chest X‑ray (to be done within 2 weeks) to assess for lung cancer in people aged 40 and over with any of the following:
persistent or recurrent chest infection
finger clubbing
supraclavicular lymphadenopathy or persistent cervical lymphadenopathy
chest signs consistent with lung cancer
thrombocytosis.
## Mesothelioma
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for mesothelioma if they have chest X‑ray findings that suggest mesothelioma.
Offer an urgent chest X‑ray (to be done within 2 weeks) to assess for mesothelioma in people aged 40 and over, if:
they have 2 or more of the following unexplained symptoms, or
they have 1 or more of the following unexplained symptoms and have ever smoked, or
they have 1 or more of the following unexplained symptoms and have been exposed to asbestos:
cough
fatigue
shortness of breath
chest pain
weight loss
appetite loss.
Consider an urgent chest X‑ray (to be done within 2 weeks) to assess for mesothelioma in people aged 40 and over with either:
finger clubbing or
chest signs compatible with pleural disease.
# Upper gastrointestinal tract cancers
## Oesophageal cancer
Offer urgent, direct access upper gastrointestinal endoscopy (to be done within 2 weeks) to assess for oesophageal cancer in people:
with dysphagia or
aged 55 and over with weight loss and any of the following:
upper abdominal pain
reflux
dyspepsia.
Consider non-urgent direct access upper gastrointestinal endoscopy to assess for oesophageal cancer in people with haematemesis.
Consider non‑urgent direct access upper gastrointestinal endoscopy to assess for oesophageal cancer in people aged 55 or over with:
treatment‑resistant dyspepsia or
upper abdominal pain with low haemoglobin levels or
raised platelet count with any of the following:
nausea
vomiting
weight loss
reflux
dyspepsia
upper abdominal pain, or
nausea or vomiting with any of the following:
weight loss
reflux
dyspepsia
upper abdominal pain.
## Pancreatic cancer
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for pancreatic cancer if they are aged 40 and over and have jaundice.
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available, to assess for pancreatic cancer in people aged 60 and over with weight loss and any of the following:
diarrhoea
back pain
abdominal pain
nausea
vomiting
constipation
new‑onset diabetes.
## Stomach cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for people with an upper abdominal mass consistent with stomach cancer.
Offer urgent direct access upper gastrointestinal endoscopy (to be done within 2 weeks) to assess for stomach cancer in people:
with dysphagia or
aged 55 and over with weight loss and any of the following:
upper abdominal pain
reflux
dyspepsia.
Consider non‑urgent direct access upper gastrointestinal endoscopy to assess for stomach cancer in people with haematemesis.
Consider non‑urgent direct access upper gastrointestinal endoscopy to assess for stomach cancer in people aged 55 or over with:
treatment‑resistant dyspepsia or
upper abdominal pain with low haemoglobin levels or
raised platelet count with any of the following:
nausea
vomiting
weight loss
reflux
dyspepsia
upper abdominal pain, or
nausea or vomiting with any of the following:
weight loss
reflux
dyspepsia
upper abdominal pain.
## Gall bladder cancer
Consider an urgent direct access ultrasound scan (to be done within 2 weeks) to assess for gall bladder cancer in people with an upper abdominal mass consistent with an enlarged gall bladder.
## Liver cancer
Consider an urgent direct access ultrasound scan (to be done within 2 weeks) to assess for liver cancer in people with an upper abdominal mass consistent with an enlarged liver.
# Lower gastrointestinal tract cancers
## Colorectal cancer
Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer if:
they are aged 40 and over with unexplained weight loss and abdominal pain or
they are aged 50 and over with unexplained rectal bleeding or
they are aged 60 and over with:
iron‑deficiency anaemia or
changes in their bowel habit, or
tests show occult blood in their faeces.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults with a rectal or abdominal mass.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for colorectal cancer in adults aged under 50 with rectal bleeding and any of the following unexplained symptoms or findings:
abdominal pain
change in bowel habit
weight loss
iron‑deficiency anaemia.
Offer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care) to assess for colorectal cancer in adults without rectal bleeding who:
are aged 50 and over with unexplained:
abdominal pain or
weight loss, or
are aged under 60 with:
changes in their bowel habit or
iron-deficiency anaemia, or
are aged 60 and over and have anaemia even in the absence of iron deficiency.
## Anal cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for anal cancer in people with an unexplained anal mass or unexplained anal ulceration.
# Breast cancer
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for breast cancer if they are:
aged 30 and over and have an unexplained breast lump with or without pain or
aged 50 and over with any of the following symptoms in one nipple only:
discharge
retraction
-ther changes of concern.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for breast cancer in people:
with skin changes that suggest breast cancer or
aged 30 and over with an unexplained lump in the axilla.
Consider non-urgent referral in people aged under 30 with an unexplained breast lump with or without pain. See also recommendations 1.16.2 and 1.16.3 for information about seeking specialist advice.
# Gynaecological cancers
## Ovarian cancer
The recommendations in this section have been incorporated from NICE's guideline on ovarian cancer and have not been updated. The recommendations for ovarian cancer apply to women aged 18 and over.
Make an urgent referral to a gynaecological cancer service if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids).
Carry out tests in primary care (see recommendations 1.5.6 to 1.5.9) if a woman (especially if aged 50 or over) reports having any of the following symptoms on a persistent or frequent basis – particularly more than 12 times per month:
persistent abdominal distension (women often refer to this as 'bloating')
feeling full (early satiety) and/or loss of appetite
pelvic or abdominal pain
increased urinary urgency and/or frequency.
Consider carrying out tests in primary care (see recommendations 1.5.6 to 1.5.9) if a woman reports unexplained weight loss, fatigue or changes in bowel habit.
Advise any woman who is not suspected of having ovarian cancer to return to her GP if her symptoms become more frequent and/or persistent.
Carry out appropriate tests for ovarian cancer (see recommendations 1.5.6 to 1.5.9) in any woman aged 50 or over who has experienced symptoms within the last 12 months that suggest irritable bowel syndrome (IBS), because IBS rarely presents for the first time in women of this age. (See NICE's guideline on irritable bowel syndrome in adults).
Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see recommendations 1.5.1 to 1.5.5).
If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis.
If the ultrasound suggests ovarian cancer, make an urgent referral to a gynaecological cancer service.
For any woman who has normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound:
assess her carefully for other clinical causes of her symptoms and investigate if appropriate
if no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent.
## Endometrial cancer
Refer women using a suspected cancer pathway referral (for an appointment within 2 weeks) for endometrial cancer if they are aged 55 and over with post‑menopausal bleeding (unexplained vaginal bleeding more than 12 months after menstruation has stopped because of the menopause).
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for endometrial cancer in women aged under 55 with post‑menopausal bleeding.
Consider a direct access ultrasound scan to assess for endometrial cancer in women aged 55 and over with:
unexplained symptoms of vaginal discharge who:
are presenting with these symptoms for the first time or
have thrombocytosis or
report haematuria, or
visible haematuria and:
low haemoglobin levels or
thrombocytosis, or
high blood glucose levels.
## Cervical cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for women if, on examination, the appearance of their cervix is consistent with cervical cancer.
## Vulval cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for vulval cancer in women with an unexplained vulval lump, ulceration or bleeding.
## Vaginal cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for vaginal cancer in women with an unexplained palpable mass in or at the entrance to the vagina.
# Urological cancers
## Prostate cancer
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for prostate cancer if their prostate feels malignant on digital rectal examination.
Consider a prostate‑specific antigen (PSA) test and digital rectal examination to assess for prostate cancer in people with:
any lower urinary tract symptoms, such as nocturia, urinary frequency, hesitancy, urgency or retention or
erectile dysfunction or
visible haematuria.
Consider referring people with possible symptoms of prostate cancer, as specified in recommendation 1.6.2, using a suspected cancer pathway referral (for an appointment within 2 weeks) for prostate cancer if their PSA levels are above the threshold for their age in table 1. Take into account the person's preferences and any comorbidities when making the decision.
Age (years)
Prostate-specific antigen threshold (micrograms/litre)
Below 40
Use clinical judgement
to 49
More than 2.5
to 59
More than 3.5
to 69
More than 4.5
to 79
More than 6.5
Above 79
Use clinical judgement
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on PSA testing for prostate cancer .
Full details of the evidence and the committee's discussion are in evidence review A: PSA testing for prostate cancer.
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## Bladder cancer
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for bladder cancer if they are:
aged 45 and over and have:
unexplained visible haematuria without urinary tract infection or
visible haematuria that persists or recurs after successful treatment of urinary tract infection, or
aged 60 and over and have unexplained non‑visible haematuria and either dysuria or a raised white cell count on a blood test.
Consider non-urgent referral for bladder cancer in people aged 60 and over with recurrent or persistent unexplained urinary tract infection.
## Renal cancer
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for renal cancer if they are aged 45 and over and have:
unexplained visible haematuria without urinary tract infection or
visible haematuria that persists or recurs after successful treatment of urinary tract infection.
## Testicular cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for testicular cancer in men if they have a non‑painful enlargement or change in shape or texture of the testis.
Consider a direct access ultrasound scan for testicular cancer in men with unexplained or persistent testicular symptoms.
## Penile cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for penile cancer in men if they have:
a penile mass or ulcerated lesion, when a sexually transmitted infection has been excluded as a cause, or
a persistent penile lesion after treatment for a sexually transmitted infection has been completed.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for penile cancer in men with unexplained or persistent symptoms affecting the foreskin or glans.
# Skin cancers
## Malignant melanoma of the skin
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) for melanoma if they have a suspicious pigmented skin lesion with a weighted 7‑point checklist score of 3 or more.
Major features of the lesions (scoring 2 points each):
change in size
irregular shape
irregular colour.
Minor features of the lesions (scoring 1 point each):
largest diameter 7 mm or more
inflammation
-ozing
change in sensation.
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) if dermoscopy suggests melanoma of the skin.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for melanoma in people with a pigmented or non‑pigmented skin lesion that suggests nodular melanoma.
## Squamous cell carcinoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for people with a skin lesion that raises the suspicion of squamous cell carcinoma.
## Basal cell carcinoma
Consider routine referral for people if they have a skin lesion that raises the suspicion of a basal cell carcinoma. (Typical features of basal cell carcinoma include: an ulcer with a raised rolled edge; prominent fine blood vessels around a lesion; or a nodule on the skin .)
Only consider a suspected cancer pathway referral (for an appointment within 2 weeks) for people with a skin lesion that raises the suspicion of a basal cell carcinoma if there is particular concern that a delay may have a significant impact, because of factors such as lesion site or size.
Follow NICE's guidance on improving outcomes for people with skin tumours including melanoma for advice on who should excise suspected basal cell carcinomas.
# Head and neck cancers
## Laryngeal cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for laryngeal cancer in people aged 45 and over with:
persistent
unexplained hoarseness or
an unexplained lump in the neck.
## Oral cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for oral cancer in people with either:
unexplained ulceration in the oral cavity lasting for more than 3 weeks or
a persistent and unexplained lump in the neck.
Consider an urgent referral (for an appointment within 2 weeks) for assessment for possible oral cancer by a dentist in people who have either:
a lump on the lip or in the oral cavity or
a red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia.
Consider a suspected cancer pathway referral by the dentist (for an appointment within 2 weeks) for oral cancer in people when assessed by a dentist as having either:
a lump on the lip or in the oral cavity consistent with oral cancer or
a red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia.
## Thyroid cancer
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for thyroid cancer in people with an unexplained thyroid lump.
# Brain and central nervous system cancers
## Adults
Consider an urgent, direct access, MRI scan of the brain (or CT scan if MRI is contraindicated; to be done within 2 weeks) to assess for brain or central nervous system cancer in adults with progressive, sub‑acute loss of central neurological function.
## Children and young people
Consider a very urgent referral (for an appointment within 48 hours) for suspected brain or central nervous system cancer in children and young people with newly abnormal cerebellar or other central neurological function.
# Haematological cancers
## Leukaemia in adults
Consider a very urgent full blood count (within 48 hours) to assess for leukaemia in adults with any of the following:
pallor
persistent fatigue
unexplained fever
unexplained persistent or recurrent infection
generalised lymphadenopathy
unexplained bruising
unexplained bleeding
unexplained petechiae
hepatosplenomegaly.
## Leukaemia in children and young people
Refer children and young people for immediate specialist assessment for leukaemia if they have unexplained petechiae or hepatosplenomegaly.
Offer a very urgent full blood count (within 48 hours) to assess for leukaemia in children and young people with any of the following:
pallor
persistent fatigue
unexplained fever
unexplained persistent infection
generalised lymphadenopathy
persistent or unexplained bone pain
unexplained bruising
unexplained bleeding.
## Myeloma
Offer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate to assess for myeloma in people aged 60 and over with persistent bone pain, particularly back pain, or unexplained fracture.
Offer very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48 hours) to assess for myeloma in people aged 60 and over with hypercalcaemia or leukopenia and a presentation that is consistent with possible myeloma.
Consider very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48 hours) to assess for myeloma if the plasma viscosity or erythrocyte sedimentation rate and presentation are consistent with possible myeloma.
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks) if the results of protein electrophoresis or a Bence–Jones protein urine test suggest myeloma.
## Non-Hodgkin's lymphoma
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for non‑Hodgkin's lymphoma in adults presenting with unexplained lymphadenopathy or splenomegaly. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss.
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment for non‑Hodgkin's lymphoma in children and young people presenting with unexplained lymphadenopathy or splenomegaly. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss.
## Hodgkin's lymphoma
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for Hodgkin's lymphoma in adults presenting with unexplained lymphadenopathy. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus, weight loss or alcohol‑induced lymph node pain.
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment for Hodgkin's lymphoma in children and young people presenting with unexplained lymphadenopathy. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss.
# Sarcomas
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements.
## Bone sarcoma in adults
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for adults if an X‑ray suggests the possibility of bone sarcoma.
## Bone sarcoma in children and young people
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment for children and young people if an X‑ray suggests the possibility of bone sarcoma.
Consider a very urgent direct access X‑ray (to be done within 48 hours) to assess for bone sarcoma in children and young people with unexplained bone swelling or pain.
## Soft tissue sarcoma in adults
Consider an urgent direct access ultrasound scan (to be done within 2 weeks) to assess for soft tissue sarcoma in adults with an unexplained lump that is increasing in size.
Consider a suspected cancer pathway referral (for an appointment within 2 weeks) for adults if they have ultrasound scan findings that are suggestive of soft tissue sarcoma or if ultrasound findings are uncertain and clinical concern persists.
## Soft tissue sarcoma in children and young people
Consider a very urgent direct access ultrasound scan (to be done within 48 hours) to assess for soft tissue sarcoma in children and young people with an unexplained lump that is increasing in size.
Consider a very urgent referral (for an appointment within 48 hours) for children and young people if they have ultrasound scan findings that are suggestive of soft tissue sarcoma or if ultrasound findings are uncertain and clinical concern persists.
# Childhood cancers
NICE has published a guideline on babies, children and young people's experience of healthcare.
## Neuroblastoma
Consider very urgent referral (for an appointment within 48 hours) for specialist assessment for neuroblastoma in children with a palpable abdominal mass or unexplained enlarged abdominal organ.
## Retinoblastoma
Consider urgent referral (for an appointment within 2 weeks) for ophthalmological assessment for retinoblastoma in children with an absent red reflex. If there is new-onset squint that occurs together with an absent red reflex, see the recommendation on new-onset squint with loss of red reflex in NICE's guideline on suspected neurological conditions.
## Wilms' tumour
Consider very urgent referral (for an appointment within 48 hours) for specialist assessment for Wilms' tumour in children with any of the following:
a palpable abdominal mass
an unexplained enlarged abdominal organ
unexplained visible haematuria.
# Non-site-specific symptoms
Some symptoms or symptom combinations may be features of several different cancers. For some of these symptoms, the risk for each individual cancer may be low but the total risk of cancer of any type may be higher. This section includes recommendations for these symptoms.
## Symptoms of concern in children and young people
Take into account the insight and knowledge of parents and carers when considering making a referral for suspected cancer in a child or young person. Consider referral for children if their parent or carer has persistent concern or anxiety about the child's symptoms, even if the symptoms are most likely to have a benign cause.
## Symptoms of concern in adults
For people with unexplained weight loss, which is a symptom of several cancers including colorectal, gastro‑oesophageal, lung, prostate, pancreatic and urological cancer:
carry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely and
-ffer urgent investigation or a suspected cancer pathway referral (for an appointment within 2 weeks).
For people with unexplained appetite loss, which is a symptom of several cancers including lung, oesophageal, stomach, colorectal, pancreatic, bladder and renal cancer:
carry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely and
-ffer urgent investigation or a suspected cancer pathway referral (for an appointment within 2 weeks).
For people with deep vein thrombosis, which is associated with several cancers including urogenital, breast, colorectal and lung cancer:
carry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely and
consider urgent investigation or a suspected cancer pathway referral (for an appointment within 2 weeks). # Recommendations on patient support, safety netting and the diagnostic process
Use this guideline to guide referrals. If still uncertain about whether a referral is needed, consider contacting a specialist (see the recommendations on the diagnostic process). Consider a review for people with any symptom associated with increased cancer risk who do not meet the criteria for referral or investigative action (see the recommendations on safety netting).
# Patient information and support
Discuss with people with suspected cancer (and their carers as appropriate, taking account of the need for confidentiality) their preferences for being involved in decision‑making about referral options and further investigations including their potential risks and benefits.
When cancer is suspected in a child, discuss the referral decision and information to be given to the child with the parents or carers (and the child if appropriate).
Explain to people who are being referred with suspected cancer that they are being referred to a cancer service. Reassure them, as appropriate, that most people referred will not have a diagnosis of cancer, and discuss alternative diagnoses with them.
Give the person information on the possible diagnosis (both benign and malignant) in accordance with their wishes for information (see also NICE's guideline on patient experience in adult NHS services).
The information given to people with suspected cancer and their families and/or carers should cover, among other issues:
where the person is being referred to
how long they will have to wait for the appointment
how to obtain further information about the type of cancer suspected or help before the specialist appointment
what to expect from the service the person will be attending
what type of tests may be carried out, and what will happen during diagnostic procedures
how long it will take to get a diagnosis or test results
whether they can take someone with them to the appointment
who to contact if they do not receive confirmation of an appointment
-ther sources of support.
Provide information that is appropriate for the person in terms of language, ability and culture, recognising the potential for different cultural meanings associated with the possibility of cancer.
Have information available in a variety of formats on both local and national sources of information and support for people who are being referred with suspected cancer. For more information on information sharing, see the section on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services.
Reassure people in the safety netting group (see recommendation 1.15.2) who are concerned that they may have cancer that with their current symptoms their risk of having cancer is low.
Explain to people who are being offered safety netting (see recommendation 1.15.2) which symptoms to look out for and when they should return for re‑evaluation. It may be appropriate to provide written information.
When referring a person with suspected cancer to a specialist service, assess their need for continuing support while waiting for their referral appointment. This should include inviting the person to contact their healthcare professional again if they have more concerns or questions before they see a specialist.
If the person has additional support needs because of their personal circumstances, inform the specialist (with the person's agreement).
# Safety netting
Ensure that the results of investigations are reviewed and acted upon appropriately, with the healthcare professional who ordered the investigation taking or explicitly passing on responsibility for this. Be aware of the possibility of false‑negative results for chest X‑rays and tests for occult blood in faeces.
Consider a review for people with any symptom that is associated with an increased risk of cancer, but who do not meet the criteria for referral or other investigative action. The review may be:
planned within a time frame agreed with the person or
patient‑initiated if new symptoms develop, the person continues to be concerned, or their symptoms recur, persist or worsen.
# The diagnostic process
Take part in continuing education, peer review and other activities to improve and maintain clinical consulting, reasoning and diagnostic skills, in order to identify at an early stage people who may have cancer, and to communicate the possibility of cancer to the person.
Discussion with a specialist (for example, by telephone or email) should be considered if there is uncertainty about the interpretation of symptoms and signs, and whether a referral is needed. This may also enable the primary healthcare professional to communicate their concerns and a sense of urgency to secondary healthcare professionals when symptoms are not classical.
Put in place local arrangements to ensure that letters about non-urgent referrals are assessed by the specialist, so that the person can be seen more urgently if necessary.
Put in place local arrangements to ensure that there is a maximum waiting period for non‑urgent referrals, in accordance with national targets and local arrangements.
Ensure local arrangements are in place to identify people who miss their appointments so that they can be followed up.
Include all appropriate information in referral correspondence, including whether the referral is urgent or non‑urgent.
Use local referral proformas if these are in use.
Once the decision to refer has been made, make sure that the referral is made within 1 working day. # Recommendations organised by symptom and findings of primary care investigations
The recommendations in this section are displayed alphabetically by symptom then in order of urgency of the action needed, to make sure that the most urgent actions are not missed. Where there are several recommendations relating to the same cancer these have been grouped for ease of reference. Occasionally the same symptom may suggest more than one cancer site. In such instances the recommendations are displayed together and the GP should use their clinical judgement to decide on the most appropriate action.
Use this guideline to guide referrals. If still uncertain about whether a referral is needed, consider contacting a specialist (see the recommendations on the diagnostic process). Consider a review for people with any symptom associated with increased cancer risk who do not meet the criteria for referral or investigative action (see the recommendations on safety netting).
# Abdominal symptoms
See also the section on bleeding for recommendations on rectal bleeding.
Symptom and specific features
Possible cancer
Recommendation
Abdominal distension (persistent or frequent – particularly more than 12 times per month) in women, especially if 50 and over
Ovarian
Carry out tests in primary care
Measure serum CA125 in primary care
See the section on primary care investigations for more information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
Symptoms and signs
Possible cancer
Recommendation
Ascites and/or a pelvic or abdominal mass identified by physical examination (which is not obviously uterine fibroids) in women
Ovarian
Urgent referral
These recommendations apply to women aged 18 and over
Symptom and specific features
Possible cancer
Recommendation
Abdominal or pelvic mass identified by physical examination (which is not obviously uterine fibroids) in women
Ovarian
Urgent referral
These recommendations apply to women aged 18 and over
Abdominal or rectal mass
Colorectal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Splenomegaly (unexplained) in adults
Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Upper abdominal mass
consistent with stomach cancer
Stomach
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Upper abdominal mass consistent with an enlarged gall bladder
Gall bladder
Consider an urgent direct access ultrasound scan (to be done within 2 weeks)
Upper abdominal mass consistent with an enlarged liver
Liver
Consider an urgent direct access ultrasound scan (to be done within 2 weeks)
Hepatosplenomegaly
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Abdominal pain with weight loss (unexplained), 40 and over
Colorectal
Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks)
Abdominal pain (unexplained) with rectal bleeding in adults under 50
Colorectal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Abdominal pain (unexplained) without rectal bleeding, 50 and over
Colorectal
Offer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care)
Upper abdominal pain with weight loss, 55 and over
Oesophageal or stomach
Offer urgent direct access upper gastrointestinal endoscopy (to be done within 2 weeks)
Upper abdominal pain with low haemoglobin levels or raised platelet count or nausea or vomiting, 55 and over
Oesophageal or stomach
Consider non‑urgent direct access upper gastrointestinal endoscopy
Abdominal or pelvic pain (persistent or frequent – particularly more than 12 times per month) in women, especially if 50 and over
Ovarian
Carry out tests in primary care
Measure serum CA125 in primary care
See the section on primary care investigations for more information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
Abdominal pain with weight loss, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available
Irritable bowel syndrome symptoms within the last 12 months in women 50 and over
Ovarian
Carry out appropriate tests for ovarian cancer, because irritable bowel syndrome rarely presents for the first time in women of this age
Measure serum CA125 in primary care
See the section on primary care investigations for more information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
Also see the NICE guideline on irritable bowel syndrome in adults.
Symptom and specific features
Possible cancer
Recommendation
Change in bowel habit (unexplained), 60 and over
Colorectal
Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks)
Change in bowel habit (unexplained) with rectal bleeding, in adults under 50
Colorectal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Change in bowel habit without rectal bleeding, adults under 60
Colorectal
Offer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care)
Change in bowel habit (unexplained) in women
Ovarian
Consider carrying out tests in primary care
Measure serum CA125 in primary care
See the section on primary care investigations for information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
Diarrhoea or constipation with weight loss, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available
Irritable bowel syndrome symptoms within the last 12 months, in women 50 and over
Ovarian
Carry out appropriate tests for ovarian cancer, because irritable bowel syndrome rarely presents for the first time in women of this age
Measure serum CA125 in primary care
See the section on primary care investigations for more information about tests for ovarian cancer
These recommendations apply to women aged 18 and over
Also see the NICE guideline on irritable bowel syndrome in adults
Symptom and specific features
Possible cancer
Recommendation
Dyspepsia (treatment‑resistant), 55 and over
Oesophageal or stomach
Consider non‑urgent direct access upper gastrointestinal endoscopy
Dyspepsia
Dyspepsia with weight loss, 55 and over
Oesophageal or stomach
Offer urgent direct access upper gastrointestinal endoscopy (to be done within 2 weeks)
Dyspepsia with raised platelet count or nausea or vomiting, 55 and over
Oesophageal or stomach
Consider non‑urgent direct access upper gastrointestinal endoscopy
Symptom and specific features
Possible cancer
Recommendation
Dysphagia
Oesophageal or stomach
Offer urgent direct access upper gastrointestinal endoscopy (to be done within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Nausea or vomiting with weight loss, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available
Nausea or vomiting with raised platelet count or weight loss or reflux or dyspepsia or upper abdominal pain, 55 and over
Oesophageal or stomach
Consider non‑urgent direct access upper gastrointestinal endoscopy
Symptom and signs
Possible cancer
Recommendation
Prostate feels malignant on digital rectal examination, in men
Prostate
Refer men using a suspected cancer pathway referral (for an appointment within 2 weeks)
Anal mass or anal ulceration (unexplained)
Anal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Rectal
mass
Colorectal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Reflux with weight loss, 55 and over
Oesophageal or stomach
Offer urgent direct access upper gastrointestinal endoscopy (to be done within 2 weeks)
Reflux with raised platelet count or nausea or vomiting, 55 and over
Oesophageal or stomach
Consider non‑urgent direct access upper gastrointestinal endoscopy
# Bleeding
See also:
the section on urological symptoms for haematuria
the section on primary care investigations for faecal occult blood.
Symptom and specific features
Possible cancer
Recommendation
Bleeding, bruising or petechiae (unexplained)
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Haematemesis
Oesophageal or stomach
Consider non-urgent, direct access upper gastrointestinal endoscopy
Symptom and specific features
Possible cancer
Recommendation
Haemoptysis (unexplained), 40 and over
Lung
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Post‑menopausal bleeding in women 55 and over
Endometrial
Refer women using a suspected cancer pathway referral (for an appointment within 2 weeks)
Post‑menopausal bleeding in women under 55
Endometrial
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Post‑menopausal bleeding is unexplained vaginal bleeding more than 12 months after menstruation has stopped because of the menopause.
Symptom and specific features
Possible cancer
Recommendation
Rectal bleeding (unexplained), 50 and over
Colorectal
Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks)
Rectal bleeding with abdominal pain or change in bowel habit or weight loss or iron‑deficiency anaemia in adults under 50
Colorectal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Vulval bleeding (unexplained) in women
Vulval
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
# Gynaecological symptoms
See also the section on bleeding for post‑menopausal (vaginal) bleeding
Symptom and signs
Possible cancer
Recommendation
Appearance of cervix
consistent with cervical cancer
Cervical
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Vaginal discharge (unexplained) either at first presentation or with thrombocytosis or with haematuria, in women 55 and over
Endometrial
Consider a direct access ultrasound scan
Vaginal mass (unexplained and palpable) in or at the entrance to the vagina
Vaginal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Vulval bleeding (unexplained)
Vulval
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Vulval lump or ulceration (unexplained)
Vulval
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
# Lumps or masses
Symptom and specific features
Possible cancer
Recommendation
Anal mass (unexplained)
Anal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Axillary lump (unexplained), 30 and over
Breast
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Breast lump (unexplained) with or without pain, 30 and over
Breast
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Breast lump (unexplained) with or without pain, under 30
Breast
Consider non-urgent referral
See also recommendations 1.16.2 and 1.16.3 for information about seeking specialist advice
Lip or oral cavity
lump
Oral
Consider an urgent referral (for an appointment within 2 weeks) for assessment by a dentist
Consider a suspected cancer pathway referral by the dentist (for an appointment within 2 weeks) in people when assessed by a dentist as having a lump on the lip or in the oral cavity consistent with oral cancer
Lump (unexplained) that is increasing in size in adults
Soft tissue sarcoma
Consider an urgent direct access ultrasound scan (to be done within 2 weeks)
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Neck lump (unexplained), 45 and over
Laryngeal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Neck lump (persistent and unexplained)
Oral
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Penile mass (and sexually transmitted infection has been excluded as a cause) in men
Penile
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Thyroid lump (unexplained)
Thyroid
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Vaginal mass (unexplained and palpable) in or at the entrance to the vagina in women
Vaginal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Vulval lump (unexplained) in women
Vulval
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
See also the section on abdominal symptoms for abdominal, anal, pelvic and rectal lumps or masses.
Symptom and specific features
Possible cancer
Recommendation
Lymphadenopathy (unexplained) in adults
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
When considering referral for Hodgkin's lymphoma, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus, weight loss or alcohol‑induced lymph node pain
When considering referral for non‑Hodgkin's lymphoma, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Lymphadenopathy (supraclavicular or persistent cervical), 40 and over
Lung
Consider an urgent chest X‑ray (to be done within 2 weeks)
Lymphadenopathy (generalised) in adults
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Ulceration in the oral cavity (unexplained and lasting for more than 3 weeks)
Oral
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Lip or oral cavity lump
Oral
Consider an urgent referral (for an appointment within 2 weeks) for assessment by a dentist
Consider a suspected cancer pathway referral by the dentist (for an appointment within 2 weeks) in people when assessed by a dentist as having a lump on the lip or in the oral cavity consistent with oral cancer
# Neurological symptoms in adults
Symptom and specific features
Possible cancer
Recommendation
Loss of central neurological function (progressive, sub‑acute) in adults
Brain or central nervous system
Consider an urgent direct access MRI scan of the brain (or CT scan if MRI is contraindicated; to be done within 2 weeks)
# Pain
See also the section on abdominal symptoms for abdominal or pelvic pain.
Symptom and specific features
Possible cancer
Recommendation
Alcohol‑induced lymph node pain with unexplained lymphadenopathy in adults
Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Back pain with weight loss, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available
Back pain (persistent), 60 and over
Myeloma
Offer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate
See the section on primary care investigations for more information on tests for myeloma
Bone pain (persistent), 60 and over
Myeloma
Offer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate to assess for myeloma
See the section on primary care investigations for more information on tests for myeloma
Chest pain (unexplained), 40 and over, ever smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Chest pain (unexplained), 40 and over, exposed to asbestos
Mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Chest pain (unexplained) with cough or fatigue or shortness of breath or weight loss or appetite loss (unexplained), 40 and over
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
# Respiratory symptoms
Symptom and specific features
Possible cancer
Recommendation
Chest infection (persistent or recurrent), 40 and over
Lung
Consider an urgent chest X‑ray (to be done within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Chest pain (unexplained), 40 and over, ever smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Chest pain (unexplained), 40 and over, exposed to asbestos
Mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Chest pain (unexplained) with cough or fatigue or shortness of breath or weight loss or appetite loss (unexplained), 40 and over
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Cough (unexplained), 40 and over, ever smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Cough (unexplained), 40 and over, exposed to asbestos
Mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Cough (unexplained) with fatigue or shortness of breath or chest pain or weight loss or appetite loss (unexplained), 40 and over
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Hoarseness (persistent and unexplained), 45 and over
Laryngeal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and signs
Possible cancer
Recommendation
Chest signs
consistent with lung cancer, 40 and over
Lung
Consider an urgent chest X‑ray (to be done within 2 weeks)
Chest signs compatible with pleural disease, 40 and over
Mesothelioma
Consider an urgent chest X‑ray (to be done within 2 weeks)
Finger clubbing, 40 and over
Lung or mesothelioma
Consider an urgent chest X‑ray (to be done within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Shortness of breath (unexplained), 40 and over, ever smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Shortness of breath (unexplained), 40 and over, and exposed to asbestos
Mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Shortness of breath with cough or fatigue or chest pain or weight loss or appetite loss (unexplained), 40 and over
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Shortness of breath with unexplained lymphadenopathy in adults
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Shortness of breath with unexplained splenomegaly in adults
Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
# Skeletal symptoms
Symptom and specific features
Possible cancer
Recommendation
Back pain with weight loss, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available
Back pain (persistent), 60 and over
Myeloma
Offer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate
See the section on primary care investigations for more information on tests for myeloma
Symptom and specific features
Possible cancer
Recommendation
Bone pain (persistent), 60 and over
Myeloma
Offer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate to assess for myeloma
See the section on primary care investigations for more information on tests for myeloma
Symptom and specific features
Possible cancer
Recommendation
Fracture (unexplained), 60 and over
Myeloma
Offer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate
See the section on primary care investigations for more information on tests for myeloma
# Skin or surface symptoms
See also the section on lumps or masses for oral lesions.
Symptoms and signs
Possible cancer
Recommendation
Anal ulceration (unexplained)
Anal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Bruising (unexplained) in adults
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Nipple changes of concern (in one nipple only) including discharge and retraction, 50 and over
Breast
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Oral cavity red or red and white patch
consistent with erythroplakia or erythroleukoplakia
Oral
Consider urgent referral (for an appointment within 2 weeks) for assessment by a dentist
Consider a suspected cancer pathway referral by the dentist (for an appointment within 2 weeks) for people when assessed by a dentist as having a red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia
Pallor
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Penile lesion (ulcerated and sexually transmitted infection has been excluded, or persistent after treatment for a sexually transmitted infection has been completed) in men
Penile
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Penile mass (and sexually transmitted infection has been excluded as a cause) in men
Penile
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Penile symptoms
affecting the foreskin or glans (unexplained or persistent) in men
Penile
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Petechiae (unexplained) in adults
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Pruritus with unexplained splenomegaly in adults
Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Pruritus with unexplained lymphadenopathy in adults
Hodgkin's lymphoma or non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Skin changes that suggest breast cancer
Breast
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Skin lesion (pigmented and suspicious) with a weighted 7‑point checklist score of 3 or more
Melanoma
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Skin lesion (pigmented or non‑pigmented) that suggests nodular melanoma
Melanoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Skin lesion that raises the suspicion of a squamous cell carcinoma
Squamous cell carcinoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Skin lesion that raises the suspicion of a basal cell carcinoma
Basal cell carcinoma
Consider routine referral
Only consider a suspected cancer pathway referral (for an appointment within 2 weeks) if there is particular concern that a delay may have a significant impact, because of factors such as lesion site or size
Typical features of basal cell carcinoma include: an ulcer with a raised rolled edge; prominent fine blood vessels around a lesion; or a nodule on the skin (particularly pearly or waxy nodules)
Vulval lump or ulceration (unexplained) in women
Vulval
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
# Urological symptoms
Symptom and specific features
Possible cancer
Recommendation
Dysuria with unexplained non‑visible haematuria, 60 and over
Bladder
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Erectile dysfunction in men
Prostate
Consider a prostate‑specific antigen (PSA) test and digital rectal examination
See the section on primary care investigations for more information on PSA tests and digital rectal examination
Symptom and specific features
Possible cancer
Recommendation
Haematuria (visible and unexplained) either without urinary tract infection or that persists or recurs after successful treatment of urinary tract infection, 45 and over
Bladder or renal
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Haematuria (non‑visible and unexplained) with dysuria or raised white cell count on a blood test, 60 and over
Bladder
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Haematuria (visible) with low haemoglobin levels or thrombocytosis or high blood glucose levels or unexplained vaginal discharge in women 55 and over
Endometrial
Consider a direct access ultrasound scan
Haematuria (visible) in men
Prostate
Consider a prostate‑specific antigen (PSA) test and digital rectal examination
See the section on primary care investigations for more information on PSA tests and digital rectal examination
Symptom and specific features
Possible cancer
Recommendation
Testis enlargement or change in shape or texture (non‑painful) in men
Testicular
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Testicular symptoms (unexplained or persistent) in men
Testicular
Consider a direct access ultrasound scan
Symptom and specific features
Possible cancer
Recommendation
Urinary tract infection (unexplained and recurrent or persistent), 60 and over
Bladder
Consider non-urgent referral for bladder cancer in people aged 60 and over with recurrent or persistent unexplained urinary tract infection
Lower urinary tract symptoms, such as nocturia, urinary frequency, hesitancy, urgency or retention in men
Prostate
Consider a prostate‑specific antigen (PSA) test and digital rectal examination
See the section on primary care investigations for more information on PSA tests and digital rectal examination
Urinary urgency or frequency (increased and persistent or frequent – particularly more than 12 times per month) in women, especially if 50 and over
Ovarian
Carry out tests in primary care
Measure serum CA125 in primary care
See the section on primary care investigations for information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
# Non‑specific features of cancer
Symptom and specific features
Possible cancer
Recommendation
Appetite loss (unexplained)
Several, including lung, oesophageal, stomach, colorectal, pancreatic, bladder or renal
Carry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely
Offer urgent investigation or a suspected cancer pathway referral (for an appointment within 2 weeks)
Appetite loss (unexplained), 40 and over, ever smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Appetite loss (unexplained), 40 and over, exposed to asbestos
Mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Appetite loss (unexplained) with cough or fatigue or shortness of breath or chest pain or weight loss (unexplained), 40 and over
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Appetite loss or early satiety (persistent or frequent – particularly more than 12 times per month) in women, especially if 50 and over
Ovarian
Carry out tests in primary care
Measure serum CA125 in primary care
See the section on primary care investigations for information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
Symptom and specific features
Possible cancer
Recommendation
Deep vein thrombosis
Several, including urogenital, breast, colorectal and lung
Carry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely
Consider urgent investigation or a suspected cancer pathway referral (for an appointment within 2 weeks)
Symptom and specific features
Possible cancer
Recommendation
Diabetes (new onset) with weight loss, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or urgent ultrasound scan if CT is not available
Symptom and specific features
Possible cancer
Recommendation
Fatigue (unexplained), 40 and over, ever smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Fatigue (unexplained), 40 and over, exposed to asbestos
Mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Fatigue with cough or shortness of breath or chest pain or weight loss or appetite loss (unexplained), 40 and over
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Fatigue (persistent) in adults
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Fatigue (unexplained) in women
Ovarian
Carry out tests in primary care
Measure serum CA125 in primary care
See the section on primary care investigations for information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
Symptom and specific features
Possible cancer
Recommendation
Fever (unexplained)
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Fever with unexplained splenomegaly in adults
Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Fever with unexplained lymphadenopathy in adults
Hodgkin's lymphoma or non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
See also the section on respiratory symptoms for chest infection.
Symptom and specific features
Possible cancer
Recommendation
Infection (unexplained and persistent or recurrent) in adults
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Night sweats with unexplained splenomegaly in adults
Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Night sweats with unexplained lymphadenopathy in adults
Hodgkin's lymphoma or Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Symptom and specific features
Possible cancer
Recommendation
Pallor
Leukaemia
Consider a very urgent full blood count (within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Pruritus with unexplained splenomegaly in adults
Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Pruritus with unexplained lymphadenopathy in adults
Hodgkin's lymphoma or non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Symptom and specific features
Possible cancer
Recommendation
Weight loss (unexplained)
Several, including colorectal, gastro‑oesophageal, lung, prostate, pancreatic or urological cancer
Carry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely
Offer urgent investigation or a suspected cancer pathway referral (for an appointment within 2 weeks)
Weight loss (unexplained) with abdominal pain, 40 and over
Colorectal
Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks)
Weight loss (unexplained) with rectal bleeding in adults under 50
Colorectal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Weight loss (unexplained) without rectal bleeding, 50 and over
Colorectal
Offer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care)
Weight loss (unexplained), 40 and over, ever smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Weight loss (unexplained), 40 and over, exposed to asbestos
Mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Weight loss with cough or fatigue or shortness of breath or chest pain or appetite loss (unexplained), 40 and over, never smoked
Lung or mesothelioma
Offer an urgent chest X‑ray (to be done within 2 weeks)
Weight loss with unexplained splenomegaly in adults
Non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Weight loss with unexplained lymphadenopathy in adults
Hodgkin's lymphoma or non‑Hodgkin's lymphoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks). When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Weight loss with upper abdominal pain or reflux or dyspepsia, 55 and over
Oesophageal or stomach
Offer urgent direct access upper gastrointestinal endoscopy (to be done within 2 weeks)
Weight loss (unexplained) in women
Ovarian
Consider carrying out tests in primary care
Measure serum CA125 in primary care
See the section on primary care investigations for information on tests for ovarian cancer
These recommendations apply to women aged 18 and over
Weight loss with diarrhoea or back pain or abdominal pain or nausea or vomiting or constipation or new‑onset diabetes, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available
Weight loss with raised platelet count or nausea or vomiting, 55 and over
Oesophageal or stomach
Consider non-urgent direct access upper gastrointestinal endoscopy
# Primary care investigations
Investigation findings and specific features
Possible cancer
Recommendation
Anaemia (iron‑deficiency), 60 and over
Colorectal
Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks)
Anaemia (iron‑deficiency, unexplained) with rectal bleeding in adults under 50
Colorectal
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Anaemia (iron deficiency) without rectal bleeding, adults under 60
Colorectal
Offer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care)
Anaemia (non-iron-deficiency), without rectal bleeding, 60 and over
Colorectal
Offer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care)
Blood glucose levels high with visible haematuria in women 55 and over
Endometrial
Consider a direct access ultrasound scan
Diabetes (new‑onset) with weight loss, 60 and over
Pancreatic
Consider an urgent direct access CT scan (to be done within 2 weeks), or an urgent ultrasound scan if CT is not available
Haemoglobin levels low with visible haematuria in women 55 and over
Endometrial
Consider a direct access ultrasound scan
Haemoglobin levels low with upper abdominal pain, 55 and over
Oesophageal or stomach
Consider non-urgent direct access upper gastrointestinal endoscopy
Hypercalcaemia or leukopenia and presentation consistent with possible myeloma, 60 and over
Myeloma
Offer very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48 hours)
Plasma viscosity or erythrocyte sedimentation rate and presentation consistent with possible myeloma
Myeloma
Consider very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48 hours)
Platelet count raised with nausea or vomiting or weight loss or reflux or dyspepsia or upper abdominal pain, 55 and over
Oesophageal or stomach
Consider non‑urgent direct access upper gastrointestinal endoscopy
Prostate‑specific antigen
levels above the age‑specific threshold in table 1 plus lower urinary tract symptoms such as nocturia, urinary frequency, hesitancy, urgency or retention or erectile dysfunction or visible haematuria
Prostate
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Protein electrophoresis suggests myeloma
Myeloma
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Serum CA125 results
Ovarian
If serum CA125 is 35 IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis
Normal serum CA125 (less than 35 IU/ml), or CA125 of 35 IU/ml or greater but a normal ultrasound:
assess her carefully for other clinical causes of her symptoms and investigate if appropriate
if no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent.
These recommendations apply to women aged 18 and over
Thrombocytosis, 40 and over
Lung
Consider an urgent chest X‑ray (to be done within 2 weeks)
Thrombocytosis with visible haematuria or vaginal discharge (unexplained) in women 55 and over
Endometrial
Consider a direct access ultrasound scan
White cell count raised on a blood test with unexplained non‑visible haematuria, 60 and over
Bladder
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Investigation findings and specific features
Possible cancer
Recommendation
Dermoscopy suggests melanoma of the skin
Melanoma
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Examination findings and specific features
Possible cancer
Recommendation
Prostate feels malignant on digital rectal examination
Prostate
Refer men using a suspected cancer pathway referral (for an appointment within 2 weeks)
Investigation findings and specific features
Possible cancer
Recommendation
Occult blood in faeces
Colorectal
Refer adults using a suspected cancer pathway referral (for an appointment within 2 weeks)
Investigation findings and specific features
Possible cancer
Recommendation
Chest X‑ray suggests lung cancer
Lung
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Chest X‑ray suggests mesothelioma
Mesothelioma
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Ultrasound suggests ovarian cancer
Ovarian
Make an urgent referral for further investigation
These recommendations apply to women aged 18 and over
Ultrasound normal with CA125 of 35 IU/ml or greater
Ovarian
Assess carefully for other clinical causes of her symptoms and investigate if appropriate
If no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent
These recommendations apply to women aged 18 and over
Ultrasound
suggests soft tissue sarcoma or is uncertain and clinical concern persists in adults
Soft tissue sarcoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
X‑ray suggests the possibility of bone sarcoma in adults
Bone sarcoma
Consider a suspected cancer pathway referral (for an appointment within 2 weeks)
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Investigation findings and specific features
Possible cancer
Recommendation
Jaundice, 40 and over
Pancreatic
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
Investigation findings and specific features
Possible cancer
Recommendation
Bence–Jones protein urine results suggest myeloma
Myeloma
Refer people using a suspected cancer pathway referral (for an appointment within 2 weeks)
# Symptoms in children and young people
Symptom and specific features
Possible cancer
Recommendation
Hepatosplenomegaly (unexplained) in children and young people
Leukaemia
Refer for immediate specialist assessment
Abdominal mass (palpable) or enlarged abdominal organ (unexplained) in children
Neuroblastoma or Wilms' tumour
Consider very urgent referral (for an appointment within 48 hours) for specialist assessment
Splenomegaly (unexplained) in children and young people
Non‑Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Symptom and specific features
Possible cancer
Recommendation
Petechiae (unexplained) in children and young people
Leukaemia
Refer for immediate specialist assessment
Bleeding or bruising (unexplained) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Lymphadenopathy (unexplained) in children and young people
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Lymphadenopathy (generalised) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Lump (unexplained) that is increasing in size in children and young people
Soft tissue sarcoma
Consider a very urgent direct access ultrasound scan (to be done within 48 hours)
See the section on primary care investigations for more information on ultrasound scans
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
See also the section on abdominal symptoms for abdominal mass or unexplained enlarged abdominal organ, splenomegaly and hepatosplenomegaly.
Symptom and specific features
Possible cancer
Recommendation
Newly abnormal cerebellar or other central neurological function in children and young people
Brain or central nervous system cancer
Consider a very urgent referral (for an appointment within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Shortness of breath with lymphadenopathy in children and young people
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Shortness of breath with splenomegaly (unexplained) in children and young people
Non‑Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Symptom and specific features
Possible cancer
Recommendation
Bone pain (persistent or unexplained) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Bone pain (unexplained) in children and young people
Bone sarcoma
Consider a very urgent direct access X‑ray (to be done within 48 hours)
See the section on primary care investigations for more information on X‑rays
Bone swelling (unexplained) in children and young people
Bone sarcoma
Consider a very urgent direct access X‑ray (to be done within 48 hours)
See the section on primary care investigations for more information on X‑rays
Symptom and specific features
Possible cancer
Recommendation
Petechiae (unexplained) in children and young people
Leukaemia
Refer for immediate specialist assessment
Bruising (unexplained) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Pallor in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Symptom and specific features
Possible cancer
Recommendation
Haematuria (visible and unexplained) in children
Wilms' tumour
Consider very urgent referral (for an appointment within 48 hours) for specialist assessment
Symptom and specific features
Possible cancer
Recommendation
Fatigue (persistent) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Fever with lymphadenopathy (unexplained) in children and young people
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Fever with splenomegaly (unexplained) in children and young people
Non‑Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Fever (unexplained) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Infection (unexplained and persistent) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Lymphadenopathy (unexplained) in children and young people
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Lymphadenopathy (generalised) in children and young people
Leukaemia
Offer a very urgent full blood count (within 48 hours)
Night sweats with lymphadenopathy (unexplained) in children and young people
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Night sweats with splenomegaly (unexplained) in children and young people
Non‑Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Pruritus with lymphadenopathy (unexplained) in children and young people
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Pruritus with splenomegaly (unexplained) in children and young people
Non‑Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Weight loss with lymphadenopathy (unexplained) in children and young people
Non‑Hodgkin's lymphoma or Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment in children and young people. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Weight loss with splenomegaly (unexplained) in children and young people
Non‑Hodgkin's lymphoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment. When considering referral, take into account any associated symptoms
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
Examination findings and specific features
Possible cancer
Recommendation
Absent red reflex in children
Retinoblastoma
Consider urgent referral (for an appointment within 2 weeks) for ophthalmological assessment
Symptom and specific features
Possible cancer
Recommendation
Parental or carer insight, concern or anxiety about the child's or young person's symptoms (persistent)
Childhood cancer
Take into account the insight and knowledge of parents and carers when considering making a referral for suspected cancer in a child or young person
Consider referral for children if their parent or carer has persistent concern or anxiety about the child's symptoms, even if the symptoms are most likely to have a benign cause
Symptom and specific features
Possible cancer
Recommendation
Ultrasound scan suggests soft tissue sarcoma or is uncertain and clinical concern persists in children and young people
Soft tissue sarcoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements
X‑ray suggests the possibility of bone sarcoma in children and young people
Bone sarcoma
Consider a very urgent referral (for an appointment within 48 hours) for specialist assessment
Separate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16 to 24) may be referred using either pathway depending on their age and local arrangements# Terms used in this guideline
# Children
From birth to 15 years.
# Children and young people
From birth to 24 years.
# Consistent with
The finding has characteristics that could be caused by many things, including cancer.
# Direct access
When a test is done and primary care retain clinical responsibility throughout, including acting on the result.
# Immediate
An acute admission or referral occurring within a few hours, or even more quickly if necessary.
# Non‑urgent
The timescale generally used for a referral or investigation that is not considered very urgent or urgent.
# Persistent
The continuation of specified symptoms and/or signs beyond a period that would normally be associated with self‑limiting problems. The precise period will vary depending on the severity of symptoms and associated features, as assessed by the health professional.
# Raises the suspicion of
A mass or lesion that has an appearance or a feel that makes the healthcare professional believe cancer is a significant possibility.
# Safety netting
The active monitoring in primary care of people who have presented with symptoms. It has 2 separate aspects:
timely review and action after investigations
active monitoring of symptoms in people at low risk (but not no risk) of having cancer to see if their risk of cancer changes.
# Suspected cancer pathway referral
The patient is seen within the national target for cancer referrals (2 weeks at the time of publication of this guideline).
# Unexplained
Symptoms or signs that have not led to a diagnosis being made by the healthcare professional in primary care after initial assessment (including history, examination and any primary care investigations).
# Urgent
To happen or be done before 2 weeks. An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2 weeks.
# Very urgent
To happen within 48 hours.
# Young people
Aged 16 to 24 years.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Age thresholds in cancer
Longitudinal studies should be carried out to identify and quantify factors in adults that are associated with development of specific cancers at a younger age than the norm. They should be designed to inform age thresholds in clinical guidance. The primary outcome should be likelihood ratios and positive predictive values for cancer occurring in younger age groups.
## Primary care testing
Diagnostic accuracy studies of tests accessible to primary care should be carried out for a given cancer in symptomatic people. Priority areas for research should include tests for people with cough, non-visible haematuria, suspected prostate cancer, suspected pancreatic cancer, suspected cancer in childhood and young people and other suspected rare cancers. Outcomes of interest are the performance characteristics of the test, particularly sensitivity, specificity and positive and negative predictive values.
## Cancers insufficiently researched in primary care
Observational studies of symptomatic primary care patients should be used to estimate the positive predictive value of different symptoms for specific cancers. Priority areas for research are those where the evidence base is currently insufficient and should include prostate cancer, pancreatic cancer, cancer in childhood and young people and other rare cancers. Outcomes of interest are positive predictive values and likelihood ratios for cancer.
## Patient experience
Qualitative studies are needed to assess the key issues in patient experience and patient information needs in the cancer diagnostic pathway, particularly in the interval between first presentation to primary care and first appointment in secondary care. Outcomes of interest are patient satisfaction, quality of life and patient perception of the quality of care and information.
## Prostate-specific antigen testing
What is the diagnostic accuracy of using age-adjusted and fixed prostate-specific antigen thresholds for people with symptoms of prostate cancer, including those at high risk of developing prostate cancer (such as those with an African family background or a family history of prostate cancer)?
For a short explanation of why the committee made the recommendation for research see the rationale section on prostate-specific antigen testing for prostate cancer .
Full details of the evidence and the committee's discussion are in evidence review A: PSA testing for prostate cancer.
Loading. Please wait.# Rationale and impact
This section briefly explains why the committee made the recommendation and how it might affect practice.
# Prostate-specific antigen testing for prostate cancer
Recommendation 1.6.3
## Why the committee made the recommendation
The evidence on the diagnostic accuracy of fixed and age-specific prostate-specific antigen (PSA) thresholds was very uncertain because all of the studies were based on a population that had already been referred to secondary care. The 2019 guideline recommended referral if PSA levels were above the age-specific reference range. The committee agreed that referral should be considered based on PSA thresholds, but did not make a stronger recommendation because of the uncertainty in the evidence and the likely low positive predictive value of the PSA test for prevalence estimates based on UK population data. The committee noted that many prostate cancers are slow growing and might never impact a person's life expectancy. Some people might choose not to be referred to secondary care to avoid invasive investigations and treatment that might not benefit them. Therefore, the committee agreed that a patient-centred approach to referral is important, and recommended that the person's preferences and any comorbidities should be taken into account.
The committee agreed that more research is needed in this area to better understand the most appropriate thresholds that should prompt referral to secondary care for each age group. The committee noted that ethnicity and family history are important factors that affect the risk of prostate cancer. Therefore, they recommended that the data from research be stratified by these factors to determine whether different PSA levels should prompt referral in these groups. Research in this area may also help to address health inequalities in prostate cancer diagnosis and outcomes in the UK.
There was no strong evidence to differentiate between using age-specific or fixed PSA thresholds. The committee also noted that no cost-effectiveness evidence comparing age-specific thresholds with fixed thresholds was identified. However, because PSA levels increase naturally with age, the committee agreed a lower fixed PSA threshold would detect more cases of prostate cancer but also lead to unnecessary biopsies and overtreatment in some age groups. This would also be likely to result in more referrals to secondary care and have a significant impact on NHS resources. The committee therefore recommended the use of age-specific thresholds, which are already established in current practice and were recommended in the previous version of the guideline. Because of regional variations in practice (particularly in the 50 to 69 age range), the committee decided to define the age-specific PSA thresholds. The committee agreed that the thresholds used in the reviewed studies on people with symptoms of possible prostate cancer should be used in the absence of evidence to support alternative values, because these studies were most applicable to the population that the recommendation applies to. No evidence was available specifically for people under 40 or over 79, and so the committee recommended that clinical judgement is used when deciding whether to refer people in these groups to secondary care.
## How the recommendation might affect practice
Referral based on age-specific PSA thresholds is already recommended, so practice should not change significantly. Also, clarifying the age-specific thresholds will help standardise care. Taking into account patient preferences and comorbidities should also lead to a more patient-centred approach to referral.
Return to recommendation# Context
Cancer has an enormous impact, both in terms of the number of people affected by it and the individual impact it has on people with cancer and those close to them. More than 300,000 new cancers (excluding skin cancers) are diagnosed annually in the UK, across over 200 different cancer types. Each of these cancer types has different presenting features, though they sometimes overlap. Approximately one‑third of the population will develop a cancer in their lifetime. There is considerable variation in referral and testing for possible cancer, which cannot be fully explained by variation in the population.
The identification of people with possible cancer usually happens in primary care, because most people first present to a primary care clinician. Therefore, evidence from primary care should inform the identification process and was used as the basis for this guideline.
The recommendations were developed using a 'risk threshold', whereby if the risk of symptoms being caused by cancer is above a certain level, then action (investigation or referral) is warranted. The positive predictive value (PPV) was used to determine the threshold. In the previous guideline, a disparate range of percentage risks of cancer was used to form the recommendations. Few corresponded with a PPV of lower than 5%. The guideline development group (GDG) felt that, in order to improve diagnosis of cancer, a PPV threshold lower than 5% was preferable. Taking into account the financial and clinical costs of broadening the recommendations, the GDG agreed to use a 3% PPV threshold value to underpin the recommendations for suspected cancer pathway referrals and urgent direct access investigations, such as brain scanning or endoscopy. Certain exceptions to a 3% PPV threshold were agreed. Recommendations were made for children and young people at below the 3% PPV threshold, although no explicit threshold value was set. The threshold was not applied to recommendations relating to tests routinely available in primary care (including blood tests such as prostate‑specific antigen and imaging such as chest X‑ray), primary care tests that could be used in place of specialist referral, non‑urgent direct access tests and routine referrals for specialist opinion. Further information about the methods used to underpin the recommendations can be found in the full guideline.
It is well recognised that some risk factors increase the chance of a person developing cancer in the future, for example, increasing age and a family history of cancer. However, risk factors do not affect the way in which cancer presents. Of the risk factors that were reported in the evidence, only smoking (in lung cancer) and age were found to significantly influence the chance of symptoms being predictive of cancer. Therefore, these are included in the recommendations where relevant. For all other risk factors, the recommendations would be the same for people with possible symptoms of cancer, irrespective of whether they had a risk factor. However, an exception was made to include asbestos exposure in the recommendations because of the high relative risk of mesothelioma in people who have been exposed to asbestos.
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{'Introduction ': "# Safeguarding children\n\nRemember that child maltreatment:\n\nis common\n\ncan present anywhere\n\nmay co‑exist with other health problems, including suspected cancer.\n\nSee NICE's guideline on child maltreatment for clinical features that may be associated with maltreatment.\n\nPeople have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations (although this may not apply to recommendations made before 2009; see the section on recommendation wording in guideline updates below). It also has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity) and safeguarding.\n\n# How the guideline is organised\n\nThe recommendations in this guideline have been organised into 3 separate sections to help healthcare professionals find the relevant information easily. The recommendations for investigation and referral organised by site of suspected cancer are also presented in tables of recommendations organised by symptoms and investigation findings. Either section should be used in conjunction with the recommendations on patient support, safety netting and the diagnostic process.\n\n# Recommendation wording in guideline updates\n\nNICE began using standard wording to denote the strength of recommendations in guidelines that started development after January 2009. It does not apply to any recommendations ending (see update information for details about how recommendations are labelled). In particular, for recommendations labelled the word 'consider' may not necessarily be used to denote the strength of the recommendation.", 'Recommendations organised by site of cancer': "Use this guideline to guide referrals. If still uncertain about whether a referral is needed, consider contacting a specialist (see the recommendations on the diagnostic process). Consider a review for people with any symptom associated with increased cancer risk who do not meet the criteria for referral or investigative action (see the recommendations on safety netting).\n\n# Lung and pleural cancers\n\n## Lung cancer\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for lung cancer if they:\n\nhave chest X‑ray findings that suggest lung cancer or\n\nare aged 40\xa0and over with unexplained haemoptysis. \n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) to assess for lung cancer in people aged 40\xa0and over if they have 2\xa0or more of the following unexplained symptoms, or if they have ever smoked and have 1\xa0or more of the following unexplained symptoms:\n\ncough\n\nfatigue\n\nshortness of breath\n\nchest pain\n\nweight loss\n\nappetite loss. \n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) to assess for lung cancer in people aged\xa040 and over with any of the following:\n\npersistent or recurrent chest infection\n\nfinger clubbing\n\nsupraclavicular lymphadenopathy or persistent cervical lymphadenopathy\n\nchest signs consistent with lung cancer\n\nthrombocytosis. \n\n## Mesothelioma\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for mesothelioma if they have chest X‑ray findings that suggest mesothelioma. \n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) to assess for mesothelioma in people aged 40\xa0and over, if:\n\nthey have 2 or more of the following unexplained symptoms, or\n\nthey have 1 or more of the following unexplained symptoms and have ever smoked, or\n\nthey have 1 or more of the following unexplained symptoms and have been exposed to asbestos:\n\n\n\ncough\n\nfatigue\n\nshortness of breath\n\nchest pain\n\nweight loss\n\nappetite loss. \n\n\n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) to assess for mesothelioma in people aged 40\xa0and over with either:\n\nfinger clubbing or\n\nchest signs compatible with pleural disease. \n\n# Upper gastrointestinal tract cancers\n\n## Oesophageal cancer\n\nOffer urgent, direct access upper gastrointestinal endoscopy (to be done within 2\xa0weeks) to assess for oesophageal cancer in people:\n\nwith dysphagia or\n\naged 55\xa0and over with weight loss and any of the following:\n\n\n\nupper abdominal pain\n\nreflux\n\ndyspepsia. \n\n\n\nConsider non-urgent direct access upper gastrointestinal endoscopy to assess for oesophageal cancer in people with haematemesis. \n\nConsider non‑urgent direct access upper gastrointestinal endoscopy to assess for oesophageal cancer in people aged 55\xa0or over with:\n\ntreatment‑resistant dyspepsia or\n\nupper abdominal pain with low haemoglobin levels or\n\nraised platelet count with any of the following:\n\n\n\nnausea\n\nvomiting\n\nweight loss\n\nreflux\n\ndyspepsia\n\nupper abdominal pain, or\n\n\n\nnausea or vomiting with any of the following:\n\n\n\nweight loss\n\nreflux\n\ndyspepsia\n\nupper abdominal pain. \n\n\n\n## Pancreatic cancer\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for pancreatic cancer if they are aged 40\xa0and over and have jaundice. \n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available, to assess for pancreatic cancer in people aged 60\xa0and over with weight loss and any of the following:\n\ndiarrhoea\n\nback pain\n\nabdominal pain\n\nnausea\n\nvomiting\n\nconstipation\n\nnew‑onset diabetes. \n\n## Stomach cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for people with an upper abdominal mass consistent with stomach cancer. \n\nOffer urgent direct access upper gastrointestinal endoscopy (to be done within 2\xa0weeks) to assess for stomach cancer in people:\n\nwith dysphagia or\n\naged 55\xa0and over with weight loss and any of the following:\n\n\n\nupper abdominal pain\n\nreflux\n\ndyspepsia. \n\n\n\nConsider non‑urgent direct access upper gastrointestinal endoscopy to assess for stomach cancer in people with haematemesis. \n\nConsider non‑urgent direct access upper gastrointestinal endoscopy to assess for stomach cancer in people aged 55\xa0or over with:\n\ntreatment‑resistant dyspepsia or\n\nupper abdominal pain with low haemoglobin levels or\n\nraised platelet count with any of the following:\n\n\n\nnausea\n\nvomiting\n\nweight loss\n\nreflux\n\ndyspepsia\n\nupper abdominal pain, or\n\n\n\nnausea or vomiting with any of the following:\n\n\n\nweight loss\n\nreflux\n\ndyspepsia\n\nupper abdominal pain. \n\n\n\n## Gall bladder cancer\n\nConsider an urgent direct access ultrasound scan (to be done within 2\xa0weeks) to assess for gall bladder cancer in people with an upper abdominal mass consistent with an enlarged gall bladder. \n\n## Liver cancer\n\nConsider an urgent direct access ultrasound scan (to be done within 2\xa0weeks) to assess for liver cancer in people with an upper abdominal mass consistent with an enlarged liver. \n\n# Lower gastrointestinal tract cancers\n\n## Colorectal cancer\n\nRefer adults using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for colorectal cancer if:\n\nthey are aged 40\xa0and over with unexplained weight loss and abdominal pain or\n\nthey are aged 50\xa0and over with unexplained rectal bleeding or\n\nthey are aged 60\xa0and over with:\n\n\n\niron‑deficiency anaemia or\n\nchanges in their bowel habit, or\n\n\n\ntests show occult blood in their faeces. \n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for colorectal cancer in adults with a rectal or abdominal mass. \n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for colorectal cancer in adults aged under 50 with rectal bleeding and any of the following unexplained symptoms or findings:\n\nabdominal pain\n\nchange in bowel habit\n\nweight loss\n\niron‑deficiency anaemia. \n\nOffer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care) to assess for colorectal cancer in adults without rectal bleeding who:\n\nare aged 50\xa0and over with unexplained:\n\n\n\nabdominal pain or\n\nweight loss, or\n\n\n\nare aged under 60 with:\n\n\n\nchanges in their bowel habit or\n\niron-deficiency anaemia, or\n\n\n\nare aged 60\xa0and over and have anaemia even in the absence of iron deficiency. \n\n## Anal cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for anal cancer in people with an unexplained anal mass or unexplained anal ulceration. \n\n# Breast cancer\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for breast cancer if they are:\n\naged 30\xa0and over and have an unexplained breast lump with or without pain or\n\naged 50\xa0and over with any of the following symptoms in one nipple only:\n\n\n\ndischarge\n\nretraction\n\n\n\nother changes of concern. \n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for breast cancer in people:\n\nwith skin changes that suggest breast cancer or\n\naged 30\xa0and over with an unexplained lump in the axilla. \n\nConsider non-urgent referral in people aged under 30 with an unexplained breast lump with or without pain. See also recommendations 1.16.2 and 1.16.3 for information about seeking specialist advice. \n\n# Gynaecological cancers\n\n## Ovarian cancer\n\nThe recommendations in this section have been incorporated from NICE's guideline on ovarian cancer and have not been updated. The recommendations for ovarian cancer apply to women aged 18\xa0and over.\n\nMake an urgent referral to a gynaecological cancer service if physical examination identifies ascites and/or a pelvic or abdominal mass (which is not obviously uterine fibroids). [2011, amended 2020]\n\nCarry out tests in primary care (see recommendations 1.5.6 to 1.5.9) if a woman (especially if aged 50\xa0or over) reports having any of the following symptoms on a persistent or frequent basis – particularly more than 12\xa0times per month:\n\npersistent abdominal distension (women often refer to this as 'bloating')\n\nfeeling full (early satiety) and/or loss of appetite\n\npelvic or abdominal pain\n\nincreased urinary urgency and/or frequency. \n\nConsider carrying out tests in primary care (see recommendations 1.5.6 to 1.5.9) if a woman reports unexplained weight loss, fatigue or changes in bowel habit. \n\nAdvise any woman who is not suspected of having ovarian cancer to return to her GP if her symptoms become more frequent and/or persistent. \n\nCarry out appropriate tests for ovarian cancer (see recommendations 1.5.6 to 1.5.9) in any woman aged 50\xa0or over who has experienced symptoms within the last 12\xa0months that suggest irritable bowel syndrome (IBS), because IBS rarely presents for the first time in women of this age. (See NICE's guideline on irritable bowel syndrome in adults). \n\nMeasure serum CA125 in primary care in women with symptoms that suggest ovarian cancer (see recommendations 1.5.1 to 1.5.5). \n\nIf serum CA125 is 35\xa0IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis. \n\nIf the ultrasound suggests ovarian cancer, make an urgent referral to a gynaecological cancer service. [2011, amended 2020]\n\nFor any woman who has normal serum CA125 (less than 35\xa0IU/ml), or CA125 of 35\xa0IU/ml or greater but a normal ultrasound:\n\nassess her carefully for other clinical causes of her symptoms and investigate if appropriate\n\nif no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent. \n\n## Endometrial cancer\n\nRefer women using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for endometrial cancer if they are aged 55\xa0and over with post‑menopausal bleeding (unexplained vaginal bleeding more than 12\xa0months after menstruation has stopped because of the menopause). \n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for endometrial cancer in women aged under 55 with post‑menopausal bleeding. \n\nConsider a direct access ultrasound scan to assess for endometrial cancer in women aged 55\xa0and over with:\n\nunexplained symptoms of vaginal discharge who:\n\n\n\nare presenting with these symptoms for the first time or\n\nhave thrombocytosis or\n\nreport haematuria, or\n\n\n\nvisible haematuria and:\n\n\n\nlow haemoglobin levels or\n\nthrombocytosis, or\n\nhigh blood glucose levels. \n\n\n\n## Cervical cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for women if, on examination, the appearance of their cervix is consistent with cervical cancer. \n\n## Vulval cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for vulval cancer in women with an unexplained vulval lump, ulceration or bleeding. \n\n## Vaginal cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for vaginal cancer in women with an unexplained palpable mass in or at the entrance to the vagina. \n\n# Urological cancers\n\n## Prostate cancer\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for prostate cancer if their prostate feels malignant on digital rectal examination. \n\nConsider a prostate‑specific antigen (PSA) test and digital rectal examination to assess for prostate cancer in people with:\n\nany lower urinary tract symptoms, such as nocturia, urinary frequency, hesitancy, urgency or retention or\n\nerectile dysfunction or\n\nvisible haematuria. \n\nConsider referring people with possible symptoms of prostate cancer, as specified in recommendation 1.6.2, using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for prostate cancer if their PSA levels are above the threshold for their age in table\xa01. Take into account the person's preferences and any comorbidities when making the decision. \n\nAge (years)\n\nProstate-specific antigen threshold (micrograms/litre)\n\nBelow 40\n\nUse clinical judgement\n\nto 49\n\nMore than 2.5\n\nto 59\n\nMore than 3.5\n\nto 69\n\nMore than 4.5\n\nto 79\n\nMore than 6.5\n\nAbove 79\n\nUse clinical judgement\n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on PSA testing for prostate cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: PSA testing for prostate cancer.\n\nLoading. Please wait.\n\n## Bladder cancer\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for bladder cancer if they are:\n\naged 45\xa0and over and have:\n\n\n\nunexplained visible haematuria without urinary tract infection or\n\nvisible haematuria that persists or recurs after successful treatment of urinary tract infection, or\n\n\n\naged 60\xa0and over and have unexplained non‑visible haematuria and either dysuria or a raised white cell count on a blood test. \n\nConsider non-urgent referral for bladder cancer in people aged 60\xa0and over with recurrent or persistent unexplained urinary tract infection. \n\n## Renal cancer\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for renal cancer if they are aged 45\xa0and over and have:\n\nunexplained visible haematuria without urinary tract infection or\n\nvisible haematuria that persists or recurs after successful treatment of urinary tract infection. \n\n## Testicular cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for testicular cancer in men if they have a non‑painful enlargement or change in shape or texture of the testis. \n\nConsider a direct access ultrasound scan for testicular cancer in men with unexplained or persistent testicular symptoms. \n\n## Penile cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for penile cancer in men if they have:\n\na penile mass or ulcerated lesion, when a sexually transmitted infection has been excluded as a cause, or\n\na persistent penile lesion after treatment for a sexually transmitted infection has been completed. \n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for penile cancer in men with unexplained or persistent symptoms affecting the foreskin or glans. \n\n# Skin cancers\n\n## Malignant melanoma of the skin\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for melanoma if they have a suspicious pigmented skin lesion with a weighted 7‑point checklist score of 3\xa0or more. \n\nMajor features of the lesions (scoring 2\xa0points each):\n\nchange in size\n\nirregular shape\n\nirregular colour.\n\nMinor features of the lesions (scoring 1\xa0point each):\n\nlargest diameter 7\xa0mm or more\n\ninflammation\n\noozing\n\nchange in sensation.\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) if dermoscopy suggests melanoma of the skin. \n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for melanoma in people with a pigmented or non‑pigmented skin lesion that suggests nodular melanoma. \n\n## Squamous cell carcinoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for people with a skin lesion that raises the suspicion of squamous cell carcinoma. \n\n## Basal cell carcinoma\n\nConsider routine referral for people if they have a skin lesion that raises the suspicion of a basal cell carcinoma. (Typical features of basal cell carcinoma include: an ulcer with a raised rolled edge; prominent fine blood vessels around a lesion; or a nodule on the skin [particularly pearly or waxy nodules].) \n\nOnly consider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for people with a skin lesion that raises the suspicion of a basal cell carcinoma if there is particular concern that a delay may have a significant impact, because of factors such as lesion site or size. \n\nFollow NICE's guidance on improving outcomes for people with skin tumours including melanoma for advice on who should excise suspected basal cell carcinomas. \n\n# Head and neck cancers\n\n## Laryngeal cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for laryngeal cancer in people aged 45\xa0and over with:\n\npersistent\n unexplained hoarseness or\n\nan unexplained lump in the neck. \n\n## Oral cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for oral cancer in people with either:\n\nunexplained ulceration in the oral cavity lasting for more than 3\xa0weeks or\n\na persistent and unexplained lump in the neck. \n\nConsider an urgent referral (for an appointment within 2\xa0weeks) for assessment for possible oral cancer by a dentist in people who have either:\n\na lump on the lip or in the oral cavity or\n\na red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia. \n\nConsider a suspected cancer pathway referral by the dentist (for an appointment within 2\xa0weeks) for oral cancer in people when assessed by a dentist as having either:\n\na lump on the lip or in the oral cavity consistent with oral cancer or\n\na red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia. \n\n## Thyroid cancer\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for thyroid cancer in people with an unexplained thyroid lump. \n\n# Brain and central nervous system cancers\n\n## Adults\n\nConsider an urgent, direct access, MRI\xa0scan of the brain (or CT\xa0scan if MRI is contraindicated; to be done within 2\xa0weeks) to assess for brain or central nervous system cancer in adults with progressive, sub‑acute loss of central neurological function. \n\n## Children and young people\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for suspected brain or central nervous system cancer in children and young people with newly abnormal cerebellar or other central neurological function. \n\n# Haematological cancers\n\n## Leukaemia in adults\n\nConsider a very urgent full blood count (within 48\xa0hours) to assess for leukaemia in adults with any of the following:\n\npallor\n\npersistent fatigue\n\nunexplained fever\n\nunexplained persistent or recurrent infection\n\ngeneralised lymphadenopathy\n\nunexplained bruising\n\nunexplained bleeding\n\nunexplained petechiae\n\nhepatosplenomegaly. \n\n## Leukaemia in children and young people\n\nRefer children and young people for immediate specialist assessment for leukaemia if they have unexplained petechiae or hepatosplenomegaly. \n\nOffer a very urgent full blood count (within 48\xa0hours) to assess for leukaemia in children and young people with any of the following:\n\npallor\n\npersistent fatigue\n\nunexplained fever\n\nunexplained persistent infection\n\ngeneralised lymphadenopathy\n\npersistent or unexplained bone pain\n\nunexplained bruising\n\nunexplained bleeding. \n\n## Myeloma\n\nOffer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate to assess for myeloma in people aged 60\xa0and over with persistent bone pain, particularly back pain, or unexplained fracture. \n\nOffer very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48\xa0hours) to assess for myeloma in people aged 60\xa0and over with hypercalcaemia or leukopenia and a presentation that is consistent with possible myeloma. \n\nConsider very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48\xa0hours) to assess for myeloma if the plasma viscosity or erythrocyte sedimentation rate and presentation are consistent with possible myeloma. \n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) if the results of protein electrophoresis or a Bence–Jones protein urine test suggest myeloma. \n\n## Non-Hodgkin's lymphoma\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements.\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for non‑Hodgkin's lymphoma in adults presenting with unexplained lymphadenopathy or splenomegaly. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss. \n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment for non‑Hodgkin's lymphoma in children and young people presenting with unexplained lymphadenopathy or splenomegaly. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss. \n\n## Hodgkin's lymphoma\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements.\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for Hodgkin's lymphoma in adults presenting with unexplained lymphadenopathy. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus, weight loss or alcohol‑induced lymph node pain. \n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment for Hodgkin's lymphoma in children and young people presenting with unexplained lymphadenopathy. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss. \n\n# Sarcomas\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements.\n\n## Bone sarcoma in adults\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for adults if an X‑ray suggests the possibility of bone sarcoma. \n\n## Bone sarcoma in children and young people\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment for children and young people if an X‑ray suggests the possibility of bone sarcoma. \n\nConsider a very urgent direct access X‑ray (to be done within 48\xa0hours) to assess for bone sarcoma in children and young people with unexplained bone swelling or pain. \n\n## Soft tissue sarcoma in adults\n\nConsider an urgent direct access ultrasound scan (to be done within 2\xa0weeks) to assess for soft tissue sarcoma in adults with an unexplained lump that is increasing in size. \n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) for adults if they have ultrasound scan findings that are suggestive of soft tissue sarcoma or if ultrasound findings are uncertain and clinical concern persists. \n\n## Soft tissue sarcoma in children and young people\n\nConsider a very urgent direct access ultrasound scan (to be done within 48\xa0hours) to assess for soft tissue sarcoma in children and young people with an unexplained lump that is increasing in size. \n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for children and young people if they have ultrasound scan findings that are suggestive of soft tissue sarcoma or if ultrasound findings are uncertain and clinical concern persists. \n\n# Childhood cancers\n\nNICE has published a guideline on babies, children and young people's experience of healthcare.\n\n## Neuroblastoma\n\nConsider very urgent referral (for an appointment within 48\xa0hours) for specialist assessment for neuroblastoma in children with a palpable abdominal mass or unexplained enlarged abdominal organ. \n\n## Retinoblastoma\n\nConsider urgent referral (for an appointment within 2\xa0weeks) for ophthalmological assessment for retinoblastoma in children with an absent red reflex. If there is new-onset squint that occurs together with an absent red reflex, see the recommendation on new-onset squint with loss of red reflex in NICE's guideline on suspected neurological conditions. \n\n## Wilms' tumour\n\nConsider very urgent referral (for an appointment within 48\xa0hours) for specialist assessment for Wilms' tumour in children with any of the following:\n\na palpable abdominal mass\n\nan unexplained enlarged abdominal organ\n\nunexplained visible haematuria. \n\n# Non-site-specific symptoms\n\nSome symptoms or symptom combinations may be features of several different cancers. For some of these symptoms, the risk for each individual cancer may be low but the total risk of cancer of any type may be higher. This section includes recommendations for these symptoms.\n\n## Symptoms of concern in children and young people\n\nTake into account the insight and knowledge of parents and carers when considering making a referral for suspected cancer in a child or young person. Consider referral for children if their parent or carer has persistent concern or anxiety about the child's symptoms, even if the symptoms are most likely to have a benign cause. \n\n## Symptoms of concern in adults\n\nFor people with unexplained weight loss, which is a symptom of several cancers including colorectal, gastro‑oesophageal, lung, prostate, pancreatic and urological cancer:\n\ncarry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely and\n\noffer urgent investigation or a suspected cancer pathway referral (for an appointment within 2\xa0weeks). \n\nFor people with unexplained appetite loss, which is a symptom of several cancers including lung, oesophageal, stomach, colorectal, pancreatic, bladder and renal cancer:\n\ncarry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely and\n\noffer urgent investigation or a suspected cancer pathway referral (for an appointment within 2\xa0weeks). \n\nFor people with deep vein thrombosis, which is associated with several cancers including urogenital, breast, colorectal and lung cancer:\n\ncarry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely and\n\nconsider urgent investigation or a suspected cancer pathway referral (for an appointment within 2\xa0weeks). ", 'Recommendations on patient support, safety netting and the diagnostic process': "Use this guideline to guide referrals. If still uncertain about whether a referral is needed, consider contacting a specialist (see the recommendations on the diagnostic process). Consider a review for people with any symptom associated with increased cancer risk who do not meet the criteria for referral or investigative action (see the recommendations on safety netting).\n\n# Patient information and support\n\nDiscuss with people with suspected cancer (and their carers as appropriate, taking account of the need for confidentiality) their preferences for being involved in decision‑making about referral options and further investigations including their potential risks and benefits. \n\nWhen cancer is suspected in a child, discuss the referral decision and information to be given to the child with the parents or carers (and the child if appropriate). \n\nExplain to people who are being referred with suspected cancer that they are being referred to a cancer service. Reassure them, as appropriate, that most people referred will not have a diagnosis of cancer, and discuss alternative diagnoses with them. \n\nGive the person information on the possible diagnosis (both benign and malignant) in accordance with their wishes for information (see also NICE's guideline on patient experience in adult NHS services). \n\nThe information given to people with suspected cancer and their families and/or carers should cover, among other issues:\n\nwhere the person is being referred to\n\nhow long they will have to wait for the appointment\n\nhow to obtain further information about the type of cancer suspected or help before the specialist appointment\n\nwhat to expect from the service the person will be attending\n\nwhat type of tests may be carried out, and what will happen during diagnostic procedures\n\nhow long it will take to get a diagnosis or test results\n\nwhether they can take someone with them to the appointment\n\nwho to contact if they do not receive confirmation of an appointment\n\nother sources of support. \n\nProvide information that is appropriate for the person in terms of language, ability and culture, recognising the potential for different cultural meanings associated with the possibility of cancer. \n\nHave information available in a variety of formats on both local and national sources of information and support for people who are being referred with suspected cancer. For more information on information sharing, see the section on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services. \n\nReassure people in the safety netting group (see recommendation\xa01.15.2) who are concerned that they may have cancer that with their current symptoms their risk of having cancer is low. \n\nExplain to people who are being offered safety netting (see recommendation\xa01.15.2) which symptoms to look out for and when they should return for re‑evaluation. It may be appropriate to provide written information. \n\nWhen referring a person with suspected cancer to a specialist service, assess their need for continuing support while waiting for their referral appointment. This should include inviting the person to contact their healthcare professional again if they have more concerns or questions before they see a specialist. \n\nIf the person has additional support needs because of their personal circumstances, inform the specialist (with the person's agreement). \n\n# Safety netting\n\nEnsure that the results of investigations are reviewed and acted upon appropriately, with the healthcare professional who ordered the investigation taking or explicitly passing on responsibility for this. Be aware of the possibility of false‑negative results for chest X‑rays and tests for occult blood in faeces. \n\nConsider a review for people with any symptom that is associated with an increased risk of cancer, but who do not meet the criteria for referral or other investigative action. The review may be:\n\nplanned within a time frame agreed with the person or\n\npatient‑initiated if new symptoms develop, the person continues to be concerned, or their symptoms recur, persist or worsen. \n\n# The diagnostic process\n\nTake part in continuing education, peer review and other activities to improve and maintain clinical consulting, reasoning and diagnostic skills, in order to identify at an early stage people who may have cancer, and to communicate the possibility of cancer to the person. \n\nDiscussion with a specialist (for example, by telephone or email) should be considered if there is uncertainty about the interpretation of symptoms and signs, and whether a referral is needed. This may also enable the primary healthcare professional to communicate their concerns and a sense of urgency to secondary healthcare professionals when symptoms are not classical. \n\nPut in place local arrangements to ensure that letters about non-urgent referrals are assessed by the specialist, so that the person can be seen more urgently if necessary. \n\nPut in place local arrangements to ensure that there is a maximum waiting period for non‑urgent referrals, in accordance with national targets and local arrangements. \n\nEnsure local arrangements are in place to identify people who miss their appointments so that they can be followed up. \n\nInclude all appropriate information in referral correspondence, including whether the referral is urgent or non‑urgent. \n\nUse local referral proformas if these are in use. \n\nOnce the decision to refer has been made, make sure that the referral is made within 1\xa0working day. ", 'Recommendations organised by symptom and findings of primary care investigations': "The recommendations in this section are displayed alphabetically by symptom then in order of urgency of the action needed, to make sure that the most urgent actions are not missed. Where there are several recommendations relating to the same cancer these have been grouped for ease of reference. Occasionally the same symptom may suggest more than one cancer site. In such instances the recommendations are displayed together and the GP should use their clinical judgement to decide on the most appropriate action.\n\nUse this guideline to guide referrals. If still uncertain about whether a referral is needed, consider contacting a specialist (see the recommendations on the diagnostic process). Consider a review for people with any symptom associated with increased cancer risk who do not meet the criteria for referral or investigative action (see the recommendations on safety netting).\n\n# Abdominal symptoms\n\nSee also the section on bleeding for recommendations on rectal bleeding.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nAbdominal distension (persistent or frequent – particularly more than 12\xa0times per month) in women, especially if 50 and over\n\nOvarian\n\nCarry out tests in primary care [1.5.2]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for more information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nSymptoms and signs\n\nPossible cancer\n\nRecommendation\n\nAscites and/or a pelvic or abdominal mass identified by physical examination (which is not obviously uterine fibroids) in women\n\nOvarian\n\nUrgent referral [1.5.1]\n\nThese recommendations apply to women aged 18\xa0and over\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nAbdominal or pelvic mass identified by physical examination (which is not obviously uterine fibroids) in women\n\nOvarian\n\nUrgent referral [1.5.1]\n\nThese recommendations apply to women aged 18\xa0and over\n\nAbdominal or rectal mass\n\nColorectal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.2]\n\nSplenomegaly (unexplained) in adults\n\nNon‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nUpper abdominal mass\n consistent with stomach cancer\n\nStomach\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.2.6]\n\nUpper abdominal mass consistent with an enlarged gall bladder\n\nGall bladder\n\nConsider an urgent direct access ultrasound scan (to be done within 2\xa0weeks) [1.2.10]\n\nUpper abdominal mass consistent with an enlarged liver\n\nLiver\n\nConsider an urgent direct access ultrasound scan (to be done within 2\xa0weeks) [1.2.11]\n\nHepatosplenomegaly\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nAbdominal pain with weight loss (unexplained), 40 and over\n\nColorectal\n\nRefer adults using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.1]\n\nAbdominal pain (unexplained) with rectal bleeding in adults under 50\n\nColorectal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.3]\n\nAbdominal pain (unexplained) without rectal bleeding, 50\xa0and over\n\nColorectal\n\nOffer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care) [1.3.4]\n\nUpper abdominal pain with weight loss, 55\xa0and over\n\nOesophageal or stomach\n\nOffer urgent direct access upper gastrointestinal endoscopy (to be done within 2\xa0weeks) [1.2.1] [1.2.7]\n\nUpper abdominal pain with low haemoglobin levels or raised platelet count or nausea or vomiting, 55 and over\n\nOesophageal or stomach\n\nConsider non‑urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\nAbdominal or pelvic pain (persistent or frequent – particularly more than 12 times per month) in women, especially if 50\xa0and over\n\nOvarian\n\nCarry out tests in primary care [1.5.2]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for more information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nAbdominal pain with weight loss, 60\xa0and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available [1.2.5]\n\nIrritable bowel syndrome symptoms within the last 12\xa0months in women 50\xa0and over\n\nOvarian\n\nCarry out appropriate tests for ovarian cancer, because irritable bowel syndrome rarely presents for the first time in women of this age [1.5.5]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for more information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nAlso see the NICE guideline on irritable bowel syndrome in adults.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nChange in bowel habit (unexplained), 60\xa0and over\n\nColorectal\n\nRefer adults using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.1]\n\nChange in bowel habit (unexplained) with rectal bleeding, in adults under 50\n\nColorectal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.3]\n\nChange in bowel habit without rectal bleeding, adults under 60\n\nColorectal\n\nOffer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care) [1.3.4]\n\n\n\nChange in bowel habit (unexplained) in women\n\nOvarian\n\nConsider carrying out tests in primary care [1.5.3]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nDiarrhoea or constipation with weight loss, 60 and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available [1.2.5]\n\nIrritable bowel syndrome symptoms within the last 12\xa0months, in women 50\xa0and over\n\nOvarian\n\nCarry out appropriate tests for ovarian cancer, because irritable bowel syndrome rarely presents for the first time in women of this age [1.5.5]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for more information about tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nAlso see the NICE guideline on irritable bowel syndrome in adults\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nDyspepsia (treatment‑resistant), 55\xa0and over\n\nOesophageal or stomach\n\nConsider non‑urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\nDyspepsia\n\nDyspepsia with weight loss, 55\xa0and over\n\nOesophageal or stomach\n\nOffer urgent direct access upper gastrointestinal endoscopy (to be done within 2\xa0weeks) [1.2.1] [1.2.7]\n\nDyspepsia with raised platelet count or nausea or vomiting, 55\xa0and over\n\nOesophageal or stomach\n\nConsider non‑urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nDysphagia\n\nOesophageal or stomach\n\nOffer urgent direct access upper gastrointestinal endoscopy (to be done within 2\xa0weeks) [1.2.1, 1.2.7]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nNausea or vomiting with weight loss, 60\xa0and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available [1.2.5]\n\nNausea or vomiting with raised platelet count or weight loss or reflux or dyspepsia or upper abdominal pain, 55\xa0and over\n\nOesophageal or stomach\n\nConsider non‑urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\nSymptom and signs\n\nPossible cancer\n\nRecommendation\n\nProstate feels malignant on digital rectal examination, in men\n\nProstate\n\nRefer men using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.1]\n\nAnal mass or anal ulceration (unexplained)\n\nAnal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.5]\n\nRectal\n mass\n\nColorectal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.2]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nReflux with weight loss, 55\xa0and over\n\nOesophageal or stomach\n\nOffer urgent direct access upper gastrointestinal endoscopy (to be done within 2\xa0weeks) [1.2.1] [1.2.7]\n\nReflux with raised platelet count or nausea or vomiting, 55\xa0and over\n\nOesophageal or stomach\n\nConsider non‑urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\n# Bleeding\n\nSee also:\n\nthe section on urological symptoms for haematuria\n\nthe section on primary care investigations for faecal occult blood.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nBleeding, bruising or petechiae (unexplained)\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nHaematemesis\n\nOesophageal or stomach\n\nConsider non-urgent, direct access upper gastrointestinal endoscopy [1.2.2] [1.2.8]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nHaemoptysis (unexplained), 40\xa0and over\n\nLung\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.1.1]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nPost‑menopausal bleeding in women 55\xa0and over\n\nEndometrial\n\nRefer women using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.10]\n\nPost‑menopausal bleeding in women under 55\n\nEndometrial\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.11]\n\nPost‑menopausal bleeding is unexplained vaginal bleeding more than 12\xa0months after menstruation has stopped because of the menopause.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nRectal bleeding (unexplained), 50\xa0and over\n\nColorectal\n\nRefer adults using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.1]\n\nRectal bleeding with abdominal pain or change in bowel habit or weight loss or iron‑deficiency anaemia in adults under 50\n\nColorectal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.3]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nVulval bleeding (unexplained) in women\n\nVulval\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.14]\n\n# Gynaecological symptoms\n\nSee also the section on bleeding for post‑menopausal (vaginal) bleeding\n\nSymptom and signs\n\nPossible cancer\n\nRecommendation\n\nAppearance of cervix\n consistent with cervical cancer\n\nCervical\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.13]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nVaginal discharge (unexplained) either at first presentation or with thrombocytosis or with haematuria, in women 55\xa0and over\n\nEndometrial\n\nConsider a direct access ultrasound scan [1.5.12]\n\nVaginal mass (unexplained and palpable) in or at the entrance to the vagina\n\nVaginal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.15]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nVulval bleeding (unexplained)\n\nVulval\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.14]\n\nVulval lump or ulceration (unexplained)\n\nVulval\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.14]\n\n# Lumps or masses\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nAnal mass (unexplained)\n\nAnal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.5]\n\nAxillary lump (unexplained), 30\xa0and over\n\nBreast\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.4.2]\n\nBreast lump (unexplained) with or without pain, 30\xa0and over\n\nBreast\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.4.1]\n\nBreast lump (unexplained) with or without pain, under 30\n\nBreast\n\nConsider non-urgent referral\n\nSee also recommendations\xa01.16.2 and 1.16.3 for information about seeking specialist advice [1.4.3]\n\nLip or oral cavity\n lump\n\nOral\n\nConsider an urgent referral (for an appointment within 2\xa0weeks) for assessment by a dentist [1.8.3]\n\nConsider a suspected cancer pathway referral by the dentist (for an appointment within 2\xa0weeks) in people when assessed by a dentist as having a lump on the lip or in the oral cavity consistent with oral cancer [1.8.4]\n\nLump (unexplained) that is increasing in size in adults\n\nSoft tissue sarcoma\n\nConsider an urgent direct access ultrasound scan (to be done within 2\xa0weeks) [1.11.4]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nNeck lump (unexplained), 45\xa0and over\n\nLaryngeal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.8.1]\n\nNeck lump (persistent and unexplained)\n\nOral\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.8.2]\n\nPenile mass (and sexually transmitted infection has been excluded as a cause) in men\n\nPenile\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.9]\n\nThyroid lump (unexplained)\n\nThyroid\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.8.5]\n\nVaginal mass (unexplained and palpable) in or at the entrance to the vagina in women\n\nVaginal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.15]\n\nVulval lump (unexplained) in women\n\nVulval\n\nConsider a suspected cancer pathway referral (for an appointment within 2 weeks) [1.5.14]\n\nSee also the section on abdominal symptoms for abdominal, anal, pelvic and rectal lumps or masses.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nLymphadenopathy (unexplained) in adults\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks)\n\nWhen considering referral for Hodgkin's lymphoma, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus, weight loss or alcohol‑induced lymph node pain [1.10.10]\n\nWhen considering referral for non‑Hodgkin's lymphoma, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nLymphadenopathy (supraclavicular or persistent cervical), 40\xa0and over\n\nLung\n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.3]\n\nLymphadenopathy (generalised) in adults\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nUlceration in the oral cavity (unexplained and lasting for more than 3\xa0weeks)\n\nOral\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.8.2]\n\nLip or oral cavity lump\n\nOral\n\nConsider an urgent referral (for an appointment within 2\xa0weeks) for assessment by a dentist [1.8.3]\n\nConsider a suspected cancer pathway referral by the dentist (for an appointment within 2\xa0weeks) in people when assessed by a dentist as having a lump on the lip or in the oral cavity consistent with oral cancer [1.8.4]\n\n# Neurological symptoms in adults\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nLoss of central neurological function (progressive, sub‑acute) in adults\n\nBrain or central nervous system\n\nConsider an urgent direct access MRI scan of the brain (or CT scan if MRI is contraindicated; to be done within 2\xa0weeks) [1.9.1]\n\n# Pain\n\nSee also the section on abdominal symptoms for abdominal or pelvic pain.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nAlcohol‑induced lymph node pain with unexplained lymphadenopathy in adults\n\nHodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.10]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nBack pain with weight loss, 60\xa0and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available [1.2.5]\n\nBack pain (persistent), 60\xa0and over\n\nMyeloma\n\nOffer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate [1.10.4]\n\nSee the section on primary care investigations for more information on tests for myeloma\n\nBone pain (persistent), 60\xa0and over\n\nMyeloma\n\nOffer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate to assess for myeloma [1.10.4]\n\nSee the section on primary care investigations for more information on tests for myeloma\n\nChest pain (unexplained), 40\xa0and over, ever smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nChest pain (unexplained), 40\xa0and over, exposed to asbestos\n\nMesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.5]\n\nChest pain (unexplained) with cough or fatigue or shortness of breath or weight loss or appetite loss (unexplained), 40\xa0and over\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\n# Respiratory symptoms\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nChest infection (persistent or recurrent), 40\xa0and over\n\nLung\n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.3]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nChest pain (unexplained), 40\xa0and over, ever smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nChest pain (unexplained), 40\xa0and over, exposed to asbestos\n\nMesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.5]\n\nChest pain (unexplained) with cough or fatigue or shortness of breath or weight loss or appetite loss (unexplained), 40\xa0and over\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nCough (unexplained), 40\xa0and over, ever smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nCough (unexplained), 40\xa0and over, exposed to asbestos\n\nMesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.5]\n\nCough (unexplained) with fatigue or shortness of breath or chest pain or weight loss or appetite loss (unexplained), 40\xa0and over\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nHoarseness (persistent and unexplained), 45\xa0and over\n\nLaryngeal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.8.1]\n\nSymptom and signs\n\nPossible cancer\n\nRecommendation\n\nChest signs\n consistent with lung cancer, 40\xa0and over\n\nLung\n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.3]\n\nChest signs compatible with pleural disease, 40\xa0and over\n\nMesothelioma\n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.6]\n\nFinger clubbing, 40\xa0and over\n\nLung or mesothelioma\n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.3] [1.1.6]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nShortness of breath (unexplained), 40\xa0and over, ever smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nShortness of breath (unexplained), 40\xa0and over, and exposed to asbestos\n\nMesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.5]\n\nShortness of breath with cough or fatigue or chest pain or weight loss or appetite loss (unexplained), 40\xa0and over\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nShortness of breath with unexplained lymphadenopathy in adults\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nShortness of breath with unexplained splenomegaly in adults\n\nNon‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\n# Skeletal symptoms\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nBack pain with weight loss, 60\xa0and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available [1.2.5]\n\nBack pain (persistent), 60\xa0and over\n\nMyeloma\n\nOffer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate [1.10.4]\n\nSee the section on primary care investigations for more information on tests for myeloma\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nBone pain (persistent), 60\xa0and over\n\nMyeloma\n\nOffer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate to assess for myeloma [1.10.4]\n\nSee the section on primary care investigations for more information on tests for myeloma\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nFracture (unexplained), 60\xa0and over\n\nMyeloma\n\nOffer a full blood count and blood tests for calcium and plasma viscosity or erythrocyte sedimentation rate [1.10.4]\n\nSee the section on primary care investigations for more information on tests for myeloma\n\n# Skin or surface symptoms\n\nSee also the section on lumps or masses for oral lesions.\n\nSymptoms and signs\n\nPossible cancer\n\nRecommendation\n\nAnal ulceration (unexplained)\n\nAnal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.5]\n\nBruising (unexplained) in adults\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nNipple changes of concern (in one nipple only) including discharge and retraction, 50\xa0and over\n\nBreast\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.4.1]\n\nOral cavity red or red and white patch\n consistent with erythroplakia or erythroleukoplakia\n\nOral\n\nConsider urgent referral (for an appointment within 2\xa0weeks) for assessment by a dentist [1.8.3]\n\nConsider a suspected cancer pathway referral by the dentist (for an appointment within 2\xa0weeks) for people when assessed by a dentist as having a red or red and white patch in the oral cavity consistent with erythroplakia or erythroleukoplakia [1.8.4]\n\nPallor\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nPenile lesion (ulcerated and sexually transmitted infection has been excluded, or persistent after treatment for a sexually transmitted infection has been completed) in men\n\nPenile\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.9]\n\nPenile mass (and sexually transmitted infection has been excluded as a cause) in men\n\nPenile\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.9]\n\nPenile symptoms\n affecting the foreskin or glans (unexplained or persistent) in men\n\nPenile\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.10]\n\nPetechiae (unexplained) in adults\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nPruritus with unexplained splenomegaly in adults\n\nNon‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nPruritus with unexplained lymphadenopathy in adults\n\nHodgkin's lymphoma or non‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.10]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nSkin changes that suggest breast cancer\n\nBreast\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.4.2]\n\nSkin lesion (pigmented and suspicious) with a weighted 7‑point checklist score of 3\xa0or more\n\nMelanoma\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.7.1]\n\nSkin lesion (pigmented or non‑pigmented) that suggests nodular melanoma\n\nMelanoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.7.3]\n\nSkin lesion that raises the suspicion of a squamous cell carcinoma\n\nSquamous cell carcinoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.7.4]\n\nSkin lesion that raises the suspicion of a basal cell carcinoma\n\nBasal cell carcinoma\n\nConsider routine referral [1.7.5]\n\nOnly consider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) if there is particular concern that a delay may have a significant impact, because of factors such as lesion site or size [1.7.6]\n\nTypical features of basal cell carcinoma include: an ulcer with a raised rolled edge; prominent fine blood vessels around a lesion; or a nodule on the skin (particularly pearly or waxy nodules)\n\nVulval lump or ulceration (unexplained) in women\n\nVulval\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.5.14]\n\n# Urological symptoms\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nDysuria with unexplained non‑visible haematuria, 60\xa0and over\n\nBladder\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.4]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nErectile dysfunction in men\n\nProstate\n\nConsider a prostate‑specific antigen (PSA) test and digital rectal examination [1.6.2]\n\nSee the section on primary care investigations for more information on PSA tests and digital rectal examination\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nHaematuria (visible and unexplained) either without urinary tract infection or that persists or recurs after successful treatment of urinary tract infection, 45\xa0and over\n\nBladder or renal\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.4] [1.6.6]\n\nHaematuria (non‑visible and unexplained) with dysuria or raised white cell count on a blood test, 60\xa0and over\n\nBladder\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.4]\n\nHaematuria (visible) with low haemoglobin levels or thrombocytosis or high blood glucose levels or unexplained vaginal discharge in women 55\xa0and over\n\nEndometrial\n\nConsider a direct access ultrasound scan [1.5.12]\n\nHaematuria (visible) in men\n\nProstate\n\nConsider a prostate‑specific antigen (PSA) test and digital rectal examination [1.6.2]\n\nSee the section on primary care investigations for more information on PSA tests and digital rectal examination\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nTestis enlargement or change in shape or texture (non‑painful) in men\n\nTesticular\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.7]\n\nTesticular symptoms (unexplained or persistent) in men\n\nTesticular\n\nConsider a direct access ultrasound scan [1.6.8]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nUrinary tract infection (unexplained and recurrent or persistent), 60\xa0and over\n\nBladder\n\nConsider non-urgent referral for bladder cancer in people aged 60\xa0and over with recurrent or persistent unexplained urinary tract infection [1.6.5]\n\nLower urinary tract symptoms, such as nocturia, urinary frequency, hesitancy, urgency or retention in men\n\nProstate\n\nConsider a prostate‑specific antigen (PSA) test and digital rectal examination [1.6.2]\n\nSee the section on primary care investigations for more information on PSA tests and digital rectal examination\n\nUrinary urgency or frequency (increased and persistent or frequent – particularly more than 12\xa0times per month) in women, especially if 50\xa0and over\n\nOvarian\n\nCarry out tests in primary care [1.5.2]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\n# Non‑specific features of cancer\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nAppetite loss (unexplained)\n\nSeveral, including lung, oesophageal, stomach, colorectal, pancreatic, bladder or renal\n\nCarry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely\n\nOffer urgent investigation or a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.13.3]\n\nAppetite loss (unexplained), 40\xa0and over, ever smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nAppetite loss (unexplained), 40\xa0and over, exposed to asbestos\n\nMesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.5]\n\nAppetite loss (unexplained) with cough or fatigue or shortness of breath or chest pain or weight loss (unexplained), 40\xa0and over\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nAppetite loss or early satiety (persistent or frequent – particularly more than 12\xa0times per month) in women, especially if 50\xa0and over\n\nOvarian\n\nCarry out tests in primary care [1.5.2]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nDeep vein thrombosis\n\nSeveral, including urogenital, breast, colorectal and lung\n\nCarry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely\n\nConsider urgent investigation or a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.13.4]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nDiabetes (new onset) with weight loss, 60 and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or urgent ultrasound scan if CT is not available [1.2.5]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nFatigue (unexplained), 40\xa0and over, ever smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nFatigue (unexplained), 40\xa0and over, exposed to asbestos\n\nMesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.5]\n\nFatigue with cough or shortness of breath or chest pain or weight loss or appetite loss (unexplained), 40\xa0and over\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nFatigue (persistent) in adults\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nFatigue (unexplained) in women\n\nOvarian\n\nCarry out tests in primary care [1.5.2]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nFever (unexplained)\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nFever with unexplained splenomegaly in adults\n\nNon‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nFever with unexplained lymphadenopathy in adults\n\nHodgkin's lymphoma or non‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.10]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nSee also the section on respiratory symptoms for chest infection.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nInfection (unexplained and persistent or recurrent) in adults\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nNight sweats with unexplained splenomegaly in adults\n\nNon‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nNight sweats with unexplained lymphadenopathy in adults\n\nHodgkin's lymphoma or Non‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.10]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nPallor\n\nLeukaemia\n\nConsider a very urgent full blood count (within 48\xa0hours) [1.10.1]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nPruritus with unexplained splenomegaly in adults\n\nNon‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nPruritus with unexplained lymphadenopathy in adults\n\nHodgkin's lymphoma or non‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.10]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nWeight loss (unexplained)\n\nSeveral, including colorectal, gastro‑oesophageal, lung, prostate, pancreatic or urological cancer\n\nCarry out an assessment for additional symptoms, signs or findings that may help to clarify which cancer is most likely\n\nOffer urgent investigation or a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.13.2]\n\nWeight loss (unexplained) with abdominal pain, 40\xa0and over\n\nColorectal\n\nRefer adults using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.1]\n\nWeight loss (unexplained) with rectal bleeding in adults under 50\n\nColorectal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.3]\n\nWeight loss (unexplained) without rectal bleeding, 50\xa0and over\n\nColorectal\n\nOffer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care) [1.3.4]\n\nWeight loss (unexplained), 40\xa0and over, ever smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nWeight loss (unexplained), 40\xa0and over, exposed to asbestos\n\nMesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.5]\n\nWeight loss with cough or fatigue or shortness of breath or chest pain or appetite loss (unexplained), 40\xa0and over, never smoked\n\nLung or mesothelioma\n\nOffer an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.2] [1.1.5]\n\nWeight loss with unexplained splenomegaly in adults\n\nNon‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nWeight loss with unexplained lymphadenopathy in adults\n\nHodgkin's lymphoma or non‑Hodgkin's lymphoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks). When considering referral, take into account any associated symptoms [1.10.8] [1.10.10]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nWeight loss with upper abdominal pain or reflux or dyspepsia, 55\xa0and over\n\nOesophageal or stomach\n\nOffer urgent direct access upper gastrointestinal endoscopy (to be done within 2\xa0weeks) [1.2.1] [1.2.7]\n\nWeight loss (unexplained) in women\n\nOvarian\n\nConsider carrying out tests in primary care [1.5.3]\n\nMeasure serum CA125 in primary care [1.5.6]\n\nSee the section on primary care investigations for information on tests for ovarian cancer\n\nThese recommendations apply to women aged 18\xa0and over\n\nWeight loss with diarrhoea or back pain or abdominal pain or nausea or vomiting or constipation or new‑onset diabetes, 60\xa0and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available [1.2.5]\n\nWeight loss with raised platelet count or nausea or vomiting, 55\xa0and over\n\nOesophageal or stomach\n\nConsider non-urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\n# Primary care investigations\n\nInvestigation findings and specific features\n\nPossible cancer\n\nRecommendation\n\nAnaemia (iron‑deficiency), 60\xa0and over\n\nColorectal\n\nRefer adults using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.1]\n\nAnaemia (iron‑deficiency, unexplained) with rectal bleeding in adults under 50\n\nColorectal\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.3]\n\nAnaemia (iron deficiency) without rectal bleeding, adults under 60\n\nColorectal\n\nOffer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care) [1.3.4]\n\nAnaemia (non-iron-deficiency), without rectal bleeding, 60\xa0and over\n\nColorectal\n\nOffer testing with quantitative faecal immunochemical tests (see the NICE diagnostics guidance on quantitative faecal immunochemical tests to guide referral for colorectal cancer in primary care) [1.3.4]\n\nBlood glucose levels high with visible haematuria in women 55\xa0and over\n\nEndometrial\n\nConsider a direct access ultrasound scan [1.5.12]\n\nDiabetes (new‑onset) with weight loss, 60\xa0and over\n\nPancreatic\n\nConsider an urgent direct access CT scan (to be done within 2\xa0weeks), or an urgent ultrasound scan if CT is not available [1.2.5]\n\nHaemoglobin levels low with visible haematuria in women 55\xa0and over\n\nEndometrial\n\nConsider a direct access ultrasound scan [1.5.12]\n\nHaemoglobin levels low with upper abdominal pain, 55\xa0and over\n\nOesophageal or stomach\n\nConsider non-urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\nHypercalcaemia or leukopenia and presentation consistent with possible myeloma, 60\xa0and over\n\nMyeloma\n\nOffer very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48\xa0hours) [1.10.5]\n\nPlasma viscosity or erythrocyte sedimentation rate and presentation consistent with possible myeloma\n\nMyeloma\n\nConsider very urgent protein electrophoresis and a Bence–Jones protein urine test (within 48\xa0hours) [1.10.6]\n\nPlatelet count raised with nausea or vomiting or weight loss or reflux or dyspepsia or upper abdominal pain, 55\xa0and over\n\nOesophageal or stomach\n\nConsider non‑urgent direct access upper gastrointestinal endoscopy [1.2.3] [1.2.9]\n\nProstate‑specific antigen\n levels above the age‑specific threshold in table 1 plus lower urinary tract symptoms such as nocturia, urinary frequency, hesitancy, urgency or retention or erectile dysfunction or visible haematuria\n\nProstate\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.3]\n\nProtein electrophoresis suggests myeloma\n\nMyeloma\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.10.7]\n\nSerum CA125 results\n\nOvarian\n\nIf serum CA125 is 35\xa0IU/ml or greater, arrange an ultrasound scan of the abdomen and pelvis [1.5.7]\n\nNormal serum CA125 (less than 35\xa0IU/ml), or CA125 of 35\xa0IU/ml or greater but a normal ultrasound:\n\nassess her carefully for other clinical causes of her symptoms and investigate if appropriate\n\nif no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent. [1.5.9]\n\nThese recommendations apply to women aged 18\xa0and over\n\nThrombocytosis, 40\xa0and over\n\nLung\n\nConsider an urgent chest X‑ray (to be done within 2\xa0weeks) [1.1.3]\n\nThrombocytosis with visible haematuria or vaginal discharge (unexplained) in women 55\xa0and over\n\nEndometrial\n\nConsider a direct access ultrasound scan [1.5.12]\n\nWhite cell count raised on a blood test with unexplained non‑visible haematuria, 60\xa0and over\n\nBladder\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.4]\n\nInvestigation findings and specific features\n\nPossible cancer\n\nRecommendation\n\nDermoscopy suggests melanoma of the skin\n\nMelanoma\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.7.2]\n\nExamination findings and specific features\n\nPossible cancer\n\nRecommendation\n\nProstate feels malignant on digital rectal examination\n\nProstate\n\nRefer men using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.6.1]\n\nInvestigation findings and specific features\n\nPossible cancer\n\nRecommendation\n\nOccult blood in faeces\n\nColorectal\n\nRefer adults using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.3.1]\n\nInvestigation findings and specific features\n\nPossible cancer\n\nRecommendation\n\nChest X‑ray suggests lung cancer\n\nLung\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.1.1]\n\nChest X‑ray suggests mesothelioma\n\nMesothelioma\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.1.4]\n\nUltrasound suggests ovarian cancer\n\nOvarian\n\nMake an urgent referral for further investigation [1.5.8]\n\nThese recommendations apply to women aged 18\xa0and over\n\nUltrasound normal with CA125 of 35\xa0IU/ml or greater\n\nOvarian\n\nAssess carefully for other clinical causes of her symptoms and investigate if appropriate\n\nIf no other clinical cause is apparent, advise her to return to her GP if her symptoms become more frequent and/or persistent [1.5.9]\n\nThese recommendations apply to women aged 18\xa0and over\n\nUltrasound\n suggests soft tissue sarcoma or is uncertain and clinical concern persists in adults\n\nSoft tissue sarcoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.11.5]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nX‑ray suggests the possibility of bone sarcoma in adults\n\nBone sarcoma\n\nConsider a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.11.1]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nInvestigation findings and specific features\n\nPossible cancer\n\nRecommendation\n\nJaundice, 40\xa0and over\n\nPancreatic\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.2.4]\n\nInvestigation findings and specific features\n\nPossible cancer\n\nRecommendation\n\nBence–Jones protein urine results suggest myeloma\n\nMyeloma\n\nRefer people using a suspected cancer pathway referral (for an appointment within 2\xa0weeks) [1.10.7]\n\n# Symptoms in children and young people\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nHepatosplenomegaly (unexplained) in children and young people\n\nLeukaemia\n\nRefer for immediate specialist assessment [1.10.2]\n\nAbdominal mass (palpable) or enlarged abdominal organ (unexplained) in children\n\nNeuroblastoma or Wilms' tumour\n\nConsider very urgent referral (for an appointment within 48\xa0hours) for specialist assessment [1.12.1] [1.12.3]\n\nSplenomegaly (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss [1.10.9]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nPetechiae (unexplained) in children and young people\n\nLeukaemia\n\nRefer for immediate specialist assessment [1.10.2]\n\nBleeding or bruising (unexplained) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nLymphadenopathy (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss [1.10.9] [1.10.11]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nLymphadenopathy (generalised) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nLump (unexplained) that is increasing in size in children and young people\n\nSoft tissue sarcoma\n\nConsider a very urgent direct access ultrasound scan (to be done within 48\xa0hours) [1.11.6]\n\nSee the section on primary care investigations for more information on ultrasound scans\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nSee also the section on abdominal symptoms for abdominal mass or unexplained enlarged abdominal organ, splenomegaly and hepatosplenomegaly.\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nNewly abnormal cerebellar or other central neurological function in children and young people\n\nBrain or central nervous system cancer\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) [1.9.2]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nShortness of breath with lymphadenopathy in children and young people\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9] [1.10.11]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nShortness of breath with splenomegaly (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nBone pain (persistent or unexplained) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nBone pain (unexplained) in children and young people\n\nBone sarcoma\n\nConsider a very urgent direct access X‑ray (to be done within 48\xa0hours) [1.11.3]\n\nSee the section on primary care investigations for more information on X‑rays\n\nBone swelling (unexplained) in children and young people\n\nBone sarcoma\n\nConsider a very urgent direct access X‑ray (to be done within 48\xa0hours) [1.11.3]\n\nSee the section on primary care investigations for more information on X‑rays\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nPetechiae (unexplained) in children and young people\n\nLeukaemia\n\nRefer for immediate specialist assessment [1.10.2]\n\nBruising (unexplained) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nPallor in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nHaematuria (visible and unexplained) in children\n\nWilms' tumour\n\nConsider very urgent referral (for an appointment within 48\xa0hours) for specialist assessment [1.12.3]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nFatigue (persistent) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nFever with lymphadenopathy (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9] [1.10.11]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nFever with splenomegaly (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nFever (unexplained) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nInfection (unexplained and persistent) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nLymphadenopathy (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms, particularly fever, night sweats, shortness of breath, pruritus or weight loss [1.10.9] [1.10.11]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nLymphadenopathy (generalised) in children and young people\n\nLeukaemia\n\nOffer a very urgent full blood count (within 48\xa0hours) [1.10.3]\n\nNight sweats with lymphadenopathy (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9] [1.10.11]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nNight sweats with splenomegaly (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nPruritus with lymphadenopathy (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9] [1.10.11]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nPruritus with splenomegaly (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nWeight loss with lymphadenopathy (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma or Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment in children and young people. When considering referral, take into account any associated symptoms [1.10.9] [1.10.11]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nWeight loss with splenomegaly (unexplained) in children and young people\n\nNon‑Hodgkin's lymphoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment. When considering referral, take into account any associated symptoms [1.10.9]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nExamination findings and specific features\n\nPossible cancer\n\nRecommendation\n\nAbsent red reflex in children\n\nRetinoblastoma\n\nConsider urgent referral (for an appointment within 2\xa0weeks) for ophthalmological assessment [1.12.2]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nParental or carer insight, concern or anxiety about the child's or young person's symptoms (persistent)\n\nChildhood cancer\n\nTake into account the insight and knowledge of parents and carers when considering making a referral for suspected cancer in a child or young person\n\nConsider referral for children if their parent or carer has persistent concern or anxiety about the child's symptoms, even if the symptoms are most likely to have a benign cause [1.13.1]\n\nSymptom and specific features\n\nPossible cancer\n\nRecommendation\n\nUltrasound scan suggests soft tissue sarcoma or is uncertain and clinical concern persists in children and young people\n\nSoft tissue sarcoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment [1.11.7]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements\n\nX‑ray suggests the possibility of bone sarcoma in children and young people\n\nBone sarcoma\n\nConsider a very urgent referral (for an appointment within 48\xa0hours) for specialist assessment [1.11.2]\n\nSeparate recommendations have been made for adults and for children and young people to reflect that there are different referral pathways. In practice young people (aged 16\xa0to 24) may be referred using either pathway depending on their age and local arrangements", 'Terms used in this guideline': '# Children\n\nFrom birth to 15\xa0years.\n\n# Children and young people\n\nFrom birth to 24\xa0years.\n\n# Consistent with\n\nThe finding has characteristics that could be caused by many things, including cancer.\n\n# Direct access\n\nWhen a test is done and primary care retain clinical responsibility throughout, including acting on the result.\n\n# Immediate\n\nAn acute admission or referral occurring within a few hours, or even more quickly if necessary.\n\n# Non‑urgent\n\nThe timescale generally used for a referral or investigation that is not considered very urgent or urgent.\n\n# Persistent\n\nThe continuation of specified symptoms and/or signs beyond a period that would normally be associated with self‑limiting problems. The precise period will vary depending on the severity of symptoms and associated features, as assessed by the health professional.\n\n# Raises the suspicion of\n\nA mass or lesion that has an appearance or a feel that makes the healthcare professional believe cancer is a significant possibility.\n\n# Safety netting\n\nThe active monitoring in primary care of people who have presented with symptoms. It has 2\xa0separate aspects:\n\ntimely review and action after investigations\n\nactive monitoring of symptoms in people at low risk (but not no risk) of having cancer to see if their risk of cancer changes.\n\n# Suspected cancer pathway referral\n\nThe patient is seen within the national target for cancer referrals (2\xa0weeks at the time of publication of this guideline).\n\n# Unexplained\n\nSymptoms or signs that have not led to a diagnosis being made by the healthcare professional in primary care after initial assessment (including history, examination and any primary care investigations).\n\n# Urgent\n\nTo happen or be done before 2\xa0weeks. An urgent referral means that the woman is referred to a gynaecological cancer service within the national target in England and Wales for referral for suspected cancer, which is currently 2\xa0weeks.\n\n# Very urgent\n\nTo happen within 48\xa0hours.\n\n# Young people\n\nAged 16\xa0to 24\xa0years.', 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Age thresholds in cancer\n\nLongitudinal studies should be carried out to identify and quantify factors in adults that are associated with development of specific cancers at a younger age than the norm. They should be designed to inform age thresholds in clinical guidance. The primary outcome should be likelihood ratios and positive predictive values for cancer occurring in younger age groups.\n\n## Primary care testing\n\nDiagnostic accuracy studies of tests accessible to primary care should be carried out for a given cancer in symptomatic people. Priority areas for research should include tests for people with cough, non-visible haematuria, suspected prostate cancer, suspected pancreatic cancer, suspected cancer in childhood and young people and other suspected rare cancers. Outcomes of interest are the performance characteristics of the test, particularly sensitivity, specificity and positive and negative predictive values.\n\n## Cancers insufficiently researched in primary care\n\nObservational studies of symptomatic primary care patients should be used to estimate the positive predictive value of different symptoms for specific cancers. Priority areas for research are those where the evidence base is currently insufficient and should include prostate cancer, pancreatic cancer, cancer in childhood and young people and other rare cancers. Outcomes of interest are positive predictive values and likelihood ratios for cancer.\n\n## Patient experience\n\nQualitative studies are needed to assess the key issues in patient experience and patient information needs in the cancer diagnostic pathway, particularly in the interval between first presentation to primary care and first appointment in secondary care. Outcomes of interest are patient satisfaction, quality of life and patient perception of the quality of care and information.\n\n## Prostate-specific antigen testing\n\nWhat is the diagnostic accuracy of using age-adjusted and fixed prostate-specific antigen thresholds for people with symptoms of prostate cancer, including those at high risk of developing prostate cancer (such as those with an African family background or a family history of prostate cancer)?\n\nFor a short explanation of why the committee made the recommendation for research see the rationale section on prostate-specific antigen testing for prostate cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: PSA testing for prostate cancer.\n\nLoading. Please wait.", 'Rationale and impact': "This section briefly explains why the committee made the recommendation and how it might affect practice.\n\n# Prostate-specific antigen testing for prostate cancer\n\nRecommendation 1.6.3\n\n## Why the committee made the recommendation\n\nThe evidence on the diagnostic accuracy of fixed and age-specific prostate-specific antigen (PSA) thresholds was very uncertain because all of the studies were based on a population that had already been referred to secondary care. The 2019 guideline recommended referral if PSA levels were above the age-specific reference range. The committee agreed that referral should be considered based on PSA thresholds, but did not make a stronger recommendation because of the uncertainty in the evidence and the likely low positive predictive value of the PSA test for prevalence estimates based on UK population data. The committee noted that many prostate cancers are slow growing and might never impact a person's life expectancy. Some people might choose not to be referred to secondary care to avoid invasive investigations and treatment that might not benefit them. Therefore, the committee agreed that a patient-centred approach to referral is important, and recommended that the person's preferences and any comorbidities should be taken into account.\n\nThe committee agreed that more research is needed in this area to better understand the most appropriate thresholds that should prompt referral to secondary care for each age group. The committee noted that ethnicity and family history are important factors that affect the risk of prostate cancer. Therefore, they recommended that the data from research be stratified by these factors to determine whether different PSA levels should prompt referral in these groups. Research in this area may also help to address health inequalities in prostate cancer diagnosis and outcomes in the UK.\n\nThere was no strong evidence to differentiate between using age-specific or fixed PSA thresholds. The committee also noted that no cost-effectiveness evidence comparing age-specific thresholds with fixed thresholds was identified. However, because PSA levels increase naturally with age, the committee agreed a lower fixed PSA threshold would detect more cases of prostate cancer but also lead to unnecessary biopsies and overtreatment in some age groups. This would also be likely to result in more referrals to secondary care and have a significant impact on NHS resources. The committee therefore recommended the use of age-specific thresholds, which are already established in current practice and were recommended in the previous version of the guideline. Because of regional variations in practice (particularly in the 50\xa0to 69 age range), the committee decided to define the age-specific PSA thresholds. The committee agreed that the thresholds used in the reviewed studies on people with symptoms of possible prostate cancer should be used in the absence of evidence to support alternative values, because these studies were most applicable to the population that the recommendation applies to. No evidence was available specifically for people under\xa040 or over\xa079, and so the committee recommended that clinical judgement is used when deciding whether to refer people in these groups to secondary care.\n\n## How the recommendation might affect practice\n\nReferral based on age-specific PSA thresholds is already recommended, so practice should not change significantly. Also, clarifying the age-specific thresholds will help standardise care. Taking into account patient preferences and comorbidities should also lead to a more patient-centred approach to referral.\n\nReturn to recommendation", 'Context': "Cancer has an enormous impact, both in terms of the number of people affected by it and the individual impact it has on people with cancer and those close to them. More than 300,000\xa0new cancers (excluding skin cancers) are diagnosed annually in the UK, across over 200\xa0different cancer types. Each of these cancer types has different presenting features, though they sometimes overlap. Approximately one‑third of the population will develop a cancer in their lifetime. There is considerable variation in referral and testing for possible cancer, which cannot be fully explained by variation in the population.\n\nThe identification of people with possible cancer usually happens in primary care, because most people first present to a primary care clinician. Therefore, evidence from primary care should inform the identification process and was used as the basis for this guideline.\n\nThe recommendations were developed using a 'risk threshold', whereby if the risk of symptoms being caused by cancer is above a certain level, then action (investigation or referral) is warranted. The positive predictive value (PPV) was used to determine the threshold. In the previous guideline, a disparate range of percentage risks of cancer was used to form the recommendations. Few corresponded with a PPV of lower than 5%. The guideline development group (GDG) felt that, in order to improve diagnosis of cancer, a PPV threshold lower than 5% was preferable. Taking into account the financial and clinical costs of broadening the recommendations, the GDG agreed to use a 3% PPV threshold value to underpin the recommendations for suspected cancer pathway referrals and urgent direct access investigations, such as brain scanning or endoscopy. Certain exceptions to a 3% PPV threshold were agreed. Recommendations were made for children and young people at below the 3% PPV threshold, although no explicit threshold value was set. The threshold was not applied to recommendations relating to tests routinely available in primary care (including blood tests such as prostate‑specific antigen and imaging such as chest X‑ray), primary care tests that could be used in place of specialist referral, non‑urgent direct access tests and routine referrals for specialist opinion. Further information about the methods used to underpin the recommendations can be found in the full guideline.\n\nIt is well recognised that some risk factors increase the chance of a person developing cancer in the future, for example, increasing age and a family history of cancer. However, risk factors do not affect the way in which cancer presents. Of the risk factors that were reported in the evidence, only smoking (in lung cancer) and age were found to significantly influence the chance of symptoms being predictive of cancer. Therefore, these are included in the recommendations where relevant. For all other risk factors, the recommendations would be the same for people with possible symptoms of cancer, irrespective of whether they had a risk factor. However, an exception was made to include asbestos exposure in the recommendations because of the high relative risk of mesothelioma in people who have been exposed to asbestos."}
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https://www.nice.org.uk/guidance/ng12
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This guideline covers identifying children, young people and adults with symptoms that could be caused by cancer. It outlines appropriate investigations in primary care, and selection of people to refer for a specialist opinion. It aims to help people understand what to expect if they have symptoms that may suggest cancer.
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816f2a4652e5909c6a841074ebad1b6209bb4bad
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nice
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Prostate cancer: diagnosis and management
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Prostate cancer: diagnosis and management
This guideline covers the diagnosis and management of prostate cancer in secondary care, including information on the best way to diagnose and identify different stages of the disease, and how to manage adverse effects of treatment. It also includes recommendations on follow-up in primary care for people diagnosed with prostate cancer.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information and decision support for people with prostate cancer, their partners and carers
## Information
For advice on communication and patient-centred care throughout the patient journey, follow the recommendations in the NICE guidelines on improving outcomes in urological cancers and improving supportive and palliative care for adults with cancer.
Offer people with prostate cancer information tailored to their own needs. This information should be given by a healthcare professional (for example, a consultant or specialist nurse) and may be supported by written and visual media.
Offer people with prostate cancer advice on how to get information and support from websites, local and national cancer information services, and from cancer support groups.
Choose or recommend information resources for people with prostate cancer that are clear, reliable and up to date. Ask for feedback from people with prostate cancer and their partners or carers to identify the highest quality information resources.
## Decision support
Find out the extent to which the person wishes to be involved in their decision making, and ensure that they have sufficient information to do so.
Use an up-to-date decision aid in all urological cancer multidisciplinary teams (MDTs). Healthcare professionals trained in its use should offer it to people with localised prostate cancer when making treatment decisions.
Use nomograms together with people with prostate cancer to help:
with decision making
predict biopsy results
predict pathological stage
predict risk of treatment failure.
Explain the reliability, validity and limitations of any predictions made using nomograms.
Discuss all relevant management options in this guideline with people with prostate cancer and their partners or carers, even if they are not available through their local services.
Tell people with prostate cancer:
about treatment options and their risks and benefits in an objective, unbiased manner and
that there is limited evidence for some treatment options.
Ensure that mechanisms are in place so people with prostate cancer and their primary care providers have access to specialist services throughout the course of their disease.
Tell people with prostate cancer and their partners or carers about the effects of prostate cancer and the treatment options on their:
sexual function
physical appearance
continence
-ther aspects of masculinity. Support people and their partners or carers in making treatment decisions, taking into account the effects on quality of life as well as survival.
Offer people with prostate cancer, and their partners or carers, the opportunity to talk to a healthcare professional experienced in dealing with psychosexual issues at any stage of the condition and its treatment.
# Assessment and diagnosis
## MRI and biopsy
Do not routinely offer multiparametric MRI to people with prostate cancer who are not going to be able to have radical treatment.
Offer multiparametric MRI as the first-line investigation for people with suspected clinically localised prostate cancer. Report the results using a 5‑point Likert scale.
Offer multiparametric MRI-influenced prostate biopsy to people whose Likert score is 3 or more.
Consider omitting a prostate biopsy for people whose multiparametric MRI Likert score is 1 or 2, but only after discussing the risks and benefits with the person and reaching a shared decision (see box 1). If a person opts to have a biopsy, offer systematic prostate biopsy.
There is more than 1 type of prostate biopsy. The most common approach is transrectal ultrasound-guided (TRUS) biopsy. The data in box 1 comes from the PROMIS and ProtecT studies, which used TRUS. There is no equivalent data for other types of biopsy. The ranges given in box 1 reflect different definitions of clinically significant prostate cancer (UCL1 and UCL2; see PROMIS publications).
Box 1 Factors to consider when discussing the options for people whose multiparametric MRI Likert score is 1 or 2
Advantages of undergoing prostate biopsy
You may have prostate cancer that the MRI scan missed:
between 11 and 28 out of 100 people with a low-risk MRI actually have clinically significant cancer
there are many effective treatments for clinically significant cancer, which work best for disease that is caught early; this means that, if you actually do have clinically significant cancer that the MRI missed, you will have a better chance of long-term survival if the biopsy finds it.
Disadvantages of undergoing prostate biopsy
There is no guarantee that a prostate biopsy will find any disease that is there. Prostate biopsies find less than half of the clinically significant prostate cancers that MRI scans miss.
You may be diagnosed with clinically insignificant prostate cancer. This is disease that is unlikely to be life-threatening, but will need monitoring and may lead to treatment. Therefore, if someone has prostate cancer that truly is clinically insignificant, it is better not to find it. Between 18 and 23 out of 100 people with a low-risk MRI get a diagnosis of clinically insignificant prostate cancer if they have a prostate biopsy.
The most common type of biopsy, transrectal ultrasound-guided (TRUS), has some rare but important complications. The most serious is sepsis, which develops in a bit fewer than 1 out of 100 people. Other serious complications, including acute urinary retention, severe haematuria and severe rectal bleeding may need hospitalisation.
TRUS biopsy has fewer serious complications that make it unpleasant to undergo for some people.
On average:
-ut of 100 people feel light-headed or dizzy immediately after the biopsy
-ut of 100 people report pain; in 15 of them, it will last for at least 2 weeks; 7 will consider it a moderate or serious problem
-ut of 100 people develop a fever; in 3 of them, it will last for at least 2 weeks; 5 will consider it a moderate or serious problem
-ut of 100 people have blood in their urine; in 20 of them, it will last for at least 2 weeks; 6 will consider it a moderate or serious problem
-ut of 100 people have blood in their bowel movements; in 5 of them, it will last for at least 2 weeks; 2 will consider it a moderate or serious problem
-ut of 100 people have blood in their semen; in 60 of them, it will last for at least 2 weeks; 25 will consider it a moderate or serious problem.
Do not offer mapping transperineal template biopsy as part of an initial assessment, unless as part of a clinical trial.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on MRI and biopsy .
Full details of the evidence and the committee's discussion are in evidence review D: diagnosing and identifying clinically significant prostate cancer.
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Help people decide whether to have an MRI or prostate biopsy by discussing:
their prostate-specific antigen (PSA) level
their digital rectal examination (DRE) findings (including an estimate of prostate size)
any comorbidities, together with their risk factors (including increasing age and black African–Caribbean family background)
any history of a previous negative prostate biopsy.Do not automatically offer a prostate biopsy on the basis of serum PSA level alone.
Give people and their partners or carers information, support and adequate time to decide whether or not they wish to have an MRI or prostate biopsy. Explain the risks (including the increased chance of having to live with the diagnosis of clinically insignificant prostate cancer) and benefits.
If the clinical suspicion of prostate cancer is high, because of a high PSA value and evidence of bone metastases (identified by a positive isotope bone scan or sclerotic metastases on plain radiographs), do not offer prostate biopsy for histological confirmation unless this is needed as part of a clinical trial.
Have a core member of the urological cancer MDT review the risk factors of all people who have had a negative first prostate biopsy. Discuss with the person that:
there is still a risk that prostate cancer is present and
the risk is slightly higher if any of the following risk factors are present:
the biopsy showed high-grade prostatic intra-epithelial neoplasia (HGPIN)
the biopsy showed atypical small acinar proliferation (ASAP)
abnormal DRE.
## If the MRI or biopsy is negative
For people with a negative biopsy who have an MRI Likert score of 3 or more, discuss the possibility of significant disease in an MDT meeting with a view to repeating the prostate biopsy.
For people who have a raised PSA and MRI Likert score of 1 or 2, and who have not had a prostate biopsy, repeat PSA test at 3 to 6 months and:
-ffer prostate biopsy if there is a strong suspicion of prostate cancer (for example, PSA density greater than 0.15 nanogram/ml/ml or PSA velocity greater than 0.75 nanogram/ml/year, or strong family history), taking into account their life expectancy and comorbidities
discharge the person to primary care if the level of suspicion is low; advise PSA follow up at 6 months and then every year, and set a PSA level for primary care at which to re‑refer based on PSA density (0.15 nanogram/ml/ml) or velocity (0.75 nanogram/ml/year).
For people who have a raised PSA, an MRI Likert score of 1 or 2 (or a contraindication to MRI), and negative biopsy, repeat PSA at 3 to 6 months and:
-ffer prostate biopsy if there is a strong suspicion of prostate cancer (for example, PSA density greater than 0.15 nanogram/ml/ml or PSA velocity greater than 0.75 nanogram/ml/year, or strong family history), taking into account their life expectancy and comorbidities
discharge the person to primary care if the level of suspicion is low; advise PSA follow up every 2 years, and set a PSA level for primary care at which to re‑refer, based on PSA density (0.15 nanogram/ml/ml) or velocity (0.75 nanogram/ml/year).
The PROGENSA PCA3 assay and the Prostate Health Index is not recommended in people having investigations for suspected prostate cancer who have had a negative or inconclusive prostate biopsy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on if the MRI or biopsy is negative .
Full details of the evidence and the committee's discussion are in evidence review E: following up people at risk of prostate cancer.
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## Staging
Consider CT for people with histologically proven prostate cancer for whom MRI is contraindicated if knowledge of the T or N stage could affect management.
Urological cancer MDTs should assign a risk category (see table 1) to all people with newly diagnosed localised or locally advanced prostate cancer.
Cambridge Prognostic Group
Criteria
Gleason score 6 (grade group 1)
andprostate-specific antigen (PSA) less than 10 microgram/litre
andStages T1–T2
Gleason score 3 + 4 = 7 (grade group 2) or PSA 10 microgram/litre to 20 microgram/litreandStages T1–T2
Gleason score 3 + 4 = 7 (grade group 2) and PSA 10 microgram/litre to 20 microgram/litre and Stages T1–T2orGleason 4 + 3 = 7 (grade group 3) and Stages T1–T2
One of: Gleason score 8 (grade group 4), PSA more than 20 microgram/litre, Stage T3
Two or more of: Gleason score 8 (grade group 4), PSA more than 20 microgram/litre, Stage T3orGleason score 9 to 10 (grade group 5)orStage T4
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on risk stratification for localised or locally advanced prostate cancer
Full details of the evidence and the committee's discussion are in evidence review I: risk stratification for localised prostate cancer.
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Do not routinely offer isotope bone scans to people with Cambridge Prognostic Group (CPG) 1 or 2 localised prostate cancer.
For a short explanation of how the committee amended this recommendation to take into account the 5‑tier CPG risk model and how it might affect practice, see the rationale and impact section on bone scans for newly diagnosed prostate cancer .
Full details of the committee's discussion on how the recommendations were amended to take into account the 5‑tier CPG risk model are in evidence review I: risk stratification for localised prostate cancer.
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Offer isotope bone scans when hormonal therapy is being deferred as part of watchful waiting to asymptomatic people who are at high risk of developing bone complications.
# Localised and locally advanced prostate cancer
Before radical treatment, explain to people and, if they wish, their partner, that radical treatment for prostate cancer will result in an alteration of sexual experience, and may result in loss of sexual function.
Explain to people and, if they wish, their partner, about the potential loss of ejaculation and fertility associated with radical treatment for prostate cancer. Offer sperm storage.
Warn people undergoing radical treatment for prostate cancer of the likely effects of the treatment on their urinary function.
Offer a urological assessment to people who have troublesome urinary symptoms before treatment.
People with prostate cancer who are candidates for radical treatment should have the opportunity to discuss the range of treatment modalities and their serious side effects in relation to their treatment options with a specialist surgical oncologist and a specialist clinical oncologist.
Explain to people that there is a small increase in the risk of colorectal cancer after radical external beam radiotherapy for prostate cancer.
## Treatment options for localised and locally advanced prostate cancer
When discussing treatment options with people with CPG 1, 2 and 3 localised prostate cancer, use box 2 to discuss the benefits and harms with them and refer to the NICE guideline on shared decision making.
Box 2 Factors to consider when discussing active surveillance, radical prostatectomy or radical radiotherapy as treatment options for people with CPG 1, 2 and 3 localised prostate cancer, using evidence from a large UK trial
What are the treatment options for people with localised prostate cancer?
There are 3 options for treatment:
active surveillance (the trial used the intention-to-treat method of analysis and some of the patients in the active surveillance arm may therefore have undergone prostatectomy or radiotherapy during the follow-up period)
radical prostatectomy
radical radiotherapy.
What effect does each treatment option have on survival at 10 years?
The evidence does not show a difference in the number of deaths from prostate cancer among people offered active surveillance, prostatectomy or radical radiotherapy.
People who had not died of prostate cancer were:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
What effect does each treatment option have on disease progression at 10 years?
There is good evidence that both prostatectomy and radiotherapy reduce disease progression compared with active surveillance.
Signs of disease progression were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
The trial defined disease progression as:
evidence of metastases or
diagnosis of clinical T3 or T4 disease or
need for long-term androgen deprivation therapy or
rectal fistula or the need for a urinary catheter owing to local tumour growth.
Disease progression was suspected if there was:
any rise in prostate-specific antigen (PSA) of more than 20% between consecutive measures at any time during follow up or
any rise in PSA level of 50% or more in any 12‑month period confirmed by repeat tests or
any indication of the appearance of symptomatic systemic disease.
What effect does each treatment option have on the rate of development of distant metastases at 10 years?
There is good evidence that both prostatectomy and radiotherapy reduce the rate of development of distant metastases compared with active surveillance.
Distant metastases were developed in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
What effect does each treatment option have on urinary function?
There is some evidence that urinary function is better for people offered active surveillance or radiotherapy than those offered prostatectomy.
At 6 months, problems with urinary continence were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
At 6 years, problems with urinary continence were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
At 6 months, moderate to severe urinary incontinence problems were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
At 6 years, moderate to severe urinary incontinence problems were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
What effect does each treatment option have on erectile dysfunction?
There is some limited evidence that sexual function is better for people offered active surveillance or radiotherapy than those offered prostatectomy.
At 6 months, moderate or severe problems with erectile dysfunction were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
At 6 years, moderate or severe problems with erectile dysfunction were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
What effect does each treatment option have on bowel function?
There is some evidence that bowel function is better for people offered active surveillance or prostatectomy than those offered radiotherapy in the short term.
At 6 months, problems with faecal incontinence more than once per week were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
At 6 years, problems with faecal incontinence more than once per week were reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
At 6 months, moderate to severe impact of bowel habits on quality of life was reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
At 6 years, moderate to severe impact of bowel habits on quality of life was reported in:
-ut of 100 patients offered active surveillance
-ut of 100 patients offered radical prostatectomy
-ut of 100 patients offered radical radiotherapy.
For people with CPG 1 localised prostate cancer:
-ffer active surveillance
consider radical prostatectomy or radical radiotherapy if active surveillance is not suitable or acceptable to the person.
For people with CPG 2 localised prostate cancer, offer a choice between active surveillance, radical prostatectomy or radical radiotherapy if radical treatment is suitable.
For people with CPG 3 localised prostate cancer:
-ffer radical prostatectomy or radical radiotherapy and
consider active surveillance (in line with recommendation 1.3.14) for people who choose not to have immediate radical treatment.
Do not offer active surveillance to people with CPG 4 and 5 localised and locally advanced prostate cancer.
Offer radical prostatectomy or radical radiotherapy to people with CPG 4 and 5 localised and locally advanced prostate cancer when it is likely the person's cancer can be controlled in the long term.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment options for localised and locally advanced prostate cancer .
Full details of the evidence and the committee's discussion are in evidence review G: active surveillance, radical prostatectomy or radical radiotherapy in people with localised prostate cancer. Full details of the committee's discussion on how the recommendations were amended to take into account the 5‑tier CPG risk model are in evidence review I: risk stratification for localised prostate cancer.
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## Multiparametric MRI and protocol for active surveillance
Offer multiparametric MRI to people having active surveillance who have not had an MRI previously. If the MRI results do not agree with the biopsy findings, offer a new MRI-influenced biopsy.
Consider using the protocol in table 2 for people who have chosen active surveillance.
Timing
Tests (if there is concern about clinical or prostate-specific antigen changes at any time during active surveillance, reassess with multiparametric MRI and/or re‑biopsy)
Year 1 of active surveillance
Every 3 to 4 months: measure prostate-specific antigen (PSA; could be carried out in primary care if there are agreed shared-care protocols and recall systems)
Throughout active surveillance: monitor PSA kinetics (could include PSA density and velocity)
At 12 months: digital rectal examination (DRE; should be done by a healthcare professional with expertise and confidence in performing DRE. In a large UK trial that informed this protocol, DREs were carried out by a urologist or a nurse specialist)
At 12 to 18 months: multiparametric MRI
Year 2 and every year thereafter until active surveillance ends
Every 6 months: measure PSA (could be carried out in primary care if there are agreed shared-care protocols and recall systems)
Throughout active surveillance: monitor PSA kinetics (could include PSA density and velocity)
Every 12 months: DRE (should be done by a healthcare professional with expertise and confidence in performing DRE. In a large UK trial that informed this protocol, DREs were carried out by a urologist or a nurse specialist)
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multiparametric MRI for active surveillance .
Full details of the evidence and the committee's discussion are in evidence review F: identifying prostate cancer clinical progression in people with low- to intermediate-risk cancer.
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If a person wishes to move from active surveillance to radical treatment at any stage in their care, make a shared decision to do so based on the person's preferences, comorbidities and life expectancy.
Offer radical treatment to people with localised prostate cancer who had chosen an active surveillance regimen and who now have evidence of disease progression.
## Radical treatment
Commissioners of urology services should consider providing robotic surgery to treat localised prostate cancer.
Commissioners should base robotic systems for the surgical treatment of localised prostate cancer in centres that are expected to perform at least 150 robot-assisted laparoscopic radical prostatectomies per year to ensure they are cost effective.
For people having radical external beam radiotherapy for localised prostate cancer:
-ffer hypofractionated radiotherapy (60 Gy in 20 fractions) using image-guided intensity modulated radiation therapy (IMRT), unless contraindicated or
-ffer conventional radiotherapy (74 Gy in 37 fractions) to people who cannot have hypofractionated radiotherapy.
Offer people with localised and locally advanced prostate cancer receiving radical external beam radiotherapy with curative intent planned treatment techniques that optimise the dose to the tumour while minimising the risks of normal tissue damage.
Offer people with CPG 2, 3, 4 and 5 localised or locally advanced prostate cancer a combination of radical radiotherapy and androgen deprivation therapy, rather than radical radiotherapy or androgen deprivation therapy alone.
Offer people with CPG 2, 3, 4 and 5 localised or locally advanced prostate cancer 6 months of androgen deprivation therapy before, during or after radical external beam radiotherapy.
Consider continuing androgen deprivation therapy for up to 3 years for people with CPG 4 and 5 localised or locally advanced prostate cancer, and discuss the benefits and risks of this option with them.
Consider brachytherapy in combination with external beam radiotherapy for people with CPG 2, 3, 4 and 5 localised or locally advanced prostate cancer.
Do not offer brachytherapy alone to people with CPG 4 and 5 localised or locally advanced prostate cancer.
For a short explanation of why the committee made the recommendations on radiotherapy and how they might affect practice, see the rationale and impact section on radiotherapy .
Full details of the evidence and the committee's discussion are in evidence review C: radical radiotherapy. Full details of the committee's discussion on how the recommendations were amended to take into account the 5-tier CPG risk model are in evidence review I: risk stratification for localised prostate cancer.
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Discuss the option of docetaxel chemotherapy with people who have newly diagnosed non‑metastatic prostate cancer who:
are starting long-term androgen deprivation therapy and
have no significant comorbidities and
have high-risk disease, as shown by:
T3/T4 staging or
Gleason score 8 to 10 or
PSA greater than 40 microgram/litre.Explain the benefits and harms (see box 3) and make a shared decision about whether the person should have this treatment. In May 2019, this was an off-label use of docetaxel. See NICE's guidance on prescribing medicines for further information.
For people having docetaxel chemotherapy:
start treatment within 12 weeks of starting androgen deprivation therapy
use six 3‑weekly cycles at a dose of 75 mg/m2 (with or without daily prednisolone).
Do not offer high-intensity focused ultrasound and cryotherapy to people with localised prostate cancer, other than in the context of controlled clinical trials comparing their use with established interventions. NICE's interventional procedures guidance on high-intensity focused ultrasound for prostate cancer, cryotherapy for recurrent prostate cancer and cryotherapy as a primary treatment for prostate cancer evaluated the safety and efficacy of cryotherapy and high-intensity focused ultrasound for the treatment of prostate cancer. NICE guidelines provide guidance on the appropriate treatment and care of people with specific diseases and conditions within the NHS. Because there was a lack of evidence on quality-of-life benefits and long-term survival, these interventions are not recommended in this guideline.NICE's interventional procedures guidance on focal therapy using high-intensity focused ultrasound for localised prostate cancer and focal therapy using cryoablation for localised prostate cancer found no major safety concerns, but evidence on efficacy is limited in quantity and there is a concern that prostate cancer is commonly multifocal.
Box 3 Factors to consider when discussing the option of docetaxel chemotherapy for people with high-risk, non-metastatic prostate cancer
What does treatment with docetaxel involve?
Docetaxel chemotherapy is given at 6 appointments, each 3 weeks apart. It is given as an intravenous infusion that takes about 1 hour.
What are the benefits of docetaxel treatment for people with high-risk, non-metastatic prostate cancer?
There is clear, high-quality evidence that docetaxel chemotherapy delays disease progression in people with high-risk, non-metastatic disease.
In a large UK randomised trial (James et al. 2016), the average person who did not receive docetaxel experienced disease progression about 5 years after the start of the trial, whereas the average person receiving docetaxel experienced disease progression after about 6 years.
We do not yet know whether docetaxel improves survival in people with high-risk, non-metastatic disease and we will only be confident about whether it does when trials have been running for longer.
In a large UK randomised trial, 80 out of 100 people with high-risk disease who did not receive docetaxel were still alive after 5 years compared with 84 out of 100 people who did. However, this difference could be because of chance.
What are the risks associated with docetaxel treatment?
A large UK randomised trial found that:
-ut of 100 people who took docetaxel developed febrile neutropenia (that is, they got a fever because the chemotherapy had reduced their white blood cells' ability to fight infection).
-ut of 100 people who took docetaxel died because of infections that, in the opinion of the investigators, they might not have developed if they had not received docetaxel.
-ut of 100 people who took docetaxel felt unusually weak or tired.
-ut of 100 people who took docetaxel experienced gastrointestinal symptoms (including diarrhoea, abdominal pain, constipation and/or vomiting).
-ut of 100 people who took docetaxel experienced respiratory symptoms (including breathlessness and/or chest infections).
-ut of 100 people who took docetaxel experienced problems with their nervous systems (for example, numbness or weakness).
-ut of 100 people who took docetaxel experienced problems with their nails that were serious enough to interfere with their daily lives.
For a short explanation of why the committee made the recommendations on docetaxel chemotherapy and how they might affect practice, see the rationale and impact section on docetaxel chemotherapy .
Full details of the evidence and the committee's discussion are in evidence review B: docetaxel in people with hormone-sensitive prostate cancer.
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## Watchful waiting
People with localised prostate cancer who have chosen watchful waiting and who have evidence of significant disease progression (that is, rapidly rising PSA level or bone pain) should have their situation reviewed by a member of the urological cancer MDT.
## Locally advanced prostate cancer
Consider pelvic radiotherapy for people with locally advanced prostate cancer who have a higher than 15% risk of pelvic lymph node involvement and who are to receive neoadjuvant hormonal therapy and radical radiotherapy.
Risk of pelvic node lymph involvement estimated using the Roach formula: %LN risk = 2/3 PSA + (10 × ).
Do not offer immediate post-operative radiotherapy after radical prostatectomy, even to people with margin-positive disease, other than in the context of a clinical trial.
Do not offer adjuvant hormonal therapy in addition to radical prostatectomy, even to people with margin-positive disease, other than in the context of a clinical trial.
Do not offer high-intensity focused ultrasound and cryotherapy to people with locally advanced prostate cancer other than in the context of controlled clinical trials comparing their use with established interventions. NICE's interventional procedures guidance on high-intensity focused ultrasound for prostate cancer, cryotherapy for recurrent prostate cancer and cryotherapy as a primary treatment for prostate cancer evaluated the safety and efficacy of cryotherapy and high-intensity focused ultrasound for the treatment of prostate cancer. NICE guidelines provide guidance on the appropriate treatment and care of people with specific diseases and conditions within the NHS. Because there was a lack of evidence on quality-of-life benefits and long-term survival, these interventions are not recommended in this guideline.
Do not offer bisphosphonates for the prevention of bone metastases in people with prostate cancer.
## Managing adverse effects of radical treatment
Offer people who have had radical treatment for prostate cancer access to specialist erectile dysfunction services.
Offer people with prostate cancer who experience loss of erectile function phosphodiesterase type 5 (PDE5) inhibitors to improve their chance of spontaneous erections.
If PDE5 inhibitors do not restore erectile function or are contraindicated, offer people vacuum devices, intraurethral inserts or penile injections, or penile prostheses as an alternative.
Ensure that people with prostate cancer who have troublesome urinary symptoms after treatment have access to specialist continence services for assessment, diagnosis and conservative treatment. This could include coping strategies, pelvic floor muscle re-education, bladder retraining and pharmacotherapy.
Refer people with prostate cancer who have intractable stress incontinence to a specialist surgeon for consideration of an artificial urinary sphincter.
Do not offer injection of bulking agents into the distal urinary sphincter to treat stress incontinence in people with prostate cancer.
Offer people with signs or symptoms of radiation-induced enteropathy care from a team of professionals with expertise in radiation-induced enteropathy (who may include oncologists, gastroenterologists, bowel surgeons, dietitians and specialist nurses).
Include the nature and treatment of radiation-induced enteropathy in training programmes for oncologists and gastroenterologists.
Carry out full investigations, including flexible sigmoidoscopy, in people who have symptoms of radiation-induced enteropathy to exclude inflammatory bowel disease or malignancy of the large bowel and to ascertain the nature of the radiation injury. Use caution when performing anterior wall rectal biopsy after brachytherapy because of the risk of fistulation.
## Follow up for people with localised or locally advanced prostate cancer having radical treatment or on watchful waiting
A urologist or specialist nurse should discuss the purpose, duration, frequency and location of follow up with each person with localised and locally advanced prostate cancer, and if they wish, their partner or carers.
A urologist or specialist nurse should advise people with prostate cancer about potential longer‑term adverse effects of treatment and when and how to report them.
Check PSA levels for all people with prostate cancer who are having radical treatment no earlier than 6 weeks after treatment, at least every 6 months for the first 2 years, and then at least once a year after that.
Do not routinely offer DRE to people with localised prostate cancer who are not on active surveillance while their PSA remains at baseline levels.
After at least 6 months' initial follow up, consider a remote follow‑up strategy for people with a stable PSA who have had no significant treatment complications, unless they are taking part in a clinical trial that needs formal clinic-based follow up.
Follow up people with prostate cancer who have chosen a watchful waiting regimen with no curative intent in primary care only if protocols for this have been agreed between the local urological cancer MDT and the relevant primary care organisation(s). Measure their PSA at least once a year.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow up .
Full details of the evidence and the committee's discussion are in evidence review H: follow-up protocols after radical treatment.
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## Managing relapse after radical treatment
Analyse serial PSA levels after radical treatment using the same assay technique as used before.
Do not offer biopsy of the prostatic bed to people with prostate cancer who have had a radical prostatectomy.
Only offer biopsy of the prostate after radiotherapy to people with prostate cancer who might have local salvage therapy in the context of a clinical trial.
For people with evidence of biochemical relapse after radical treatment who are thinking about having radical salvage therapy:
do not offer routine MRI scanning before salvage radiotherapy in people with prostate cancer
-ffer an isotope bone scan if symptoms or PSA trends are suggestive of metastases.
Take into account that biochemical relapse (a rising PSA) alone should not mean an immediate change in treatment is needed.
Estimate PSA doubling time if biochemical relapse occurs. Base this on a minimum of 3 measurements over at least a 6‑month period.
Offer people with biochemical relapse after radical prostatectomy, with no known metastases, radical radiotherapy to the prostatic bed.
Consider entry to appropriate clinical trials for people with biochemical relapse.
Do not routinely offer hormonal therapy to people with prostate cancer who have a biochemical relapse unless they have:
symptomatic local disease progression or
any proven metastases or
a PSA doubling time of less than 3 months.
# People having hormone therapy
Consider intermittent therapy for people having long-term androgen deprivation therapy (not in the adjuvant setting). Discuss with the person (and their partner, family or carers if they wish):
the rationale for intermittent therapy
the limited evidence for reduction in side effects from intermittent therapy
the effect of intermittent therapy on progression of prostate cancer.
For people who are having intermittent androgen deprivation therapy:
measure PSA every 3 months and
restart androgen deprivation therapy if PSA is 10 nanogram/ml or above, or if there is symptomatic progression.
## Managing adverse effects of hormone therapy
Offer medroxyprogesterone (20 mg per day), initially for 10 weeks, to manage troublesome hot flushes caused by long-term androgen suppression. Evaluate the effect at the end of the treatment period. In May 2019, this was an off-label use of medroxyprogesterone. See NICE's guidance on prescribing medicines for further information.
Consider cyproterone acetate (50 mg twice a day for 4 weeks) to treat troublesome hot flushes if medroxyprogesterone is not effective or not tolerated.
Tell people that there is no good-quality evidence for the use of complementary therapies to treat troublesome hot flushes.
Before they start androgen deprivation therapy, tell people and, if they wish, their partner, that long-term androgen deprivation will cause a reduction in libido and possible loss of sexual function.
Advise people and, if they wish, their partner, about the potential loss of ejaculation and fertility associated with long-term androgen deprivation and offer sperm storage.
Ensure that people starting androgen deprivation therapy have access to specialist erectile dysfunction services.
Consider referring people who are having long-term androgen deprivation therapy, and their partners, for psychosexual counselling.
Offer PDE5 inhibitors to people having long-term androgen deprivation therapy who experience loss of erectile function.
If PDE5 inhibitors fail to restore erectile function or are contraindicated, offer a choice of:
intraurethral inserts
penile injections
penile prostheses
vacuum devices.
Do not routinely offer bisphosphonates to prevent osteoporosis in people with prostate cancer having androgen deprivation therapy.
Consider assessing fracture risk in people with prostate cancer who are having androgen deprivation therapy, in line with the NICE guideline on osteoporosis: assessing the risk of fragility fracture.
Offer bisphosphonates to people who are having androgen deprivation therapy and have osteoporosis.
Consider denosumab for people who are having androgen deprivation therapy and have osteoporosis if bisphosphonates are contraindicated or not tolerated.
For people starting long-term bicalutamide monotherapy (longer than 6 months), offer prophylactic radiotherapy to both breast buds within the first month of treatment. Use a single fraction of 8 Gy using orthovoltage, or electron beam radiotherapy.
If radiotherapy does not prevent gynaecomastia, consider weekly tamoxifen. In May 2019, this was an off-label use of tamoxifen. See NICE's guidance on prescribing medicines for further information.
Tell people who are starting androgen deprivation therapy that fatigue is a recognised side effect of this therapy, and might not be because of their prostate cancer.
Offer people who are starting or having androgen deprivation therapy supervised resistance and aerobic exercise at least twice a week for 12 weeks to reduce fatigue and improve quality of life.
# Metastatic prostate cancer
## Information and support
Offer people with metastatic prostate cancer tailored information and access to specialist urology and palliative care teams to address their specific needs. Give them the opportunity to discuss any significant changes in their disease status or symptoms as these occur.
Integrate palliative interventions at any stage into coordinated care, and facilitate any transitions between care settings as smoothly as possible.
Discuss personal preferences for palliative care as early as possible with people with metastatic prostate cancer, their partners and carers. Tailor treatment/care plans accordingly, and identify the preferred place of care.
Ensure that palliative care is available when needed and is not limited to the end of life. Care should not be restricted to being associated with hospice care.
Offer a regular assessment of needs to people with metastatic prostate cancer.
## Initial treatment
Offer docetaxel chemotherapy to people with newly diagnosed metastatic prostate cancer who do not have significant comorbidities as follows:
start treatment within 12 weeks of starting androgen deprivation therapy and
use six 3‑weekly cycles at a dose of 75 mg/m2 (with or without daily prednisolone). In May 2019, this was an off-label use of docetaxel. See NICE's guidance on prescribing medicines for further information.
For a short explanation of why the committee made these recommendations and how they might affect practice, see rationale and impact section on docetaxel chemotherapy .
Full details of the evidence and the committee's discussion are in evidence review B: docetaxel in people with hormone-sensitive prostate cancer.
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Offer bilateral orchidectomy to all people with metastatic prostate cancer as an alternative to continuous luteinising hormone-releasing hormone agonist therapy.
Do not offer combined androgen blockade as a first-line treatment for people with metastatic prostate cancer.
For people with metastatic prostate cancer who are willing to accept the adverse impact on overall survival and gynaecomastia with the aim of retaining sexual function, offer anti-androgen monotherapy with bicalutamide (150 mg). In May 2019, this was an off-label use of bicalutamide. See NICE's information on prescribing medicines for further information.
Begin androgen deprivation therapy and stop bicalutamide treatment in people with metastatic prostate cancer who are taking bicalutamide monotherapy and who do not maintain satisfactory sexual function.
## Hormone-relapsed metastatic prostate cancer
Recommendations 1.5.12, 1.5.13 and 1.5.14 are from the NICE technology appraisal guidance on docetaxel for the treatment of hormone-refractory metastatic prostate cancer.
Discuss the treatment options for people with prostate cancer who develop biochemical evidence of hormone-relapsed disease at the urological cancer MDT. Seek an oncologist and/or specialist palliative care opinion, as appropriate.
Docetaxel is recommended, within its licensed indications, as a treatment option for people with hormone-refractory prostate cancer only if their Karnofsky Performance-Status score is 60% or more.
It is recommended that treatment with docetaxel should be stopped:
at the completion of planned treatment of up to 10 cycles or
if severe adverse events occur or
in the presence of progression of disease as evidenced by clinical or laboratory criteria, or by imaging studies.
Repeat cycles of treatment with docetaxel are not recommended if the disease recurs after completion of the planned course of chemotherapy.
Offer a corticosteroid such as dexamethasone (0.5 mg daily) as third-line hormonal therapy after androgen deprivation therapy and anti-androgen therapy to people with hormone-relapsed prostate cancer.
Offer spinal MRI to people with hormone-relapsed prostate cancer shown to have extensive metastases in the spine (for example, on a bone scan) if they develop any spinal-related symptoms.
Do not routinely offer spinal MRI to all people with hormone-relapsed prostate cancer and known bone metastases.
For advice on treatments for metastatic hormone-relapsed prostate cancer previously treated with docetaxel, including genomic biomarker-based treatment, see the NICE technology appraisal guidance on our topic page on prostate cancer. The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain.
## Bone-targeted therapies
For people with hormone-relapsed metastatic prostate cancer, consider zoledronic acid to prevent or reduce skeletal-related events.
Consider oral or intravenous bisphosphonates for pain relief for people with hormone-relapsed metastatic prostate cancer when other treatments, including analgesics and palliative radiotherapy, have not given satisfactory pain relief.
For NICE technology appraisal guidance on treatments for people with bone metastases from prostate cancer, see the NICE technology appraisal guidance on our topic page on prostate cancer.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bone-targeted therapies (bisphosphonates) .
Full details of the evidence and the committee's discussion are in evidence review A: bisphosphonates.
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## Pelvic-targeted therapies
Offer decompression of the upper urinary tract by percutaneous nephrostomy or by insertion of a double J stent to people with obstructive uropathy secondary to hormone-relapsed prostate cancer.
Discuss the option of no intervention as a treatment choice with people with obstructive uropathy secondary to hormone-relapsed prostate cancer.
# Terms used in this guideline
## Active surveillance
This is part of a 'curative' strategy and is aimed at people with localised prostate cancer for whom radical treatments are suitable, keeping them within a 'window of curability' whereby only those whose tumours are showing signs of progressing, or those with a preference for intervention are considered for radical treatment. Active surveillance may thus avoid or delay the need for radiotherapy or surgery.
## External beam radiotherapy (EBRT)
This is radiotherapy given by using ionising radiation (for example, high-energy X‑rays) produced in a machine and directed at the tumour from outside the patient.
## Grade group
This refers to the 2019 International Society of Urological Pathology grade groupings for prostate cancer.
## Hormone-relapsed (also known as hormone-resistant, hormone-refractory and castrate-resistant) prostate cancer
Refers to prostate cancer after failure of primary androgen deprivation therapy.
## Locally advanced prostate cancer
For the purposes of this guideline, this includes T3 and T4 prostate cancer.
## Localised prostate cancer
Cancer that has been staged as T1 or T2 (confined to the prostate gland).
## Multiparametric MRI of the prostate
An MRI study that incorporates anatomical and functional information about the prostate. The minimum functional information includes T2‑weighted, diffusion-weighted imaging and dynamic contrast-enhanced imaging.
## Multiparametric MRI-influenced prostate biopsy
The information from the multiparametric MRI scan taken before prostate biopsy is used to determine the best needle placement. In rare cases, the biopsy may be MRI-guided (the needle is inserted within the MRI machine). In most cases, the biopsy that follows the multiparametric MRI will be ultrasound-guided, but the specific area(s) targeted will be predetermined by the multiparametric MRI data.
## Prostatectomy
Surgery to remove part, or all of the prostate gland. Radical prostatectomy aims at the removal of the entire prostate gland and lymph nodes. This can be done by an open approach or by keyhole technique (laparoscopic or robotically assisted laparoscopic prostatectomy).
## Prostate biopsy
A template biopsy is normally done under a general anaesthetic, and involves taking transperineal core biopsies using a grid system. This might involve taking multiple cores from multiple sites, but usually 2 to 3 cores from 8 sites. A mapping template biopsy is when 20 sites are systematically sampled, with 2 or 3 cores per site, sometimes meaning over 50 core biopsies are taken.
This is sampling 6 or 8 sites from the prostate using a transperineal route under local anaesthetic.
This is when core biopsies of the prostate are taken via the rectum under local anaesthetic.
The site for biopsy can be targeted based on multiparametric MRI findings, or systematically but not guided by MRI. Most often there is a combination of both targeted and systematic MRI. The method used for the biopsy can be either transperineal or TRUS.
## Watchful waiting
This is part of a strategy for 'controlling' rather than 'curing' prostate cancer and is aimed at people with localised prostate cancer who do not ever wish to have curative treatment, or it is not suitable for them. Instead, it involves the deferred use of hormone therapy. Watchful waiting avoids the use of surgery or radiation, but implies that curative treatment will not be attempted.# Recommendations for research
The guideline committee has made the following recommendations for research.
As part of the 2021 update, the guideline committee made an additional recommendation for research on the diagnostic accuracy of staging investigations for Cambridge Prognostic Group (CPG) 3 prostate cancer.
# Key recommendations for research
## Follow up during active surveillance
What is the most suitable surveillance protocol (including the role of digital rectal examination and prostate-specific antigen measures) for people for whom active surveillance is appropriate, as assessed by multiparametric MRI and biopsy, when there are no clinical concerns during follow up?
For a short explanation of why the committee made the recommendation for research, see the rationale section on multiparametric MRI for active surveillance .
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## Follow up after radical treatment
What is the most clinically and cost-effective follow‑up protocol for people with prostate cancer who have had radical treatment, with specific regard to risk stratification, duration of follow up, frequency of follow‑up appointments, the type of examination or blood tests, and the roles of primary and secondary care in follow up?
For a short explanation of why the committee made the recommendation for research, see the rationale section on follow up .
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## Diagnosis of clinically significant cancer
What is the most clinically and cost-effective pathway for diagnosing clinically significant prostate cancer?
For a short explanation of why the committee made the recommendation for research, see the rationale section on MRI and biopsy .
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## Progression of cancer
What is the most clinically and cost-effective pathway for excluding the clinically significant progression of cancer in people with CPG 1, 2 and 3 prostate cancer?
For a short explanation of why the committee made the recommendation for research, see the rationale section on multiparametric MRI for active surveillance .
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## Natural history of prostate cancer
What is the natural history of people with a Likert score on MRI of less than 3 without biopsy at long-term follow up?
For a short explanation of why the committee made the recommendation for research, see the rationale section on MRI and biopsy .
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# Other recommendations for research
## Staging investigations for CPG 3 prostate cancer
What is the diagnostic accuracy of staging investigations for CPG 3 prostate cancer?
For a short explanation of why the committee made the recommendation for research, see the rationale section on risk stratification for localised or locally advanced prostate cancer .
Full details of the evidence and the committee's discussion are in evidence review I: risk stratification for localised prostate cancer.
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## Diagnosing prostate cancer
In patients with negative MRI (Likert score 1 or 2), what is the next best diagnostic investigation to rule out clinically significant prostate cancer?
What is the diagnostic accuracy of transperineal mapping biopsy compared with transperineal non-mapping biopsy in the diagnosis of clinically significant prostate cancer?
## Zoledronic acid
What is the effectiveness and cost effectiveness of different scheduling of zoledronic acid in the prevention and reduction of skeletal events in people with hormone-refractory prostate cancer?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# MRI and biopsy
Recommendations 1.2.1 to 1.2.5
## Why the committee made the recommendations
The committee saw no new evidence to suggest that any changes were needed to the recommendations on imaging in people who are not going to have radical treatment.
There was good evidence that showed that multiparametric MRI is useful in identifying lesions before biopsy, and the combination of MRI with prostate biopsy leads to better identification of clinically significant prostate cancer than systematic prostate biopsy alone. The committee recommended using a 5‑point Likert scale because this scale takes into account clinical factors and not just the lesion size, improving the diagnostic ability of multiparametric MRI.
The committee made a recommendation to consider omitting prostate biopsy for people whose multiparametric MRI Likert score is 1 or 2 because there was some evidence that this is safe to do. However, there is a small risk that in some cases significant cancers may be missed, so the committee recommended clinicians discuss the risk and benefits with the person.
Based on their expertise and economic evidence, the committee recommended not offering mapping transperineal template biopsy as an initial biopsy, because the technique is currently too resource intensive to be used as an initial assessment – it requires general anaesthetic and extensive histological analysis. The committee recognised that this technique could be allowed as part of a clinical trial because it is often used as the benchmark or gold standard test in those trials. The committee did not see any evidence that allowed them to clearly differentiate between transperineal (non-mapping) and transrectal biopsy, so it agreed to refer to 'prostate biopsy' throughout the recommendations.
As there was limited evidence on the most effective pathway for excluding clinically significant progression of prostate cancer in people with low to intermediate risk, the committee made a recommendation for research on this topic. They also identified that there was a gap in the evidence on the most suitable surveillance protocol in this population group.
## How the recommendations might affect practice
The recommendations should not have a significant resource impact as many centres already perform MRI-influenced biopsy. Since all people who have a biopsy will previously have had an MRI, using the MRI to target the biopsy will be more efficient and need fewer biopsy cores to be taken. Health economic evidence shows that MRI-influenced prostate biopsy may be more cost effective than systematic prostate biopsy as it takes less time and is more efficient in identifying clinically significant cancer.
Return to recommendations
# If the MRI or biopsy is negative
Recommendations 1.2.10 to 1.2.13
## Why the committee made the recommendations
There was no clinical evidence in this area, therefore the committee used evidence from economic modelling that showed people with a negative diagnosis of prostate cancer can still be at substantial risk of having prostate cancer, so follow up is important. The evidence showed that the prevalence of initially undetected, but clinically significant, prostate cancer varies based on a person's diagnostic history, so their diagnostic history should influence the frequency of follow up.
The committee recommended that people with a Likert 3 score should be discussed at a multidisciplinary team (MDT) meeting. It made the recommendation because these cases can be difficult to deal with. Scoring of scans may fluctuate by 20% between raters and therefore a discussion in an MDT is warranted. The committee noted that this does not necessarily imply the full cancer MDT, but is subject to local arrangement.
The follow-up strategies recommended for primary care are based on standard prostate-specific antigen (PSA) tests, with which primary care healthcare professionals are familiar. The committee agreed it was important that specialist healthcare professionals should calculate thresholds for re‑referral and provide these when discharging people, rather than expecting the calculations to be made in primary care.
The recommendations in NICE's previous guidance on PCA3 assay and the Prostate Health Index (NICE diagnostic guidance 17) are updated by this guideline. The committee saw no evidence that either technique represents an effective use of NHS resources in the follow up of people who have had a negative transrectal ultrasound-guided (TRUS) prostate biopsy, and therefore the committee did not recommend use of these technologies.
The committee identified a gap in the evidence for the performance of transperineal route (non-mapping) biopsy, and therefore made a recommendation for research in this area.
The committee also noted that there is limited long-term follow‑up evidence on the natural history of people whose multiparametric MRI Likert score is 1 or 2. In addition, there is limited evidence on the number of people whose multiparametric MRI is Likert score 1 or 2, who have normal PSA density and kinetics and who are found to have clinically significant cancer. Further recommendations for research were made in these areas to help provide evidence across the prostate cancer treatment pathway.
## How the recommendations might affect practice
Currently, there is substantial variation in clinical practice in the follow up of people with a negative prostate biopsy. The committee's recommendations should help to standardise practice.
Other recommendations made by the committee make it likely that more people will have a negative diagnosis on the basis of low-risk multiparametric MRI findings and no biopsy. This is a new population who will need effective follow‑up strategies, and the recommendations give guidance on approaches that are likely to provide a good balance of benefits, harms and costs for this group.
The committee were confident that none of the recommendations would have a significant resource impact, as they are based on PSA measurements that are commonly used within primary care settings. In addition, if further multiparametric MRI is needed during follow up, the evidence showed that MRI-influenced prostate biopsy may be more cost effective than systematic prostate biopsy, as it takes less time and is more efficient in identifying clinically significant cancer.
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# Risk stratification for localised or locally advanced prostate cancer
Recommendation 1.2.15
## Why the committee made the recommendation
The 2019 guideline used a 3‑tier model for risk stratification. The committee agreed that newer evidence shows 5‑tier risk stratification models are better at predicting prostate cancer-specific mortality than 3‑tier models. More accurate prognosis will mean that more people are given the most effective treatment. The committee recommended the 5‑tier Cambridge Prognostic Group (CPG) model over other 5‑tier models because it has been tested in UK populations.
## Impact on other recommendations
The committee considered the impact of recommending the CPG risk stratification model on other recommendations in the guideline. Recommendations were amended as necessary, taking into account the original evidence for each recommendation and the committee's knowledge and experience.
## How the recommendation might affect practice
The committee were confident that recommending the 5‑tier CPG risk stratification model would not have a significant resource impact. This was because PSA, Gleason score and clinical stage are used to calculate both the CPG model and the previously recommended 3‑tier model. The CPG uses an integrated tumour (T) stage based on combined clinical, radiological and pathological information to classify T1, T2, T3 and T4 cancers without further sub-division. MDTs will need to be aware of the new 5‑tier model when assessing patient risk.
Under the 5‑tier CPG risk stratification model more people would be in the lowest risk group (CPG 1) than were previously categorised as 'low risk'. The previous 'intermediate-risk' group now consists of some people in CPG 1, and all people in CPG 2 and CPG 3, and recommendations that were previously for people at 'intermediate risk' would now apply to a smaller group. Most people in CPG 4 and CPG 5 align to the previous 'high-risk' group, so the number of people in this category would not substantially change. These changes are not expected to affect treatment choices in a way that would have a significant resource impact.
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# Bone scans for newly diagnosed prostate cancer
Recommendation 1.2.16
## Why the committee made the recommendation
The 2019 guideline recommended that bone scans should not be used for people with low-risk prostate cancer. This recommendation was amended to refer to the CPG 1 and 2 populations. The committee were aware that this population is broader than the original low-risk population, but agreed that it was in line with current practice not to offer bone scans to these groups because they have very low risks of bone metastases. The committee highlighted the lack of evidence on when to offer staging investigations to the CPG 3 group and the potential resource impact of the investigations, and made a recommendation for research in this area.
## How the recommendation might affect practice
Recommendations where low risk was replaced with CPG 1 and 2 will apply to a broader population due to the inclusion of people with T2b prostate cancer. However, the committee agreed that the associated resource impact of this change would be minimal because it is in line with current practice.
Return to recommendation
# Treatment options for localised and locally advanced prostate cancer
Recommendations 1.3.7 to 1.3.12
## Why the committee made the recommendations
The committee agreed that active surveillance, radical radiotherapy and radical prostatectomy may be suitable for different people. Therefore, it included a preference decision box for clinicians to use to help people with prostate cancer make the right choice for themselves. The information in the box comes from the UK ProtecT trial, which included people with CPG 1 to 3 prostate cancer. However, the committee noted that people with CPG 3 prostate cancer comprised a small proportion of the people in this trial. Therefore, the information in the box might not directly apply to this group, but may still be useful when discussing the risk of side effects for different treatment options.
The 2019 guideline recommended that a choice of active surveillance, radical radiotherapy or radical prostatectomy should be offered to people with low-risk prostate cancer (equivalent to the CPG 1 group in the 5‑tier model that is now recommended). The committee noted that since the 2019 guideline was published, practice in this area has changed and there is now more concern about overtreatment of low-risk cancer. They noted that the UK ProtecT trial, which is most applicable to the population with CPG 1 prostate cancer, showed statistically significant benefit from radical treatment and a higher risk of adverse events. It was therefore recommended that active surveillance should be offered to people with CPG 1 prostate cancer and radical treatment considered if active surveillance is not acceptable or unsuitable.
In the 2019 guideline, radical treatment was recommended for people with intermediate-risk prostate cancer, with active surveillance considered if this was unacceptable to the person with prostate cancer. The CPG model divides this intermediate-risk group into CPG 2 and CPG 3 prostate cancer and the committee made different recommendations for these groups because they have different risks of prostate cancer related mortality. The committee recommended that people with CPG 2 prostate cancer should be offered a choice of radical prostatectomy, radical radiotherapy or active surveillance. The ProtecT trial included people with CPG 2 prostate cancer. However, the risk of prostate cancer related mortality is higher in the CPG 2 population than in people with CPG 1 prostate cancer and so the choice between active surveillance and radical treatment is more finely balanced.
Radical prostatectomy or radical radiotherapy was recommended for people with CPG 3 prostate cancer, in line with the 2019 recommendation for people with intermediate-risk prostate cancer. This is because the risk of prostate cancer related mortality is higher for this group than the CPG 2 group and the committee thought that the survival benefit from radical treatment would likely outweigh the side effects. The committee also recommended that active surveillance could be considered if radical treatment is unacceptable to the patient, in line with the 2019 recommendation.
The 2019 recommendation not to offer active surveillance to people with high-risk prostate cancer was updated to refer to people with CPG 4 and 5 prostate cancer. The committee agreed that these groups were equivalent, and that active surveillance would not be a suitable treatment option for these people.
## How the recommendations might affect practice
Recommendations where low risk was replaced with CPG 1 are likely to apply to a broader population due to the inclusion of people with T2b prostate cancer. However, the committee agreed that the associated resource impact of this change would be minimal because although there is more emphasis on active surveillance, the other treatment options are still available.
Return to recommendations
# Multiparametric MRI for active surveillance
Recommendations 1.3.13 and 1.3.14
## Why the committee made the recommendations
The committee made recommendations based on a good body of evidence that multiparametric MRI can be used as part of an active surveillance protocol to identify clinically significant cancer, or restage prostate cancer after diagnosis. The committee took into account the benefits seen in using multiparametric MRI pre‑biopsy in people who have not had a biopsy and who have suspected prostate cancer. The committee concluded that this benefit can be extended to people having active surveillance without having had an MRI to allow for confirmation or reclassification of the prostate cancer.
The committee amended the protocol for active surveillance based on their expertise and good evidence on PSA-derived measures to monitor, and the use of multiparametric MRI to identify, clinically significant prostate cancer. The committee kept the use of digital rectal examination (DRE) in this population because they did not see any new evidence to not recommend it for this group. In addition, DRE was part of the protocol in 1 of the studies included in the evidence review.
Because of the limited evidence on the most effective pathway for excluding clinically significant progression of prostate cancer in people with low to intermediate risk, the committee made recommendations for research in this area. They also identified that there was a gap in the evidence on the most suitable surveillance protocol for this population group, including the use of DRE.
## How the recommendations might affect practice
The use of multiparametric MRI in people who are enrolled on active surveillance will influence active surveillance protocols across the country. Multiparametric MRI is clinically and cost effective, because clinically significant cancers are more likely to be identified, therefore decisions on treatment can be made earlier in the diagnosis pathway saving on future treatment costs.
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# Radiotherapy
Recommendations 1.3.19 and 1.3.21 to 1.3.25
## Why the committee made the recommendations
The 2014 and 2019 recommendations on hormone treatment and brachytherapy for intermediate and high-risk prostate cancer were amended to cover the CPG 2 to 5 groups. The committee agreed these groups are broadly equivalent to the groups in the 2019 guideline and reflect the populations that will have radical radiotherapy. The recommendations for high-risk prostate cancer were amended to CPG 4 and 5 as these are the equivalent groups.
In 2019, the committee considered a large body of evidence showing that hypofractionated radiotherapy and conventional radiotherapy were equally effective. The committee noted that hypofractionated radiotherapy is associated with higher rates of acute gastrointestinal toxicity, but overall it could enable people to have a better quality of life because they would need to make fewer clinic visits. Fewer clinic visits for hypofractionated radiotherapy would also mean fewer resources were needed compared with conventional radiotherapy treatment. Therefore, hypofractionated radiotherapy was recommended as the first option.
The committee agreed that 60 Gy in 20 fractions was the optimal dose for people having hypofractionated radiotherapy. This was the dosage used in the large UK CHHiP trial that was associated with greater efficacy compared with a 57 Gy schedule, although the 60 Gy schedule did also show slightly greater toxicity.
The 2019 committee considered evidence from a large trial that showed a reduction in biochemical failure (for example, local recurrence or distant metastases) associated with the use of low dose-rate brachytherapy plus external beam radiotherapy for people with high-risk localised prostate cancer (now updated to the equivalent CPG 4 and 5 groups in the recommendation). As a result, the committee amended the 2014 recommendation so it was not limited to high dose-rate brachytherapy. The committee also agreed that as most centres do not offer both types of brachytherapy, the advice gives clinicians a choice of either high dose-rate or low dose-rate brachytherapy.
## How the recommendations might affect practice
As hypofractionated radiotherapy is already routinely used in practice (alongside other non-radiotherapy treatment options) for people with localised prostate cancer, these recommendations are unlikely to have an impact on resources.
For brachytherapy (high dose-rate or low dose-rate), the committee agreed that only a small number of people (typically those with CPG 4 and 5 prostate cancer) would currently have brachytherapy, so the changes to the recommendations are unlikely to have a significant impact on current practice.
Recommendations where intermediate risk was replaced with CPG 2 and 3 are likely to apply to a smaller group of people. Therefore, the committee agreed that the changes were unlikely to result in an increased use of resources.
Recommendations for high-risk prostate cancer were changed to be for CPG 4 and 5, but because these groups are equivalent there would be no resource impact.
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# Docetaxel chemotherapy
Recommendations 1.3.26 and 1.3.27 and recommendation 1.5.6
## Why the committee made the recommendations
There was good evidence that showed docetaxel improves overall survival, prostate cancer-specific survival and clinical progression-free survival in people with newly diagnosed metastatic prostate cancer who are starting long-term hormone therapy. The committee agreed these benefits outweighed the potential harms of the treatment.
The evidence also showed docetaxel slows clinical progression in people with newly diagnosed high-risk, non-metastatic cancer starting long-term hormone therapy. However, the evidence did not show any extension of overall survival. Because of the known toxicities associated with docetaxel treatment, the benefits and harms are more finely balanced in this population. As a result, the committee identified this decision as being preference sensitive, and the person's values and preferences are likely to be particularly important in their decision about the best course of action for them.
The committee also made a recommendation for research as it identified a gap in the evidence related to there being no universal definition of locally advanced prostate cancer. A risk stratification study will help identify patients at various levels of risks, and help tailor treatment according to need.
## How the recommendations might affect practice
Off‑label use of docetaxel in people diagnosed with hormone‑sensitive metastatic prostate cancer is current practice, therefore the recommendation for the metastatic prostate cancer population is likely to have no impact. However, this does not include high‑risk, non‑metastatic prostate cancer. Therefore, the recommendation for this population could result in an increase in the number of people with high‑risk, non‑metastatic prostate cancer receiving docetaxel chemotherapy. Although this could result in an increase in some shorter‑term costs to the NHS, the economic evidence showed a reduction in longer‑term management costs, with the net effect that docetaxel is likely to be cost‑saving in the long term in this population and, once its benefits are also taken into account, almost certain to represent a good use of NHS resources.
Return to recommendations 1.3.26 and 1.3.27
Return to recommendation 1.5.6
# Follow up
Recommendations 1.3.45 to 1.3.50
## Why the committee made the recommendations
The committee saw no new evidence to suggest any changes were needed to the recommendations on follow‑up strategies after radical treatment. The committee did not change the existing recommendations that DRE should not be offered, as there was no new evidence to suggest it was beneficial for people who were not on active surveillance.
Based on their expertise, the committee amended the recommendations on the location of the follow up. The committee discussed different strategies already in use across the country such as shared care, supported self-management and telephone‑based follow up. Because it had not looked at the specific evidence for these, it was unable to recommend a specific programme. The committee agreed that the 2‑year follow up recommended in the previous guideline was conservative, and based on their expertise, people with no complications and with a stable PSA could be cared for outside of the hospital environment. Complex cases might need longer contact with hospital-based services.
Given the lack of evidence, the committee also made a recommendation for research in this area.
## How the recommendations might affect practice
The committee noted that follow‑up strategies are variable across the country and the recommendations will therefore have a varied resource impact across the country depending on the level of follow up that is currently in place locally. Depending on the changes implemented, there may be a large resource impact.
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# Bone-targeted therapies (bisphosphonates)
Recommendations 1.5.19 to 1.5.21
## Why the committee made the recommendations
There was some evidence that showed zoledronic acid prolonged the time without skeletal-related events in people with hormone-refractory metastatic prostate cancer. However, the committee could not make a stronger recommendation because the evidence did not show whether zoledronic acid affects mortality in this population.
There was no new evidence that could affect the existing recommendation on the administration of bisphosphonates for pain relief for people with hormone-refractory metastatic prostate cancer.
## How the recommendations might affect practice
There may be a small increase in the cost of hormone-refractory metastatic prostate cancer treatment, but as zoledronic acid is now out of patent, this should limit the cost impact.
Return to recommendations# Context
Prostate cancer is the most common cancer in men, and the second most common cancer in the UK. In 2014, there were over 46,000 new diagnoses of prostate cancer, which accounts for 13% of all new cancers diagnosed. About 1 in 8 people will get prostate cancer at some point in their life.
Prostate cancer can also affect trans women, as the prostate is usually conserved after gender‑confirming surgery, but it is not clear how common it is in this population.
More than 50% of prostate cancer diagnoses in the UK each year are in people aged 70 years and over (2012), and the incidence rate is highest in people aged 90 years and over (2012 to 2014). Out of every 10 prostate cancer cases, 4 are only diagnosed at a late stage in England (2014) and Northern Ireland (2010 to 2014). Incidence rates are projected to rise by 12% between 2014 and 2035 in the UK to 233 cases per 100,000 in 2035.
A total of 84% of people aged 60 to 69 years at diagnosis in 2010/2011 are predicted to survive for 10 or more years after diagnosis. When diagnosed at the earliest stage, virtually all people with prostate cancer survive 5 years or more: this is compared with less than a third of people surviving 5 years or more when diagnosed at the latest stage.
There were approximately 11,000 deaths from prostate cancer in 2014. Mortality rates from prostate cancer are highest in people aged 90 years and over (2012 to 2014). Over the past decade, mortality rates have decreased by more than 13% in the UK. Mortality rates are projected to fall by 16% between 2014 and 2035 to 48 deaths per 100,000 people in 2035.
People with an African family background are at higher risk of prostate cancer (lifetime risk of approximately 1 in 4). Prostate cancer is inversely associated with deprivation, with a higher incidence of cases found in more affluent areas of the UK.
Costs for the inpatient treatment of prostate cancer are predicted to rise to £320.6 million per year in 2020 (from £276.9 million per year in 2010).
This guidance was updated in 2014 to include several treatments that have been licensed for the management of hormone-relapsed metastatic prostate cancer since the publication of the original NICE guideline in 2008.
Since the update in 2014, there have been changes in the way that prostate cancer is diagnosed and treated. Advances in imaging technology, especially multiparametric MRI, have led to changes in practice, and new evidence about some prostate cancer treatments means that some recommendations needed to be updated.
Since the update in 2019 there has been new evidence on risk categorisation models for localised and locally advanced prostate cancer. Therefore, recommendations on risk categorisation and subsequent recommendations on treatments for different risk categories needed to be updated.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and decision support for people with prostate cancer, their partners and carers\n\n## Information\n\nFor advice on communication and patient-centred care throughout the patient journey, follow the recommendations in the NICE guidelines on improving outcomes in urological cancers and improving supportive and palliative care for adults with cancer. \n\nOffer people with prostate cancer information tailored to their own needs. This information should be given by a healthcare professional (for example, a consultant or specialist nurse) and may be supported by written and visual media. \n\nOffer people with prostate cancer advice on how to get information and support from websites, local and national cancer information services, and from cancer support groups. \n\nChoose or recommend information resources for people with prostate cancer that are clear, reliable and up to date. Ask for feedback from people with prostate cancer and their partners or carers to identify the highest quality information resources. \n\n## Decision support\n\nFind out the extent to which the person wishes to be involved in their decision making, and ensure that they have sufficient information to do so. \n\nUse an up-to-date decision aid in all urological cancer multidisciplinary teams (MDTs). Healthcare professionals trained in its use should offer it to people with localised prostate cancer when making treatment decisions. \n\nUse nomograms together with people with prostate cancer to help:\n\nwith decision making\n\npredict biopsy results\n\npredict pathological stage\n\npredict risk of treatment failure. \n\nExplain the reliability, validity and limitations of any predictions made using nomograms. \n\nDiscuss all relevant management options in this guideline with people with prostate cancer and their partners or carers, even if they are not available through their local services. \n\nTell people with prostate cancer:\n\nabout treatment options and their risks and benefits in an objective, unbiased manner and\n\nthat there is limited evidence for some treatment options. \n\nEnsure that mechanisms are in place so people with prostate cancer and their primary care providers have access to specialist services throughout the course of their disease. \n\nTell people with prostate cancer and their partners or carers about the effects of prostate cancer and the treatment options on their:\n\nsexual function\n\nphysical appearance\n\ncontinence\n\nother aspects of masculinity. Support people and their partners or carers in making treatment decisions, taking into account the effects on quality of life as well as survival. \n\nOffer people with prostate cancer, and their partners or carers, the opportunity to talk to a healthcare professional experienced in dealing with psychosexual issues at any stage of the condition and its treatment. \n\n# Assessment and diagnosis\n\n## MRI and biopsy\n\nDo not routinely offer multiparametric MRI to people with prostate cancer who are not going to be able to have radical treatment. \n\nOffer multiparametric MRI as the first-line investigation for people with suspected clinically localised prostate cancer. Report the results using a 5‑point Likert scale. \n\nOffer multiparametric MRI-influenced prostate biopsy to people whose Likert score is 3\xa0or more. \n\nConsider omitting a prostate biopsy for people whose multiparametric MRI Likert score is 1\xa0or\xa02, but only after discussing the risks and benefits with the person and reaching a shared decision (see box\xa01). If a person opts to have a biopsy, offer systematic prostate biopsy. \n\nThere is more than 1\xa0type of prostate biopsy. The most common approach is transrectal ultrasound-guided (TRUS) biopsy. The data in box\xa01 comes from the PROMIS and ProtecT studies, which used TRUS. There is no equivalent data for other types of biopsy. The ranges given in box\xa01 reflect different definitions of clinically significant prostate cancer (UCL1 and UCL2; see PROMIS publications).\n\nBox 1 Factors to consider when discussing the options for people whose multiparametric MRI Likert score is 1 or 2\n\nAdvantages of undergoing prostate biopsy\n\nYou may have prostate cancer that the MRI scan missed:\n\nbetween 11\xa0and 28\xa0out of 100\xa0people with a low-risk MRI actually have clinically significant cancer\n\nthere are many effective treatments for clinically significant cancer, which work best for disease that is caught early; this means that, if you actually do have clinically significant cancer that the MRI missed, you will have a better chance of long-term survival if the biopsy finds it.\n\nDisadvantages of undergoing prostate biopsy\n\nThere is no guarantee that a prostate biopsy will find any disease that is there. Prostate biopsies find less than half of the clinically significant prostate cancers that MRI scans miss.\n\nYou may be diagnosed with clinically insignificant prostate cancer. This is disease that is unlikely to be life-threatening, but will need monitoring and may lead to treatment. Therefore, if someone has prostate cancer that truly is clinically insignificant, it is better not to find it. Between 18\xa0and 23\xa0out of 100\xa0people with a low-risk MRI get a diagnosis of clinically insignificant prostate cancer if they have a prostate biopsy.\n\nThe most common type of biopsy, transrectal ultrasound-guided (TRUS), has some rare but important complications. The most serious is sepsis, which develops in a bit fewer than 1\xa0out of 100\xa0people. Other serious complications, including acute urinary retention, severe haematuria and severe rectal bleeding may need hospitalisation.\n\nTRUS biopsy has fewer serious complications that make it unpleasant to undergo for some people.\n\nOn average:\n\nout of 100\xa0people feel light-headed or dizzy immediately after the biopsy\n\nout of 100\xa0people report pain; in 15 of them, it will last for at least 2\xa0weeks; 7 will consider it a moderate or serious problem\n\nout of 100\xa0people develop a fever; in 3 of them, it will last for at least 2\xa0weeks; 5 will consider it a moderate or serious problem\n\nout of 100\xa0people have blood in their urine; in 20 of them, it will last for at least 2\xa0weeks; 6 will consider it a moderate or serious problem\n\nout of 100\xa0people have blood in their bowel movements; in 5 of them, it will last for at least 2\xa0weeks; 2 will consider it a moderate or serious problem\n\nout of 100\xa0people have blood in their semen; in 60 of them, it will last for at least 2\xa0weeks; 25 will consider it a moderate or serious problem.\n\nDo not offer mapping transperineal template biopsy as part of an initial assessment, unless as part of a clinical trial. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on MRI and biopsy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: diagnosing and identifying clinically significant prostate cancer.\n\nLoading. Please wait.\n\nHelp people decide whether to have an MRI or prostate biopsy by discussing:\n\ntheir prostate-specific antigen (PSA) level\n\ntheir digital rectal examination (DRE) findings (including an estimate of prostate size)\n\nany comorbidities, together with their risk factors (including increasing age and black African–Caribbean family background)\n\nany history of a previous negative prostate biopsy.Do not automatically offer a prostate biopsy on the basis of serum PSA level alone. \n\nGive people and their partners or carers information, support and adequate time to decide whether or not they wish to have an MRI or prostate biopsy. Explain the risks (including the increased chance of having to live with the diagnosis of clinically insignificant prostate cancer) and benefits. \n\nIf the clinical suspicion of prostate cancer is high, because of a high PSA value and evidence of bone metastases (identified by a positive isotope bone scan or sclerotic metastases on plain radiographs), do not offer prostate biopsy for histological confirmation unless this is needed as part of a clinical trial. \n\nHave a core member of the urological cancer MDT review the risk factors of all people who have had a negative first prostate biopsy. Discuss with the person that:\n\nthere is still a risk that prostate cancer is present and\n\nthe risk is slightly higher if any of the following risk factors are present:\n\n\n\nthe biopsy showed high-grade prostatic intra-epithelial neoplasia (HGPIN)\n\nthe biopsy showed atypical small acinar proliferation (ASAP)\n\nabnormal DRE. \n\n\n\n## If the MRI or biopsy is negative\n\nFor people with a negative biopsy who have an MRI Likert score of 3\xa0or more, discuss the possibility of significant disease in an MDT meeting with a view to repeating the prostate biopsy. \n\nFor people who have a raised PSA and MRI Likert score of 1\xa0or\xa02, and who have not had a prostate biopsy, repeat PSA test at 3\xa0to 6\xa0months and:\n\noffer prostate biopsy if there is a strong suspicion of prostate cancer (for example, PSA density greater than 0.15\xa0nanogram/ml/ml or PSA velocity greater than 0.75\xa0nanogram/ml/year, or strong family history), taking into account their life expectancy and comorbidities\n\ndischarge the person to primary care if the level of suspicion is low; advise PSA follow up at 6\xa0months and then every year, and set a PSA level for primary care at which to re‑refer based on PSA density (0.15\xa0nanogram/ml/ml) or velocity (0.75\xa0nanogram/ml/year). \n\nFor people who have a raised PSA, an MRI Likert score of 1\xa0or\xa02 (or a contraindication to MRI), and negative biopsy, repeat PSA at 3\xa0to 6\xa0months and:\n\noffer prostate biopsy if there is a strong suspicion of prostate cancer (for example, PSA density greater than 0.15\xa0nanogram/ml/ml or PSA velocity greater than 0.75\xa0nanogram/ml/year, or strong family history), taking into account their life expectancy and comorbidities\n\ndischarge the person to primary care if the level of suspicion is low; advise PSA follow\xa0up every 2\xa0years, and set a PSA level for primary care at which to re‑refer, based on PSA density (0.15\xa0nanogram/ml/ml) or velocity (0.75\xa0nanogram/ml/year). \n\nThe PROGENSA\xa0PCA3 assay and the Prostate Health Index is not recommended in people having investigations for suspected prostate cancer who have had a negative or inconclusive prostate biopsy. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on if the MRI or biopsy is negative\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: following up people at risk of prostate cancer.\n\nLoading. Please wait.\n\n## Staging\n\nConsider CT for people with histologically proven prostate cancer for whom MRI is contraindicated if knowledge of the T\xa0or\xa0N\xa0stage could affect management. \n\nUrological cancer MDTs should assign a risk category (see table\xa01) to all people with newly diagnosed localised or locally advanced prostate cancer. \n\nCambridge Prognostic Group\n\nCriteria\n\n\n\nGleason score\xa06 (grade group\xa01)\n\nandprostate-specific antigen (PSA) less than 10\xa0microgram/litre\n\nandStages T1–T2\n\n\n\nGleason score 3 + 4 = 7 (grade group\xa02)\xa0or\xa0PSA 10\xa0microgram/litre to 20\xa0microgram/litreandStages T1–T2\n\n\n\nGleason score 3 + 4 = 7 (grade group 2)\xa0and\xa0PSA 10\xa0microgram/litre to 20\xa0microgram/litre\xa0and\xa0Stages T1–T2orGleason 4 + 3 = 7 (grade group 3)\xa0and\xa0Stages T1–T2\n\n\n\nOne of: Gleason score\xa08 (grade group\xa04), PSA more than\u200920\xa0microgram/litre, Stage\xa0T3\n\n\n\nTwo or more of: Gleason score\xa08 (grade group\xa04), PSA more than\u200920\xa0microgram/litre, Stage\xa0T3orGleason score\xa09\xa0to 10 (grade group\xa05)orStage T4\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on risk stratification for localised or locally advanced prostate cancer\n\nFull details of the evidence and the committee's discussion are in evidence review I: risk stratification for localised prostate cancer.\n\nLoading. Please wait.\n\nDo not routinely offer isotope bone scans to people with Cambridge Prognostic Group (CPG)\xa01\xa0or 2 localised prostate cancer. [2008, amended 2021]\n\nFor a short explanation of how the committee amended this recommendation to take into account the 5‑tier CPG risk model and how it might affect practice, see the rationale and impact section on bone scans for newly diagnosed prostate cancer\xa0.\n\nFull details of the committee's discussion on how the recommendations were amended to take into account the 5‑tier CPG risk model are in evidence review I: risk stratification for localised prostate cancer.\n\nLoading. Please wait.\n\nOffer isotope bone scans when hormonal therapy is being deferred as part of watchful waiting to asymptomatic people who are at high risk of developing bone complications. \n\n# Localised and locally advanced prostate cancer\n\nBefore radical treatment, explain to people and, if they wish, their partner, that radical treatment for prostate cancer will result in an alteration of sexual experience, and may result in loss of sexual function. [2008, amended 2014]\n\nExplain to people and, if they wish, their partner, about the potential loss of ejaculation and fertility associated with radical treatment for prostate cancer. Offer sperm storage. [2008, amended 2014]\n\nWarn people undergoing radical treatment for prostate cancer of the likely effects of the treatment on their urinary function. [2008, amended 2014]\n\nOffer a urological assessment to people who have troublesome urinary symptoms before treatment. \n\nPeople with prostate cancer who are candidates for radical treatment should have the opportunity to discuss the range of treatment modalities and their serious side effects in relation to their treatment options with a specialist surgical oncologist and a specialist clinical oncologist. \n\nExplain to people that there is a small increase in the risk of colorectal cancer after radical external beam radiotherapy for prostate cancer. \n\n## Treatment options for localised and locally advanced prostate cancer\n\nWhen discussing treatment options with people with CPG\xa01, 2\xa0and 3 localised prostate cancer, use box\xa02 to discuss the benefits and harms with them and refer to the NICE guideline on shared decision making. [2019, amended 2021]\n\nBox\xa02 Factors to consider when discussing active surveillance, radical prostatectomy or radical radiotherapy as treatment options for people with CPG\xa01, 2\xa0and 3 localised prostate cancer, using evidence from a large UK trial\n\nWhat are the treatment options for people with localised prostate cancer?\n\nThere are 3\xa0options for treatment:\n\nactive surveillance (the trial used the intention-to-treat method of analysis and some of the patients in the active surveillance arm may therefore have undergone prostatectomy or radiotherapy during the follow-up period)\n\nradical prostatectomy\n\nradical radiotherapy.\n\nWhat effect does each treatment option have on survival at 10\xa0years?\n\nThe evidence does not show a difference in the number of deaths from prostate cancer among people offered active surveillance, prostatectomy or radical radiotherapy.\n\nPeople who had not died of prostate cancer were:\n\nout of 100\xa0patients offered active surveillance\n\nout of 100\xa0patients offered radical prostatectomy\n\nout of 100\xa0patients offered radical radiotherapy.\n\nWhat effect does each treatment option have on disease progression at 10\xa0years?\n\nThere is good evidence that both prostatectomy and radiotherapy reduce disease progression compared with active surveillance.\n\nSigns of disease progression were reported in:\n\nout of 100\xa0patients offered active surveillance\n\nout of 100\xa0patients offered radical prostatectomy\n\nout of 100\xa0patients offered radical radiotherapy.\n\nThe trial defined disease progression as:\n\nevidence of metastases or\n\ndiagnosis of clinical T3 or T4 disease or\n\nneed for long-term androgen deprivation therapy or\n\nrectal fistula or the need for a urinary catheter owing to local tumour growth.\n\nDisease progression was suspected if there was:\n\nany rise in prostate-specific antigen (PSA) of more than 20% between consecutive measures at any time during follow up or\n\nany rise in PSA level of 50% or more in any 12‑month period confirmed by repeat tests or\n\nany indication of the appearance of symptomatic systemic disease.\n\nWhat effect does each treatment option have on the rate of development of distant metastases at 10\xa0years?\n\nThere is good evidence that both prostatectomy and radiotherapy reduce the rate of development of distant metastases compared with active surveillance.\n\nDistant metastases were developed in:\n\nout of 100\xa0patients offered active surveillance\n\nout of 100\xa0patients offered radical prostatectomy\n\nout of 100\xa0patients offered radical radiotherapy.\n\nWhat effect does each treatment option have on urinary function?\n\nThere is some evidence that urinary function is better for people offered active surveillance or radiotherapy than those offered prostatectomy.\n\nAt 6\xa0months, problems with urinary continence were reported in:\n\nout of 100\xa0patients offered active surveillance\n\nout of 100\xa0patients offered radical prostatectomy\n\nout of 100\xa0patients offered radical radiotherapy.\n\nAt 6\xa0years, problems with urinary continence were reported in:\n\nout of 100\xa0patients offered active surveillance\n\nout of 100\xa0patients offered radical prostatectomy\n\nout of 100\xa0patients offered radical radiotherapy.\n\nAt 6\xa0months, moderate to severe urinary incontinence problems were reported in:\n\nout of 100\xa0patients offered active surveillance\n\nout of 100\xa0patients offered radical prostatectomy\n\nout of 100\xa0patients offered radical radiotherapy.\n\nAt 6\xa0years, moderate to severe urinary incontinence problems were reported in:\n\nout of 100\xa0patients offered active surveillance\n\nout of 100\xa0patients offered radical prostatectomy\n\nout of 100\xa0patients offered radical radiotherapy.\n\nWhat effect does each treatment option have on erectile dysfunction?\n\nThere is some limited evidence that sexual function is better for people offered active surveillance or radiotherapy than those offered prostatectomy.\n\nAt 6\xa0months, moderate or severe problems with erectile dysfunction were reported in:\n\nout of 100 patients offered active surveillance\n\nout of 100 patients offered radical prostatectomy\n\nout of 100 patients offered radical radiotherapy.\n\nAt 6\xa0years, moderate or severe problems with erectile dysfunction were reported in:\n\nout of 100 patients offered active surveillance\n\nout of 100 patients offered radical prostatectomy\n\nout of 100 patients offered radical radiotherapy.\n\nWhat effect does each treatment option have on bowel function?\n\nThere is some evidence that bowel function is better for people offered active surveillance or prostatectomy than those offered radiotherapy in the short term.\n\nAt 6\xa0months, problems with faecal incontinence more than once per week were reported in:\n\nout of 100 patients offered active surveillance\n\nout of 100 patients offered radical prostatectomy\n\nout of 100 patients offered radical radiotherapy.\n\nAt 6\xa0years, problems with faecal incontinence more than once per week were reported in:\n\nout of 100 patients offered active surveillance\n\nout of 100 patients offered radical prostatectomy\n\nout of 100 patients offered radical radiotherapy.\n\nAt 6\xa0months, moderate to severe impact of bowel habits on quality of life was reported in:\n\nout of 100 patients offered active surveillance\n\nout of 100 patients offered radical prostatectomy\n\nout of 100 patients offered radical radiotherapy.\n\nAt 6\xa0years, moderate to severe impact of bowel habits on quality of life was reported in:\n\nout of 100 patients offered active surveillance\n\nout of 100 patients offered radical prostatectomy\n\nout of 100 patients offered radical radiotherapy.\n\nFor people with CPG\xa01 localised prostate cancer:\n\noffer active surveillance\n\nconsider radical prostatectomy or radical radiotherapy if active surveillance is not suitable or acceptable to the person. [2019, amended 2021]\n\nFor people with CPG\xa02 localised prostate cancer, offer a choice between active surveillance, radical prostatectomy or radical radiotherapy if radical treatment is suitable. [2019, amended 2021]\n\nFor people with CPG\xa03 localised prostate cancer:\n\noffer radical prostatectomy or radical radiotherapy and\n\nconsider active surveillance (in line with recommendation 1.3.14) for people who choose not to have immediate radical treatment. [2019, amended 2021]\n\nDo not offer active surveillance to people with CPG\xa04\xa0and 5 localised and locally advanced prostate cancer. [2019, amended 2021]\n\nOffer radical prostatectomy or radical radiotherapy to people with CPG\xa04\xa0and 5 localised and locally advanced prostate cancer when it is likely the person's cancer can be controlled in the long term. [2019, amended 2021]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on treatment options for localised and locally advanced prostate cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: active surveillance, radical prostatectomy or radical radiotherapy in people with localised prostate cancer. Full details of the committee's discussion on how the recommendations were amended to take into account the 5‑tier CPG risk model are in evidence review I: risk stratification for localised prostate cancer.\n\nLoading. Please wait.\n\n## Multiparametric MRI and protocol for active surveillance\n\nOffer multiparametric MRI to people having active surveillance who have not had an MRI previously. If the MRI results do not agree with the biopsy findings, offer a new MRI-influenced biopsy. \n\nConsider using the protocol in table\xa02 for people who have chosen active surveillance. \n\nTiming\n\nTests (if there is concern about clinical or prostate-specific antigen changes at any time during active surveillance, reassess with multiparametric MRI and/or re‑biopsy)\n\nYear\xa01 of active surveillance\n\nEvery 3\xa0to 4\xa0months: measure prostate-specific antigen (PSA; could be carried out in primary care if there are agreed shared-care protocols and recall systems)\n\nThroughout active surveillance: monitor PSA kinetics (could include PSA density and velocity)\n\nAt 12\xa0months: digital rectal examination (DRE; should be done by a healthcare professional with expertise and confidence in performing DRE. In a large UK trial that informed this protocol, DREs were carried out by a urologist or a nurse specialist)\n\nAt 12\xa0to 18\xa0months: multiparametric MRI\n\nYear\xa02 and every year thereafter until active surveillance ends\n\nEvery 6\xa0months: measure PSA (could be carried out in primary care if there are agreed shared-care protocols and recall systems)\n\nThroughout active surveillance: monitor PSA kinetics (could include PSA density and velocity)\n\nEvery 12\xa0months: DRE (should be done by a healthcare professional with expertise and confidence in performing DRE. In a large UK trial that informed this protocol, DREs were carried out by a urologist or a nurse specialist)\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multiparametric MRI for active surveillance\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: identifying prostate cancer clinical progression in people with low- to intermediate-risk cancer.\n\nLoading. Please wait.\n\nIf a person wishes to move from active surveillance to radical treatment at any stage in their care, make a shared decision to do so based on the person's preferences, comorbidities and life expectancy. \n\nOffer radical treatment to people with localised prostate cancer who had chosen an active surveillance regimen and who now have evidence of disease progression. \n\n## Radical treatment\n\nCommissioners of urology services should consider providing robotic surgery to treat localised prostate cancer. \n\nCommissioners should base robotic systems for the surgical treatment of localised prostate cancer in centres that are expected to perform at least 150\xa0robot-assisted laparoscopic radical prostatectomies per year to ensure they are cost effective. \n\nFor people having radical external beam radiotherapy for localised prostate cancer:\n\noffer hypofractionated radiotherapy (60\xa0Gy in 20\xa0fractions) using image-guided intensity modulated radiation therapy (IMRT), unless contraindicated or\n\noffer conventional radiotherapy (74\xa0Gy in 37\xa0fractions) to people who cannot have hypofractionated radiotherapy. \n\nOffer people with localised and locally advanced prostate cancer receiving radical external beam radiotherapy with curative intent planned treatment techniques that optimise the dose to the tumour while minimising the risks of normal tissue damage. \n\nOffer people with CPG\xa02, 3, 4 and 5 localised or locally advanced prostate cancer a combination of radical radiotherapy and androgen deprivation therapy, rather than radical radiotherapy or androgen deprivation therapy alone. [2014, amended 2021]\n\nOffer people with CPG 2, 3, 4 and 5 localised or locally advanced prostate cancer 6\xa0months of androgen deprivation therapy before, during or after radical external beam radiotherapy. [2014, amended 2021]\n\nConsider continuing androgen deprivation therapy for up to 3\xa0years for people with CPG\xa04 and 5 localised or locally advanced prostate cancer, and discuss the benefits and risks of this option with them. [2014, amended 2021]\n\nConsider brachytherapy in combination with external beam radiotherapy for people with CPG\xa02, 3, 4 and 5 localised or locally advanced prostate cancer. [2019, amended 2021]\n\nDo not offer brachytherapy alone to people with CPG\xa04 and 5 localised or locally advanced prostate cancer. [2008, amended 2021]\n\nFor a short explanation of why the committee made the recommendations on radiotherapy and how they might affect practice, see the rationale and impact section on radiotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: radical radiotherapy. Full details of the committee's discussion on how the recommendations were amended to take into account the 5-tier CPG risk model are in evidence review I: risk stratification for localised prostate cancer.\n\nLoading. Please wait.\n\nDiscuss the option of docetaxel chemotherapy with people who have newly diagnosed non‑metastatic prostate cancer who:\n\nare starting long-term androgen deprivation therapy and\n\nhave no significant comorbidities and\n\nhave high-risk disease, as shown by:\n\n\n\nT3/T4 staging or\n\nGleason score 8\xa0to\xa010 or\n\nPSA greater than 40\xa0microgram/litre.Explain the benefits and harms (see box\xa03) and make a shared decision about whether the person should have this treatment. In May\xa02019, this was an off-label use of docetaxel. See NICE's guidance on prescribing medicines for further information.\n\n\n\nFor people having docetaxel chemotherapy:\n\nstart treatment within 12\xa0weeks of starting androgen deprivation therapy\n\nuse six 3‑weekly cycles at a dose of 75\xa0mg/m2 (with or without daily prednisolone). \n\nDo not offer high-intensity focused ultrasound and cryotherapy to people with localised prostate cancer, other than in the context of controlled clinical trials comparing their use with established interventions. NICE's interventional procedures guidance on high-intensity focused ultrasound for prostate cancer, cryotherapy for recurrent prostate cancer and cryotherapy as a primary treatment for prostate cancer evaluated the safety and efficacy of cryotherapy and high-intensity focused ultrasound for the treatment of prostate cancer. NICE guidelines provide guidance on the appropriate treatment and care of people with specific diseases and conditions within the NHS. Because there was a lack of evidence on quality-of-life benefits and long-term survival, these interventions are not recommended in this guideline.NICE's interventional procedures guidance on focal therapy using high-intensity focused ultrasound for localised prostate cancer and focal therapy using cryoablation for localised prostate cancer found no major safety concerns, but evidence on efficacy is limited in quantity and there is a concern that prostate cancer is commonly multifocal.\n\nBox\xa03 Factors to consider when discussing the option of docetaxel chemotherapy for people with high-risk, non-metastatic prostate cancer\n\nWhat does treatment with docetaxel involve?\n\nDocetaxel chemotherapy is given at 6\xa0appointments, each 3\xa0weeks apart. It is given as an intravenous infusion that takes about 1\xa0hour.\n\nWhat are the benefits of docetaxel treatment for people with high-risk, non-metastatic prostate cancer?\n\nThere is clear, high-quality evidence that docetaxel chemotherapy delays disease progression in people with high-risk, non-metastatic disease.\n\nIn a large UK randomised trial (James et al. 2016), the average person who did not receive docetaxel experienced disease progression about 5\xa0years after the start of the trial, whereas the average person receiving docetaxel experienced disease progression after about 6\xa0years.\n\nWe do not yet know whether docetaxel improves survival in people with high-risk, non-metastatic disease and we will only be confident about whether it does when trials have been running for longer.\n\nIn a large UK randomised trial, 80\xa0out of 100\xa0people with high-risk disease who did not receive docetaxel were still alive after 5\xa0years compared with 84\xa0out of 100\xa0people who did. However, this difference could be because of chance.\n\nWhat are the risks associated with docetaxel treatment?\n\nA large UK randomised trial found that:\n\nout of 100\xa0people who took docetaxel developed febrile neutropenia (that is, they got a fever because the chemotherapy had reduced their white blood cells' ability to fight infection).\n\nout of 100 people who took docetaxel died because of infections that, in the opinion of the investigators, they might not have developed if they had not received docetaxel.\n\nout of 100 people who took docetaxel felt unusually weak or tired.\n\nout of 100 people who took docetaxel experienced gastrointestinal symptoms (including diarrhoea, abdominal pain, constipation and/or vomiting).\n\nout of 100 people who took docetaxel experienced respiratory symptoms (including breathlessness and/or chest infections).\n\nout of 100 people who took docetaxel experienced problems with their nervous systems (for example, numbness or weakness).\n\nout of 100 people who took docetaxel experienced problems with their nails that were serious enough to interfere with their daily lives.\n\nFor a short explanation of why the committee made the recommendations on docetaxel chemotherapy and how they might affect practice, see the rationale and impact section on docetaxel chemotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: docetaxel in people with hormone-sensitive prostate cancer.\n\nLoading. Please wait.\n\n## Watchful waiting\n\nPeople with localised prostate cancer who have chosen watchful waiting and who have evidence of significant disease progression (that is, rapidly rising PSA level or bone pain) should have their situation reviewed by a member of the urological cancer MDT. \n\n## Locally advanced prostate cancer\n\nConsider pelvic radiotherapy for people with locally advanced prostate cancer who have a higher than 15% risk of pelvic lymph node involvement and who are to receive neoadjuvant hormonal therapy and radical radiotherapy. \n\nRisk of pelvic node lymph involvement estimated using the Roach formula: %LN risk = 2/3 PSA + (10 × [Gleason score - 6]).\n\nDo not offer immediate post-operative radiotherapy after radical prostatectomy, even to people with margin-positive disease, other than in the context of a clinical trial. \n\nDo not offer adjuvant hormonal therapy in addition to radical prostatectomy, even to people with margin-positive disease, other than in the context of a clinical trial. \n\nDo not offer high-intensity focused ultrasound and cryotherapy to people with locally advanced prostate cancer other than in the context of controlled clinical trials comparing their use with established interventions. NICE's interventional procedures guidance on high-intensity focused ultrasound for prostate cancer, cryotherapy for recurrent prostate cancer and cryotherapy as a primary treatment for prostate cancer evaluated the safety and efficacy of cryotherapy and high-intensity focused ultrasound for the treatment of prostate cancer. NICE guidelines provide guidance on the appropriate treatment and care of people with specific diseases and conditions within the NHS. Because there was a lack of evidence on quality-of-life benefits and long-term survival, these interventions are not recommended in this guideline.\n\nDo not offer bisphosphonates for the prevention of bone metastases in people with prostate cancer. \n\n## Managing adverse effects of radical treatment\n\nOffer people who have had radical treatment for prostate cancer access to specialist erectile dysfunction services. [2008, amended 2014]\n\nOffer people with prostate cancer who experience loss of erectile function phosphodiesterase type\xa05 (PDE5) inhibitors to improve their chance of spontaneous erections. \n\nIf PDE5 inhibitors do not restore erectile function or are contraindicated, offer people vacuum devices, intraurethral inserts or penile injections, or penile prostheses as an alternative. \n\nEnsure that people with prostate cancer who have troublesome urinary symptoms after treatment have access to specialist continence services for assessment, diagnosis and conservative treatment. This could include coping strategies, pelvic floor muscle re-education, bladder retraining and pharmacotherapy. \n\nRefer people with prostate cancer who have intractable stress incontinence to a specialist surgeon for consideration of an artificial urinary sphincter. \n\nDo not offer injection of bulking agents into the distal urinary sphincter to treat stress incontinence in people with prostate cancer. \n\nOffer people with signs or symptoms of radiation-induced enteropathy care from a team of professionals with expertise in radiation-induced enteropathy (who may include oncologists, gastroenterologists, bowel surgeons, dietitians and specialist nurses). \n\nInclude the nature and treatment of radiation-induced enteropathy in training programmes for oncologists and gastroenterologists. \n\nCarry out full investigations, including flexible sigmoidoscopy, in people who have symptoms of radiation-induced enteropathy to exclude inflammatory bowel disease or malignancy of the large bowel and to ascertain the nature of the radiation injury. Use caution when performing anterior wall rectal biopsy after brachytherapy because of the risk of fistulation. \n\n## Follow up for people with localised or locally advanced prostate cancer having radical treatment or on watchful waiting\n\nA urologist or specialist nurse should discuss the purpose, duration, frequency and location of follow up with each person with localised and locally advanced prostate cancer, and if they wish, their partner or carers. \n\nA urologist or specialist nurse should advise people with prostate cancer about potential longer‑term adverse effects of treatment and when and how to report them. \n\nCheck PSA levels for all people with prostate cancer who are having radical treatment no earlier than 6\xa0weeks after treatment, at least every 6\xa0months for the first 2\xa0years, and then at least once a year after that. \n\nDo not routinely offer DRE to people with localised prostate cancer who are not on active surveillance while their PSA remains at baseline levels. \n\nAfter at least 6\xa0months' initial follow\xa0up, consider a remote follow‑up strategy for people with a stable PSA who have had no significant treatment complications, unless they are taking part in a clinical trial that needs formal clinic-based follow\xa0up. \n\nFollow up people with prostate cancer who have chosen a watchful waiting regimen with no curative intent in primary care only if protocols for this have been agreed between the local urological cancer MDT and the relevant primary care organisation(s). Measure their PSA at least once a year. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on follow up\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: follow-up protocols after radical treatment.\n\nLoading. Please wait.\n\n## Managing relapse after radical treatment\n\nAnalyse serial PSA levels after radical treatment using the same assay technique as used before. \n\nDo not offer biopsy of the prostatic bed to people with prostate cancer who have had a radical prostatectomy. \n\nOnly offer biopsy of the prostate after radiotherapy to people with prostate cancer who might have local salvage therapy in the context of a clinical trial. \n\nFor people with evidence of biochemical relapse after radical treatment who are thinking about having radical salvage therapy:\n\ndo not offer routine MRI scanning before salvage radiotherapy in people with prostate cancer\n\noffer an isotope bone scan if symptoms or PSA trends are suggestive of metastases. \n\nTake into account that biochemical relapse (a rising PSA) alone should not mean an immediate change in treatment is needed. \n\nEstimate PSA doubling time if biochemical relapse occurs. Base this on a minimum of 3\xa0measurements over at least a 6‑month period. \n\nOffer people with biochemical relapse after radical prostatectomy, with no known metastases, radical radiotherapy to the prostatic bed. \n\nConsider entry to appropriate clinical trials for people with biochemical relapse. \n\nDo not routinely offer hormonal therapy to people with prostate cancer who have a biochemical relapse unless they have:\n\nsymptomatic local disease progression or\n\nany proven metastases or\n\na PSA doubling time of less than 3\xa0months. \n\n# People having hormone therapy\n\nConsider intermittent therapy for people having long-term androgen deprivation therapy (not in the adjuvant setting). Discuss with the person (and their partner, family or carers if they wish):\n\nthe rationale for intermittent therapy\n\nthe limited evidence for reduction in side effects from intermittent therapy\n\nthe effect of intermittent therapy on progression of prostate cancer. \n\nFor people who are having intermittent androgen deprivation therapy:\n\nmeasure PSA every 3\xa0months and\n\nrestart androgen deprivation therapy if PSA is 10\xa0nanogram/ml or above, or if there is symptomatic progression. \n\n## Managing adverse effects of hormone therapy\n\nOffer medroxyprogesterone (20\xa0mg per day), initially for 10\xa0weeks, to manage troublesome hot flushes caused by long-term androgen suppression. Evaluate the effect at the end of the treatment period. In May\xa02019, this was an off-label use of medroxyprogesterone. See NICE's guidance on prescribing medicines for further information.\n\nConsider cyproterone acetate (50\xa0mg twice a day for 4\xa0weeks) to treat troublesome hot flushes if medroxyprogesterone is not effective or not tolerated. \n\nTell people that there is no good-quality evidence for the use of complementary therapies to treat troublesome hot flushes. \n\nBefore they start androgen deprivation therapy, tell people and, if they wish, their partner, that long-term androgen deprivation will cause a reduction in libido and possible loss of sexual function. \n\nAdvise people and, if they wish, their partner, about the potential loss of ejaculation and fertility associated with long-term androgen deprivation and offer sperm storage. \n\nEnsure that people starting androgen deprivation therapy have access to specialist erectile dysfunction services. \n\nConsider referring people who are having long-term androgen deprivation therapy, and their partners, for psychosexual counselling. \n\nOffer PDE5 inhibitors to people having long-term androgen deprivation therapy who experience loss of erectile function. \n\nIf PDE5 inhibitors fail to restore erectile function or are contraindicated, offer a choice of:\n\nintraurethral inserts\n\npenile injections\n\npenile prostheses\n\nvacuum devices. \n\nDo not routinely offer bisphosphonates to prevent osteoporosis in people with prostate cancer having androgen deprivation therapy. \n\nConsider assessing fracture risk in people with prostate cancer who are having androgen deprivation therapy, in line with the NICE guideline on osteoporosis: assessing the risk of fragility fracture. \n\nOffer bisphosphonates to people who are having androgen deprivation therapy and have osteoporosis. \n\nConsider denosumab for people who are having androgen deprivation therapy and have osteoporosis if bisphosphonates are contraindicated or not tolerated. \n\nFor people starting long-term bicalutamide monotherapy (longer than 6\xa0months), offer prophylactic radiotherapy to both breast buds within the first month of treatment. Use a single fraction of 8\xa0Gy using orthovoltage, or electron beam radiotherapy. \n\nIf radiotherapy does not prevent gynaecomastia, consider weekly tamoxifen. In May\xa02019, this was an off-label use of tamoxifen. See NICE's guidance on prescribing medicines for further information.\n\nTell people who are starting androgen deprivation therapy that fatigue is a recognised side effect of this therapy, and might not be because of their prostate cancer. \n\nOffer people who are starting or having androgen deprivation therapy supervised resistance and aerobic exercise at least twice a week for 12\xa0weeks to reduce fatigue and improve quality of life. \n\n# Metastatic prostate cancer\n\n## Information and support\n\nOffer people with metastatic prostate cancer tailored information and access to specialist urology and palliative care teams to address their specific needs. Give them the opportunity to discuss any significant changes in their disease status or symptoms as these occur. \n\nIntegrate palliative interventions at any stage into coordinated care, and facilitate any transitions between care settings as smoothly as possible. \n\nDiscuss personal preferences for palliative care as early as possible with people with metastatic prostate cancer, their partners and carers. Tailor treatment/care plans accordingly, and identify the preferred place of care. \n\nEnsure that palliative care is available when needed and is not limited to the end of life. Care should not be restricted to being associated with hospice care. \n\nOffer a regular assessment of needs to people with metastatic prostate cancer. \n\n## Initial treatment\n\nOffer docetaxel chemotherapy to people with newly diagnosed metastatic prostate cancer who do not have significant comorbidities as follows:\n\nstart treatment within 12\xa0weeks of starting androgen deprivation therapy and\n\nuse six 3‑weekly cycles at a dose of 75\xa0mg/m2 (with or without daily prednisolone). In May\xa02019, this was an off-label use of docetaxel. See NICE's guidance on prescribing medicines for further information.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see rationale and impact section on docetaxel chemotherapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: docetaxel in people with hormone-sensitive prostate cancer.\n\nLoading. Please wait.\n\nOffer bilateral orchidectomy to all people with metastatic prostate cancer as an alternative to continuous luteinising hormone-releasing hormone agonist therapy. \n\nDo not offer combined androgen blockade as a first-line treatment for people with metastatic prostate cancer. \n\nFor people with metastatic prostate cancer who are willing to accept the adverse impact on overall survival and gynaecomastia with the aim of retaining sexual function, offer anti-androgen monotherapy with bicalutamide (150\xa0mg). In May\xa02019, this was an off-label use of bicalutamide. See NICE's information on prescribing medicines for further information.\n\nBegin androgen deprivation therapy and stop bicalutamide treatment in people with metastatic prostate cancer who are taking bicalutamide monotherapy and who do not maintain satisfactory sexual function. \n\n## Hormone-relapsed metastatic prostate cancer\n\nRecommendations\xa01.5.12, 1.5.13 and 1.5.14 are from the NICE technology appraisal guidance on docetaxel for the treatment of hormone-refractory metastatic prostate cancer.\n\nDiscuss the treatment options for people with prostate cancer who develop biochemical evidence of hormone-relapsed disease at the urological cancer MDT. Seek an oncologist and/or specialist palliative care opinion, as appropriate. \n\nDocetaxel is recommended, within its licensed indications, as a treatment option for people with hormone-refractory prostate cancer only if their Karnofsky Performance-Status score is 60% or more. \n\nIt is recommended that treatment with docetaxel should be stopped:\n\nat the completion of planned treatment of up to 10\xa0cycles or\n\nif severe adverse events occur or\n\nin the presence of progression of disease as evidenced by clinical or laboratory criteria, or by imaging studies. \n\nRepeat cycles of treatment with docetaxel are not recommended if the disease recurs after completion of the planned course of chemotherapy. \n\nOffer a corticosteroid such as dexamethasone (0.5\xa0mg daily) as third-line hormonal therapy after androgen deprivation therapy and anti-androgen therapy to people with hormone-relapsed prostate cancer. \n\nOffer spinal MRI to people with hormone-relapsed prostate cancer shown to have extensive metastases in the spine (for example, on a bone scan) if they develop any spinal-related symptoms. \n\nDo not routinely offer spinal MRI to all people with hormone-relapsed prostate cancer and known bone metastases. \n\nFor advice on treatments for metastatic hormone-relapsed prostate cancer previously treated with docetaxel, including genomic biomarker-based treatment, see the NICE technology appraisal guidance on our topic page on prostate cancer. The point at which to use genomic biomarker-based therapy in solid tumour treatment pathways is uncertain. \n\n## Bone-targeted therapies\n\nFor people with hormone-relapsed metastatic prostate cancer, consider zoledronic acid to prevent or reduce skeletal-related events. \n\nConsider oral or intravenous bisphosphonates for pain relief for people with hormone-relapsed metastatic prostate cancer when other treatments, including analgesics and palliative radiotherapy, have not given satisfactory pain relief. \n\nFor NICE technology appraisal guidance on treatments for people with bone metastases from prostate cancer, see the NICE technology appraisal guidance on our topic page on prostate cancer. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on bone-targeted therapies (bisphosphonates)\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: bisphosphonates.\n\nLoading. Please wait.\n\n## Pelvic-targeted therapies\n\nOffer decompression of the upper urinary tract by percutaneous nephrostomy or by insertion of a double J\xa0stent to people with obstructive uropathy secondary to hormone-relapsed prostate cancer. \n\nDiscuss the option of no intervention as a treatment choice with people with obstructive uropathy secondary to hormone-relapsed prostate cancer. \n\n# Terms used in this guideline\n\n## Active surveillance\n\nThis is part of a 'curative' strategy and is aimed at people with localised prostate cancer for whom radical treatments are suitable, keeping them within a 'window of curability' whereby only those whose tumours are showing signs of progressing, or those with a preference for intervention are considered for radical treatment. Active surveillance may thus avoid or delay the need for radiotherapy or surgery.\n\n## External beam radiotherapy (EBRT)\n\nThis is radiotherapy given by using ionising radiation (for example, high-energy X‑rays) produced in a machine and directed at the tumour from outside the patient.\n\n## Grade group\n\nThis refers to the 2019 International Society of Urological Pathology grade groupings for prostate cancer.\n\n## Hormone-relapsed (also known as hormone-resistant, hormone-refractory and castrate-resistant) prostate cancer\n\nRefers to prostate cancer after failure of primary androgen deprivation therapy.\n\n## Locally advanced prostate cancer\n\nFor the purposes of this guideline, this includes T3 and T4 prostate cancer.\n\n## Localised prostate cancer\n\nCancer that has been staged as T1 or T2 (confined to the prostate gland).\n\n## Multiparametric MRI of the prostate\n\nAn MRI study that incorporates anatomical and functional information about the prostate. The minimum functional information includes T2‑weighted, diffusion-weighted imaging and dynamic contrast-enhanced imaging.\n\n## Multiparametric MRI-influenced prostate biopsy\n\nThe information from the multiparametric MRI scan taken before prostate biopsy is used to determine the best needle placement. In rare cases, the biopsy may be MRI-guided (the needle is inserted within the MRI machine). In most cases, the biopsy that follows the multiparametric MRI will be ultrasound-guided, but the specific area(s) targeted will be predetermined by the multiparametric MRI data.\n\n## Prostatectomy\n\nSurgery to remove part, or all of the prostate gland. Radical prostatectomy aims at the removal of the entire prostate gland and lymph nodes. This can be done by an open approach or by keyhole technique (laparoscopic or robotically assisted laparoscopic prostatectomy).\n\n## Prostate biopsy\n\nA template biopsy is normally done under a general anaesthetic, and involves taking transperineal core biopsies using a grid system. This might involve taking multiple cores from multiple sites, but usually 2\xa0to\xa03\xa0cores from 8\xa0sites. A mapping template biopsy is when 20\xa0sites are systematically sampled, with 2\xa0or\xa03\xa0cores per site, sometimes meaning over 50\xa0core biopsies are taken.\n\nThis is sampling 6\xa0or\xa08\xa0sites from the prostate using a transperineal route under local anaesthetic.\n\nThis is when core biopsies of the prostate are taken via the rectum under local anaesthetic.\n\nThe site for biopsy can be targeted based on multiparametric MRI findings, or systematically but not guided by MRI. Most often there is a combination of both targeted and systematic MRI. The method used for the biopsy can be either transperineal or TRUS.\n\n## Watchful waiting\n\nThis is part of a strategy for 'controlling' rather than 'curing' prostate cancer and is aimed at people with localised prostate cancer who do not ever wish to have curative treatment, or it is not suitable for them. Instead, it involves the deferred use of hormone therapy. Watchful waiting avoids the use of surgery or radiation, but implies that curative treatment will not be attempted.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\nAs part of the 2021 update, the guideline committee made an additional recommendation for research on the diagnostic accuracy of staging investigations for Cambridge Prognostic Group (CPG)\xa03 prostate cancer.\n\n# Key recommendations for research\n\n## Follow up during active surveillance\n\nWhat is the most suitable surveillance protocol (including the role of digital rectal examination [DRE] and prostate-specific antigen [PSA] measures) for people for whom active surveillance is appropriate, as assessed by multiparametric MRI and biopsy, when there are no clinical concerns during follow\xa0up?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on multiparametric MRI for active surveillance\xa0.\n\nLoading. Please wait.\n\n## Follow\xa0up after radical treatment\n\nWhat is the most clinically and cost-effective follow‑up protocol for people with prostate cancer who have had radical treatment, with specific regard to risk stratification, duration of follow\xa0up, frequency of follow‑up appointments, the type of examination or blood tests, and the roles of primary and secondary care in follow up?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on follow up\xa0.\n\nLoading. Please wait.\n\n## Diagnosis of clinically significant cancer\n\nWhat is the most clinically and cost-effective pathway for diagnosing clinically significant prostate cancer?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on MRI and biopsy\xa0.\n\nLoading. Please wait.\n\n## Progression of cancer\n\nWhat is the most clinically and cost-effective pathway for excluding the clinically significant progression of cancer in people with CPG\xa01, 2 and 3 prostate cancer?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on multiparametric MRI for active surveillance\xa0.\n\nLoading. Please wait.\n\n## Natural history of prostate cancer\n\nWhat is the natural history of people with a Likert score on MRI of less than\xa03 without biopsy at long-term follow\xa0up?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on MRI and biopsy\xa0.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Staging investigations for CPG\xa03 prostate cancer\n\nWhat is the diagnostic accuracy of staging investigations for CPG\xa03 prostate cancer?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on risk stratification for localised or locally advanced prostate cancer\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: risk stratification for localised prostate cancer.\n\nLoading. Please wait.\n\n## Diagnosing prostate cancer\n\nIn patients with negative MRI (Likert score 1\xa0or\xa02), what is the next best diagnostic investigation to rule out clinically significant prostate cancer?\n\nWhat is the diagnostic accuracy of transperineal mapping biopsy compared with transperineal non-mapping biopsy in the diagnosis of clinically significant prostate cancer?\n\n## Zoledronic acid\n\nWhat is the effectiveness and cost effectiveness of different scheduling of zoledronic acid in the prevention and reduction of skeletal events in people with hormone-refractory prostate cancer?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# MRI and biopsy\n\nRecommendations 1.2.1 to 1.2.5\n\n## Why the committee made the recommendations\n\nThe committee saw no new evidence to suggest that any changes were needed to the recommendations on imaging in people who are not going to have radical treatment.\n\nThere was good evidence that showed that multiparametric MRI is useful in identifying lesions before biopsy, and the combination of MRI with prostate biopsy leads to better identification of clinically significant prostate cancer than systematic prostate biopsy alone. The committee recommended using a 5‑point Likert scale because this scale takes into account clinical factors and not just the lesion size, improving the diagnostic ability of multiparametric MRI.\n\nThe committee made a recommendation to consider omitting prostate biopsy for people whose multiparametric MRI Likert score is 1\xa0or\xa02 because there was some evidence that this is safe to do. However, there is a small risk that in some cases significant cancers may be missed, so the committee recommended clinicians discuss the risk and benefits with the person.\n\nBased on their expertise and economic evidence, the committee recommended not offering mapping transperineal template biopsy as an initial biopsy, because the technique is currently too resource intensive to be used as an initial assessment – it requires general anaesthetic and extensive histological analysis. The committee recognised that this technique could be allowed as part of a clinical trial because it is often used as the benchmark or gold standard test in those trials. The committee did not see any evidence that allowed them to clearly differentiate between transperineal (non-mapping) and transrectal biopsy, so it agreed to refer to 'prostate biopsy' throughout the recommendations.\n\nAs there was limited evidence on the most effective pathway for excluding clinically significant progression of prostate cancer in people with low to intermediate risk, the committee made a recommendation for research on this topic. They also identified that there was a gap in the evidence on the most suitable surveillance protocol in this population group.\n\n## How the recommendations might affect practice\n\nThe recommendations should not have a significant resource impact as many centres already perform MRI-influenced biopsy. Since all people who have a biopsy will previously have had an MRI, using the MRI to target the biopsy will be more efficient and need fewer biopsy cores to be taken. Health economic evidence shows that MRI-influenced prostate biopsy may be more cost effective than systematic prostate biopsy as it takes less time and is more efficient in identifying clinically significant cancer.\n\nReturn to recommendations\n\n# If the MRI or biopsy is negative\n\nRecommendations 1.2.10 to 1.2.13\n\n## Why the committee made the recommendations\n\nThere was no clinical evidence in this area, therefore the committee used evidence from economic modelling that showed people with a negative diagnosis of prostate cancer can still be at substantial risk of having prostate cancer, so follow\xa0up is important. The evidence showed that the prevalence of initially undetected, but clinically significant, prostate cancer varies based on a person's diagnostic history, so their diagnostic history should influence the frequency of follow\xa0up.\n\nThe committee recommended that people with a Likert 3\xa0score should be discussed at a multidisciplinary team (MDT) meeting. It made the recommendation because these cases can be difficult to deal with. Scoring of scans may fluctuate by 20% between raters and therefore a discussion in an MDT is warranted. The committee noted that this does not necessarily imply the full cancer MDT, but is subject to local arrangement.\n\nThe follow-up strategies recommended for primary care are based on standard prostate-specific antigen (PSA) tests, with which primary care healthcare professionals are familiar. The committee agreed it was important that specialist healthcare professionals should calculate thresholds for re‑referral and provide these when discharging people, rather than expecting the calculations to be made in primary care.\n\nThe recommendations in NICE's previous guidance on PCA3 assay and the Prostate Health Index (NICE diagnostic guidance 17) are updated by this guideline. The committee saw no evidence that either technique represents an effective use of NHS resources in the follow\xa0up of people who have had a negative transrectal ultrasound-guided (TRUS) prostate biopsy, and therefore the committee did not recommend use of these technologies.\n\nThe committee identified a gap in the evidence for the performance of transperineal route (non-mapping) biopsy, and therefore made a recommendation for research in this area.\n\nThe committee also noted that there is limited long-term follow‑up evidence on the natural history of people whose multiparametric MRI Likert score is 1\xa0or\xa02. In addition, there is limited evidence on the number of people whose multiparametric MRI is Likert score 1\xa0or\xa02, who have normal PSA density and kinetics and who are found to have clinically significant cancer. Further recommendations for research were made in these areas to help provide evidence across the prostate cancer treatment pathway.\n\n## How the recommendations might affect practice\n\nCurrently, there is substantial variation in clinical practice in the follow\xa0up of people with a negative prostate biopsy. The committee's recommendations should help to standardise practice.\n\nOther recommendations made by the committee make it likely that more people will have a negative diagnosis on the basis of low-risk multiparametric MRI findings and no biopsy. This is a new population who will need effective follow‑up strategies, and the recommendations give guidance on approaches that are likely to provide a good balance of benefits, harms and costs for this group.\n\nThe committee were confident that none of the recommendations would have a significant resource impact, as they are based on PSA measurements that are commonly used within primary care settings. In addition, if further multiparametric MRI is needed during follow\xa0up, the evidence showed that MRI-influenced prostate biopsy may be more cost effective than systematic prostate biopsy, as it takes less time and is more efficient in identifying clinically significant cancer.\n\nReturn to recommendations\n\n# Risk stratification for localised or locally advanced prostate cancer\n\nRecommendation 1.2.15\n\n## Why the committee made the recommendation\n\nThe 2019 guideline used a 3‑tier model for risk stratification. The committee agreed that newer evidence shows 5‑tier risk stratification models are better at predicting prostate cancer-specific mortality than 3‑tier models. More accurate prognosis will mean that more people are given the most effective treatment. The committee recommended the 5‑tier Cambridge Prognostic Group (CPG) model over other 5‑tier models because it has been tested in UK populations.\n\n## Impact on other recommendations\n\nThe committee considered the impact of recommending the CPG risk stratification model on other recommendations in the guideline. Recommendations were amended as necessary, taking into account the original evidence for each recommendation and the committee's knowledge and experience.\n\n## How the recommendation might affect practice\n\nThe committee were confident that recommending the 5‑tier CPG risk stratification model would not have a significant resource impact. This was because PSA, Gleason score and clinical stage are used to calculate both the CPG model and the previously recommended 3‑tier model. The CPG uses an integrated tumour (T) stage based on combined clinical, radiological and pathological information to classify T1, T2, T3 and T4 cancers without further sub-division. MDTs will need to be aware of the new 5‑tier model when assessing patient risk.\n\nUnder the 5‑tier CPG risk stratification model more people would be in the lowest risk group (CPG\xa01) than were previously categorised as 'low risk'. The previous 'intermediate-risk' group now consists of some people in CPG\xa01, and all people in CPG\xa02 and CPG\xa03, and recommendations that were previously for people at 'intermediate risk' would now apply to a smaller group. Most people in CPG\xa04 and CPG\xa05 align to the previous 'high-risk' group, so the number of people in this category would not substantially change. These changes are not expected to affect treatment choices in a way that would have a significant resource impact.\n\nReturn to recommendation\n\n# Bone scans for newly diagnosed prostate cancer\n\nRecommendation 1.2.16\n\n## Why the committee made the recommendation\n\nThe 2019 guideline recommended that bone scans should not be used for people with low-risk prostate cancer. This recommendation was amended to refer to the CPG\xa01\xa0and 2 populations. The committee were aware that this population is broader than the original low-risk population, but agreed that it was in line with current practice not to offer bone scans to these groups because they have very low risks of bone metastases. The committee highlighted the lack of evidence on when to offer staging investigations to the CPG\xa03 group and the potential resource impact of the investigations, and made a recommendation for research in this area.\n\n## How the recommendation might affect practice\n\nRecommendations where low risk was replaced with CPG\xa01\xa0and 2 will apply to a broader population due to the inclusion of people with T2b prostate cancer. However, the committee agreed that the associated resource impact of this change would be minimal because it is in line with current practice.\n\nReturn to recommendation\n\n# Treatment options for localised and locally advanced prostate cancer\n\nRecommendations 1.3.7 to 1.3.12\n\n## Why the committee made the recommendations\n\nThe committee agreed that active surveillance, radical radiotherapy and radical prostatectomy may be suitable for different people. Therefore, it included a preference decision box for clinicians to use to help people with prostate cancer make the right choice for themselves. The information in the box comes from the UK ProtecT trial, which included people with CPG\xa01\xa0to 3 prostate cancer. However, the committee noted that people with CPG\xa03 prostate cancer comprised a small proportion of the people in this trial. Therefore, the information in the box might not directly apply to this group, but may still be useful when discussing the risk of side effects for different treatment options.\n\nThe 2019 guideline recommended that a choice of active surveillance, radical radiotherapy or radical prostatectomy should be offered to people with low-risk prostate cancer (equivalent to the CPG\xa01 group in the 5‑tier model that is now recommended). The committee noted that since the 2019 guideline was published, practice in this area has changed and there is now more concern about overtreatment of low-risk cancer. They noted that the UK ProtecT trial, which is most applicable to the population with CPG\xa01 prostate cancer, showed statistically significant benefit from radical treatment and a higher risk of adverse events. It was therefore recommended that active surveillance should be offered to people with CPG\xa01 prostate cancer and radical treatment considered if active surveillance is not acceptable or unsuitable.\n\nIn the 2019 guideline, radical treatment was recommended for people with intermediate-risk prostate cancer, with active surveillance considered if this was unacceptable to the person with prostate cancer. The CPG model divides this intermediate-risk group into CPG\xa02 and CPG\xa03 prostate cancer and the committee made different recommendations for these groups because they have different risks of prostate cancer related mortality. The committee recommended that people with CPG\xa02 prostate cancer should be offered a choice of radical prostatectomy, radical radiotherapy or active surveillance. The ProtecT trial included people with CPG\xa02 prostate cancer. However, the risk of prostate cancer related mortality is higher in the CPG\xa02 population than in people with CPG\xa01 prostate cancer and so the choice between active surveillance and radical treatment is more finely balanced.\n\nRadical prostatectomy or radical radiotherapy was recommended for people with CPG\xa03 prostate cancer, in line with the 2019 recommendation for people with intermediate-risk prostate cancer. This is because the risk of prostate cancer related mortality is higher for this group than the CPG\xa02 group and the committee thought that the survival benefit from radical treatment would likely outweigh the side effects. The committee also recommended that active surveillance could be considered if radical treatment is unacceptable to the patient, in line with the 2019 recommendation.\n\nThe 2019 recommendation not to offer active surveillance to people with high-risk prostate cancer was updated to refer to people with CPG\xa04\xa0and 5 prostate cancer. The committee agreed that these groups were equivalent, and that active surveillance would not be a suitable treatment option for these people.\n\n## How the recommendations might affect practice\n\nRecommendations where low risk was replaced with CPG\xa01 are likely to apply to a broader population due to the inclusion of people with T2b prostate cancer. However, the committee agreed that the associated resource impact of this change would be minimal because although there is more emphasis on active surveillance, the other treatment options are still available.\n\nReturn to recommendations\n\n# Multiparametric MRI for active surveillance\n\nRecommendations 1.3.13 and 1.3.14\n\n## Why the committee made the recommendations\n\nThe committee made recommendations based on a good body of evidence that multiparametric MRI can be used as part of an active surveillance protocol to identify clinically significant cancer, or restage prostate cancer after diagnosis. The committee took into account the benefits seen in using multiparametric MRI pre‑biopsy in people who have not had a biopsy and who have suspected prostate cancer. The committee concluded that this benefit can be extended to people having active surveillance without having had an MRI to allow for confirmation or reclassification of the prostate cancer.\n\nThe committee amended the protocol for active surveillance based on their expertise and good evidence on PSA-derived measures to monitor, and the use of multiparametric MRI to identify, clinically significant prostate cancer. The committee kept the use of digital rectal examination (DRE) in this population because they did not see any new evidence to not recommend it for this group. In addition, DRE was part of the protocol in 1 of the studies included in the evidence review.\n\nBecause of the limited evidence on the most effective pathway for excluding clinically significant progression of prostate cancer in people with low to intermediate risk, the committee made recommendations for research in this area. They also identified that there was a gap in the evidence on the most suitable surveillance protocol for this population group, including the use of DRE.\n\n## How the recommendations might affect practice\n\nThe use of multiparametric MRI in people who are enrolled on active surveillance will influence active surveillance protocols across the country. Multiparametric MRI is clinically and cost effective, because clinically significant cancers are more likely to be identified, therefore decisions on treatment can be made earlier in the diagnosis pathway saving on future treatment costs.\n\nReturn to recommendations\n\n# Radiotherapy\n\nRecommendations 1.3.19 and 1.3.21 to 1.3.25\n\n## Why the committee made the recommendations\n\nThe 2014 and 2019 recommendations on hormone treatment and brachytherapy for intermediate and high-risk prostate cancer were amended to cover the CPG\xa02 to 5 groups. The committee agreed these groups are broadly equivalent to the groups in the 2019 guideline and reflect the populations that will have radical radiotherapy. The recommendations for high-risk prostate cancer were amended to CPG\xa04 and 5 as these are the equivalent groups.\n\nIn 2019, the committee considered a large body of evidence showing that hypofractionated radiotherapy and conventional radiotherapy were equally effective. The committee noted that hypofractionated radiotherapy is associated with higher rates of acute gastrointestinal toxicity, but overall it could enable people to have a better quality of life because they would need to make fewer clinic visits. Fewer clinic visits for hypofractionated radiotherapy would also mean fewer resources were needed compared with conventional radiotherapy treatment. Therefore, hypofractionated radiotherapy was recommended as the first option.\n\nThe committee agreed that 60\xa0Gy in 20\xa0fractions was the optimal dose for people having hypofractionated radiotherapy. This was the dosage used in the large UK CHHiP trial that was associated with greater efficacy compared with a 57\xa0Gy schedule, although the 60\xa0Gy schedule did also show slightly greater toxicity.\n\nThe 2019 committee considered evidence from a large trial that showed a reduction in biochemical failure (for example, local recurrence or distant metastases) associated with the use of low dose-rate brachytherapy plus external beam radiotherapy for people with high-risk localised prostate cancer (now updated to the equivalent CPG\xa04 and 5 groups in the recommendation). As a result, the committee amended the 2014 recommendation so it was not limited to high dose-rate brachytherapy. The committee also agreed that as most centres do not offer both types of brachytherapy, the advice gives clinicians a choice of either high dose-rate or low dose-rate brachytherapy.\n\n## How the recommendations might affect practice\n\nAs hypofractionated radiotherapy is already routinely used in practice (alongside other non-radiotherapy treatment options) for people with localised prostate cancer, these recommendations are unlikely to have an impact on resources.\n\nFor brachytherapy (high dose-rate or low dose-rate), the committee agreed that only a small number of people (typically those with CPG\xa04 and 5 prostate cancer) would currently have brachytherapy, so the changes to the recommendations are unlikely to have a significant impact on current practice.\n\nRecommendations where intermediate risk was replaced with CPG\xa02 and 3 are likely to apply to a smaller group of people. Therefore, the committee agreed that the changes were unlikely to result in an increased use of resources.\n\nRecommendations for high-risk prostate cancer were changed to be for CPG\xa04 and 5, but because these groups are equivalent there would be no resource impact.\n\nReturn to recommendations\n\n# Docetaxel chemotherapy\n\nRecommendations 1.3.26 and 1.3.27 and recommendation 1.5.6\n\n## Why the committee made the recommendations\n\nThere was good evidence that showed docetaxel improves overall survival, prostate cancer-specific survival and clinical progression-free survival in people with newly diagnosed metastatic prostate cancer who are starting long-term hormone therapy. The committee agreed these benefits outweighed the potential harms of the treatment.\n\nThe evidence also showed docetaxel slows clinical progression in people with newly diagnosed high-risk, non-metastatic cancer starting long-term hormone therapy. However, the evidence did not show any extension of overall survival. Because of the known toxicities associated with docetaxel treatment, the benefits and harms are more finely balanced in this population. As a result, the committee identified this decision as being preference sensitive, and the person's values and preferences are likely to be particularly important in their decision about the best course of action for them.\n\nThe committee also made a recommendation for research as it identified a gap in the evidence related to there being no universal definition of locally advanced prostate cancer. A risk stratification study will help identify patients at various levels of risks, and help tailor treatment according to need.\n\n## How the recommendations might affect practice\n\nOff‑label use of docetaxel in people diagnosed with hormone‑sensitive metastatic prostate cancer is current practice, therefore the recommendation for the metastatic prostate cancer population is likely to have no impact. However, this does not include high‑risk, non‑metastatic prostate cancer. Therefore, the recommendation for this population could result in an increase in the number of people with high‑risk, non‑metastatic prostate cancer receiving docetaxel chemotherapy. Although this could result in an increase in some shorter‑term costs to the NHS, the economic evidence showed a reduction in longer‑term management costs, with the net effect that docetaxel is likely to be cost‑saving in the long term in this population and, once its benefits are also taken into account, almost certain to represent a good use of NHS resources.\n\nReturn to recommendations 1.3.26 and 1.3.27\n\nReturn to recommendation 1.5.6\n\n# Follow up\n\nRecommendations 1.3.45 to 1.3.50\n\n## Why the committee made the recommendations\n\nThe committee saw no new evidence to suggest any changes were needed to the recommendations on follow‑up strategies after radical treatment. The committee did not change the existing recommendations that DRE should not be offered, as there was no new evidence to suggest it was beneficial for people who were not on active surveillance.\n\nBased on their expertise, the committee amended the recommendations on the location of the follow up. The committee discussed different strategies already in use across the country such as shared care, supported self-management and telephone‑based follow up. Because it had not looked at the specific evidence for these, it was unable to recommend a specific programme. The committee agreed that the 2‑year follow up recommended in the previous guideline was conservative, and based on their expertise, people with no complications and with a stable PSA could be cared for outside of the hospital environment. Complex cases might need longer contact with hospital-based services.\n\nGiven the lack of evidence, the committee also made a recommendation for research in this area.\n\n## How the recommendations might affect practice\n\nThe committee noted that follow‑up strategies are variable across the country and the recommendations will therefore have a varied resource impact across the country depending on the level of follow up that is currently in place locally. Depending on the changes implemented, there may be a large resource impact.\n\nReturn to recommendations\n\n# Bone-targeted therapies (bisphosphonates)\n\nRecommendations 1.5.19 to 1.5.21\n\n## Why the committee made the recommendations\n\nThere was some evidence that showed zoledronic acid prolonged the time without skeletal-related events in people with hormone-refractory metastatic prostate cancer. However, the committee could not make a stronger recommendation because the evidence did not show whether zoledronic acid affects mortality in this population.\n\nThere was no new evidence that could affect the existing recommendation on the administration of bisphosphonates for pain relief for people with hormone-refractory metastatic prostate cancer.\n\n## How the recommendations might affect practice\n\nThere may be a small increase in the cost of hormone-refractory metastatic prostate cancer treatment, but as zoledronic acid is now out of patent, this should limit the cost impact.\n\nReturn to recommendations", 'Context': 'Prostate cancer is the most common cancer in men, and the second most common cancer in the UK. In 2014, there were over 46,000\xa0new diagnoses of prostate cancer, which accounts for 13% of all new cancers diagnosed. About 1\xa0in\xa08\xa0people will get prostate cancer at some point in their life.\n\nProstate cancer can also affect trans women, as the prostate is usually conserved after gender‑confirming surgery, but it is not clear how common it is in this population.\n\nMore than 50% of prostate cancer diagnoses in the UK each year are in people aged 70\xa0years and over (2012), and the incidence rate is highest in people aged 90\xa0years and over (2012 to 2014). Out of every 10\xa0prostate cancer cases, 4\xa0are only diagnosed at a late stage in England (2014) and Northern Ireland (2010\xa0to 2014). Incidence rates are projected to rise by 12% between 2014 and 2035 in the UK to 233\xa0cases per 100,000 in\xa02035.\n\nA total of 84% of people aged 60\xa0to 69\xa0years at diagnosis in 2010/2011 are predicted to survive for 10\xa0or more years after diagnosis. When diagnosed at the earliest stage, virtually all people with prostate cancer survive 5\xa0years or more: this is compared with less than a third of people surviving 5\xa0years or more when diagnosed at the latest stage.\n\nThere were approximately 11,000\xa0deaths from prostate cancer in 2014. Mortality rates from prostate cancer are highest in people aged 90\xa0years and over (2012\xa0to 2014). Over the past decade, mortality rates have decreased by more than 13% in the UK. Mortality rates are projected to fall by 16% between 2014 and 2035 to 48\xa0deaths per 100,000\xa0people in\xa02035.\n\nPeople with an African family background are at higher risk of prostate cancer (lifetime risk of approximately 1\xa0in\xa04). Prostate cancer is inversely associated with deprivation, with a higher incidence of cases found in more affluent areas of the UK.\n\nCosts for the inpatient treatment of prostate cancer are predicted to rise to £320.6\xa0million per year in 2020 (from £276.9\xa0million per year in\xa02010).\n\nThis guidance was updated in 2014 to include several treatments that have been licensed for the management of hormone-relapsed metastatic prostate cancer since the publication of the original NICE guideline in\xa02008.\n\nSince the update in 2014, there have been changes in the way that prostate cancer is diagnosed and treated. Advances in imaging technology, especially multiparametric MRI, have led to changes in practice, and new evidence about some prostate cancer treatments means that some recommendations needed to be updated.\n\nSince the update in 2019 there has been new evidence on risk categorisation models for localised and locally advanced prostate cancer. Therefore, recommendations on risk categorisation and subsequent recommendations on treatments for different risk categories needed to be updated.'}
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https://www.nice.org.uk/guidance/ng131
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This guideline covers the diagnosis and management of prostate cancer in secondary care, including information on the best way to diagnose and identify different stages of the disease, and how to manage adverse effects of treatment. It also includes recommendations on follow-up in primary care for people diagnosed with prostate cancer.
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6da83759c9137629fdcd2bf335dac69abceb07e8
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nice
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Belimumab for treating active autoantibody-positive systemic lupus erythematosus
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Belimumab for treating active autoantibody-positive systemic lupus erythematosus
Evidence-based recommendations on belimumab (Benlysta) for treating active autoantibody-positive systemic lupus erythematosus.
# Recommendations
Belimumab is recommended as an option as add-on treatment for active autoantibody-positive systemic lupus erythematosus in people with high disease activity despite standard treatment, only if:
high disease activity is defined as at least 1 serological biomarker (positive anti-double-stranded DNA or low complement) and a SELENA‑SLEDAI score of greater than or equal to 10
treatment is continued beyond 24 weeks only if the SELENA‑SLEDAI score has improved by 4 points or more
the company provides belimumab according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the managed access agreement for belimumab for systemic lupus erythematosus (NICE technology appraisal guidance 397).
Standard therapies include non-steroidal anti-inflammatory drugs, corticosteroids, antimalarials and immunosuppressants. Other treatments include biological disease-modifying antirheumatic drugs such as rituximab.
Clinical trial evidence suggests that, after a year of treatment, belimumab plus standard therapy reduces disease activity more than standard therapy alone. However, the results are uncertain because the trials were short, so the long-term benefit is unknown. Also, the effect of belimumab compared with rituximab is unknown.
The cost-effectiveness estimates are also uncertain. But there is an unmet need for effective treatments in people with systemic lupus erythematosus, and some benefits of belimumab may not be taken into account in the cost-effectiveness results. For people with high disease activity despite standard treatment, the most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, belimumab is recommended for these people.# Information about belimumab
# Marketing authorisation indication
The intravenous formulation of belimumab (Benlysta, GlaxoSmithKline) 'is indicated as add-on therapy in patients aged 5 years and older with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti‑dsDNA and low complement) despite standard therapy'. The subcutaneous formulation 'is indicated as add-on therapy in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti‑dsDNA and low complement) despite standard therapy'.
# Dosage in the marketing authorisation
The dosage schedules are available in the summary of product characteristics for the intravenous formulation of belimumab and the summary of product characteristics for the subcutaneous formulation of belimumab.
# Price
The list price of belimumab for the intravenous infusion is £121.50 for a 120‑mg vial and £405.00 for a 400‑mg vial (excluding VAT; BNF online accessed November 2021). The list price for the subcutaneous injection is £222.75 for a 200‑mg pre-filled pen (excluding VAT; company submission).
The company has a commercial arrangement for both formulations. This makes belimumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected using the British Isles Lupus Assessment Group Biologics Register (BILAG‑BR) and additional clinical trial evidence presented in the company's updated submission to address uncertainties identified during the original appraisal. As a condition of the managed access arrangement, the company was required to collect real-world data from the BILAG registry after treatment with belimumab, including on its efficacy, safety and effect on health-related quality of life.
The committee agreed that some of the issues raised in the ERG report had been resolved after technical engagement. These included that there is no evidence for using belimumab in people with severe active central nervous system lupus (key issue 1), that cyclophosphamide is not a relevant comparator (key issue 2), and that intravenous and subcutaneous formulations of belimumab are likely to be clinically comparable (key issue 7).
The committee agreed that there is unresolved uncertainty with the issues raised in the ERG report about the uncertainty on organ damage utility multipliers (key issue 12) and the sampling order of organ damage and death in the model (key issue 13). However, it thought that it was unlikely that these issues would have a significant effect on the cost-effectiveness results.
# Belimumab as a treatment option
## People with systemic lupus erythematous would welcome belimumab as a continuing treatment option
Systemic lupus erythematosus is a chronic autoimmune condition that causes inflammation in the body's tissues and can affect the whole body. The patient experts explained that people with the condition often have frequent disease flares and more severe symptoms that can result in hospital admissions. This can affect a person's ability to work, complete everyday activities and socialise. The patient experts described how this causes stress and anxiety, which can trigger further disease flares. They described how the condition can affect fertility by causing recurrent miscarriages and severe disease flares. The patient experts further explained that, even when their condition is clinically stable, they still have symptoms that affect their daily life such as fatigue, headaches, joint pain and reduced mental acuity. These symptoms can make it challenging to care for themselves and others. One patient expert explained that treatment with belimumab as an add‑on to standard therapy has significantly reduced their disease flares and that they have been able to reduce their daily corticosteroid dose. The patient experts explained that treatment with belimumab has helped to improve other day-to-day symptoms of the condition, and this has improved their overall quality of life. They described the burden of having to travel long distances to have belimumab intravenous infusions administered in hospital, and that they have nausea from the pre-infusion medication. However, they continue with the treatment because they think that their condition is responding well to it. One patient expert also described the benefits of using the new subcutaneous formulation of belimumab because of being able to self-administer it at home with little disruption to daily life and the minimal side effects. At the second committee meeting, the patient expert explained that they had tried several other treatment options including azathioprine, mycophenolate mofetil and rituximab, but that none of these treatments had effectively reduced their disease activity. They explained that there are few treatment options currently available for people with systemic lupus erythematosus and that they would have no alternative treatment option if belimumab was not made available through routine NHS commissioning. The patient expert explained that the prospect of belimumab being withdrawn was a significant worry for them and many other people with severe refractory disease that has only responded to belimumab. The committee concluded that people with systemic lupus erythematosus would welcome belimumab continuing to be a treatment option.
# Treatment pathway and positioning
## The company's updated population is appropriate
The marketing authorisation for belimumab states that it is indicated for systemic lupus erythematosus that has a high disease activity despite standard therapy. The committee discussed that, in the original appraisal, belimumab was recommended for systemic lupus erythematosus with high disease activity (HDA‑1) despite standard therapy. HDA‑1 is a Safety of Estrogens in Lupus Erythematosus: National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA‑SLEDAI) score of greater than or equal to 10, and 2 serological biomarkers (positive anti-double-stranded DNA and low complement). The company and clinical experts explained that, based on the data collected through the BILAG registry, this HDA‑1 population was too restrictive in clinical practice. This is because people will often have high levels of disease activity but only 1 of the 2 defined serological biomarkers. So, the company presented a broader high-disease-activity population (HDA‑2) as part of its base case. This included people with a SELENA‑SLEDAI score of greater than or equal to 10 and only 1 serological biomarker. The clinical experts considered that the company's new high-disease-activity population was clinically relevant and would allow more people access to belimumab. The committee concluded that the company's updated population was appropriate for decision making.
# Comparators
## Standard therapy is a relevant comparator
The committee heard that standard therapy for treating systemic lupus erythematosus is likely to consist of non-steroidal anti-inflammatory drugs, corticosteroids, antimalarials and immunosuppressants. It was aware that some standard therapies are not licensed for use in systemic lupus erythematosus but are used off label in clinical practice. The committee noted that belimumab is indicated as an add-on therapy to standard care. It understood that standard therapy was included in the scope for the appraisal and concluded that it was a relevant comparator.
## Rituximab is a relevant comparator
The committee discussed the updated NHS England clinical commissioning policy on rituximab for refractory systemic lupus erythematosus in adults and post-pubescent children. It noted that, while rituximab is currently not licensed for treating systemic lupus erythematosus, it is available as a treatment option through this commissioning policy. The committee discussed the eligibility criteria for rituximab outlined in the commissioning policy, which recommends considering using licensed and NICE-approved treatments, such as belimumab, first. The clinical experts explained that, based on the data collected from the BILAG registry, only a very small number of people on rituximab would be eligible for belimumab because of the differences in the eligibility criteria. They explained that people having belimumab will generally have more severe disease because of the current eligibility criterion of a SELENA‑SLEDAI score of greater than or equal to 10. However, they pointed out that people with renal or central nervous system complications would not be eligible for belimumab and would have rituximab instead. The clinical experts also explained that some people who are eligible for belimumab may have experienced adverse reactions or no improvement in their disease activity after treatment with rituximab. Therefore, this population would not be eligible for rituximab. The committee heard that, if belimumab is not recommended for routine commissioning, more people would potentially have treatment with rituximab in its absence. The committee noted that rituximab was included in the final scope for the appraisal and is being used in clinical practice through the commissioning policy. It concluded that rituximab was a relevant comparator.
# Clinical effectiveness
## Belimumab improves the SRI-4 response rate at 52 weeks compared with standard therapy
The company submission included the BLISS 52 and BLISS 76 randomised controlled trials comparing intravenous belimumab plus standard therapy (from now, referred to as belimumab) with placebo plus standard therapy (from now, referred to as standard therapy). The company presented results for the new HDA‑2 population based on the pooled trials and new evidence from the BLISS SC randomised controlled trial comparing a new subcutaneous formulation of belimumab with standard therapy. The primary outcome of all studies was the response rate at week 52 compared with baseline. This was assessed with the Systemic Lupus Erythematosus Responder Index‑4 (SRI‑4), which is a composite measure of disease activity. Belimumab showed a statistically significant improvement in SRI‑4 response rate at 52 weeks compared with standard therapy in the HDA‑2 population across the BLISS SC, and pooled BLISS 52 and BLISS 76 trials (pooled BLISS 52 and BLISS 76: odds ratio 2.29, 95% confidence interval 1.61 to 3.26; BLISS SC: odds ratio 1.79, 95% CI 1.17 to 2.74). The committee concluded that belimumab improved SRI‑4 response rate at 52 weeks compared with standard therapy.
## The BLISS long-term extension studies do not provide long-term effectiveness evidence for belimumab compared with standard therapy
The company included new evidence from the BLISS long-term extension studies. These were single-arm continuation studies of people enrolled in the BLISS randomised controlled trials (see section 3.5). People who had been randomised to have belimumab continued treatment with belimumab, and people in the placebo groups were switched to belimumab in all long-term extension studies:
The BLISS 76 US long-term extension study included people in the US who had completed the BLISS 76 trial. The primary outcome was mean Systemic Lupus Erythematosus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) change from baseline, which is a measure of organ damage. In the total population, the mean SDI change was 0.4 (standard deviation 0.68) at 7 years.
The BLISS 52/76 non-US long-term extension study included people not from the US who had completed either the BLISS 52 or BLISS 76 trials. In the total population, the mean SDI change was 0.2 (standard deviation 0.56) at 8 years.
The BLISS SC long-term extension study included people who had completed the BLISS SC trial. The number of people whose condition responded according to the SRI‑4 at 6 months was 16.1% in the placebo-to-belimumab group and 76.3% in the belimumab group.The committee noted that the long-term extension studies did not have comparator arms. It concluded that they did not provide long-term effectiveness evidence for belimumab compared with standard therapy.
## There is still uncertainty about the clinical and cost effectiveness of belimumab compared with rituximab
The company explained that no new clinical trial evidence directly comparing belimumab with rituximab had been identified after the original appraisal. It also stated that an indirect comparison based on the EXPLORER trial, which compared rituximab with placebo, was not appropriate. This is because the EXPLORER trial did not meet its primary end point, and for other reasons, such as the trial population including people with more severe disease than people in the BLISS trials. The committee heard that a comparison between belimumab and rituximab was available from the observational prospective cohort BILAG‑BR sub-study, which was presented as part of the company's submission. This study was designed to fulfil the managed access requirements from the original appraisal. A multilevel regression analysis done by the University of Manchester compared the efficacy of belimumab with rituximab based on data collected from the sub-study. The eligibility criteria in the study reflected the high disease activity (HDA‑1) population recommended in the original appraisal and included people having belimumab, rituximab or other non-biological treatments. Outcome measures assessed in the analysis included measures of disease activity (change in BILAG‑2004, SLEDAI‑2K and SDI scores), and health-related quality of life measured using generic and disease-specific instruments. The results suggested that, for most outcome measures, a similar level of change in disease activity was seen for belimumab and rituximab at 12 months of follow up (actual results are confidential and cannot be reported here). The company considered that there was a high likelihood of confounding and selection bias in this regression analysis. It thought that the data was not appropriate for comparing treatment efficacy, so did not do an indirect treatment comparison. The committee noted that the regression analysis based on the observational data did provide a comparison in a UK population relevant to the decision problem. It acknowledged that the analysis was based on small numbers, and the long-term comparative effectiveness between treatments could not be determined based on the 12 months of data collected in the registry for belimumab. The committee considered that because rituximab is a relevant comparator (see section 3.4), it would have preferred to see an indirect treatment comparison between belimumab and rituximab in the relevant population. The company did not provide an indirect comparison between belimumab and rituximab in response to the appraisal consultation document. It considered that as the BILAG‑BR sub-study only collected data for the HDA‑1 population, an indirect comparison in the target HDA‑2 population would not be possible. The company also highlighted that because there is limited long-term effectiveness data for rituximab in people with systemic lupus erythematosus, a reliable and robust indirect treatment comparison cannot be done. The committee recognised that conducting an indirect treatment comparison in the traditional sense may be difficult, but it noted that the company had used an adjusted indirect comparison to compare organ damage progression for people on belimumab and standard care (see section 3.8). It considered that the company could have also explored alternative adjustment methods to inform the treatment comparison between belimumab and rituximab using the data collected from the registry. The committee discussed that because the criteria in the new HDA‑2 target population was wider than considered previously, it would still include people who meet the HDA‑1 criteria and are currently having belimumab in clinical practice. Therefore, the committee considered that the company should have explored data from the BILAG‑BR sub-study to compare efficacy between belimumab and rituximab. It concluded that in the absence of this comparison, the uncertainty about the relative clinical and cost effectiveness of belimumab and rituximab remains.
## The results of the propensity score-matched analysis may not be relevant to NHS clinical practice
The company's long-term extension studies did not have comparator arms. So, it did a propensity score-matched analysis to compare results from people who had belimumab in the BLISS 76 US long-term extension study with the results from people who had standard therapy in the external Toronto Lupus Cohort (n=99 in each cohort). The primary end point of the propensity score-matched analysis was to compare organ damage progression (mean change in SDI score) from baseline to year 5 in people having treatment with belimumab or standard therapy with 5 or more years of follow up. The results showed that people having treatment with belimumab had statistically significantly less organ damage (5‑year SDI change of 0.283, 95% CI 0.166 to 0.400) compared with people having standard therapy alone (5‑year SDI change of 0.717, 95% CI 0.500 to 0.934). The committee considered that it was unclear why the company had selected the Toronto Lupus Cohort as the source of data for the standard therapy arm in the propensity score-matched analysis. The company explained that it identified the cohort through a systematic literature review of people with systemic lupus erythematosus with 5 or more years of follow up. It selected the Toronto Lupus Cohort because of its size and because it matched on most of the variables needed for the propensity score-matched analysis. The company explained that it did not identify a comparable cohort from the UK through the literature review. The committee considered that it would have preferred data from a UK registry to have been used, but acknowledged the company's comments that such evidence may not be available. The ERG highlighted that it was unclear how selection criteria had been applied to determine that the Toronto Lupus Cohort was the most appropriate source from the systematic review. The committee noted the ERG's critique that the sample size in the BLISS‑76 US long-term extension study decreased by almost half in the propensity score-matched analysis, suggesting large differences in the baseline characteristics compared with the Toronto Lupus Cohort. The committee noted a consultation comment that the Toronto Lupus Cohort may not be appropriate for comparison because it included people with systemic lupus erythematosus in a different country, up to 30 years ago. The stakeholder highlighted that changes in medical care since this time may influence organ damage development and its associated costs. The committee discussed how the 2 cohorts used in the propensity score-matched analysis were from the US and Canada. Because of this, the committee considered that there was uncertainty in the generalisability of the treatment effect observed in the analysis to the target population who would have belimumab in England. The committee concluded that the results of the propensity score-matched analysis may not be relevant to NHS clinical practice.
## The results of the propensity score-matched analysis are likely biased in favour of belimumab
The committee noted that several important variables were not included in the company's propensity score-matched analysis, including measures of socioeconomic outcomes, disease progression and disease activity over time. It discussed the ERG's critique that there were also differences between the populations in the cohorts before matching. These included differences in the rates of smoking, which were higher in the Toronto Lupus Cohort. Because of this, the committee considered that it was likely that people from the Toronto Lupus Cohort would have had worse outcomes, even after matching, because of the influence of these unmatched variables on organ damage progression. In response to consultation, the company explained that it was not suitable to match on variables such as disease progression and disease activity over time because these could be potential confounders in the analysis. The clinical expert agreed that disease activity over time was a potential confounder and that including it could bias the results in either direction. The committee noted the ERG's critique that these variables are important prognostic factors that may need to be adjusted for, to give an unbiased treatment comparison. The committee heard that most people withdrew from the BLISS 76 US long-term extension study before 5 years. So, people who continued having belimumab at 5 years were likely to have progressed less or had a better response than people who had belimumab for 1 to 4 years before stopping treatment. The committee recalled testimony from a patient expert, who described the burden of attending hospital for regular intravenous infusions of belimumab. It agreed that it was likely that people who stayed on belimumab for 5 years had low disease activity, a good response to treatment or both. The company explained that it had presented the reasons for discontinuation in the BLISS 76 US long-term extension study in its submission. The main reasons for discontinuation were adverse events and patient request. Other reasons for withdrawal included lack of efficacy, physician choice, lack of adherence and loss to follow up. The ERG considered that it was plausible that lack of efficacy would have been a factor in withdrawals stated for other reasons. The clinical experts explained that in clinical trials and clinical practice, people may decide to stop maintenance treatment for reasons other than lack of efficacy, such as their disease being well controlled or in remission, or because they are planning to start a family. They described how systemic lupus erythematosus is a relapsing-remitting disease meaning that a person's disease activity and their resulting need for treatment would vary over time. The committee discussed the ERG's critique that without further data, it is unclear to what extent people who stopped taking belimumab before 5 years were different to those who continued to take belimumab beyond 5 years in the long-term extension study. It discussed that, although some people may have dropped out because they were benefiting, most people would have remained in the trial if they were benefiting from belimumab and those who were not available for analysis at 5 years were likely to have progressed or had a poorer response. The committee concluded that the results of the propensity score-matched analysis were likely biased in favour of belimumab.
# Cost effectiveness
## The model structure is unchanged from the original appraisal and is suitable for decision making
The company presented a microsimulation model with an annual cycle length and lifetime time horizon. The model structure was unchanged from the original appraisal. Two separate models were presented for each formulation of belimumab. The models used the new HDA‑2 population (see section 3.2), with patient baseline characteristics drawn from the pooled BLISS 52 and BLISS 76 trials for the intravenous belimumab model, and from BLISS SC for the subcutaneous belimumab model. The company used the average patient weight from the BILAG registry for the intravenous model. In the original appraisal, this was taken from the pooled BLISS 52 and BLISS 76 trials. The committee concluded that, because the model structure remained unchanged from the original appraisal, it was suitable for decision making.
## The committee understood why the company had adjusted the model to reflect the observed long-term data available for belimumab
In the original appraisal, the company simulated long-term effects of belimumab on disease progression using a natural history model based on observational data from a cohort of people with systemic lupus erythematosus (the Johns Hopkins lupus cohort). In this review, the company explained that the newly available BLISS long-term extension studies (BLISS 52 and BLISS 76) were incorporated to extrapolate long-term effects on disease progression. The company considered that, compared with results from the propensity score-matched analysis (see section 3.8), its model overestimated organ damage progression in the belimumab arm but underestimated progression in the standard therapy arm. So, the company simulated its model using several calibration factors until the results matched the observed results from the propensity score-matched analysis at 5 years. The chosen calibration factor (0.491) was then applied to belimumab 'responders' only (see section 3.13) for up to 6 years and was used to adjust the time-to-event risk equations for organ damage probabilities in the models. The ERG noted that this implied that the annual risk of organ damage for belimumab was adjusted downwards by 50.9%. The committee understood why the company had adjusted organ damage progression in the original model to reflect the observed long-term data available for belimumab but had concerns about how this had been done (see section 3.12).
## The company's calibration factor to adjust for long-term organ damage is not suitable for decision making
The ERG noted that the main issue with applying the calibration factor was that the propensity score-matched analysis it was based on had several methodological issues (see section 3.8 and section 3.9). Another concern was that the model assumptions in the original appraisal assumed a constant treatment effect of belimumab on disease activity reduction after 1 year (based on the trial data). The committee considered that this was already an optimistic assumption in terms of the long-term treatment effect of belimumab. This was particularly so when taking into account that some people stopped treatment in the long-term extension studies (that is, after 1 year) because of a lack of efficacy. The committee also considered that adding the calibration factor would have further increased the treatment benefit of belimumab. It noted the ERG's comments that the company's calibration factor was derived using the entire modelled belimumab cohort (including people whose condition responded and did not respond to belimumab, classified as 'responders' and 'non-responders' respectively – see section 3.13). The ERG noted that the propensity score-matched analysis on which the calibration factor was based only included people who had treatment for 5 years or longer and so would have experienced a good response to treatment. Therefore, it considered that only 'responders' to belimumab should have been used in the model to derive the calibration factor. In response to the ERG's critique, the company provided a scenario analysis using 'responders' only to derive a calibration factor. The scenario analysis resulted in a calibration factor of 0.536, which was slightly less favourable for belimumab than the original calibration factor used in the company's base case. The committee noted that applying the new calibration factor had a small impact on the incremental cost-effectiveness ratio (ICER). It was concerned that the difference between the new and original calibration factor was smaller than expected and that removing 'non-responders' only had a small impact on organ damage progression of the entire modelled belimumab cohort at 5 years. The ERG suggested that this may mean that organ damage of 'non-responders' may be underestimated in the model and that this could bias the derivation of the calibration factor. The clinical experts explained that this small difference could be because 'non-responders' would likely have their standard therapy adjusted and this may improve their disease activity for some time. The committee discussed that because the calibration factor is applied as a multiplication to the model, this means that any associated error and uncertainty is likely to accumulate over time. It recalled its concern about the appropriateness of the propensity score-matched analysis that formed the basis of the calibration factor. The committee noted the ERG's critique that applying the calibration factor that has been estimated based on 5 years is likely to underestimate organ damage progression in the preceding years. It noted the uncertainty in applying the calibration factor constantly to belimumab 'responders' who stopped treatment at years 2 to 4 in the model. The committee discussed how the ERG was not able to fully validate the company's new calibration factor and that it likely overestimated the treatment benefit of belimumab. The committee concluded that the company's calibration factor to adjust for long-term organ damage was not suitable for decision-making.
## It is unclear whether the modelled response to treatment for belimumab 'non-responders' is consistent with the BLISS trials
In the original appraisal, the committee heard from clinical experts that people would likely stop treatment with belimumab after 24 weeks if they had not experienced any improvement in their disease control during this time (in line with summary of product characteristics for belimumab). The clinical experts indicated in the original appraisal that a SELENA‑SLEDAI score reduction of 4 points would generally be considered a reasonable improvement and the committee noted that this was aligned with the 24‑week treatment continuation rule in the company's model. In the model, people on belimumab with a reduction of 4 or more points in SELENA‑SLEDAI score at week 24 were classified as 'responders'. SELENA‑SLEDAI scores were estimated based on a regression model, given that there was not a 24‑week time point in the model. The committee noted that, at 24 weeks, 34.1% of people from the HDA‑2 subgroup were classified as 'non-responders' using the regression model and stopped treatment with belimumab. The committee did not think it was clinically plausible that nearly half of these modelled 'non-responders' (46.5%) would have had a SELENA‑SLEDAI score reduction of 4 or more at 52 weeks after reverting to standard therapy alone at 24 weeks, as predicted by the company's model. The ERG noted that the model could have underestimated belimumab costs compared with clinical practice because people having a response to belimumab at 52 weeks were initially classified as 'non-responders' and therefore modelled to stop treatment with belimumab. The company explained that this observation did not mean that these people were incorrectly classified in the model as 'non-responders'. It highlighted that no one classed as a belimumab 'non-responder' at 24 weeks had a SELENA‑SLEDAI reduction of 4 or more points. The clinical experts explained that standard care for lupus treatments in clinical trials includes a combination of immunosuppressants, hydroxychloroquine and high-dose corticosteroids. Because of this, they considered that it was possible for some people to have a benefit with standard therapies, particularly because regular care in clinical trials is usually better than clinical practice. The clinical experts considered that people whose condition has not responded to belimumab would have their standard therapy adjusted, for example, by dose escalation. This may result in an improvement in disease activity within 3 to 6 months of changing treatments for some people. The committee was not convinced that people whose condition has not responded to belimumab at 24 weeks would have a significant improvement in disease activity at 52 weeks on standard therapy alone. It considered that a 6‑month cycle length may have been more appropriate to use in the model to align with the 24‑week continuation rule. In response to the appraisal consultation document, the company presented a post hoc analysis of the pooled BLISS 52 and BLISS 76 trial data, which showed that 34.5% of 'non-responders' to belimumab at week 24 became 'responders' at week 52. The ERG considered that compared with the trial data, the company's model overestimated the number of 'non-responders' to belimumab at week 24 who became 'responders' at week 52. The company explained that this was because while 'non-responders' could continue to have belimumab in the BLISS trials, their steroid therapy was not allowed to be adjusted after week 40. However, in the model, 'non-responders' stopped belimumab treatment at 24 weeks and would then have their steroid therapy adjusted to improve disease control to reflect clinical practice. The committee noted the ERG's concern that disease activity in 'non-responders' to belimumab may be underestimated in the model compared with the BLISS trials. The ERG explained that it was unable to validate the extended benefit that 'non-responders' receive in the model after stopping treatment with belimumab. The committee understood that the impact of this on the cost-effectiveness results was unknown. It concluded that it was unclear whether the modelled response to treatment for belimumab 'non-responders' was consistent with the BLISS trials.
## Disease activity should be based on the BLISS trials for the first 52 weeks for people whose condition has not responded to belimumab
The ERG suggested that there was an error in the company's model because 'non-responders' had the same reduction in disease activity as people having standard therapy at 52 weeks. It considered that this likely meant the treatment benefit of belimumab was overestimated. This is because the BLISS trials showed that people whose condition did not respond to belimumab had a smaller reduction in disease activity than people having standard therapy in the first 52 weeks. The company considered that this was not an error in the model, but an assumption that 'non-responders' took the average standard therapy score from week 52 onwards. The company explained that this assumption was made because 'non-responders' to belimumab at week 24 switched to standard therapy for the remainder of the modelled time horizon (see section 3.13). The ERG explained that, because the model had a yearly cycle, this assumption did not capture any disadvantage that 'non-responders' to belimumab may have in the first 52 weeks, and was not in line with the BLISS trials. The company's scenario analysis assumed a return to standard therapy efficacy for 'non-responders' by week 76 instead of at 52 weeks as in the company's base case. The committee noted that this had a small effect on the ICER. In response to the appraisal consultation document, the company acknowledged the ERG's comments and presented a further scenario analysis. This added an additional cost to belimumab 'non-responders' in year 1 of the model to allow for treatment of their high disease activity. The committee noted that this also had a small effect on the ICER. It discussed the ERG's base case, which used the BLISS evidence to incorporate the difference in disease activity between 'non-responders' and people having standard therapy in the first 52 weeks. The committee preferred the ERG's approach and concluded that disease activity for people whose condition has not responded to belimumab should be based on the BLISS trials for the first 52 weeks.
## There is still uncertainty around the effect of the error in utility estimation on the cost-effectiveness results
The ERG explained that the company's utility regression model used to estimate utility values excluded key organ damage coefficients without re-estimating the remaining coefficients used in the regression equation. The company agreed that this was an error but did not provide a re-estimated model during technical engagement or in response to the appraisal consultation document. Instead, the company presented scenario analyses to explore the effect of varying the regression utility coefficients (log of age, constant, SLEDAI score, ethnicity) in the regression equation by 1 standard deviation in each direction. The committee considered that the company scenarios likely explored the full impact on the cost-effectiveness results but noted that ICERs increased or decreased by around £3,000 per quality-adjusted life year (QALY) gained with only 1 of the coefficients varied. It noted the ERG's critique that the ICERs could increase or decrease further with combinations of coefficients varied but that the variation by 1 standard deviation was likely substantial. The committee considered that it would have preferred the company to provide a re-estimated model to resolve the uncertainty in the cost-effectiveness results. Therefore, the committee concluded that there is still uncertainty around the effect of the error in utility estimation on the cost-effectiveness results.
# Cost-effectiveness estimates
## The committee would be prepared to accept an ICER greater than £20,000
NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. So, the committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee discussed that the ERG's analyses may be slightly pessimistic because they did not adjust for the long-term data available for belimumab. However, it did not accept the company's base cases because of the issues around the appropriateness of the propensity score-matched analysis and the company's calibration factor. Furthermore, it considered that there was uncertainty about the cost-effectiveness estimates because it was unclear whether the disease activity of 'non-responders' to belimumab had been underestimated in the model and because of the company's error in utility estimation. The committee noted that the clinical evidence presented by the company did not inform a reliable long-term comparison of belimumab with standard therapy, and the company had not presented an indirect comparison or cost-effectiveness results compared with rituximab, which it considered to be a relevant comparator. The committee was willing to be flexible despite these uncertainties, which would otherwise limit what would be an acceptable ICER. It took into consideration the unmet need for effective treatments in people with systemic lupus erythematosus and the additional benefits of belimumab that may not be captured in the cost-effectiveness results (see section 3.19). Therefore, it agreed that it would consider ICERs near to the upper end of the range normally considered a cost-effective use of NHS resources.
## Belimumab compared with standard therapy is cost effective
After consultation, the company updated its confidential patient access scheme for belimumab. The company's deterministic base-case ICER (using the updated patient access scheme for belimumab) compared with standard therapy was £12,335 per QALY gained for the intravenous formulation of belimumab and £8,480 per QALY gained for the subcutaneous formulation. The ERG presented analyses including the committee's preferred modelling assumptions, which:
removed the calibration factor (see section 3.12)
used the BLISS trial evidence to incorporate the difference in disease activity between people whose condition has not responded to belimumab and people having standard therapy in the first 52 weeks (see section 3.14).Using the updated patient access scheme for belimumab, the ERG's deterministic base-case ICERs were £30,278 per QALY gained for the intravenous formulation of belimumab and £29,313 per QALY gained for the subcutaneous formulation. The committee considered that the most plausible ICERs for belimumab compared with standard therapy would likely fall in between the company's and ERG's base-case deterministic ICERs. Therefore, it considered that both formulations of belimumab would be a cost-effective use of NHS resources.
# Other factors
## There are no equality issues that can be addressed in this technology appraisal
The committee understood that systemic lupus erythematosus mainly affects women, particularly those of child-bearing age. The patient experts explained that there is a risk of harm to an unborn baby (if taken during pregnancy) and infertility with most immunosuppressive and biological treatments. This can make family planning challenging. The clinical experts explained that neither rituximab nor belimumab is considered safer than the other for use in pregnancy. However, because belimumab has a short biological half-life and so is administered monthly, this makes it easier to organise a planned conception compared with rituximab which has a much longer-lasting effect. The committee recognised that if belimumab was not recommended, then this could potentially make it more difficult for women of reproductive age to plan a pregnancy. The committee heard how the condition is more common in people from an African, Caribbean and Asian family background and that they tend to have poorer health outcomes than people from other family backgrounds. It noted stakeholder comments that anti-double-stranded-DNA antibodies may be less common in people from certain ethnic groups, and that any recommendation about belimumab use stating this as a criterion could be considered as discriminatory. The committee was aware that the company's updated population meant that only 1 of the 2 biomarkers was needed for someone to be eligible for treatment with belimumab. It also heard that administering intravenous belimumab in a specialist centre may be a barrier to accessing treatment if a person lives far away and has to take time off work to have regular infusions. The committee discussed that having a subcutaneous formulation that can be self-administered may improve access to belimumab but noted that the subcutaneous formulation is currently not licensed in children. It noted a stakeholder comment that while childhood systemic lupus erythematous is relatively rare, it usually has a more severe presentation than in adults. This may have a significant impact on a child's education and caring requirements for parents. The committee understood that the intravenous formulation of belimumab is currently being used in children aged 5 years and older through the NHS England's Commissioning Medicines for Children in Specialised Services. It noted comments received during consultation that if belimumab was not recommended for routine commissioning, then this may increase inequalities in access to rituximab. This is because rituximab is only available as an intravenous infusion administered at a specialist centre and some people may struggle to access these centres. Furthermore, rituximab is currently not commissioned for use in children who have not started puberty. The committee concluded that issues about differences in prevalence or incidence of a condition and healthcare implementation cannot be addressed in a technology appraisal.
## There are additional benefits of belimumab that may not be captured in the cost-effectiveness analysis
The company considers belimumab as an add‑on to standard therapy to be innovative because it reduces disease activity and corticosteroid use in people with systemic lupus erythematosus. The committee agreed that these are important benefits and recognised that belimumab is the only medicine specifically licensed for treating systemic lupus erythematosus. It recalled comments received during consultation and from the patient experts highlighting that there is an unmet need for effective treatments in people with systemic lupus erythematosus, particularly in those with severe refractory disease. The committee recognised that the subcutaneous formulation of belimumab, which can be self-administered at home, can offer benefits over the intravenous formulation. The patient experts explained that the intravenous formulation of belimumab also offers significant benefits compared with rituximab. This includes a shorter infusion time and minimal side effects after the infusion. The clinical experts explained that people with rare autoimmune rheumatic diseases such as systemic lupus erythematosus are at an increased risk of adverse and serious effects if they contract COVID‑19. They explained that there is some evidence that people having treatment with rituximab are likely to have a low or undetectable immune response to COVID‑19 vaccinations. This is because rituximab works by depleting a person's B cells, which interferes with the immune system's ability to develop a response to new antigens. The clinical experts explained that because the biological half-life of rituximab is between 6 and 12 months, this means that vaccination efficacy may be significantly reduced if it is given during this time. The committee noted that it had not seen any data on the level of immune response to COVID‑19 vaccinations in people having belimumab. The clinical experts confirmed that they were not aware of any such evidence but would expect that because belimumab does not have the same impact on a person's B cells as rituximab and has a much shorter biological half-life, it would likely have a less severe impact on vaccine efficacy. The committee concluded that there are additional benefits of belimumab that may not be captured in the cost-effectiveness analysis.
# Conclusion
## Belimumab is recommended for routine use
The committee recognised that people with systemic lupus erythematous have benefitted from treatment with belimumab, and that using the subcutaneous formulation at home has advantages. It acknowledged that belimumab compared with standard therapy improves disease outcomes, but that comparative long-term evidence is lacking. It considered that some of the assumptions used in the modelling were not appropriate and that there was uncertainty about the cost-effectiveness estimates. The committee noted that rituximab was a relevant comparator but that the company had not presented any indirect comparison or cost-effectiveness results for belimumab compared with rituximab. However, it took into consideration the unmet need for effective treatments in people with systemic lupus erythematosus and that there are benefits of belimumab that may not be captured in the cost-effectiveness results. The committee considered that the most plausible ICERs using its preferred modelling assumptions were within the range that NICE normally considers to be a cost-effective use of NHS resources. So, it recommended belimumab for treating active autoantibody-positive systemic lupus erythematosus.
|
{'Recommendations': 'Belimumab is recommended as an option as add-on treatment for active autoantibody-positive systemic lupus erythematosus in people with high disease activity despite standard treatment, only if:\n\nhigh disease activity is defined as at least 1\xa0serological biomarker (positive anti-double-stranded DNA or low complement) and a SELENA‑SLEDAI score of greater than or equal to\xa010\n\ntreatment is continued beyond 24\xa0weeks only if the SELENA‑SLEDAI score has improved by 4\xa0points or more\n\nthe company provides belimumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the managed access agreement for belimumab for systemic lupus erythematosus (NICE technology appraisal guidance 397).\n\nStandard therapies include non-steroidal anti-inflammatory drugs, corticosteroids, antimalarials and immunosuppressants. Other treatments include biological disease-modifying antirheumatic drugs such as rituximab.\n\nClinical trial evidence suggests that, after a year of treatment, belimumab plus standard therapy reduces disease activity more than standard therapy alone. However, the results are uncertain because the trials were short, so the long-term benefit is unknown. Also, the effect of belimumab compared with rituximab is unknown.\n\nThe cost-effectiveness estimates are also uncertain. But there is an unmet need for effective treatments in people with systemic lupus erythematosus, and some benefits of belimumab may not be taken into account in the cost-effectiveness results. For people with high disease activity despite standard treatment, the most likely cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources. So, belimumab is recommended for these people.', 'Information about belimumab': "# Marketing authorisation indication\n\nThe intravenous formulation of belimumab (Benlysta, GlaxoSmithKline) 'is indicated as add-on therapy in patients aged 5\xa0years and older with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti‑dsDNA and low complement) despite standard therapy'. The subcutaneous formulation 'is indicated as add-on therapy in adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) with a high degree of disease activity (e.g., positive anti‑dsDNA and low complement) despite standard therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedules are available in the summary of product characteristics for the intravenous formulation of belimumab and the summary of product characteristics for the subcutaneous formulation of belimumab.\n\n# Price\n\nThe list price of belimumab for the intravenous infusion is £121.50 for a 120‑mg vial and £405.00 for a 400‑mg vial (excluding VAT; BNF online accessed November\xa02021). The list price for the subcutaneous injection is £222.75 for a 200‑mg pre-filled pen (excluding VAT; company submission).\n\nThe company has a commercial arrangement for both formulations. This makes belimumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by GlaxoSmithKline, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected using the British Isles Lupus Assessment Group Biologics Register (BILAG‑BR) and additional clinical trial evidence presented in the company's updated submission to address uncertainties identified during the original appraisal. As a condition of the managed access arrangement, the company was required to collect real-world data from the BILAG registry after treatment with belimumab, including on its efficacy, safety and effect on health-related quality of life.\n\nThe committee agreed that some of the issues raised in the ERG report had been resolved after technical engagement. These included that there is no evidence for using belimumab in people with severe active central nervous system lupus (key issue\xa01), that cyclophosphamide is not a relevant comparator (key issue\xa02), and that intravenous and subcutaneous formulations of belimumab are likely to be clinically comparable (key issue\xa07).\n\nThe committee agreed that there is unresolved uncertainty with the issues raised in the ERG report about the uncertainty on organ damage utility multipliers (key issue\xa012) and the sampling order of organ damage and death in the model (key issue\xa013). However, it thought that it was unlikely that these issues would have a significant effect on the cost-effectiveness results.\n\n# Belimumab as a treatment option\n\n## People with systemic lupus erythematous would welcome belimumab as a continuing treatment option\n\nSystemic lupus erythematosus is a chronic autoimmune condition that causes inflammation in the body's tissues and can affect the whole body. The patient experts explained that people with the condition often have frequent disease flares and more severe symptoms that can result in hospital admissions. This can affect a person's ability to work, complete everyday activities and socialise. The patient experts described how this causes stress and anxiety, which can trigger further disease flares. They described how the condition can affect fertility by causing recurrent miscarriages and severe disease flares. The patient experts further explained that, even when their condition is clinically stable, they still have symptoms that affect their daily life such as fatigue, headaches, joint pain and reduced mental acuity. These symptoms can make it challenging to care for themselves and others. One patient expert explained that treatment with belimumab as an add‑on to standard therapy has significantly reduced their disease flares and that they have been able to reduce their daily corticosteroid dose. The patient experts explained that treatment with belimumab has helped to improve other day-to-day symptoms of the condition, and this has improved their overall quality of life. They described the burden of having to travel long distances to have belimumab intravenous infusions administered in hospital, and that they have nausea from the pre-infusion medication. However, they continue with the treatment because they think that their condition is responding well to it. One patient expert also described the benefits of using the new subcutaneous formulation of belimumab because of being able to self-administer it at home with little disruption to daily life and the minimal side effects. At the second committee meeting, the patient expert explained that they had tried several other treatment options including azathioprine, mycophenolate mofetil and rituximab, but that none of these treatments had effectively reduced their disease activity. They explained that there are few treatment options currently available for people with systemic lupus erythematosus and that they would have no alternative treatment option if belimumab was not made available through routine NHS commissioning. The patient expert explained that the prospect of belimumab being withdrawn was a significant worry for them and many other people with severe refractory disease that has only responded to belimumab. The committee concluded that people with systemic lupus erythematosus would welcome belimumab continuing to be a treatment option.\n\n# Treatment pathway and positioning\n\n## The company's updated population is appropriate\n\nThe marketing authorisation for belimumab states that it is indicated for systemic lupus erythematosus that has a high disease activity despite standard therapy. The committee discussed that, in the original appraisal, belimumab was recommended for systemic lupus erythematosus with high disease activity (HDA‑1) despite standard therapy. HDA‑1 is a Safety of Estrogens in Lupus Erythematosus: National Assessment – Systemic Lupus Erythematosus Disease Activity Index (SELENA‑SLEDAI) score of greater than or equal to\xa010, and 2\xa0serological biomarkers (positive anti-double-stranded DNA and low complement). The company and clinical experts explained that, based on the data collected through the BILAG registry, this HDA‑1 population was too restrictive in clinical practice. This is because people will often have high levels of disease activity but only 1\xa0of the 2\xa0defined serological biomarkers. So, the company presented a broader high-disease-activity population (HDA‑2) as part of its base case. This included people with a SELENA‑SLEDAI score of greater than or equal to\xa010 and only 1\xa0serological biomarker. The clinical experts considered that the company's new high-disease-activity population was clinically relevant and would allow more people access to belimumab. The committee concluded that the company's updated population was appropriate for decision making.\n\n# Comparators\n\n## Standard therapy is a relevant comparator\n\nThe committee heard that standard therapy for treating systemic lupus erythematosus is likely to consist of non-steroidal anti-inflammatory drugs, corticosteroids, antimalarials and immunosuppressants. It was aware that some standard therapies are not licensed for use in systemic lupus erythematosus but are used off label in clinical practice. The committee noted that belimumab is indicated as an add-on therapy to standard care. It understood that standard therapy was included in the scope for the appraisal and concluded that it was a relevant comparator.\n\n## Rituximab is a relevant comparator\n\nThe committee discussed the updated NHS England clinical commissioning policy on rituximab for refractory systemic lupus erythematosus in adults and post-pubescent children. It noted that, while rituximab is currently not licensed for treating systemic lupus erythematosus, it is available as a treatment option through this commissioning policy. The committee discussed the eligibility criteria for rituximab outlined in the commissioning policy, which recommends considering using licensed and NICE-approved treatments, such as belimumab, first. The clinical experts explained that, based on the data collected from the BILAG registry, only a very small number of people on rituximab would be eligible for belimumab because of the differences in the eligibility criteria. They explained that people having belimumab will generally have more severe disease because of the current eligibility criterion of a SELENA‑SLEDAI score of greater than or equal to\xa010. However, they pointed out that people with renal or central nervous system complications would not be eligible for belimumab and would have rituximab instead. The clinical experts also explained that some people who are eligible for belimumab may have experienced adverse reactions or no improvement in their disease activity after treatment with rituximab. Therefore, this population would not be eligible for rituximab. The committee heard that, if belimumab is not recommended for routine commissioning, more people would potentially have treatment with rituximab in its absence. The committee noted that rituximab was included in the final scope for the appraisal and is being used in clinical practice through the commissioning policy. It concluded that rituximab was a relevant comparator.\n\n# Clinical effectiveness\n\n## Belimumab improves the SRI-4 response rate at 52\xa0weeks compared with standard therapy\n\nThe company submission included the BLISS\xa052 and BLISS\xa076 randomised controlled trials comparing intravenous belimumab plus standard therapy (from now, referred to as belimumab) with placebo plus standard therapy (from now, referred to as standard therapy). The company presented results for the new HDA‑2 population based on the pooled trials and new evidence from the BLISS\xa0SC randomised controlled trial comparing a new subcutaneous formulation of belimumab with standard therapy. The primary outcome of all studies was the response rate at week\xa052 compared with baseline. This was assessed with the Systemic Lupus Erythematosus Responder Index‑4 (SRI‑4), which is a composite measure of disease activity. Belimumab showed a statistically significant improvement in SRI‑4 response rate at 52\xa0weeks compared with standard therapy in the HDA‑2 population across the BLISS\xa0SC, and pooled BLISS\xa052 and BLISS\xa076 trials (pooled BLISS\xa052 and BLISS\xa076: odds ratio 2.29, 95% confidence interval [CI] 1.61 to 3.26; BLISS\xa0SC: odds ratio 1.79, 95% CI 1.17\xa0to 2.74). The committee concluded that belimumab improved SRI‑4 response rate at 52\xa0weeks compared with standard therapy.\n\n## The BLISS long-term extension studies do not provide long-term effectiveness evidence for belimumab compared with standard therapy\n\nThe company included new evidence from the BLISS long-term extension studies. These were single-arm continuation studies of people enrolled in the BLISS randomised controlled trials (see section\xa03.5). People who had been randomised to have belimumab continued treatment with belimumab, and people in the placebo groups were switched to belimumab in all long-term extension studies:\n\nThe BLISS\xa076 US long-term extension study included people in the US who had completed the BLISS\xa076 trial. The primary outcome was mean Systemic Lupus Erythematosus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) change from baseline, which is a measure of organ damage. In the total population, the mean SDI change was\xa00.4 (standard deviation\xa00.68) at 7\xa0years.\n\nThe BLISS\xa052/76 non-US long-term extension study included people not from the US who had completed either the BLISS\xa052 or BLISS\xa076 trials. In the total population, the mean SDI change was\xa00.2 (standard deviation\xa00.56) at 8\xa0years.\n\nThe BLISS\xa0SC long-term extension study included people who had completed the BLISS\xa0SC trial. The number of people whose condition responded according to the SRI‑4 at 6\xa0months was 16.1% in the placebo-to-belimumab group and 76.3% in the belimumab group.The committee noted that the long-term extension studies did not have comparator arms. It concluded that they did not provide long-term effectiveness evidence for belimumab compared with standard therapy.\n\n## There is still uncertainty about the clinical and cost effectiveness of belimumab compared with rituximab\n\nThe company explained that no new clinical trial evidence directly comparing belimumab with rituximab had been identified after the original appraisal. It also stated that an indirect comparison based on the EXPLORER trial, which compared rituximab with placebo, was not appropriate. This is because the EXPLORER trial did not meet its primary end point, and for other reasons, such as the trial population including people with more severe disease than people in the BLISS trials. The committee heard that a comparison between belimumab and rituximab was available from the observational prospective cohort BILAG‑BR sub-study, which was presented as part of the company's submission. This study was designed to fulfil the managed access requirements from the original appraisal. A multilevel regression analysis done by the University of Manchester compared the efficacy of belimumab with rituximab based on data collected from the sub-study. The eligibility criteria in the study reflected the high disease activity (HDA‑1) population recommended in the original appraisal and included people having belimumab, rituximab or other non-biological treatments. Outcome measures assessed in the analysis included measures of disease activity (change in BILAG‑2004, SLEDAI‑2K and SDI scores), and health-related quality of life measured using generic and disease-specific instruments. The results suggested that, for most outcome measures, a similar level of change in disease activity was seen for belimumab and rituximab at 12\xa0months of follow up (actual results are confidential and cannot be reported here). The company considered that there was a high likelihood of confounding and selection bias in this regression analysis. It thought that the data was not appropriate for comparing treatment efficacy, so did not do an indirect treatment comparison. The committee noted that the regression analysis based on the observational data did provide a comparison in a UK population relevant to the decision problem. It acknowledged that the analysis was based on small numbers, and the long-term comparative effectiveness between treatments could not be determined based on the 12\xa0months of data collected in the registry for belimumab. The committee considered that because rituximab is a relevant comparator (see section\xa03.4), it would have preferred to see an indirect treatment comparison between belimumab and rituximab in the relevant population. The company did not provide an indirect comparison between belimumab and rituximab in response to the appraisal consultation document. It considered that as the BILAG‑BR sub-study only collected data for the HDA‑1 population, an indirect comparison in the target HDA‑2 population would not be possible. The company also highlighted that because there is limited long-term effectiveness data for rituximab in people with systemic lupus erythematosus, a reliable and robust indirect treatment comparison cannot be done. The committee recognised that conducting an indirect treatment comparison in the traditional sense may be difficult, but it noted that the company had used an adjusted indirect comparison to compare organ damage progression for people on belimumab and standard care (see section 3.8). It considered that the company could have also explored alternative adjustment methods to inform the treatment comparison between belimumab and rituximab using the data collected from the registry. The committee discussed that because the criteria in the new HDA‑2 target population was wider than considered previously, it would still include people who meet the HDA‑1 criteria and are currently having belimumab in clinical practice. Therefore, the committee considered that the company should have explored data from the BILAG‑BR sub-study to compare efficacy between belimumab and rituximab. It concluded that in the absence of this comparison, the uncertainty about the relative clinical and cost effectiveness of belimumab and rituximab remains.\n\n## The results of the propensity score-matched analysis may not be relevant to NHS clinical practice\n\nThe company's long-term extension studies did not have comparator arms. So, it did a propensity score-matched analysis to compare results from people who had belimumab in the BLISS\xa076 US long-term extension study with the results from people who had standard therapy in the external Toronto Lupus Cohort (n=99 in each cohort). The primary end point of the propensity score-matched analysis was to compare organ damage progression (mean change in SDI score) from baseline to year\xa05 in people having treatment with belimumab or standard therapy with 5\xa0or more years of follow up. The results showed that people having treatment with belimumab had statistically significantly less organ damage (5‑year SDI change of 0.283, 95% CI 0.166\xa0to\xa00.400) compared with people having standard therapy alone (5‑year SDI change of 0.717, 95%\xa0CI 0.500\xa0to\xa00.934). The committee considered that it was unclear why the company had selected the Toronto Lupus Cohort as the source of data for the standard therapy arm in the propensity score-matched analysis. The company explained that it identified the cohort through a systematic literature review of people with systemic lupus erythematosus with 5\xa0or more years of follow up. It selected the Toronto Lupus Cohort because of its size and because it matched on most of the variables needed for the propensity score-matched analysis. The company explained that it did not identify a comparable cohort from the UK through the literature review. The committee considered that it would have preferred data from a UK registry to have been used, but acknowledged the company's comments that such evidence may not be available. The ERG highlighted that it was unclear how selection criteria had been applied to determine that the Toronto Lupus Cohort was the most appropriate source from the systematic review. The committee noted the ERG's critique that the sample size in the BLISS‑76 US long-term extension study decreased by almost half in the propensity score-matched analysis, suggesting large differences in the baseline characteristics compared with the Toronto Lupus Cohort. The committee noted a consultation comment that the Toronto Lupus Cohort may not be appropriate for comparison because it included people with systemic lupus erythematosus in a different country, up to 30\xa0years ago. The stakeholder highlighted that changes in medical care since this time may influence organ damage development and its associated costs. The committee discussed how the 2\xa0cohorts used in the propensity score-matched analysis were from the US and Canada. Because of this, the committee considered that there was uncertainty in the generalisability of the treatment effect observed in the analysis to the target population who would have belimumab in England. The committee concluded that the results of the propensity score-matched analysis may not be relevant to NHS clinical practice.\n\n## The results of the propensity score-matched analysis are likely biased in favour of belimumab\n\nThe committee noted that several important variables were not included in the company's propensity score-matched analysis, including measures of socioeconomic outcomes, disease progression and disease activity over time. It discussed the ERG's critique that there were also differences between the populations in the cohorts before matching. These included differences in the rates of smoking, which were higher in the Toronto Lupus Cohort. Because of this, the committee considered that it was likely that people from the Toronto Lupus Cohort would have had worse outcomes, even after matching, because of the influence of these unmatched variables on organ damage progression. In response to consultation, the company explained that it was not suitable to match on variables such as disease progression and disease activity over time because these could be potential confounders in the analysis. The clinical expert agreed that disease activity over time was a potential confounder and that including it could bias the results in either direction. The committee noted the ERG's critique that these variables are important prognostic factors that may need to be adjusted for, to give an unbiased treatment comparison. The committee heard that most people withdrew from the BLISS\xa076 US long-term extension study before 5\xa0years. So, people who continued having belimumab at 5\xa0years were likely to have progressed less or had a better response than people who had belimumab for 1\xa0to 4\xa0years before stopping treatment. The committee recalled testimony from a patient expert, who described the burden of attending hospital for regular intravenous infusions of belimumab. It agreed that it was likely that people who stayed on belimumab for 5\xa0years had low disease activity, a good response to treatment or both. The company explained that it had presented the reasons for discontinuation in the BLISS\xa076 US long-term extension study in its submission. The main reasons for discontinuation were adverse events and patient request. Other reasons for withdrawal included lack of efficacy, physician choice, lack of adherence and loss to follow up. The ERG considered that it was plausible that lack of efficacy would have been a factor in withdrawals stated for other reasons. The clinical experts explained that in clinical trials and clinical practice, people may decide to stop maintenance treatment for reasons other than lack of efficacy, such as their disease being well controlled or in remission, or because they are planning to start a family. They described how systemic lupus erythematosus is a relapsing-remitting disease meaning that a person's disease activity and their resulting need for treatment would vary over time. The committee discussed the ERG's critique that without further data, it is unclear to what extent people who stopped taking belimumab before 5\xa0years were different to those who continued to take belimumab beyond 5\xa0years in the long-term extension study. It discussed that, although some people may have dropped out because they were benefiting, most people would have remained in the trial if they were benefiting from belimumab and those who were not available for analysis at 5\xa0years were likely to have progressed or had a poorer response. The committee concluded that the results of the propensity score-matched analysis were likely biased in favour of belimumab.\n\n# Cost effectiveness\n\n## The model structure is unchanged from the original appraisal and is suitable for decision making\n\nThe company presented a microsimulation model with an annual cycle length and lifetime time horizon. The model structure was unchanged from the original appraisal. Two separate models were presented for each formulation of belimumab. The models used the new HDA‑2 population (see section\xa03.2), with patient baseline characteristics drawn from the pooled BLISS\xa052 and BLISS\xa076 trials for the intravenous belimumab model, and from BLISS\xa0SC for the subcutaneous belimumab model. The company used the average patient weight from the BILAG registry for the intravenous model. In the original appraisal, this was taken from the pooled BLISS\xa052 and BLISS\xa076 trials. The committee concluded that, because the model structure remained unchanged from the original appraisal, it was suitable for decision making.\n\n## The committee understood why the company had adjusted the model to reflect the observed long-term data available for belimumab\n\nIn the original appraisal, the company simulated long-term effects of belimumab on disease progression using a natural history model based on observational data from a cohort of people with systemic lupus erythematosus (the Johns Hopkins lupus cohort). In this review, the company explained that the newly available BLISS long-term extension studies (BLISS\xa052 and BLISS\xa076) were incorporated to extrapolate long-term effects on disease progression. The company considered that, compared with results from the propensity score-matched analysis (see section\xa03.8), its model overestimated organ damage progression in the belimumab arm but underestimated progression in the standard therapy arm. So, the company simulated its model using several calibration factors until the results matched the observed results from the propensity score-matched analysis at 5\xa0years. The chosen calibration factor (0.491) was then applied to belimumab 'responders' only (see section 3.13) for up to 6\xa0years and was used to adjust the time-to-event risk equations for organ damage probabilities in the models. The ERG noted that this implied that the annual risk of organ damage for belimumab was adjusted downwards by 50.9%. The committee understood why the company had adjusted organ damage progression in the original model to reflect the observed long-term data available for belimumab but had concerns about how this had been done (see section 3.12).\n\n## The company's calibration factor to adjust for long-term organ damage is not suitable for decision making\n\nThe ERG noted that the main issue with applying the calibration factor was that the propensity score-matched analysis it was based on had several methodological issues (see section\xa03.8 and section 3.9). Another concern was that the model assumptions in the original appraisal assumed a constant treatment effect of belimumab on disease activity reduction after 1\xa0year (based on the trial data). The committee considered that this was already an optimistic assumption in terms of the long-term treatment effect of belimumab. This was particularly so when taking into account that some people stopped treatment in the long-term extension studies (that is, after 1\xa0year) because of a lack of efficacy. The committee also considered that adding the calibration factor would have further increased the treatment benefit of belimumab. It noted the ERG's comments that the company's calibration factor was derived using the entire modelled belimumab cohort (including people whose condition responded and did not respond to belimumab, classified as 'responders' and 'non-responders' respectively – see section 3.13). The ERG noted that the propensity score-matched analysis on which the calibration factor was based only included people who had treatment for 5\xa0years or longer and so would have experienced a good response to treatment. Therefore, it considered that only 'responders' to belimumab should have been used in the model to derive the calibration factor. In response to the ERG's critique, the company provided a scenario analysis using 'responders' only to derive a calibration factor. The scenario analysis resulted in a calibration factor of 0.536, which was slightly less favourable for belimumab than the original calibration factor used in the company's base case. The committee noted that applying the new calibration factor had a small impact on the incremental cost-effectiveness ratio (ICER). It was concerned that the difference between the new and original calibration factor was smaller than expected and that removing 'non-responders' only had a small impact on organ damage progression of the entire modelled belimumab cohort at 5\xa0years. The ERG suggested that this may mean that organ damage of 'non-responders' may be underestimated in the model and that this could bias the derivation of the calibration factor. The clinical experts explained that this small difference could be because 'non-responders' would likely have their standard therapy adjusted and this may improve their disease activity for some time. The committee discussed that because the calibration factor is applied as a multiplication to the model, this means that any associated error and uncertainty is likely to accumulate over time. It recalled its concern about the appropriateness of the propensity score-matched analysis that formed the basis of the calibration factor. The committee noted the ERG's critique that applying the calibration factor that has been estimated based on 5\xa0years is likely to underestimate organ damage progression in the preceding years. It noted the uncertainty in applying the calibration factor constantly to belimumab 'responders' who stopped treatment at years\xa02\xa0to\xa04 in the model. The committee discussed how the ERG was not able to fully validate the company's new calibration factor and that it likely overestimated the treatment benefit of belimumab. The committee concluded that the company's calibration factor to adjust for long-term organ damage was not suitable for decision-making.\n\n## It is unclear whether the modelled response to treatment for belimumab 'non-responders' is consistent with the BLISS trials\n\nIn the original appraisal, the committee heard from clinical experts that people would likely stop treatment with belimumab after 24\xa0weeks if they had not experienced any improvement in their disease control during this time (in line with summary of product characteristics for belimumab). The clinical experts indicated in the original appraisal that a SELENA‑SLEDAI score reduction of 4\xa0points would generally be considered a reasonable improvement and the committee noted that this was aligned with the 24‑week treatment continuation rule in the company's model. In the model, people on belimumab with a reduction of 4\xa0or more points in SELENA‑SLEDAI score at week\xa024 were classified as 'responders'. SELENA‑SLEDAI scores were estimated based on a regression model, given that there was not a 24‑week time point in the model. The committee noted that, at 24\xa0weeks, 34.1% of people from the HDA‑2 subgroup were classified as 'non-responders' using the regression model and stopped treatment with belimumab. The committee did not think it was clinically plausible that nearly half of these modelled 'non-responders' (46.5%) would have had a SELENA‑SLEDAI score reduction of 4\xa0or more at 52\xa0weeks after reverting to standard therapy alone at 24\xa0weeks, as predicted by the company's model. The ERG noted that the model could have underestimated belimumab costs compared with clinical practice because people having a response to belimumab at 52\xa0weeks were initially classified as 'non-responders' and therefore modelled to stop treatment with belimumab. The company explained that this observation did not mean that these people were incorrectly classified in the model as 'non-responders'. It highlighted that no one classed as a belimumab 'non-responder' at 24\xa0weeks had a SELENA‑SLEDAI reduction of 4\xa0or more points. The clinical experts explained that standard care for lupus treatments in clinical trials includes a combination of immunosuppressants, hydroxychloroquine and high-dose corticosteroids. Because of this, they considered that it was possible for some people to have a benefit with standard therapies, particularly because regular care in clinical trials is usually better than clinical practice. The clinical experts considered that people whose condition has not responded to belimumab would have their standard therapy adjusted, for example, by dose escalation. This may result in an improvement in disease activity within 3\xa0to 6\xa0months of changing treatments for some people. The committee was not convinced that people whose condition has not responded to belimumab at 24\xa0weeks would have a significant improvement in disease activity at 52\xa0weeks on standard therapy alone. It considered that a 6‑month cycle length may have been more appropriate to use in the model to align with the 24‑week continuation rule. In response to the appraisal consultation document, the company presented a post hoc analysis of the pooled BLISS\xa052 and BLISS\xa076 trial data, which showed that 34.5% of 'non-responders' to belimumab at week\xa024 became 'responders' at week\xa052. The ERG considered that compared with the trial data, the company's model overestimated the number of 'non-responders' to belimumab at week\xa024 who became 'responders' at week\xa052. The company explained that this was because while 'non-responders' could continue to have belimumab in the BLISS trials, their steroid therapy was not allowed to be adjusted after week\xa040. However, in the model, 'non-responders' stopped belimumab treatment at 24\xa0weeks and would then have their steroid therapy adjusted to improve disease control to reflect clinical practice. The committee noted the ERG's concern that disease activity in 'non-responders' to belimumab may be underestimated in the model compared with the BLISS trials. The ERG explained that it was unable to validate the extended benefit that 'non-responders' receive in the model after stopping treatment with belimumab. The committee understood that the impact of this on the cost-effectiveness results was unknown. It concluded that it was unclear whether the modelled response to treatment for belimumab 'non-responders' was consistent with the BLISS trials.\n\n## Disease activity should be based on the BLISS trials for the first 52\xa0weeks for people whose condition has not responded to belimumab\n\nThe ERG suggested that there was an error in the company's model because 'non-responders' had the same reduction in disease activity as people having standard therapy at 52\xa0weeks. It considered that this likely meant the treatment benefit of belimumab was overestimated. This is because the BLISS trials showed that people whose condition did not respond to belimumab had a smaller reduction in disease activity than people having standard therapy in the first 52\xa0weeks. The company considered that this was not an error in the model, but an assumption that 'non-responders' took the average standard therapy score from week\xa052 onwards. The company explained that this assumption was made because 'non-responders' to belimumab at week\xa024 switched to standard therapy for the remainder of the modelled time horizon (see section\xa03.13). The ERG explained that, because the model had a yearly cycle, this assumption did not capture any disadvantage that 'non-responders' to belimumab may have in the first 52\xa0weeks, and was not in line with the BLISS trials. The company's scenario analysis assumed a return to standard therapy efficacy for 'non-responders' by week\xa076 instead of at 52\xa0weeks as in the company's base case. The committee noted that this had a small effect on the ICER. In response to the appraisal consultation document, the company acknowledged the ERG's comments and presented a further scenario analysis. This added an additional cost to belimumab 'non-responders' in year\xa01 of the model to allow for treatment of their high disease activity. The committee noted that this also had a small effect on the ICER. It discussed the ERG's base case, which used the BLISS evidence to incorporate the difference in disease activity between 'non-responders' and people having standard therapy in the first 52\xa0weeks. The committee preferred the ERG's approach and concluded that disease activity for people whose condition has not responded to belimumab should be based on the BLISS trials for the first 52\xa0weeks.\n\n## There is still uncertainty around the effect of the error in utility estimation on the cost-effectiveness results\n\nThe ERG explained that the company's utility regression model used to estimate utility values excluded key organ damage coefficients without re-estimating the remaining coefficients used in the regression equation. The company agreed that this was an error but did not provide a re-estimated model during technical engagement or in response to the appraisal consultation document. Instead, the company presented scenario analyses to explore the effect of varying the regression utility coefficients (log of age, constant, SLEDAI score, ethnicity) in the regression equation by 1\xa0standard deviation in each direction. The committee considered that the company scenarios likely explored the full impact on the cost-effectiveness results but noted that ICERs increased or decreased by around £3,000 per quality-adjusted life year (QALY) gained with only 1\xa0of the coefficients varied. It noted the ERG's critique that the ICERs could increase or decrease further with combinations of coefficients varied but that the variation by 1\xa0standard deviation was likely substantial. The committee considered that it would have preferred the company to provide a re-estimated model to resolve the uncertainty in the cost-effectiveness results. Therefore, the committee concluded that there is still uncertainty around the effect of the error in utility estimation on the cost-effectiveness results.\n\n# Cost-effectiveness estimates\n\n## The committee would be prepared to accept an ICER greater than £20,000\n\nNICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. So, the committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee discussed that the ERG's analyses may be slightly pessimistic because they did not adjust for the long-term data available for belimumab. However, it did not accept the company's base cases because of the issues around the appropriateness of the propensity score-matched analysis and the company's calibration factor. Furthermore, it considered that there was uncertainty about the cost-effectiveness estimates because it was unclear whether the disease activity of 'non-responders' to belimumab had been underestimated in the model and because of the company's error in utility estimation. The committee noted that the clinical evidence presented by the company did not inform a reliable long-term comparison of belimumab with standard therapy, and the company had not presented an indirect comparison or cost-effectiveness results compared with rituximab, which it considered to be a relevant comparator. The committee was willing to be flexible despite these uncertainties, which would otherwise limit what would be an acceptable ICER. It took into consideration the unmet need for effective treatments in people with systemic lupus erythematosus and the additional benefits of belimumab that may not be captured in the cost-effectiveness results (see section 3.19). Therefore, it agreed that it would consider ICERs near to the upper end of the range normally considered a cost-effective use of NHS resources.\n\n## Belimumab compared with standard therapy is cost effective\n\nAfter consultation, the company updated its confidential patient access scheme for belimumab. The company's deterministic base-case ICER (using the updated patient access scheme for belimumab) compared with standard therapy was £12,335 per QALY gained for the intravenous formulation of belimumab and £8,480 per QALY gained for the subcutaneous formulation. The ERG presented analyses including the committee's preferred modelling assumptions, which:\n\nremoved the calibration factor (see section\xa03.12)\n\nused the BLISS trial evidence to incorporate the difference in disease activity between people whose condition has not responded to belimumab and people having standard therapy in the first 52\xa0weeks (see section\xa03.14).Using the updated patient access scheme for belimumab, the ERG's deterministic base-case ICERs were £30,278 per QALY gained for the intravenous formulation of belimumab and £29,313 per QALY gained for the subcutaneous formulation. The committee considered that the most plausible ICERs for belimumab compared with standard therapy would likely fall in between the company's and ERG's base-case deterministic ICERs. Therefore, it considered that both formulations of belimumab would be a cost-effective use of NHS resources.\n\n# Other factors\n\n## There are no equality issues that can be addressed in this technology appraisal\n\nThe committee understood that systemic lupus erythematosus mainly affects women, particularly those of child-bearing age. The patient experts explained that there is a risk of harm to an unborn baby (if taken during pregnancy) and infertility with most immunosuppressive and biological treatments. This can make family planning challenging. The clinical experts explained that neither rituximab nor belimumab is considered safer than the other for use in pregnancy. However, because belimumab has a short biological half-life and so is administered monthly, this makes it easier to organise a planned conception compared with rituximab which has a much longer-lasting effect. The committee recognised that if belimumab was not recommended, then this could potentially make it more difficult for women of reproductive age to plan a pregnancy. The committee heard how the condition is more common in people from an African, Caribbean and Asian family background and that they tend to have poorer health outcomes than people from other family backgrounds. It noted stakeholder comments that anti-double-stranded-DNA antibodies may be less common in people from certain ethnic groups, and that any recommendation about belimumab use stating this as a criterion could be considered as discriminatory. The committee was aware that the company's updated population meant that only 1\xa0of the 2\xa0biomarkers was needed for someone to be eligible for treatment with belimumab. It also heard that administering intravenous belimumab in a specialist centre may be a barrier to accessing treatment if a person lives far away and has to take time off work to have regular infusions. The committee discussed that having a subcutaneous formulation that can be self-administered may improve access to belimumab but noted that the subcutaneous formulation is currently not licensed in children. It noted a stakeholder comment that while childhood systemic lupus erythematous is relatively rare, it usually has a more severe presentation than in adults. This may have a significant impact on a child's education and caring requirements for parents. The committee understood that the intravenous formulation of belimumab is currently being used in children aged 5\xa0years and older through the NHS England's Commissioning Medicines for Children in Specialised Services. It noted comments received during consultation that if belimumab was not recommended for routine commissioning, then this may increase inequalities in access to rituximab. This is because rituximab is only available as an intravenous infusion administered at a specialist centre and some people may struggle to access these centres. Furthermore, rituximab is currently not commissioned for use in children who have not started puberty. The committee concluded that issues about differences in prevalence or incidence of a condition and healthcare implementation cannot be addressed in a technology appraisal.\n\n## There are additional benefits of belimumab that may not be captured in the cost-effectiveness analysis\n\nThe company considers belimumab as an add‑on to standard therapy to be innovative because it reduces disease activity and corticosteroid use in people with systemic lupus erythematosus. The committee agreed that these are important benefits and recognised that belimumab is the only medicine specifically licensed for treating systemic lupus erythematosus. It recalled comments received during consultation and from the patient experts highlighting that there is an unmet need for effective treatments in people with systemic lupus erythematosus, particularly in those with severe refractory disease. The committee recognised that the subcutaneous formulation of belimumab, which can be self-administered at home, can offer benefits over the intravenous formulation. The patient experts explained that the intravenous formulation of belimumab also offers significant benefits compared with rituximab. This includes a shorter infusion time and minimal side effects after the infusion. The clinical experts explained that people with rare autoimmune rheumatic diseases such as systemic lupus erythematosus are at an increased risk of adverse and serious effects if they contract COVID‑19. They explained that there is some evidence that people having treatment with rituximab are likely to have a low or undetectable immune response to COVID‑19 vaccinations. This is because rituximab works by depleting a person's B\xa0cells, which interferes with the immune system's ability to develop a response to new antigens. The clinical experts explained that because the biological half-life of rituximab is between 6 and 12\xa0months, this means that vaccination efficacy may be significantly reduced if it is given during this time. The committee noted that it had not seen any data on the level of immune response to COVID‑19 vaccinations in people having belimumab. The clinical experts confirmed that they were not aware of any such evidence but would expect that because belimumab does not have the same impact on a person's B\xa0cells as rituximab and has a much shorter biological half-life, it would likely have a less severe impact on vaccine efficacy. The committee concluded that there are additional benefits of belimumab that may not be captured in the cost-effectiveness analysis.\n\n# Conclusion\n\n## Belimumab is recommended for routine use\n\nThe committee recognised that people with systemic lupus erythematous have benefitted from treatment with belimumab, and that using the subcutaneous formulation at home has advantages. It acknowledged that belimumab compared with standard therapy improves disease outcomes, but that comparative long-term evidence is lacking. It considered that some of the assumptions used in the modelling were not appropriate and that there was uncertainty about the cost-effectiveness estimates. The committee noted that rituximab was a relevant comparator but that the company had not presented any indirect comparison or cost-effectiveness results for belimumab compared with rituximab. However, it took into consideration the unmet need for effective treatments in people with systemic lupus erythematosus and that there are benefits of belimumab that may not be captured in the cost-effectiveness results. The committee considered that the most plausible ICERs using its preferred modelling assumptions were within the range that NICE normally considers to be a cost-effective use of NHS resources. So, it recommended belimumab for treating active autoantibody-positive systemic lupus erythematosus."}
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https://www.nice.org.uk/guidance/ta752
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Evidence-based recommendations on belimumab (Benlysta) for treating active autoantibody-positive systemic lupus erythematosus.
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3a7eb8c76c94ec8cd958b20af731844f6d9fd645
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nice
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Cenobamate for treating focal onset seizures in epilepsy
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Cenobamate for treating focal onset seizures in epilepsy
Evidence-based recommendations on cenobamate (Ontozry) for treating focal onset seizures with or without secondary generalised seizures in adults with drug-resistant epilepsy that has not been adequately controlled with at least 2 antiseizure medicines.
# Recommendations
Cenobamate is recommended as an option for treating focal onset seizures with or without secondary generalised seizures in adults with drug-resistant epilepsy that has not been adequately controlled with at least 2 antiseizure medicines. It is recommended only if:
it is used as an add-on treatment, after at least 1 other add-on treatment has not controlled seizures, and
treatment is started in a tertiary epilepsy service.
This recommendation is not intended to affect treatment with cenobamate that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatment for focal onset seizures includes many antiseizure medicines used on their own and in combination. Treatment options for focal onset seizures after at least 2 antiseizure medicines are not very effective.
Short-term clinical evidence shows that cenobamate reduces the number of seizures. It also increases how many people stop having any seizures. It is uncertain how this compares with other antiseizure medicines because cenobamate has not been directly compared with them. The results of an indirect comparison are uncertain because the clinical trials included are short and have different designs. Because it is unclear how the benefit of cenobamate compares with its risks, it should only be started in a tertiary epilepsy service.
Taking into account uncertainties with the clinical evidence, the most likely cost-effectiveness estimates for cenobamate are within what NICE normally considers an acceptable use of NHS resources. So, it is recommended for drug-resistant epilepsy as an add-on treatment in a tertiary epilepsy service, after at least 1 add-on treatment has not controlled symptoms.# Information about cenobamate
# Marketing authorisation indication
Cenobamate (Ontozry, Arvelle Therapeutics) is indicated for the 'adjunctive treatment of focal onset seizures with or without secondary generalisation in adults with epilepsy who have not been adequately controlled despite treatment with at least 2 anti-epileptic medicinal products'.
# Dosage in the marketing authorisation
The dosage schedule for cenobamate is available in the summary of product characteristics.
# Price
Titration packs of 14 to 28 tablets are available in different doses ranging from 12.5 mg to 200 mg and costing between £85.54 to £165.62 per pack. Maintenance packs of 28 tablets are available in doses ranging from 50 mg to 200 mg costing £91 to £182 per pack. Estimated cost for the maintenance phase of treatment is £206 per person every 28 days (£7.37 per day).# Committee discussion
The appraisal committee considered evidence submitted by Arvelle Therapeutics, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## Drug-resistant epilepsy has a substantial physical and psychological burden on patients and their families and caregivers
Epilepsy is a neurological disorder characterised by recurrent spontaneous focal or generalised seizures. They happen because of a disruption in the normal balance between excitation and inhibition in the brain. Focal onset seizures start in 1 side of the brain and affect over 60% of people with epilepsy. There are 3 types of focal onset seizures: focal aware, focal impaired awareness and focal-to-bilateral tonic-clonic seizures. Focal-to-bilateral tonic-clonic seizures are the most severe form with the highest risk of morbidity and mortality. The patient experts explained that having epilepsy may be overwhelming and distressing, especially because of the inability to do some activities such as driving. This can cause loss of independence and social isolation. While physical effects vary, they can be debilitating, affecting people's ability to concentrate and work. Psychological stress, anxiety and fear of having seizures in public can affect people's confidence to do even simple daily tasks. Behavioural changes, psychological and physical symptoms resulting from seizures can negatively affect daily life and quality of life. Epilepsy also increases the risk of death and is associated with comorbidities such as stroke. The patient and clinical experts explained that people with drug-resistant epilepsy (epilepsy that has not been controlled by 2 antiseizure medicines) usually need some help from families or caregivers. The committee concluded that there is a substantial physical and psychological burden associated with having uncontrolled seizures in drug-resistant epilepsy that affects both patients and their families or caregivers.
# Current clinical management
## People with drug-resistant epilepsy have limited treatment options
Epilepsy is primarily managed with a range of antiseizure medicines. If they do not control the seizures, non-pharmacological, invasive options are considered. This includes resective surgery and vagal nerve stimulation. The NICE guideline on the diagnosis and management of epilepsies recommends that people with focal onset seizures start on monotherapy with carbamazepine or lamotrigine. If these are not suitable or not tolerated, levetiracetam, oxcarbazepine or sodium valproate may be offered (sodium valproate is subject to additional safety advice, see NICE's implementation support on valproate in children, young people and adults: summary of NICE guidance and safety advice). If treatment does not control seizures, the guideline recommends add-on (combination) therapy with lamotrigine, levetiracetam, carbamazepine, clobazam, gabapentin, oxcarbazepine, topiramate or sodium valproate. If add-on treatment is ineffective, the guideline recommends referral to a tertiary epilepsy specialist who can consider other add-on therapy options such as eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin or zonisamide. Brivaracetam acetate and perampanel may also be offered. This guideline is currently being updated. The clinical experts explained that the pharmacological management of epilepsy is highly individualised and different medicines may be trialled, combined or sequenced depending on a person's circumstances, tolerability, drug interactions, biological targets and mechanisms of action. This means the treatment pathway is complex and not clearly defined and some or all medicines may be used depending on patient and clinician preference. Most antiseizure medicines are taken more than once daily. Cenobamate is taken once a day which is more convenient and so people are more likely to take the treatment as intended. The clinical experts agreed that while the treatment pathway does not wholly represent clinical practice, it is broadly accurate. They explained that medicines are applied using a 'start low, go slow' approach, with a small starting dose and slow dose increments. Usually, it may take 1 year to confirm whether a medicine is ineffective. Despite treatments with 2 appropriate and tolerated antiseizure medicines, up to 30% of people have drug-resistant epilepsy and do not become and stay seizure free. A patient expert explained that they had tried 9 medicines and their seizures were still not controlled. They highlighted the important balance of seizure control, tolerability and interactions when taking more than 1 medicine. The clinical experts explained that for people with drug-resistant epilepsy the options available have limited effectiveness. Also, the chance of having a year free from seizures decreases with each medicine trialled.
## Cenobamate should be used as an add-on therapy in specialist epilepsy centres after at least 1 add-on therapy does not control symptoms to establish evidence about its long-term effectiveness and safety
The marketing authorisation for cenobamate is for adjunctive treatment of adults 'who have not been adequately controlled despite treatment with at least 2 anti-epileptic medicinal products'. The committee considered that this wording could be open to interpretation. In its submission, the company positioned cenobamate as an add-on option after at least 1 add-on treatment had failed to control seizures. The clinical experts explained that cenobamate is likely to be first used in specialist epilepsy centres for people with drug-resistant epilepsy, because of concerns about potential long-term adverse effects of treatment. One clinical expert advised that cenobamate is not currently an attractive option as an initial add-on treatment because of its moderate risk of adverse effects. However, if cenobamate has been shown to be effective in controlling seizures in a clinical setting with a good tolerability and safety profile, clinicians are likely to consider using it earlier in the pathway. The clinical experts explained that clinicians are likely to be overly cautious at first, because experience from previous antiseizure medicines suggest that efficacy of some medicines reported in trials may not be reflected in clinical practice. The committee considered that cenobamate would likely be used later in the pathway as long-term evidence of its efficacy and adverse effect profile is established. Therefore, it concluded that positioning cenobamate as an add-on treatment after at least 1 other add-on treatment has not controlled seizures was appropriate. These add-on treatments are currently started in tertiary epilepsy services (see section 3.2).
# Comparator treatments
## The relevant comparators are add-on options offered by epilepsy specialists after at least 1 add-on treatment does not control symptoms
The NICE scope specified relevant comparators as established add-on treatments. This included, but is not limited to, brivaracetam acetate, carbamazepine, eslicarbazepine acetate, lacosamide, levetiracetam and perampanel. In its submission, the company included only 'third generation' medicines used as add-on options after at least 1 add-on treatment had not controlled seizures in its network meta-analyses (brivaracetam acetate, eslicarbazepine acetate, lacosamide and perampanel). It stated that most drug-resistant epilepsy is likely to be treated with 'third generation' medicines because of fewer drug interactions, milder adverse events and novel mechanisms of action. It also stated that the other medicines are not relevant to UK clinical practice. The ERG disagreed, noting that there is no consensus that cenobamate should only be compared with 'third generation' medicines, and that published evidence from systematic reviews suggest that older medicines are as efficacious as newer medicines. The ERG noted that some of the treatments in the NICE guideline are no longer used. But some, such as zonisamide, clobazam and topiramate are still used for different purposes as add-on medicines. For example, clobazam is used as a short-term treatment. The company did not provide any relevant comparative evidence for cenobamate compared with these comparators or with any treatments that would be used earlier in the treatment pathway. Therefore, the committee concluded that it would be appropriate to appraise cenobamate for drug-resistant epilepsy only as an add-on option after at least 1 add-on treatment has not controlled seizures. The appropriate comparators would be most of those listed at this point in the NICE treatment pathway. That is, eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin, zonisamide, brivaracetam acetate and perampanel (see section 3.2).
# Clinical evidence
## Key short-term clinical evidence for cenobamate comes from 2 randomised controlled trials
The main evidence for cenobamate came from 2 registrational trials, C013 and C017. These are multinational, multicentre, double-blind trials. They compared cenobamate with placebo in a total of 659 adults (aged 18 to 70) with drug-resistant focal seizures despite treatment with at least 1 antiseizure medicine in the last 1 or 2 years, who had 1 to 3 concomitant medicines at baseline that continued during the trial (background therapy). People with progressive central nervous system disease or 'psychiatric illness, psychological, or behavioural problems' were excluded from the trials. C017 had a higher threshold for inclusion for seizure frequency at baseline (at least 8 focal onset seizures over the 8‑week phase before randomisation) compared with C013 (at least 3 seizures over 28 days). C013 included 1 cenobamate arm (200 mg once daily) whereas C017, a dose finding study, included 3 arms (100 mg, 200 mg and 400 mg, all once daily). Both trials had 6‑week titration periods, but C013 had a 6‑week maintenance phase, compared with 12 weeks in C017. The primary end point of C013 was the percentage change from baseline in seizure frequency per 28 days in the treatment period. In C017, it was at least a 50% reduction in seizures from baseline during the maintenance period. The results showed that for this outcome, 25.5% of people in the placebo arm had at least a 50% reduction in seizure frequency compared with 40.2%, 56.1% and 64.2% in the 100 mg, 200 mg and 400 mg arms, respectively.
## Clinically meaningful outcomes to patients are seizure freedom (100% reduction in seizures) or near seizure freedom (at least 90% reduction)
The clinical experts explained that the regulatory end point used in epilepsy trials of at least 50% reduction in seizures compared with baseline may not be as meaningful to patients as seizure freedom. This is because a 50% reduction may not change a person's level of independence or ability to do daily activities, and its impact may depend on the starting seizure frequency. The main aim of treatment is to retain or regain independence by prolonged and reliable periods of seizure freedom or near seizure freedom. The clinical experts suggested that 'near seizure freedom' may also be a good outcome as relapses most commonly happen when people forget to take their medicine, resulting in a seizure, rather than being because of lack of efficacy of the medicine. The clinical experts noted that a reduction in particular types of seizure may also represent meaningful clinical outcomes, such as reducing more severe seizures or seizures that happen at night. The committee considered that at least 1 year of follow up is needed to ascertain whether a person is seizure free. This is the same length of time needed for other potential benefits of seizure freedom to happen, such as the ability to re-apply for a driving license.
## Longer-term effectiveness and safety evidence of cenobamate comes from 2 open-label single-arm observational studies (C017-OLE and C021)
Two open-label extension, single-arm studies provided longer-term effectiveness and safety data. C017‑OLE used 300 mg of cenobamate for 355 people who had completed the C017 trial. C021 is an ongoing phase 3, single-arm, open-label, multinational, multicentre study including 1,347 people with drug-resistant focal onset seizures. Cenobamate doses from 200 mg to 400 mg were titrated over 12 weeks (starting from 12.5 mg), followed by a 40‑week maintenance period. The results showed that 23.2% of people were seizure free for at least 1 year during the C017‑OLE study. The ERG noted that long-term evidence was at risk of attrition bias because many people left the study during follow up and there was no comparative evidence in the open-label extension arm of the study.
## People in cenobamate trials are representative of people likely to have treatment in clinical practice
The committee considered that the baseline rates of seizures were extremely high and variable across the groups in the cenobamate trials. The ERG noted that these baseline rates may not reflect the experience of people likely to be seen in clinical practice, and importantly may confound outcomes of the trial through regression to the mean. This is because there are natural variations in the number of seizures over time. So, inclusion criteria requiring a high baseline seizure rate would mean more people would be recruited during a period of high seizure frequency that would naturally reduce over time. The committee considered whether the high baseline seizure frequency rate could be a treatment effect modifier. The company explained that it had done subgroup analyses based on number of seizures at baseline (with a threshold of 6 seizures) and seizure types and the results were consistent. The clinical experts emphasised that the absolute number of seizures in a trial is not important, as long as it represents a person's typical rate. The clinical experts agreed that the high number of seizures in the trials is representative of people with drug-resistant epilepsy likely to have treatment with cenobamate in tertiary centres in clinical practice. They noted that high seizure frequency at baseline is common in regulatory trials because it allows outcomes to be reached sooner. This decreases trial duration and minimises the risk of unnecessary drug exposure. The committee considered that excluding people with psychiatric comorbidities and other exclusion criteria in the trial would limit generalisability of the outcomes, but that this is typical of regulatory trials. It concluded that people in cenobamate trials have a high baseline seizure rate but are likely to be representative of people likely to have cenobamate in clinical practice.
## C013 should be included in the company's clinical and cost-effectiveness analyses
The company excluded C013 from its clinical and cost-effectiveness analyses. This was because it did not consider that its use reflected clinical practice, because the 6‑week maintenance period was too short and it did not include a 400 mg dose cenobamate arm. The ERG highlighted that the mean dose of 200 mg used in C013 was more representative of the mean dose used in C021, which would likely reflect clinical practice. It also noted that the short maintenance period was similar to that of comparator trials, notably brivaracetam acetate. One clinical expert considered that a 6‑week maintenance period in a trial setting is acceptable. The clinical experts explained that brivaracetam is often used without a titration phase and noted that most medicines are used differently in clinical practice compared with trials. The company highlighted that the shorter maintenance period for brivaracetam acetate reflected the treatment period because titration periods are not used in clinical practice. The committee concluded that data from C013 should be included the analyses. This is because the dose used was relevant to clinical practice and the duration of the maintenance phase was similar to other trials included in the network meta-analysis.
# Network meta-analyses
## Modified intention-to-treat (mITT) data for the entire treatment period should be used in the network meta-analyses
The company used mITT data for the maintenance phase only from C017 in its network meta-analyses, whereas comparator trials used mITT data for the entire treatment period (both titration and maintenance phases). The committee noted that higher levels of seizure reduction were seen in C017 using mITT data over the maintenance period compared with using data over the entire treatment period. The clinical experts explained that until the medicine is titrated to an effective dose, seizures can continue to happen, so it may be more appropriate to consider seizure reduction after the titration phase. The committee appreciated that seizures may happen during the titration phase. But it agreed that for consistency with other comparator trials, mITT data for the treatment phase of cenobamate trials should be used in analyses. Because of slower titration in clinical practice this may represent a substantial proportion of time on treatment.
## The ERG placebo-adjusted joint synthesis network meta-analysis including mITT data for the treatment period for both C013 and C017 is preferred
In its original submission, the company used network meta-analyses to compare cenobamate using mITT data from the maintenance phase of C017 only with 4 other third generation medicines (brivaracetam acetate, eslicarbazepine acetate, lacosamide and perampanel). It did network meta-analyses on 4 outcomes: at least 50% reduction in seizure frequency, seizure freedom, any treatment-emergent adverse events and stopping because of treatment-emergent adverse events. The ERG highlighted key limitations of the network meta-analyses. These included the absence of trials directly comparing active drugs (all options linked by placebo), comparability of trial populations being unclear because of a lack of reported baseline characteristics, titration periods that are shorter and more intense than would be seen in clinical practice, and the follow-up periods being generally shorter than the recommended 1 year needed to assess treatment success (see section 3.6). In addition, it noted the large variation in placebo response seen across the trials, implying there were different populations studied. It also noted that the company had modelled the different levels of seizure frequency reduction (at least 50% and 100%) as independent outcomes. The ERG corrected for the variable placebo response and correlation between seizure reduction outcomes using a placebo-adjusted joint synthesis model with mITT data from the combined titration and maintenance phases for both C013 and C017. The company accepted the ERG's revised model but still considered including C013 to be inappropriate. The committee concluded that the ERG's network meta-analysis was appropriate but many of the key limitations of the analysis remained.
## Compared with placebo and other third generation medicines cenobamate is clinically effective at reducing seizures in the short term, but long-term evidence is uncertain
The committee acknowledged the methodological limitations of the network meta-analyses (see section 3.11). But, it noted the clinical experts' comments that many of these issues were characteristic of most epilepsy trials. Based on the results of the ERG's placebo-adjusted joint synthesis network meta-analysis for seizure reduction during the treatment period, the committee agreed that cenobamate was clinically effective at controlling seizures in the short term and probably more so than the other drugs included in the evidence network. It acknowledged the longer-term data for cenobamate that the company had provided from its open-label extension studies. The committee considered that the high baseline seizure frequencies in the studies could result in regression to the mean (see section 3.8). It also noted that the long-term evidence had potential for attrition bias and there was no long-term comparative evidence with other drugs. It concluded that cenobamate's relative long-term effectiveness is still uncertain.
# Adverse effects of treatment
## The long-term adverse effect profile of cenobamate is uncertain
The ERG highlighted a potential trend for higher occurrence of treatment-emergent adverse events for cenobamate compared with brivaracetam and lacosamide. It also noted higher rates of stopping treatment because of treatment-emergent adverse events based on evidence from the network meta-analyses. There was evidence of a dose–response relationship for safety and tolerability, with severe reactions seen in the short-term studies if starting doses were high or titration rapid. The most common adverse events were somnolence, dizziness and fatigue. The company considered that these could be explained by the rapid dosing schedule in the trial and would not reflect clinical practice. The clinical experts considered that the adverse event profile was similar to other add-on therapies at this point in the pathway (see section 3.2 and section 3.4). The committee considered the short duration of the trials and the clinical experts' comments that they are likely to use cenobamate cautiously at first to evaluate its safety profile in clinical practice over a longer period. It concluded that the overall balance between efficacy and long-term adverse effect profile of cenobamate is uncertain. More information about this can only be collected in larger head-to-head trials.
# The company's economic model
## An economic model using only 3 response-based health states is preferred
The company used a de novo Markov model to compare the cost effectiveness of cenobamate with 4 other third generation medicines over a lifetime. The model has 5 mutually exclusive health states based on level of response defined by degree of reduction in seizure frequency:
no response (less than 50% reduction in seizure frequency)
moderate response (50% to less than 75% reduction)
high response (75% to less than 90% reduction)
very high response (90% to below 100% reduction)
seizure freedom (100% reduction). All patients start in the 'no response' state, then move between the 5 states until they stop treatment or die. Higher levels of response are associated with higher health-related quality of life and lower healthcare resource use. The company assumed that the risk of mortality in the 5 response states was higher than in the general population but that excess mortality was lower in 'seizure freedom' state (hazard ratio 1.6) compared with the other health states (hazard ratio 2.4). People who stop treatment move to the 'subsequent antiseizure medicine' state, comprising other medicines, and can progress to having non-pharmacological treatment with vagal nerve stimulation or surgery. The company assumed that the proportion of people with each level of response is independent of the previous line of treatment. It also modelled adverse drug reactions and carer disutility. The ERG considered that the 5 response state model was inappropriate because most of the comparator trials only reported the proportion achieving a 50% reduction in seizures (see section 3.5). This meant most of the model inputs were based on clinical opinion and 1 cenobamate trial, C017. Therefore, the ERG combined moderate to very high response into a single category to align with evidence available for comparator treatments. This was equivalent to the 3‑state model seen in previous appraisals and the NICE guideline. The committee considered that while a more granular 5‑state model may capture important differences in health states, there is minimal evidence available in comparator trials to populate the model. It noted that a model structure that is not based on response level but absolute numbers of seizures might be preferable to capture true differences in health-related quality of life and resource use. It concluded that the relative efficacy was the most important outcome to consider and the 3‑state model is most appropriate model to evaluate this.
# Assumptions in the economic model
## Transition probabilities should be estimated using C013 and C017 data and adjusted for placebo response
The company estimated transition probabilities between the different response states based on time-to-response data between study visits 3 to 5 (titration period) and study visits 6 to 9 (maintenance period) from C017 only. Transition probabilities for comparators depended on cenobamate transitions and risk ratios from the ERG network meta-analyses results. The company confirmed that the placebo response in C017 had not been adjusted before estimating the transition probabilities. The committee considered that both C013 and C017 data should have been used to inform transition probabilities and would have preferred if the placebo response had been adjusted. The company modelled transition probabilities in cycles 6 to 26 using C017‑OLE data (duration of follow up) and in cycles 27 to 462 using average transition probabilities from cycles 6 to 26, leading to continual improvement over time. The ERG considered that the assumption that people will continue to improve over time is highly uncertain. As such, in its base case, the ERG used the probability of at least 50% or 100% response from the network meta-analyses and applied it to the first 20 weeks of the model. In cycle 6, people stay in the same response health state unless the treatment does not work, informed by time to stopping treatment in C017‑OLE and C021. The committee considered that there was minimal long-term data to suggest that there would be continued improvement over time. Therefore, it preferred the ERG's base case.
## The assumption that all treatments would have the same stopping rate from cycle 6 is appropriate
The company assumed that people would stop treatments based on naive comparisons of the 4 comparators' open-label extension observational studies that compared the risk ratios from C017‑OLE and C021 (cenobamate) with single arms from comparator trials. The ERG considered the naive comparison inappropriate because it does not consider heterogeneity between study design and population and potential confounding from any other trial effects. In addition, it was unclear whether C017‑OLE and C021 should be combined because the hazards of stopping treatment did not converge, suggesting that the populations may be different. In the ERG's base case, it used the odds ratios from the network meta-analysis for 'all-cause discontinuation' to inform the probability of stopping treatment in the short term (first 6 cycles), because it provided the best comparative evidence. The company considered this would bias against cenobamate because of the rapid titration periods in trials included in the network meta-analysis, which would vary for different comparators (brivaracetam is often used without titration). For people continuing treatment, the ERG assumed that the same stopping rates would apply for all options from cycle 6. The committee considered that given the uncertainty in the relative long-term effectiveness of cenobamate compared with other third generation medicines, the ERG's assumption that the same stopping rates after cycle 6 was most appropriate.
# Utility values in the economic model
## Utility values from the company study and the NICE guideline on epilepsies are highly uncertain but give similar results
The company did not collect EQ‑5D data in its registrational trials. To inform patient utility values for each response health state, the company used a mapping algorithm from a survey of SF‑36 and QOLIE‑31‑P questionnaires (361 people with focal onset seizures in epilepsy). The ERG considered that the company's mapping algorithm did not reflect variability in the observed SF‑6D utility index scores and underestimated the range of predicted utilities. The ERG highlighted the need for better utility data and that the utility values were highly uncertain, with some overlap between states. In the probabilistic sensitivity analysis, random utilities in higher response states were often lower than those in lower response states, so the company manually changed them to prevent illogical values. The committee noted that the company's utility values were substantially lower than those used in NICE's guideline on epilepsies (from now, CG137). Also, the differences in utilities between the response states were quite small, suggesting that there is little gain in utility moving from moderate to high response compared with high response to seizure freedom. The ERG noted that the differences between health states were similar for both the utility set derived from the company study and the CG137 utility set. This meant the absolute utility values had a minimal effect on the incremental cost-effectiveness ratio (ICER). The patient experts highlighted that there is a big difference between having seizures and seizure freedom, such as independence and ability to drive or work. The ERG highlighted the difference between health-related quality of life that is reflected in the utility values and broader quality of life that could include employment and other factors. It considered that the small difference in utility between seizure freedom and no response is seen in published studies such as Selai et al. 2005. The committee considered that both the utility value set from the company study and the utility value set used in CG137 are highly uncertain and could potentially underestimate the benefit of seizure freedom. It concluded that both utility value sets could be considered because of the minimal differences in relative benefit.
## The company's estimates of caregiver disutility lack face validity
The company modelled caregiver disutility based on a caregiver survey (n=86). The ERG considered that this study was small and poorly reported and had concerns about how disutilities from the study were derived. Because of the lack of reporting by the company, the ERG was unable to evaluate the survey's methodology or the validity of the estimates. For its base case, the ERG excluded the carer disutility but agreed that a caregiver disutility was appropriate in principle for a proportion of people. The committee considered that the disutilities from the survey were much higher than those it had seen in other conditions, even when there is significant carer burden. The clinical experts explained that people with uncontrolled epilepsy would need some sort of help and that living alone increases the risk of mortality with epilepsy. The committee considered that for people who become seizure free, carer disutility may not be completely removed because of associated comorbidities needing care. The clinical experts explained that removing the uncertainty of seizure events happening has a large effect on caring. The committee noted that the benefit for carers was of a similar size to the benefit for patients. While the committee recognised that there is some level of carer burden, it considered the company's values disproportionate and preferred to use the ERG's base case. However, it noted that that this would likely underestimate the benefits of cenobamate, because a more effective treatment would be likely to generate some carer benefits.
# Resource use
## The resource use estimated from clinical experts likely overestimates costs of treatment
The company explained that there was no UK-specific resource use data for the population with drug-resistant epilepsy and it had not attempted to collect any data. In its base case, it included resource use including costs for drug administration, routine monitoring and epilepsy management (acute management and acute treatment) over a 28‑day period. But, in evaluating these it relied heavily on clinical opinion. For people whose epilepsy showed no response to treatment, the company estimated that most would see a GP, neurologist and epilepsy nurse within a 28‑day period. The clinical experts explained that typical monitoring would involve 6‑monthly follow up with a neurologist and additional contact as needed, whether it is from an epilepsy nurse, GP or the emergency department. They emphasised that the pattern of seizures is important and if the pattern is normal, but high, the person is unlikely to attend the emergency department. The clinical experts noted that people with drug-resistant epilepsy tend to be seen more in hospital rather than in primary care, although most of the monitoring is done in this setting. The patient experts explained that they routinely see a neurologist and would see an epilepsy nurse every 6 months. Because of lack of knowledge by some GPs, they normally contact the epilepsy nurse directly and rarely contact the GP. For epilepsy event management resource use, the company categorised resource use based on type of seizures (focal aware, focal awareness impaired, focal-to-bilateral tonic-clonic) and estimated hospitalisation costs of initial presentation to healthcare services, acute costs of treatment and other costs per seizure. The committee noted that the number of hospitalisations in the model likely did not reflect all patients with drug-resistant epilepsy, but may represent people with more severe disease. The ERG considered that the company estimates of 28‑day healthcare costs were high compared with published models. The company also provided a scenario using the resource costs for CG137, from Jacoby et al. 1998. The company highlighted that the data was collected in 1993 in Jacoby and epilepsy management has evolved over that time. The committee had concerns that there was no new data available since Jacoby. It considered that both the routine monitoring costs and event management costs using company assumptions could be considerably greater than seen in clinical practice. It noted that clinical opinion estimating resource use can be skewed because clinicians do not treat epilepsy in all patients with the condition and see more patients with severe disease. The committee had concerns about both the company's heavy reliance on clinical opinion and the validity of the Jacoby estimates. While it would have preferred for resource use estimates to be based on data, the committee concluded that the true values are likely to be in between the company's estimate and the estimate in the Jacoby study. It considered that the costs derived from clinical opinion would be less relevant for people with epilepsy earlier in the treatment pathway and outside of a tertiary setting, but it had not seen analysis for this population.
# Cost-effectiveness estimates
## The ERG's base case includes most of the committee's preferred assumptions
The committee preferred the following assumptions from the ERG base case:
using the ERG's placebo-adjusted, joint synthesis network meta-analyses including mITT data for treatment period for both C013 and C017 (see section 3.11)
using the 3-response health state model (see section 3.14)
modelling transition probabilities as in the ERG's base case (see section 3.15)
stopping rates are the same for cenobamate and all comparators after cycle 6 (see section 3.16)
using patient utility value sets from both available sources (see section 3.17)
excluding caregiver disutility as in the ERG's base case (see section 3.18).The committee considered that the ERG's base case included most of its preferred options. However, the ERG base case also used the same resource use assumptions as the base case. The committee considered that this was a key driver of the cost-effectiveness results and preferred to consider a range using the resource use data from the clinical expert opinion and the Jacoby study (see section 3.19).
## Cenobamate is a cost-effective use of NHS resources
The committee considered the cost effectiveness of cenobamate compared with other third generation medicines (brivaracetam acetate, eslicarbazepine acetate, lacosamide and perampanel). It recognised the limited amount of long-term evidence available (see section 3.12), the uncertainty about cenobamate's adverse effect profile (see section 3.13) and the omission of relevant comparators (see section 3.4). In the company's and ERG's base case, cenobamate dominates all other comparator treatments (that is, it is more effective and less costly than comparators). In the scenario using the Jacoby study for resource use assumptions, cenobamate was more effective and more costly than all other comparator treatments. This resulted in an ICER of £20,522 per quality adjusted life year (QALY) gained. The committee considered that the Jacoby resource use estimates were likely to be an underestimate of costs (see section 3.19) and therefore considered this to be the highest value in the range of probable ICERs. In addition, there were potential uncaptured benefits that were not included in the ICER, such as improvement in carer utility (see section 3.18). Considering this, the committee concluded that cenobamate is a cost-effective use of NHS resources for treating drug-resistant epilepsy despite significant uncertainty in the clinical data and comparisons with other treatments. It recalled the clinical experts' comments that cenobamate may be used earlier in the pathway if shown to be effective and safe in clinical practice. The committee considered that it had not seen any evidence to support its use earlier in the pathway. It agreed that it should only be used as an add-on treatment after at least 1 add-on treatment had not controlled seizures and that treatment should be started in specialist epilepsy centres (see section 3.3).
# Other factors
## No equality issues were identified
The patient submission highlighted concerns about the safe use of antiseizure medicines in pregnancy and in people with comorbidities including a learning disability. The committee noted that the summary of product characteristics states that cenobamate is not recommended for women who can have children who are not using contraception. There is also inadequate data about using cenobamate during pregnancy. These issues cannot be addressed in a technology appraisal.
## Cenobamate is an innovative medicine
Patient and clinical experts noted the high seizure freedom rates in clinical trials of cenobamate. The committee noted that the dual mode of action of cenobamate could be innovative as a new dual mechanism. But, it did not consider there was enough evidence that the benefits seen in the trial could be attributed to its mode of action, because of the short-term nature of the evidence and population differences. The committee concluded that cenobamate could be innovative by providing an alternative option for managing focal onset seizures in people with drug-resistant epilepsy. However, it did not hear that there were any additional gains in health-related quality of life that could be attributed to this over those already included in the QALY calculations.
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{'Recommendations': 'Cenobamate is recommended as an option for treating focal onset seizures with or without secondary generalised seizures in adults with drug-resistant epilepsy that has not been adequately controlled with at least 2\xa0antiseizure medicines. It is recommended only if:\n\nit is used as an add-on treatment, after at least 1 other add-on treatment has not controlled seizures, and\n\ntreatment is started in a tertiary epilepsy service.\n\nThis recommendation is not intended to affect treatment with cenobamate that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatment for focal onset seizures includes many antiseizure medicines used on their own and in combination. Treatment options for focal onset seizures after at least 2\xa0antiseizure medicines are not very effective.\n\nShort-term clinical evidence shows that cenobamate reduces the number of seizures. It also increases how many people stop having any seizures. It is uncertain how this compares with other antiseizure medicines because cenobamate has not been directly compared with them. The results of an indirect comparison are uncertain because the clinical trials included are short and have different designs. Because it is unclear how the benefit of cenobamate compares with its risks, it should only be started in a tertiary epilepsy service.\n\nTaking into account uncertainties with the clinical evidence, the most likely cost-effectiveness estimates for cenobamate are within what NICE normally considers an acceptable use of NHS resources. So, it is recommended for drug-resistant epilepsy as an add-on treatment in a tertiary epilepsy service, after at least 1 add-on treatment has not controlled symptoms.', 'Information about cenobamate': "# Marketing authorisation indication\n\nCenobamate (Ontozry, Arvelle Therapeutics) is indicated for the 'adjunctive treatment of focal onset seizures with or without secondary generalisation in adults with epilepsy who have not been adequately controlled despite treatment with at least 2\xa0anti-epileptic medicinal products'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for cenobamate is available in the summary of product characteristics.\n\n# Price\n\nTitration packs of 14 to 28\xa0tablets are available in different doses ranging from 12.5\xa0mg to 200\xa0mg and costing between £85.54 to £165.62 per pack. Maintenance packs of 28\xa0tablets are available in doses ranging from 50\xa0mg to 200\xa0mg costing £91 to £182 per pack. Estimated cost for the maintenance phase of treatment is £206 per person every 28\xa0days (£7.37 per day).", 'Committee discussion': "The appraisal committee considered evidence submitted by Arvelle Therapeutics, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Drug-resistant epilepsy has a substantial physical and psychological burden on patients and their families and caregivers\n\nEpilepsy is a neurological disorder characterised by recurrent spontaneous focal or generalised seizures. They happen because of a disruption in the normal balance between excitation and inhibition in the brain. Focal onset seizures start in 1 side of the brain and affect over 60% of people with epilepsy. There are 3\xa0types of focal onset seizures: focal aware, focal impaired awareness and focal-to-bilateral tonic-clonic seizures. Focal-to-bilateral tonic-clonic seizures are the most severe form with the highest risk of morbidity and mortality. The patient experts explained that having epilepsy may be overwhelming and distressing, especially because of the inability to do some activities such as driving. This can cause loss of independence and social isolation. While physical effects vary, they can be debilitating, affecting people's ability to concentrate and work. Psychological stress, anxiety and fear of having seizures in public can affect people's confidence to do even simple daily tasks. Behavioural changes, psychological and physical symptoms resulting from seizures can negatively affect daily life and quality of life. Epilepsy also increases the risk of death and is associated with comorbidities such as stroke. The patient and clinical experts explained that people with drug-resistant epilepsy (epilepsy that has not been controlled by 2\xa0antiseizure medicines) usually need some help from families or caregivers. The committee concluded that there is a substantial physical and psychological burden associated with having uncontrolled seizures in drug-resistant epilepsy that affects both patients and their families or caregivers.\n\n# Current clinical management\n\n## People with drug-resistant epilepsy have limited treatment options\n\nEpilepsy is primarily managed with a range of antiseizure medicines. If they do not control the seizures, non-pharmacological, invasive options are considered. This includes resective surgery and vagal nerve stimulation. The NICE guideline on the diagnosis and management of epilepsies recommends that people with focal onset seizures start on monotherapy with carbamazepine or lamotrigine. If these are not suitable or not tolerated, levetiracetam, oxcarbazepine or sodium valproate may be offered (sodium valproate is subject to additional safety advice, see NICE's implementation support on valproate in children, young people and adults: summary of NICE guidance and safety advice). If treatment does not control seizures, the guideline recommends add-on (combination) therapy with lamotrigine, levetiracetam, carbamazepine, clobazam, gabapentin, oxcarbazepine, topiramate or sodium valproate. If add-on treatment is ineffective, the guideline recommends referral to a tertiary epilepsy specialist who can consider other add-on therapy options such as eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin or zonisamide. Brivaracetam acetate and perampanel may also be offered. This guideline is currently being updated. The clinical experts explained that the pharmacological management of epilepsy is highly individualised and different medicines may be trialled, combined or sequenced depending on a person's circumstances, tolerability, drug interactions, biological targets and mechanisms of action. This means the treatment pathway is complex and not clearly defined and some or all medicines may be used depending on patient and clinician preference. Most antiseizure medicines are taken more than once daily. Cenobamate is taken once a day which is more convenient and so people are more likely to take the treatment as intended. The clinical experts agreed that while the treatment pathway does not wholly represent clinical practice, it is broadly accurate. They explained that medicines are applied using a 'start low, go slow' approach, with a small starting dose and slow dose increments. Usually, it may take 1\xa0year to confirm whether a medicine is ineffective. Despite treatments with 2 appropriate and tolerated antiseizure medicines, up to 30% of people have drug-resistant epilepsy and do not become and stay seizure free. A patient expert explained that they had tried 9\xa0medicines and their seizures were still not controlled. They highlighted the important balance of seizure control, tolerability and interactions when taking more than 1\xa0medicine. The clinical experts explained that for people with drug-resistant epilepsy the options available have limited effectiveness. Also, the chance of having a year free from seizures decreases with each medicine trialled.\n\n## Cenobamate should be used as an add-on therapy in specialist epilepsy centres after at least 1 add-on therapy does not control symptoms to establish evidence about its long-term effectiveness and safety\n\nThe marketing authorisation for cenobamate is for adjunctive treatment of adults 'who have not been adequately controlled despite treatment with at least 2\xa0anti-epileptic medicinal products'. The committee considered that this wording could be open to interpretation. In its submission, the company positioned cenobamate as an add-on option after at least 1 add-on treatment had failed to control seizures. The clinical experts explained that cenobamate is likely to be first used in specialist epilepsy centres for people with drug-resistant epilepsy, because of concerns about potential long-term adverse effects of treatment. One clinical expert advised that cenobamate is not currently an attractive option as an initial add-on treatment because of its moderate risk of adverse effects. However, if cenobamate has been shown to be effective in controlling seizures in a clinical setting with a good tolerability and safety profile, clinicians are likely to consider using it earlier in the pathway. The clinical experts explained that clinicians are likely to be overly cautious at first, because experience from previous antiseizure medicines suggest that efficacy of some medicines reported in trials may not be reflected in clinical practice. The committee considered that cenobamate would likely be used later in the pathway as long-term evidence of its efficacy and adverse effect profile is established. Therefore, it concluded that positioning cenobamate as an add-on treatment after at least 1 other add-on treatment has not controlled seizures was appropriate. These add-on treatments are currently started in tertiary epilepsy services (see section\xa03.2).\n\n# Comparator treatments\n\n## The relevant comparators are add-on options offered by epilepsy specialists after at least 1 add-on treatment does not control symptoms\n\nThe NICE scope specified relevant comparators as established add-on treatments. This included, but is not limited to, brivaracetam acetate, carbamazepine, eslicarbazepine acetate, lacosamide, levetiracetam and perampanel. In its submission, the company included only 'third generation' medicines used as add-on options after at least 1 add-on treatment had not controlled seizures in its network meta-analyses (brivaracetam acetate, eslicarbazepine acetate, lacosamide and perampanel). It stated that most drug-resistant epilepsy is likely to be treated with 'third generation' medicines because of fewer drug interactions, milder adverse events and novel mechanisms of action. It also stated that the other medicines are not relevant to UK clinical practice. The ERG disagreed, noting that there is no consensus that cenobamate should only be compared with 'third generation' medicines, and that published evidence from systematic reviews suggest that older medicines are as efficacious as newer medicines. The ERG noted that some of the treatments in the NICE guideline are no longer used. But some, such as zonisamide, clobazam and topiramate are still used for different purposes as add-on medicines. For example, clobazam is used as a short-term treatment. The company did not provide any relevant comparative evidence for cenobamate compared with these comparators or with any treatments that would be used earlier in the treatment pathway. Therefore, the committee concluded that it would be appropriate to appraise cenobamate for drug-resistant epilepsy only as an add-on option after at least 1 add-on treatment has not controlled seizures. The appropriate comparators would be most of those listed at this point in the NICE treatment pathway. That is, eslicarbazepine acetate, lacosamide, phenobarbital, phenytoin, pregabalin, tiagabine, vigabatrin, zonisamide, brivaracetam acetate and perampanel (see section\xa03.2).\n\n# Clinical evidence\n\n## Key short-term clinical evidence for cenobamate comes from 2 randomised controlled trials\n\nThe main evidence for cenobamate came from 2\xa0registrational trials, C013 and C017. These are multinational, multicentre, double-blind trials. They compared cenobamate with placebo in a total of 659\xa0adults (aged 18 to 70) with drug-resistant focal seizures despite treatment with at least 1\xa0antiseizure medicine in the last 1\xa0or 2\xa0years, who had 1 to 3 concomitant medicines at baseline that continued during the trial (background therapy). People with progressive central nervous system disease or 'psychiatric illness, psychological, or behavioural problems' were excluded from the trials. C017 had a higher threshold for inclusion for seizure frequency at baseline (at least 8 focal onset seizures over the 8‑week phase before randomisation) compared with C013 (at least 3 seizures over 28\xa0days). C013 included 1\xa0cenobamate arm (200\xa0mg once daily) whereas C017, a dose finding study, included 3\xa0arms (100\xa0mg, 200\xa0mg and 400\xa0mg, all once daily). Both trials had 6‑week titration periods, but C013 had a 6‑week maintenance phase, compared with 12\xa0weeks in C017. The primary end point of C013 was the percentage change from baseline in seizure frequency per 28\xa0days in the treatment period. In C017, it was at least a 50% reduction in seizures from baseline during the maintenance period. The results showed that for this outcome, 25.5% of people in the placebo arm had at least a 50% reduction in seizure frequency compared with 40.2%, 56.1% and 64.2% in the 100\xa0mg, 200\xa0mg and 400\xa0mg arms, respectively.\n\n## Clinically meaningful outcomes to patients are seizure freedom (100% reduction in seizures) or near seizure freedom (at least 90% reduction)\n\nThe clinical experts explained that the regulatory end point used in epilepsy trials of at least 50% reduction in seizures compared with baseline may not be as meaningful to patients as seizure freedom. This is because a 50% reduction may not change a person's level of independence or ability to do daily activities, and its impact may depend on the starting seizure frequency. The main aim of treatment is to retain or regain independence by prolonged and reliable periods of seizure freedom or near seizure freedom. The clinical experts suggested that 'near seizure freedom' may also be a good outcome as relapses most commonly happen when people forget to take their medicine, resulting in a seizure, rather than being because of lack of efficacy of the medicine. The clinical experts noted that a reduction in particular types of seizure may also represent meaningful clinical outcomes, such as reducing more severe seizures or seizures that happen at night. The committee considered that at least 1\xa0year of follow up is needed to ascertain whether a person is seizure free. This is the same length of time needed for other potential benefits of seizure freedom to happen, such as the ability to re-apply for a driving license.\n\n## Longer-term effectiveness and safety evidence of cenobamate comes from 2 open-label single-arm observational studies (C017-OLE and C021)\n\nTwo open-label extension, single-arm studies provided longer-term effectiveness and safety data. C017‑OLE used 300\xa0mg of cenobamate for 355\xa0people who had completed the C017 trial. C021 is an ongoing phase\xa03, single-arm, open-label, multinational, multicentre study including 1,347\xa0people with drug-resistant focal onset seizures. Cenobamate doses from 200\xa0mg to 400\xa0mg were titrated over 12\xa0weeks (starting from 12.5\xa0mg), followed by a 40‑week maintenance period. The results showed that 23.2% of people were seizure free for at least 1\xa0year during the C017‑OLE study. The ERG noted that long-term evidence was at risk of attrition bias because many people left the study during follow up and there was no comparative evidence in the open-label extension arm of the study.\n\n## People in cenobamate trials are representative of people likely to have treatment in clinical practice\n\nThe committee considered that the baseline rates of seizures were extremely high and variable across the groups in the cenobamate trials. The ERG noted that these baseline rates may not reflect the experience of people likely to be seen in clinical practice, and importantly may confound outcomes of the trial through regression to the mean. This is because there are natural variations in the number of seizures over time. So, inclusion criteria requiring a high baseline seizure rate would mean more people would be recruited during a period of high seizure frequency that would naturally reduce over time. The committee considered whether the high baseline seizure frequency rate could be a treatment effect modifier. The company explained that it had done subgroup analyses based on number of seizures at baseline (with a threshold of 6\xa0seizures) and seizure types and the results were consistent. The clinical experts emphasised that the absolute number of seizures in a trial is not important, as long as it represents a person's typical rate. The clinical experts agreed that the high number of seizures in the trials is representative of people with drug-resistant epilepsy likely to have treatment with cenobamate in tertiary centres in clinical practice. They noted that high seizure frequency at baseline is common in regulatory trials because it allows outcomes to be reached sooner. This decreases trial duration and minimises the risk of unnecessary drug exposure. The committee considered that excluding people with psychiatric comorbidities and other exclusion criteria in the trial would limit generalisability of the outcomes, but that this is typical of regulatory trials. It concluded that people in cenobamate trials have a high baseline seizure rate but are likely to be representative of people likely to have cenobamate in clinical practice.\n\n## C013 should be included in the company's clinical and cost-effectiveness analyses\n\nThe company excluded C013 from its clinical and cost-effectiveness analyses. This was because it did not consider that its use reflected clinical practice, because the 6‑week maintenance period was too short and it did not include a 400\xa0mg dose cenobamate arm. The ERG highlighted that the mean dose of 200\xa0mg used in C013 was more representative of the mean dose used in C021, which would likely reflect clinical practice. It also noted that the short maintenance period was similar to that of comparator trials, notably brivaracetam acetate. One clinical expert considered that a 6‑week maintenance period in a trial setting is acceptable. The clinical experts explained that brivaracetam is often used without a titration phase and noted that most medicines are used differently in clinical practice compared with trials. The company highlighted that the shorter maintenance period for brivaracetam acetate reflected the treatment period because titration periods are not used in clinical practice. The committee concluded that data from C013 should be included the analyses. This is because the dose used was relevant to clinical practice and the duration of the maintenance phase was similar to other trials included in the network meta-analysis.\n\n# Network meta-analyses\n\n## Modified intention-to-treat (mITT) data for the entire treatment period should be used in the network meta-analyses\n\nThe company used mITT data for the maintenance phase only from C017 in its network meta-analyses, whereas comparator trials used mITT data for the entire treatment period (both titration and maintenance phases). The committee noted that higher levels of seizure reduction were seen in C017 using mITT data over the maintenance period compared with using data over the entire treatment period. The clinical experts explained that until the medicine is titrated to an effective dose, seizures can continue to happen, so it may be more appropriate to consider seizure reduction after the titration phase. The committee appreciated that seizures may happen during the titration phase. But it agreed that for consistency with other comparator trials, mITT data for the treatment phase of cenobamate trials should be used in analyses. Because of slower titration in clinical practice this may represent a substantial proportion of time on treatment.\n\n## The ERG placebo-adjusted joint synthesis network meta-analysis including mITT data for the treatment period for both C013 and C017 is preferred\n\nIn its original submission, the company used network meta-analyses to compare cenobamate using mITT data from the maintenance phase of C017 only with 4 other third generation medicines (brivaracetam acetate, eslicarbazepine acetate, lacosamide and perampanel). It did network meta-analyses on 4\xa0outcomes: at least 50% reduction in seizure frequency, seizure freedom, any treatment-emergent adverse events and stopping because of treatment-emergent adverse events. The ERG highlighted key limitations of the network meta-analyses. These included the absence of trials directly comparing active drugs (all options linked by placebo), comparability of trial populations being unclear because of a lack of reported baseline characteristics, titration periods that are shorter and more intense than would be seen in clinical practice, and the follow-up periods being generally shorter than the recommended 1\xa0year needed to assess treatment success (see section\xa03.6). In addition, it noted the large variation in placebo response seen across the trials, implying there were different populations studied. It also noted that the company had modelled the different levels of seizure frequency reduction (at least 50% and 100%) as independent outcomes. The ERG corrected for the variable placebo response and correlation between seizure reduction outcomes using a placebo-adjusted joint synthesis model with mITT data from the combined titration and maintenance phases for both C013 and C017. The company accepted the ERG's revised model but still considered including C013 to be inappropriate. The committee concluded that the ERG's network meta-analysis was appropriate but many of the key limitations of the analysis remained.\n\n## Compared with placebo and other third generation medicines cenobamate is clinically effective at reducing seizures in the short term, but long-term evidence is uncertain\n\nThe committee acknowledged the methodological limitations of the network meta-analyses (see section\xa03.11). But, it noted the clinical experts' comments that many of these issues were characteristic of most epilepsy trials. Based on the results of the ERG's placebo-adjusted joint synthesis network meta-analysis for seizure reduction during the treatment period, the committee agreed that cenobamate was clinically effective at controlling seizures in the short term and probably more so than the other drugs included in the evidence network. It acknowledged the longer-term data for cenobamate that the company had provided from its open-label extension studies. The committee considered that the high baseline seizure frequencies in the studies could result in regression to the mean (see section\xa03.8). It also noted that the long-term evidence had potential for attrition bias and there was no long-term comparative evidence with other drugs. It concluded that cenobamate's relative long-term effectiveness is still uncertain.\n\n# Adverse effects of treatment\n\n## The long-term adverse effect profile of cenobamate is uncertain\n\nThe ERG highlighted a potential trend for higher occurrence of treatment-emergent adverse events for cenobamate compared with brivaracetam and lacosamide. It also noted higher rates of stopping treatment because of treatment-emergent adverse events based on evidence from the network meta-analyses. There was evidence of a dose–response relationship for safety and tolerability, with severe reactions seen in the short-term studies if starting doses were high or titration rapid. The most common adverse events were somnolence, dizziness and fatigue. The company considered that these could be explained by the rapid dosing schedule in the trial and would not reflect clinical practice. The clinical experts considered that the adverse event profile was similar to other add-on therapies at this point in the pathway (see section\xa03.2 and\xa0section 3.4). The committee considered the short duration of the trials and the clinical experts' comments that they are likely to use cenobamate cautiously at first to evaluate its safety profile in clinical practice over a longer period. It concluded that the overall balance between efficacy and long-term adverse effect profile of cenobamate is uncertain. More information about this can only be collected in larger head-to-head trials.\n\n# The company's economic model\n\n## An economic model using only 3 response-based health states is preferred\n\nThe company used a de novo Markov model to compare the cost effectiveness of cenobamate with 4 other third generation medicines over a lifetime. The model has 5 mutually exclusive health states based on level of response defined by degree of reduction in seizure frequency:\n\nno response (less than 50% reduction in seizure frequency)\n\nmoderate response (50% to less than 75% reduction)\n\nhigh response (75% to less than 90% reduction)\n\nvery high response (90% to below 100% reduction)\n\nseizure freedom (100% reduction). All patients start in the 'no response' state, then move between the 5 states until they stop treatment or die. Higher levels of response are associated with higher health-related quality of life and lower healthcare resource use. The company assumed that the risk of mortality in the 5\xa0response states was higher than in the general population but that excess mortality was lower in 'seizure freedom' state (hazard ratio\xa01.6) compared with the other health states (hazard ratio\xa02.4). People who stop treatment move to the 'subsequent antiseizure medicine' state, comprising other medicines, and can progress to having non-pharmacological treatment with vagal nerve stimulation or surgery. The company assumed that the proportion of people with each level of response is independent of the previous line of treatment. It also modelled adverse drug reactions and carer disutility. The ERG considered that the 5 response state model was inappropriate because most of the comparator trials only reported the proportion achieving a 50% reduction in seizures (see section\xa03.5). This meant most of the model inputs were based on clinical opinion and 1\xa0cenobamate trial, C017. Therefore, the ERG combined moderate to very high response into a single category to align with evidence available for comparator treatments. This was equivalent to the 3‑state model seen in previous appraisals and the NICE guideline. The committee considered that while a more granular 5‑state model may capture important differences in health states, there is minimal evidence available in comparator trials to populate the model. It noted that a model structure that is not based on response level but absolute numbers of seizures might be preferable to capture true differences in health-related quality of life and resource use. It concluded that the relative efficacy was the most important outcome to consider and the 3‑state model is most appropriate model to evaluate this.\n\n# Assumptions in the economic model\n\n## Transition probabilities should be estimated using C013 and C017 data and adjusted for placebo response\n\nThe company estimated transition probabilities between the different response states based on time-to-response data between study visits\xa03\xa0to\xa05 (titration period) and study visits\xa06 to 9 (maintenance period) from C017 only. Transition probabilities for comparators depended on cenobamate transitions and risk ratios from the ERG network meta-analyses results. The company confirmed that the placebo response in C017 had not been adjusted before estimating the transition probabilities. The committee considered that both C013 and C017 data should have been used to inform transition probabilities and would have preferred if the placebo response had been adjusted. The company modelled transition probabilities in cycles\xa06 to\xa026 using C017‑OLE data (duration of follow up) and in cycles\xa027 to\xa0462 using average transition probabilities from cycles\xa06 to\xa026, leading to continual improvement over time. The ERG considered that the assumption that people will continue to improve over time is highly uncertain. As such, in its base case, the ERG used the probability of at least 50% or 100% response from the network meta-analyses and applied it to the first 20\xa0weeks of the model. In cycle\xa06, people stay in the same response health state unless the treatment does not work, informed by time to stopping treatment in C017‑OLE and C021. The committee considered that there was minimal long-term data to suggest that there would be continued improvement over time. Therefore, it preferred the ERG's base case.\n\n## The assumption that all treatments would have the same stopping rate from cycle\xa06 is appropriate\n\nThe company assumed that people would stop treatments based on naive comparisons of the 4\xa0comparators' open-label extension observational studies that compared the risk ratios from C017‑OLE and C021 (cenobamate) with single arms from comparator trials. The ERG considered the naive comparison inappropriate because it does not consider heterogeneity between study design and population and potential confounding from any other trial effects. In addition, it was unclear whether C017‑OLE and C021 should be combined because the hazards of stopping treatment did not converge, suggesting that the populations may be different. In the ERG's base case, it used the odds ratios from the network meta-analysis for 'all-cause discontinuation' to inform the probability of stopping treatment in the short term (first 6\xa0cycles), because it provided the best comparative evidence. The company considered this would bias against cenobamate because of the rapid titration periods in trials included in the network meta-analysis, which would vary for different comparators (brivaracetam is often used without titration). For people continuing treatment, the ERG assumed that the same stopping rates would apply for all options from cycle\xa06. The committee considered that given the uncertainty in the relative long-term effectiveness of cenobamate compared with other third generation medicines, the ERG's assumption that the same stopping rates after cycle\xa06 was most appropriate.\n\n# Utility values in the economic model\n\n## Utility values from the company study and the NICE guideline on epilepsies are highly uncertain but give similar results\n\nThe company did not collect EQ‑5D data in its registrational trials. To inform patient utility values for each response health state, the company used a mapping algorithm from a survey of SF‑36 and QOLIE‑31‑P questionnaires (361\xa0people with focal onset seizures in epilepsy). The ERG considered that the company's mapping algorithm did not reflect variability in the observed SF‑6D utility index scores and underestimated the range of predicted utilities. The ERG highlighted the need for better utility data and that the utility values were highly uncertain, with some overlap between states. In the probabilistic sensitivity analysis, random utilities in higher response states were often lower than those in lower response states, so the company manually changed them to prevent illogical values. The committee noted that the company's utility values were substantially lower than those used in NICE's guideline on epilepsies (from now, CG137). Also, the differences in utilities between the response states were quite small, suggesting that there is little gain in utility moving from moderate to high response compared with high response to seizure freedom. The ERG noted that the differences between health states were similar for both the utility set derived from the company study and the CG137 utility set. This meant the absolute utility values had a minimal effect on the incremental cost-effectiveness ratio (ICER). The patient experts highlighted that there is a big difference between having seizures and seizure freedom, such as independence and ability to drive or work. The ERG highlighted the difference between health-related quality of life that is reflected in the utility values and broader quality of life that could include employment and other factors. It considered that the small difference in utility between seizure freedom and no response is seen in published studies such as Selai et al. 2005. The committee considered that both the utility value set from the company study and the utility value set used in CG137 are highly uncertain and could potentially underestimate the benefit of seizure freedom. It concluded that both utility value sets could be considered because of the minimal differences in relative benefit.\n\n## The company's estimates of caregiver disutility lack face validity\n\nThe company modelled caregiver disutility based on a caregiver survey (n=86). The ERG considered that this study was small and poorly reported and had concerns about how disutilities from the study were derived. Because of the lack of reporting by the company, the ERG was unable to evaluate the survey's methodology or the validity of the estimates. For its base case, the ERG excluded the carer disutility but agreed that a caregiver disutility was appropriate in principle for a proportion of people. The committee considered that the disutilities from the survey were much higher than those it had seen in other conditions, even when there is significant carer burden. The clinical experts explained that people with uncontrolled epilepsy would need some sort of help and that living alone increases the risk of mortality with epilepsy. The committee considered that for people who become seizure free, carer disutility may not be completely removed because of associated comorbidities needing care. The clinical experts explained that removing the uncertainty of seizure events happening has a large effect on caring. The committee noted that the benefit for carers was of a similar size to the benefit for patients. While the committee recognised that there is some level of carer burden, it considered the company's values disproportionate and preferred to use the ERG's base case. However, it noted that that this would likely underestimate the benefits of cenobamate, because a more effective treatment would be likely to generate some carer benefits.\n\n# Resource use\n\n## The resource use estimated from clinical experts likely overestimates costs of treatment\n\nThe company explained that there was no UK-specific resource use data for the population with drug-resistant epilepsy and it had not attempted to collect any data. In its base case, it included resource use including costs for drug administration, routine monitoring and epilepsy management (acute management and acute treatment) over a 28‑day period. But, in evaluating these it relied heavily on clinical opinion. For people whose epilepsy showed no response to treatment, the company estimated that most would see a GP, neurologist and epilepsy nurse within a 28‑day period. The clinical experts explained that typical monitoring would involve 6‑monthly follow up with a neurologist and additional contact as needed, whether it is from an epilepsy nurse, GP or the emergency department. They emphasised that the pattern of seizures is important and if the pattern is normal, but high, the person is unlikely to attend the emergency department. The clinical experts noted that people with drug-resistant epilepsy tend to be seen more in hospital rather than in primary care, although most of the monitoring is done in this setting. The patient experts explained that they routinely see a neurologist and would see an epilepsy nurse every 6\xa0months. Because of lack of knowledge by some GPs, they normally contact the epilepsy nurse directly and rarely contact the GP. For epilepsy event management resource use, the company categorised resource use based on type of seizures (focal aware, focal awareness impaired, focal-to-bilateral tonic-clonic) and estimated hospitalisation costs of initial presentation to healthcare services, acute costs of treatment and other costs per seizure. The committee noted that the number of hospitalisations in the model likely did not reflect all patients with drug-resistant epilepsy, but may represent people with more severe disease. The ERG considered that the company estimates of 28‑day healthcare costs were high compared with published models. The company also provided a scenario using the resource costs for CG137, from Jacoby et al. 1998. The company highlighted that the data was collected in 1993 in Jacoby and epilepsy management has evolved over that time. The committee had concerns that there was no new data available since Jacoby. It considered that both the routine monitoring costs and event management costs using company assumptions could be considerably greater than seen in clinical practice. It noted that clinical opinion estimating resource use can be skewed because clinicians do not treat epilepsy in all patients with the condition and see more patients with severe disease. The committee had concerns about both the company's heavy reliance on clinical opinion and the validity of the Jacoby estimates. While it would have preferred for resource use estimates to be based on data, the committee concluded that the true values are likely to be in between the company's estimate and the estimate in the Jacoby study. It considered that the costs derived from clinical opinion would be less relevant for people with epilepsy earlier in the treatment pathway and outside of a tertiary setting, but it had not seen analysis for this population.\n\n# Cost-effectiveness estimates\n\n## The ERG's base case includes most of the committee's preferred assumptions\n\nThe committee preferred the following assumptions from the ERG base case:\n\nusing the ERG's placebo-adjusted, joint synthesis network meta-analyses including mITT data for treatment period for both C013 and C017 (see section\xa03.11)\n\nusing the 3-response health state model (see section\xa03.14)\n\nmodelling transition probabilities as in the ERG's base case (see section\xa03.15)\n\nstopping rates are the same for cenobamate and all comparators after cycle\xa06 (see section\xa03.16)\n\nusing patient utility value sets from both available sources (see section\xa03.17)\n\nexcluding caregiver disutility as in the ERG's base case (see section\xa03.18).The committee considered that the ERG's base case included most of its preferred options. However, the ERG base case also used the same resource use assumptions as the base case. The committee considered that this was a key driver of the cost-effectiveness results and preferred to consider a range using the resource use data from the clinical expert opinion and the Jacoby study (see section\xa03.19).\n\n## Cenobamate is a cost-effective use of NHS resources\n\nThe committee considered the cost effectiveness of cenobamate compared with other third generation medicines (brivaracetam acetate, eslicarbazepine acetate, lacosamide and perampanel). It recognised the limited amount of long-term evidence available (see section\xa03.12), the uncertainty about cenobamate's adverse effect profile (see section\xa03.13) and the omission of relevant comparators (see section\xa03.4). In the company's and ERG's base case, cenobamate dominates all other comparator treatments (that is, it is more effective and less costly than comparators). In the scenario using the Jacoby study for resource use assumptions, cenobamate was more effective and more costly than all other comparator treatments. This resulted in an ICER of £20,522 per quality adjusted life year (QALY) gained. The committee considered that the Jacoby resource use estimates were likely to be an underestimate of costs (see section\xa03.19) and therefore considered this to be the highest value in the range of probable ICERs. In addition, there were potential uncaptured benefits that were not included in the ICER, such as improvement in carer utility (see section\xa03.18). Considering this, the committee concluded that cenobamate is a cost-effective use of NHS resources for treating drug-resistant epilepsy despite significant uncertainty in the clinical data and comparisons with other treatments. It recalled the clinical experts' comments that cenobamate may be used earlier in the pathway if shown to be effective and safe in clinical practice. The committee considered that it had not seen any evidence to support its use earlier in the pathway. It agreed that it should only be used as an add-on treatment after at least 1 add-on treatment had not controlled seizures and that treatment should be started in specialist epilepsy centres (see section\xa03.3).\n\n# Other factors\n\n## No equality issues were identified\n\nThe patient submission highlighted concerns about the safe use of antiseizure medicines in pregnancy and in people with comorbidities including a learning disability. The committee noted that the summary of product characteristics states that cenobamate is not recommended for women who can have children who are not using contraception. There is also inadequate data about using cenobamate during pregnancy. These issues cannot be addressed in a technology appraisal.\n\n## Cenobamate is an innovative medicine\n\nPatient and clinical experts noted the high seizure freedom rates in clinical trials of cenobamate. The committee noted that the dual mode of action of cenobamate could be innovative as a new dual mechanism. But, it did not consider there was enough evidence that the benefits seen in the trial could be attributed to its mode of action, because of the short-term nature of the evidence and population differences. The committee concluded that cenobamate could be innovative by providing an alternative option for managing focal onset seizures in people with drug-resistant epilepsy. However, it did not hear that there were any additional gains in health-related quality of life that could be attributed to this over those already included in the QALY calculations."}
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https://www.nice.org.uk/guidance/ta753
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Evidence-based recommendations on cenobamate (Ontozry) for treating focal onset seizures with or without secondary generalised seizures in adults with drug-resistant epilepsy that has not been adequately controlled with at least 2 antiseizure medicines.
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Mogamulizumab for previously treated mycosis fungoides and Sézary syndrome
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Mogamulizumab for previously treated mycosis fungoides and Sézary syndrome
Evidence-based recommendations on mogamulizumab (Poteligeo) for previously treated mycosis fungoides and Sézary syndrome in adults.
# Recommendations
Mogamulizumab is recommended, within its marketing authorisation, as an option for treating Sézary syndrome in adults who have had at least 1 systemic treatment. It is recommended only if the company provides mogamulizumab according to the commercial arrangement.
Mogamulizumab is recommended as an option for treating mycosis fungoides in adults, only if:
their condition is stage 2B or above and
they have had at least 2 systemic treatments and
the company provides mogamulizumab according to the commercial arrangement.
This recommendation is not intended to affect treatment with mogamulizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Standard care for previously treated mycosis fungoides or Sézary syndrome includes brentuximab vedotin, methotrexate, bexarotene, peginterferon and chemotherapy.
Mogamulizumab is licensed for treating mycosis fungoides and Sézary syndrome in adults who have had at least 1 systemic treatment. The company has positioned it for Sézary syndrome after 1 or more systemic treatments but only for advanced mycosis fungoides after 2 or more systemic treatments. This is because there are limited treatment options for this population.
Mogamulizumab has not been directly compared with standard care used in the NHS. It has only been directly compared with vorinostat, which is not available in the UK. Indirectly comparing mogamulizumab with evidence from people having standard care in the NHS suggests that people are likely to live longer with mogamulizumab. The evidence from this indirect comparison is uncertain because all the different factors that affect clinical outcomes may not have been considered. But it is unlikely that the evidence can be improved so the uncertainty is considered acceptable.
Mogamulizumab does not meet NICE's criteria to be considered a life-extending treatment at the end of life. Also, there is uncertainty about the cost-effectiveness evidence, but the cost-effectiveness estimates are likely to be within what NICE normally considers an acceptable use of NHS resources. So, mogamulizumab is recommended.# Information about mogamulizumab
# Marketing authorisation indication
Mogamulizumab (Poteligeo, Kyowa Kirin) is indicated for 'the treatment of adult patients with mycosis fungoides or Sézary syndrome who have received at least one prior systemic therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of mogamulizumab is £1,329 per vial containing 4 mg of mogamulizumab per ml (excluding VAT; BNF online, accessed October 2021). The company has a commercial arrangement (simple discount patient access scheme). This makes mogamulizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Kyowa Kirin, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway
## People with mycosis fungoides or Sézary syndrome would welcome a new treatment option
Cutaneous T-cell lymphoma is a rare type of non-Hodgkin lymphoma that affects the skin. It includes mycosis fungoides, the most common type, and Sézary syndrome, which is closely related. The clinical experts explained that Sézary syndrome is an aggressive disease and prognosis tends to be poor. Both patient experts described how living with a scaly itching rash all the time significantly affects their health-related quality of life. Sleep is affected. Cracks and open wounds are common, particularly on the hands and feet, which limits the ability to walk and carry out daily activities. The clinical experts explained that the disease particularly affects people's appearance and people sometimes rely on carers to help with daily activities. They confirmed that the treatments recommended in the British Association of Dermatologists and UK Cutaneous Lymphoma Group guidelines on managing primary cutaneous lymphomas after at least 1 systemic treatment were used in clinical practice. These included brentuximab vedotin, methotrexate, bexarotene, peginterferon and chemotherapy. The patient experts said that treatments such as chemotherapy had little benefit but mogamulizumab had a dramatic improvement. Mogamulizumab improved their itching and skin condition, so they could carry out daily activities more easily, and considerably improved their quality of life. The committee concluded that people with mycosis fungoides or Sézary syndrome who have had at least 1 systemic treatment would welcome an additional treatment option.
## The company proposes mogamulizumab for a subgroup of the population covered by the marketing authorisation
Mogamulizumab is indicated for treating mycosis fungoides or Sézary syndrome after at least 1 systemic treatment (see section 2.1). For the first and second committee meetings, the company proposed mogamulizumab as an option for a subgroup of the population covered by the marketing authorisation; that is, after at least 1 systemic treatment for people with severe disease that has progressed with brentuximab vedotin or if it is not appropriate. Severe disease was defined as stage 2B and above for mycosis fungoides and all stages of Sézary syndrome. Brentuximab vedotin is recommended as an option for severe CD30‑positive disease after at least 1 treatment (see NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma). The committee understood that mogamulizumab would most likely be used as an option after 1 systemic treatment for CD30-negative disease and after 2 systemic treatments for CD30-positive disease. But it noted that brentuximab could also be used later in the treatment pathway. The clinical experts explained that around 15% to 20% of people have CD30-positive disease. After the appeal, the company further refined the positioning of mogamulizumab for advanced mycosis fungoides to adults who have had 2 or more systemic treatments. It maintained the positioning in Sézary syndrome for adults who have had 1 or more systemic treatments. Few people with Sézary syndrome have CD30-positive disease. So, this positioning means that in both conditions, most people will have had brentuximab vedotin, or it will be unsuitable. The company explained that this is the population with the greatest unmet need because the only treatment options available to them are repeating previous treatments or clinical trials. The clinical experts confirmed that the company's proposed subgroup with severe disease was clinically relevant and that people in this subgroup had limited treatment options. The committee considered that there was a very high unmet need in this population. The committee concluded that the company positioned mogamulizumab for a subgroup of the population covered by the marketing authorisation and it would account for this in its recommendations.
## Standard care is the most appropriate comparator
The company originally submitted cost-effectiveness analyses, which used clinical-effectiveness data comparing mogamulizumab with vorinostat, a treatment that is not licensed or used in the UK (see section 3.4). In its revised base case after technical engagement, the company included the costs of having bexarotene alone for everyone in the standard care arm. This is because it considered it to be the most common NHS treatment for mycosis fungoides and Sézary syndrome. A clinical expert explained that triple therapy with bexarotene, extracorporeal photopheresis and peginterferon is used in clinical practice. But bexarotene alone would not generally be used, particularly for Sézary syndrome, because it was not effective. Another clinical expert suggested that chemotherapy may also be an option for people who were eligible for mogamulizumab. The committee considered that the company's approach may oversimplify a complex treatment pathway. The company also submitted clinical-effectiveness data for standard care from the hospital episode statistics (HES) database, including other relevant treatments in the standard care arm. These included methotrexate, bexarotene, peginterferon and chemotherapy. Overall, the committee concluded that standard care was the most appropriate comparator.
# Clinical evidence
## There is no trial evidence comparing mogamulizumab with standard care
The clinical evidence for mogamulizumab came from MAVORIC, a phase 3, open-label, randomised controlled trial. MAVORIC compared mogamulizumab with vorinostat in 372 adults with stage 1B to 4B relapsed or refractory mycosis fungoides or Sézary syndrome. There was no evidence directly comparing mogamulizumab with treatments currently used as NHS standard care (see section 3.3). In NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma, the ALCANZA trial was used. It compared brentuximab with the physician's choice of treatment (methotrexate or bexarotene). The committee understood that:
An anchored indirect treatment comparison using ALCANZA was not possible because there was no common treatment to connect the 2 trials.
The population in ALCANZA was different to MAVORIC because people with Sézary syndrome were excluded, everyone had CD30‑positive disease, and some had primary cutaneous anaplastic large-cell lymphoma (a subtype of cutaneous T‑cell lymphoma).
There was a high level of crossover in ALCANZA and the company did not have access to individual patient-level data to calculate crossover-adjusted survival estimates for the comparator arm.The company assumed that vorinostat was a suitable proxy for standard care in the NHS based on:
similar progression-free survival to the physician's choice arm in ALCANZA
clinical expert opinion and
similar response rates to those seen in bexarotene clinical trials.The ERG explained that if vorinostat and the physician's choice were similar, people in the physician's choice arm in ALCANZA would have longer progression-free survival and overall survival because they had less severe disease. However, overall survival for the physician's choice arm was shorter than with vorinostat. The clinical experts could not comment on vorinostat's clinical effectiveness because it is not available in the UK. However, they emphasised that mogamulizumab had been shown to be effective in delaying disease progression and improving quality of life both in the trial and in their clinical experience. The committee noted that:
mogamulizumab improved progression-free survival in MAVORIC compared with vorinostat (hazard ratio 0.43, 95% confidence interval 0.31 to 0.58)
the overall survival estimates were uncertain because MAVORIC was not powered to detect overall survival differences
% of people in the severe disease subgroup crossed over from vorinostat to mogamulizumab, so crossover adjustment was needed (see section 3.9).Overall, the committee was concerned about using these clinical-effectiveness data because vorinostat was not licensed for use in the UK and did not represent NHS standard care. The committee considered that evidence for the relative effectiveness of mogamulizumab was limited and concluded that evidence from clinical trials, used to estimate the relative treatment effect of mogamulizumab, was highly uncertain compared with NHS standard care.
## HES data suggests that mogamulizumab is likely more effective than standard care but the evidence is uncertain
Real-world data from England's HES database was presented by the company at the first committee meeting and used to support its preferred approach to extrapolating survival for the comparator arm from MAVORIC (see section 3.9). After consultation, the company submitted an unanchored indirect treatment comparison comparing mogamulizumab outcomes from MAVORIC with HES data. The committee noted that, unlike the MAVORIC data (see section 3.4), the HES data did not need any crossover adjustment. The committee noted that NICE's Decision Support Unit technical support document 18 states that all effect modifiers and prognostic factors should be accounted for in an unanchored indirect treatment comparison. This is because 'failure of this assumption leads to an unknown amount of bias' in the comparison. It noted that the MAVORIC data was only matched to the HES data for the proportion of people with mycosis fungoides and Sézary syndrome. Age (a known prognostic factor) and sex (which can potentially affect survival) were not matched. This was because the company considered that these were similar between the MAVORIC and HES data and wanted to avoid reducing the sample size unnecessarily. The ERG explained that age and sex should have been matched and pointed out that differences in mean age increased by 2.5 years after matching. After the appeal, the company submitted a scenario analysis including age and sex, which had a negligible effect on the hazard ratio for overall survival. The hazard ratio for overall survival, adjusted for age and sex, was 0.38 (95% confidence interval 0.25 to 0.59), showing mogamulizumab was associated with an improvement in overall survival compared with standard care. The committee was aware that several additional prognostic factors recognised in the literature and in a study by the Cutaneous Lymphoma International Consortium included:
stage of disease
levels of lactate dehydrogenase and
large-cell transformation.However, information on these and other prognostic factors were not available in the HES database and so could not be matched. The company considered that, in the HES database, people having systemic therapy had an Eastern Cooperative Oncology Group (ECOG) stage of 1 or less and adequate haematological, liver and kidney function. But no evidence to support this was provided. The committee noted that there were important limitations to using proxies for the stage and the duration of disease. Overall, the committee recognised that the HES analysis addressed some of the issues with the original submission and commended the company on its efforts. But the limitations of the data and the lack of information on prognostic factors meant that the indirect analysis results were uncertain. The committee considered that although there were uncertainties in the indirect comparison it was unlikely that these could have been addressed. The committee concluded that the indirect comparison suggested that mogamulizumab was more effective than standard care but that the evidence was uncertain.
## The MAVORIC subgroup with severe disease is clinically relevant but the results create uncertainty
The company used clinical-effectiveness data from a post-hoc subgroup of 287 people with severe disease in MAVORIC to reflect its proposed positioning (see section 3.2). The committee recalled that severe disease was considered a clinically relevant subgroup. But it noted that in this subgroup, it could not easily determine the proportion of people who had disease progression after brentuximab vedotin (CD30‑positive disease) and those not eligible for brentuximab vedotin (CD30‑negative disease). It was also concerned that the clinical-effectiveness data included people at different stages in the treatment pathway and did not differentiate between mycosis fungoides and Sézary syndrome. It considered that this may not be appropriate given the differences in expected survival between the conditions. The committee would have liked to have seen separate analyses by disease type and line of treatment. It recalled that all analyses used vorinostat as a comparator, which did not represent NHS standard care (see section 3.4). After the appeal, the company reweighted the MAVORIC trial data to match the characteristics of the subgroup of the population covered by the marketing authorisation, as observed in the HES data. Based on the evidence, the committee concluded that the MAVORIC subgroup with severe disease was clinically relevant. But using a mixed population, which grouped several lines of treatment together, created uncertainty. Also, MAVORIC did not compare mogamulizumab with a relevant comparator.
# Economic model
## The company's model structure is acceptable
In the company's partitioned survival model, 3 different treatment pathways were modelled:
people who did not have an allogeneic stem cell transplant
people who had an allogeneic stem cell transplant after current treatment (that is, mogamulizumab or standard care)
people who had an allogeneic stem cell transplant after subsequent treatment.The company initially used clinical expert advice to estimate the proportion of people having an allogeneic stem cell transplant after current treatment because this was not allowed in MAVORIC. After consultation, the company used HES data (see section 3.5) for this proportion. The committee was aware that the estimated treatment effect in MAVORIC may have differed if allogeneic stem cell transplant had been allowed. It recognised that some people may have an allogeneic stem cell transplant in clinical practice. But in the model, it preferred removing allogeneic stem cell transplant after current treatment, to avoid double-counting survival benefit in MAVORIC and to reduce potential bias. After the appeal, the company excluded allogeneic stem cell transplant after current treatment. The company noted that by doing this, the standard care arm included some of the benefits of allogeneic stem cell transplant but none of the costs. The committee considered that the cost-effectiveness estimates might have been lower if the costs of allogeneic stem cell transplant after current treatment were included in the submission. It understood that this had a small effect on the cost-effectiveness estimates. The committee concluded that the company's economic model structure was acceptable and that allogeneic stem cell transplant after current treatment should be excluded from the model.
## The comparative evidence from MAVORIC for time on treatment and next-treatment free survival is appropriate for decision making
The company originally modelled standard care using MAVORIC clinical-effectiveness data because it considered that vorinostat could be used as a proxy for standard care (see section 3.4). In its revised base case after technical engagement, the company preferred to use the costs of bexarotene alone for 48 weeks to represent the likely costs for people who have NHS standard care. After consultation, the company reverted to the ERG's preferred assumption of using the time on treatment for vorinostat and for relevant standard care treatments. In addition, clinical-effectiveness data for the standard care arm was updated to reflect data from the HES analysis (see section 3.5). After the appeal, the company estimated next-treatment-free survival and time on treatment for both arms from the reweighted MAVORIC trial, focusing on the refined population. The committee heard that the ERG agreed with the company's choice of distribution for next-treatment-free survival and using Kaplan–Meier curves to estimate time on treatment. Despite the limitations in the data sources, the committee concluded that the data was the most appropriate for decision making.
# Overall survival
## The exponential curve for both arms is acceptable for decision making
In MAVORIC, 72% of people in the severe subgroup crossed over from vorinostat to mogamulizumab after disease progression. Therefore, overall survival in the vorinostat arm was heavily confounded. The ERG and company agreed that an adjustment was needed to estimate what would have happened in the comparator arm if there was no crossover. In the first 2 committee meetings, the company preferred to use the inverse probability of censoring weights (IPCW) method and the ERG preferred a 2‑stage estimation method to adjust for crossover. Alongside the company's preferred IPCW crossover adjustment, it chose a log-normal curve to extrapolate overall survival in the mogamulizumab arm and applied an exponential curve to the standard care arm. The ERG preferred the exponential curve for both treatment arms. The committee preferred the ERG's approach and agreed that the company would need to make a strong case to justify using different parametric curves in each treatment arm. After the appeal, the company estimated overall survival for the mogamulizumab arm from the reweighted MAVORIC trial. The company and ERG agreed that the exponential extrapolation in the mogamulizumab arm was the best fitting curve and was clinically plausible. The company also updated the data source for overall survival in the standard care arm to the HES data after the appeal. The company chose the exponential extrapolation to estimate overall survival in the standard care arm. The company explained that although the generalised gamma was the best fitting curve, it did not consider the extrapolation to be clinically plausible because it predicted a plateau in survival. The ERG noted that the exponential extrapolation was the best fitting curve for the mogamulizumab arm but the worst fitting curve for the standard care arm. So, the ERG preferred the log-normal extrapolation because it was the second-best fitting extrapolation. The log-normal curve showed that 10% of people who had standard care would be alive at 10 years. The clinical experts explained that only people who had allogeneic stem cell transplants would be alive at 10 years. The clinical experts added that people whose disease progresses and need second- and third-line treatments do not have a good prognosis and would not be long-term survivors. The committee agreed with the company and clinical experts that because the modelling did not include people who have had allogeneic stem cell transplant, the log-normal curve was not clinically plausible. The committee concluded that the company and ERG's preferred exponential curve for the mogamulizumab arm and the company's preferred exponential curve for the standard care arm were acceptable for decision making.
## A 2-year stopping rule is not appropriate
The company included a 2‑year stopping rule for mogamulizumab in its revised base case. There was no evidence to support a stopping rule because it was not included in either the summary of product characteristics or the MAVORIC trial. The committee understood that the estimated treatment effect could have differed if a stopping rule had been used. The company suggested that the treatment effect was unlikely to differ substantially because in MAVORIC, only a small proportion of people had mogamulizumab after 2 years (the data is confidential and cannot be reported here). The committee recalled that it was not convinced that there would be a prolonged treatment benefit after stopping treatment. Before technical engagement, 1 clinical expert suggested that a 2‑year stopping rule would not be appropriate if people were still benefitting from treatment. At the committee meeting, the clinical experts explained that treatment would not normally be stopped if it was tolerated and there was an ongoing clinical benefit. The patient experts said they would feel distressed if mogamulizumab was stopped at 2 years, leaving them without any effective treatment options. The committee concluded that a 2‑year stopping rule was not appropriate.
# Utility values
## There may be an effect on carers' health-related quality of life, but this cannot be robustly modelled
The committee recalled that people with this condition sometimes rely on help from informal carers (see section 3.1). The committee noted that some people would have help from district nurses (for example, with wound dressing). Also, costs for community-based care including home visits, skin and wound care and dressings were included in the model. In the first and second committee meetings, the company's base case modelled the effect of caring on the health-related quality of life of carers by applying an additional utility gain of 0.19 when a person is in the disease control health state. This was the difference between the direct estimates of carer's health-related quality of life when caring for someone in the disease control (0.56) and subsequent treatment states (0.37) from the company's vignette study. Therefore, only the additional time a person spent in the disease control state after having mogamulizumab compared with standard care contributed to improving carer's health-related quality of life. After consultation, the company submitted 2 scenarios for carer utilities, in which:
the difference between carer utilities for the disease control and subsequent treatment health states was the same as the difference seen for the people in the trial (0.09)
absolute values for disease control and subsequent treatment states were used to show that the base case reflected a conservative approach.
The committee considered that the company's approach was not robust because the utility gain in the base case for carers was implausibly large compared with the expected utility gain for people with the condition. It recognised that there was a lack of detailed methodology on how to model carer utility. But it noted that the company used vignettes in the general population and it was not in line with NICE's guide to the methods of technology appraisal, which states that the EQ‑5D is the preferred measure of health-related quality of life in adults. The committee also did not consider it acceptable that the difference between carer utilities for the disease control and subsequent treatment health states would be the same as the difference seen for the people with the disease in the trial. This was because this was an unvalidated assumption, with no supporting evidence. Overall, the committee was not convinced that the company's approach to modelling carer utility values was appropriate. So it preferred to remove them from the base-case analysis, but recognised the burden placed on some carers. After the appeal, the company excluded carer utilities from its base-case analysis. Because the committee had recognised that there was a burden on some carers, the appeal panel considered that it must be clear how carer utilities were included in the decision making. The committee considered that including carer utilities in the modelling would have improved the cost-effectiveness estimates. Because it was not possible to robustly model them in this appraisal, the committee concluded it would consider them qualitatively in its decision making.
# End of life
## Mogamulizumab is not considered to be a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. At the first meeting, using MAVORIC data with the company's preferences, the model predicted a median survival of 21 months and a mean survival of 37 months in the standard care arm. The committee's preferred assumptions predicted a mean survival of between 33 months and 59 months in the standard care arm depending on if an IPCW or 2‑stage estimation crossover adjustment was used. The company also submitted HES data, which showed a median overall survival of around 1.3 years for people who have had 1 treatment. After consultation, the company submitted an updated HES analysis (see section 3.5) and considered that the end of life criteria had been met. The committee recognised that median life expectancy based on the new HES analysis (17.83 months) was less than 24 months. However, it noted that the mean extrapolated discounted and undiscounted life years in the standard care arm of the cost-effectiveness model based on the HES data, were 2.87 and 3.31 years respectively. The committee also considered a study by the Cutaneous Lymphoma International Consortium and the professional organisations' responses to technical engagement. After the appeal, the committee reconsidered this data and noted that the median data from the Cutaneous Lymphoma International Consortium study and the professional organisations' responses to technical engagement referred to time from diagnosis, rather than time from eligibility for second-line treatment. The committee acknowledged that time from eligibility for second-line treatment was the relevant period that should have been considered. After the appeal, the company updated the data source for overall survival in the standard care arm to the HES data. In the refined population, the HES data showed that median overall survival from time from eligibility for second-line treatment was 13 months but when the HES data was used in the model, it showed that mean overall survival was 28 months, when the exponential curve was chosen for both treatment arms. The committee noted that all other extrapolations of the HES data in the model led to a mean life expectancy greater than 28 months. The committee remained concerned about the differences between the median overall survival results from the HES analysis and the mean results produced when it was used in the model. The company considered that the mean was skewed by the long survival of around 10% of people having allogeneic stem cell transplant after current and subsequent treatments in the HES dataset. The ERG noted that people who had allogeneic stem cell transplant were part of the same cohort for which life expectancy was estimated, so their long survival does not bias life expectancy. The clinical experts explained that the life expectancy of people with the condition is variable and both the mean and median figures could be plausible. The committee recalled that cost-effectiveness results and decisions are based on mean quality-adjusted life years (QALYs) and costs. So, the committee still considered that the best estimate of expected survival came from modelling mean life expectancy. The committee noted that NICE's guide to the methods of technology appraisal states that the appraisal committee must be satisfied that:
the assumptions used in the reference case economic modelling are plausible, objective and robust and
the estimates of the extension to life are sufficiently robust.Overall, the committee was not convinced there was robust evidence that the short life-expectancy criterion had been met. It concluded that mogamulizumab could not be considered a life-extending treatment at the end of life.
# Cost-effectiveness estimates
## An acceptable ICER is towards the upper end of the range normally considered cost effective
NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty associated with the MAVORIC analysis, specifically:
The relative treatment effect of mogamulizumab compared with NHS standard care was uncertain because MAVORIC did not include the most appropriate comparator for NHS standard care (see section 3.4).
The company's preferred subgroup was limited because it included a mixed population in a single post-hoc analysis (see section 3.6).But it acknowledged that the HES analysis addressed some of the issues associated with MAVORIC (for example, comparator and crossover adjustment), and the rarity of the conditions means it would be hard to collect further data to reduce the uncertainty. It also recalled that including carer utilities and the costs of allogeneic stem cell transplant in the standard care arm would likely decrease the ICER. The committee noted that considering carer utilities and the costs of allogeneic stem cell transplant in the standard care arm would offset some uncertainty around the cost-effectiveness analyses. The committee therefore agreed that an ICER towards the upper end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) would be acceptable.
## The cost-effectiveness estimates are uncertain but are within the range normally considered cost effective
After the appeal, the company's updated base-case ICER for mogamulizumab compared with standard care was £28,233 per QALY gained, including the commercial arrangement for mogamulizumab. Adjusting the baseline characteristics of the MAVORIC trial to match the refined population had a minimal impact on the ICER. The committee understood that there was a small effect on the ICERs when including the commercial arrangement for bexarotene but the exact data is confidential so cannot be reported here. The committee considered the company's base case suitable for decision making. The company's base case included:
clinical-effectiveness data for overall survival for standard care from the unanchored indirect comparison using real-world data from the HES analysis and reweighted MAVORIC data
the exponential curve to extrapolate overall survival for mogamulizumab and standard care
allogeneic stem cell transplant excluded after current treatment.The company's base case excluded carer health-related quality of life. The committee considered the substantial uncertainty in all the cost-effectiveness estimates when applied in an NHS setting but noted the rarity of the cancer being appraised. The committee agreed that, based on its preferred assumptions, the most plausible ICER was within the range it considered acceptable for this appraisal (see section 3.13). The committee concluded that mogamulizumab was cost effective for advanced mycosis fungoides after at least 2 previous systemic treatments and for Sézary syndrome after at least 1 previous systemic treatment.
# Innovation
## Benefits not captured in the model are considered in the committee's decision making
The company considered mogamulizumab to be innovative because there are limited effective treatment options for people with advanced mycosis fungoides after at least 2 previous systemic treatments and for people with Sézary syndrome after at least 1 previous systemic treatment. The company emphasised the importance of improved health-related quality of life for these conditions, which cause lesions that affect people's appearance. The committee recalled this, the reported benefits in improving symptoms and the burden on carers. The committee also noted that the benefits of allogeneic stem cell transplant in the standard care arm were included in the modelling, but the associated costs were not. So, the committee was willing to qualitatively consider these factors. It also noted that mogamulizumab has an innovative mechanism of action. The committee concluded that mogamulizumab is innovative and the relevant benefits associated with mogamulizumab that were not captured in the modelling were considered qualitatively in determining an acceptable ICER (see section 3.13).
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{'Recommendations': "Mogamulizumab is recommended, within its marketing authorisation, as an option for treating Sézary syndrome in adults who have had at least 1\xa0systemic treatment. It is recommended only if the company provides mogamulizumab according to the commercial arrangement.\n\nMogamulizumab is recommended as an option for treating mycosis fungoides in adults, only if:\n\ntheir condition is stage\xa02B or above and\n\nthey have had at least 2\xa0systemic treatments and\n\nthe company provides mogamulizumab according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with mogamulizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for previously treated mycosis fungoides or Sézary syndrome includes brentuximab vedotin, methotrexate, bexarotene, peginterferon and chemotherapy.\n\nMogamulizumab is licensed for treating mycosis fungoides and Sézary syndrome in adults who have had at least 1\xa0systemic treatment. The company has positioned it for Sézary syndrome after 1\xa0or more systemic treatments but only for advanced mycosis fungoides after 2\xa0or more systemic treatments. This is because there are limited treatment options for this population.\n\nMogamulizumab has not been directly compared with standard care used in the NHS. It has only been directly compared with vorinostat, which is not available in the UK. Indirectly comparing mogamulizumab with evidence from people having standard care in the NHS suggests that people are likely to live longer with mogamulizumab. The evidence from this indirect comparison is uncertain because all the different factors that affect clinical outcomes may not have been considered. But it is unlikely that the evidence can be improved so the uncertainty is considered acceptable.\n\nMogamulizumab does not meet NICE's criteria to be considered a life-extending treatment at the end of life. Also, there is uncertainty about the cost-effectiveness evidence, but the cost-effectiveness estimates are likely to be within what NICE normally considers an acceptable use of NHS resources. So, mogamulizumab is recommended.", 'Information about mogamulizumab': "# Marketing authorisation indication\n\nMogamulizumab (Poteligeo, Kyowa Kirin) is indicated for 'the treatment of adult patients with mycosis fungoides or Sézary syndrome who have received at least one prior systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of mogamulizumab is £1,329 per vial containing 4\xa0mg of mogamulizumab per ml (excluding VAT; BNF online, accessed October\xa02021). The company has a commercial arrangement (simple discount patient access scheme). This makes mogamulizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Kyowa Kirin, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## People with mycosis fungoides or Sézary syndrome would welcome a new treatment option\n\nCutaneous T-cell lymphoma is a rare type of non-Hodgkin lymphoma that affects the skin. It includes mycosis fungoides, the most common type, and Sézary syndrome, which is closely related. The clinical experts explained that Sézary syndrome is an aggressive disease and prognosis tends to be poor. Both patient experts described how living with a scaly itching rash all the time significantly affects their health-related quality of life. Sleep is affected. Cracks and open wounds are common, particularly on the hands and feet, which limits the ability to walk and carry out daily activities. The clinical experts explained that the disease particularly affects people's appearance and people sometimes rely on carers to help with daily activities. They confirmed that the treatments recommended in the British Association of Dermatologists and UK Cutaneous Lymphoma Group guidelines on managing primary cutaneous lymphomas after at least 1\xa0systemic treatment were used in clinical practice. These included brentuximab vedotin, methotrexate, bexarotene, peginterferon and chemotherapy. The patient experts said that treatments such as chemotherapy had little benefit but mogamulizumab had a dramatic improvement. Mogamulizumab improved their itching and skin condition, so they could carry out daily activities more easily, and considerably improved their quality of life. The committee concluded that people with mycosis fungoides or Sézary syndrome who have had at least 1\xa0systemic treatment would welcome an additional treatment option.\n\n## The company proposes mogamulizumab for a subgroup of the population covered by the marketing authorisation\n\nMogamulizumab is indicated for treating mycosis fungoides or Sézary syndrome after at least 1\xa0systemic treatment (see section\xa02.1). For the first and second committee meetings, the company proposed mogamulizumab as an option for a subgroup of the population covered by the marketing authorisation; that is, after at least 1\xa0systemic treatment for people with severe disease that has progressed with brentuximab vedotin or if it is not appropriate. Severe disease was defined as stage\xa02B and above for mycosis fungoides and all stages of Sézary syndrome. Brentuximab vedotin is recommended as an option for severe CD30‑positive disease after at least 1\xa0treatment (see NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma). The committee understood that mogamulizumab would most likely be used as an option after 1\xa0systemic treatment for CD30-negative disease and after 2\xa0systemic treatments for CD30-positive disease. But it noted that brentuximab could also be used later in the treatment pathway. The clinical experts explained that around 15% to 20% of people have CD30-positive disease. After the appeal, the company further refined the positioning of mogamulizumab for advanced mycosis fungoides to adults who have had 2\xa0or more systemic treatments. It maintained the positioning in Sézary syndrome for adults who have had 1\xa0or more systemic treatments. Few people with Sézary syndrome have CD30-positive disease. So, this positioning means that in both conditions, most people will have had brentuximab vedotin, or it will be unsuitable. The company explained that this is the population with the greatest unmet need because the only treatment options available to them are repeating previous treatments or clinical trials. The clinical experts confirmed that the company's proposed subgroup with severe disease was clinically relevant and that people in this subgroup had limited treatment options. The committee considered that there was a very high unmet need in this population. The committee concluded that the company positioned mogamulizumab for a subgroup of the population covered by the marketing authorisation and it would account for this in its recommendations.\n\n## Standard care is the most appropriate comparator\n\nThe company originally submitted cost-effectiveness analyses, which used clinical-effectiveness data comparing mogamulizumab with vorinostat, a treatment that is not licensed or used in the UK (see section\xa03.4). In its revised base case after technical engagement, the company included the costs of having bexarotene alone for everyone in the standard care arm. This is because it considered it to be the most common NHS treatment for mycosis fungoides and Sézary syndrome. A clinical expert explained that triple therapy with bexarotene, extracorporeal photopheresis and peginterferon is used in clinical practice. But bexarotene alone would not generally be used, particularly for Sézary syndrome, because it was not effective. Another clinical expert suggested that chemotherapy may also be an option for people who were eligible for mogamulizumab. The committee considered that the company's approach may oversimplify a complex treatment pathway. The company also submitted clinical-effectiveness data for standard care from the hospital episode statistics (HES) database, including other relevant treatments in the standard care arm. These included methotrexate, bexarotene, peginterferon and chemotherapy. Overall, the committee concluded that standard care was the most appropriate comparator.\n\n# Clinical evidence\n\n## There is no trial evidence comparing mogamulizumab with standard care\n\nThe clinical evidence for mogamulizumab came from MAVORIC, a phase\xa03, open-label, randomised controlled trial. MAVORIC compared mogamulizumab with vorinostat in 372\xa0adults with stage\xa01B to\xa04B relapsed or refractory mycosis fungoides or Sézary syndrome. There was no evidence directly comparing mogamulizumab with treatments currently used as NHS standard care (see section\xa03.3). In NICE's technology appraisal guidance on brentuximab vedotin for treating CD30-positive cutaneous T-cell lymphoma, the ALCANZA trial was used. It compared brentuximab with the physician's choice of treatment (methotrexate or bexarotene). The committee understood that:\n\nAn anchored indirect treatment comparison using ALCANZA was not possible because there was no common treatment to connect the 2\xa0trials.\n\nThe population in ALCANZA was different to MAVORIC because people with Sézary syndrome were excluded, everyone had CD30‑positive disease, and some had primary cutaneous anaplastic large-cell lymphoma (a subtype of cutaneous T‑cell lymphoma).\n\nThere was a high level of crossover in ALCANZA and the company did not have access to individual patient-level data to calculate crossover-adjusted survival estimates for the comparator arm.The company assumed that vorinostat was a suitable proxy for standard care in the NHS based on:\n\nsimilar progression-free survival to the physician's choice arm in ALCANZA\n\nclinical expert opinion and\n\nsimilar response rates to those seen in bexarotene clinical trials.The ERG explained that if vorinostat and the physician's choice were similar, people in the physician's choice arm in ALCANZA would have longer progression-free survival and overall survival because they had less severe disease. However, overall survival for the physician's choice arm was shorter than with vorinostat. The clinical experts could not comment on vorinostat's clinical effectiveness because it is not available in the UK. However, they emphasised that mogamulizumab had been shown to be effective in delaying disease progression and improving quality of life both in the trial and in their clinical experience. The committee noted that:\n\nmogamulizumab improved progression-free survival in MAVORIC compared with vorinostat (hazard ratio 0.43, 95% confidence interval 0.31\xa0to\xa00.58)\n\nthe overall survival estimates were uncertain because MAVORIC was not powered to detect overall survival differences\n\n% of people in the severe disease subgroup crossed over from vorinostat to mogamulizumab, so crossover adjustment was needed (see section\xa03.9).Overall, the committee was concerned about using these clinical-effectiveness data because vorinostat was not licensed for use in the UK and did not represent NHS standard care. The committee considered that evidence for the relative effectiveness of mogamulizumab was limited and concluded that evidence from clinical trials, used to estimate the relative treatment effect of mogamulizumab, was highly uncertain compared with NHS standard care.\n\n## HES data suggests that mogamulizumab is likely more effective than standard care but the evidence is uncertain\n\nReal-world data from England's HES database was presented by the company at the first committee meeting and used to support its preferred approach to extrapolating survival for the comparator arm from MAVORIC (see section\xa03.9). After consultation, the company submitted an unanchored indirect treatment comparison comparing mogamulizumab outcomes from MAVORIC with HES data. The committee noted that, unlike the MAVORIC data (see section\xa03.4), the HES data did not need any crossover adjustment. The committee noted that NICE's Decision Support Unit technical support document\xa018 states that all effect modifiers and prognostic factors should be accounted for in an unanchored indirect treatment comparison. This is because 'failure of this assumption leads to an unknown amount of bias' in the comparison. It noted that the MAVORIC data was only matched to the HES data for the proportion of people with mycosis fungoides and Sézary syndrome. Age (a known prognostic factor) and sex (which can potentially affect survival) were not matched. This was because the company considered that these were similar between the MAVORIC and HES data and wanted to avoid reducing the sample size unnecessarily. The ERG explained that age and sex should have been matched and pointed out that differences in mean age increased by 2.5\xa0years after matching. After the appeal, the company submitted a scenario analysis including age and sex, which had a negligible effect on the hazard ratio for overall survival. The hazard ratio for overall survival, adjusted for age and sex, was 0.38 (95% confidence interval 0.25\xa0to\xa00.59), showing mogamulizumab was associated with an improvement in overall survival compared with standard care. The committee was aware that several additional prognostic factors recognised in the literature and in a study by the Cutaneous Lymphoma International Consortium included:\n\nstage of disease\n\nlevels of lactate dehydrogenase and\n\nlarge-cell transformation.However, information on these and other prognostic factors were not available in the HES database and so could not be matched. The company considered that, in the HES database, people having systemic therapy had an Eastern Cooperative Oncology Group (ECOG) stage of\xa01 or less and adequate haematological, liver and kidney function. But no evidence to support this was provided. The committee noted that there were important limitations to using proxies for the stage and the duration of disease. Overall, the committee recognised that the HES analysis addressed some of the issues with the original submission and commended the company on its efforts. But the limitations of the data and the lack of information on prognostic factors meant that the indirect analysis results were uncertain. The committee considered that although there were uncertainties in the indirect comparison it was unlikely that these could have been addressed. The committee concluded that the indirect comparison suggested that mogamulizumab was more effective than standard care but that the evidence was uncertain.\n\n## The MAVORIC subgroup with severe disease is clinically relevant but the results create uncertainty\n\nThe company used clinical-effectiveness data from a post-hoc subgroup of 287\xa0people with severe disease in MAVORIC to reflect its proposed positioning (see section\xa03.2). The committee recalled that severe disease was considered a clinically relevant subgroup. But it noted that in this subgroup, it could not easily determine the proportion of people who had disease progression after brentuximab vedotin (CD30‑positive disease) and those not eligible for brentuximab vedotin (CD30‑negative disease). It was also concerned that the clinical-effectiveness data included people at different stages in the treatment pathway and did not differentiate between mycosis fungoides and Sézary syndrome. It considered that this may not be appropriate given the differences in expected survival between the conditions. The committee would have liked to have seen separate analyses by disease type and line of treatment. It recalled that all analyses used vorinostat as a comparator, which did not represent NHS standard care (see section\xa03.4). After the appeal, the company reweighted the MAVORIC trial data to match the characteristics of the subgroup of the population covered by the marketing authorisation, as observed in the HES data. Based on the evidence, the committee concluded that the MAVORIC subgroup with severe disease was clinically relevant. But using a mixed population, which grouped several lines of treatment together, created uncertainty. Also, MAVORIC did not compare mogamulizumab with a relevant comparator.\n\n# Economic model\n\n## The company's model structure is acceptable\n\nIn the company's partitioned survival model, 3\xa0different treatment pathways were modelled:\n\npeople who did not have an allogeneic stem cell transplant\n\npeople who had an allogeneic stem cell transplant after current treatment (that is, mogamulizumab or standard care)\n\npeople who had an allogeneic stem cell transplant after subsequent treatment.The company initially used clinical expert advice to estimate the proportion of people having an allogeneic stem cell transplant after current treatment because this was not allowed in MAVORIC. After consultation, the company used HES data (see section\xa03.5) for this proportion. The committee was aware that the estimated treatment effect in MAVORIC may have differed if allogeneic stem cell transplant had been allowed. It recognised that some people may have an allogeneic stem cell transplant in clinical practice. But in the model, it preferred removing allogeneic stem cell transplant after current treatment, to avoid double-counting survival benefit in MAVORIC and to reduce potential bias. After the appeal, the company excluded allogeneic stem cell transplant after current treatment. The company noted that by doing this, the standard care arm included some of the benefits of allogeneic stem cell transplant but none of the costs. The committee considered that the cost-effectiveness estimates might have been lower if the costs of allogeneic stem cell transplant after current treatment were included in the submission. It understood that this had a small effect on the cost-effectiveness estimates. The committee concluded that the company's economic model structure was acceptable and that allogeneic stem cell transplant after current treatment should be excluded from the model.\n\n## The comparative evidence from MAVORIC for time on treatment and next-treatment free survival is appropriate for decision making\n\nThe company originally modelled standard care using MAVORIC clinical-effectiveness data because it considered that vorinostat could be used as a proxy for standard care (see section\xa03.4). In its revised base case after technical engagement, the company preferred to use the costs of bexarotene alone for 48\xa0weeks to represent the likely costs for people who have NHS standard care. After consultation, the company reverted to the ERG's preferred assumption of using the time on treatment for vorinostat and for relevant standard care treatments. In addition, clinical-effectiveness data for the standard care arm was updated to reflect data from the HES analysis (see section\xa03.5). After the appeal, the company estimated next-treatment-free survival and time on treatment for both arms from the reweighted MAVORIC trial, focusing on the refined population. The committee heard that the ERG agreed with the company's choice of distribution for next-treatment-free survival and using Kaplan–Meier curves to estimate time on treatment. Despite the limitations in the data sources, the committee concluded that the data was the most appropriate for decision making.\n\n# Overall survival\n\n## The exponential curve for both arms is acceptable for decision making\n\nIn MAVORIC, 72% of people in the severe subgroup crossed over from vorinostat to mogamulizumab after disease progression. Therefore, overall survival in the vorinostat arm was heavily confounded. The ERG and company agreed that an adjustment was needed to estimate what would have happened in the comparator arm if there was no crossover. In the first 2\xa0committee meetings, the company preferred to use the inverse probability of censoring weights (IPCW) method and the ERG preferred a 2‑stage estimation method to adjust for crossover. Alongside the company's preferred IPCW crossover adjustment, it chose a log-normal curve to extrapolate overall survival in the mogamulizumab arm and applied an exponential curve to the standard care arm. The ERG preferred the exponential curve for both treatment arms. The committee preferred the ERG's approach and agreed that the company would need to make a strong case to justify using different parametric curves in each treatment arm. After the appeal, the company estimated overall survival for the mogamulizumab arm from the reweighted MAVORIC trial. The company and ERG agreed that the exponential extrapolation in the mogamulizumab arm was the best fitting curve and was clinically plausible. The company also updated the data source for overall survival in the standard care arm to the HES data after the appeal. The company chose the exponential extrapolation to estimate overall survival in the standard care arm. The company explained that although the generalised gamma was the best fitting curve, it did not consider the extrapolation to be clinically plausible because it predicted a plateau in survival. The ERG noted that the exponential extrapolation was the best fitting curve for the mogamulizumab arm but the worst fitting curve for the standard care arm. So, the ERG preferred the log-normal extrapolation because it was the second-best fitting extrapolation. The log-normal curve showed that 10% of people who had standard care would be alive at 10\xa0years. The clinical experts explained that only people who had allogeneic stem cell transplants would be alive at 10\xa0years. The clinical experts added that people whose disease progresses and need second- and third-line treatments do not have a good prognosis and would not be long-term survivors. The committee agreed with the company and clinical experts that because the modelling did not include people who have had allogeneic stem cell transplant, the log-normal curve was not clinically plausible. The committee concluded that the company and ERG's preferred exponential curve for the mogamulizumab arm and the company's preferred exponential curve for the standard care arm were acceptable for decision making.\n\n## A 2-year stopping rule is not appropriate\n\nThe company included a 2‑year stopping rule for mogamulizumab in its revised base case. There was no evidence to support a stopping rule because it was not included in either the summary of product characteristics or the MAVORIC trial. The committee understood that the estimated treatment effect could have differed if a stopping rule had been used. The company suggested that the treatment effect was unlikely to differ substantially because in MAVORIC, only a small proportion of people had mogamulizumab after 2\xa0years (the data is confidential and cannot be reported here). The committee recalled that it was not convinced that there would be a prolonged treatment benefit after stopping treatment. Before technical engagement, 1\xa0clinical expert suggested that a 2‑year stopping rule would not be appropriate if people were still benefitting from treatment. At the committee meeting, the clinical experts explained that treatment would not normally be stopped if it was tolerated and there was an ongoing clinical benefit. The patient experts said they would feel distressed if mogamulizumab was stopped at 2\xa0years, leaving them without any effective treatment options. The committee concluded that a 2‑year stopping rule was not appropriate.\n\n# Utility values\n\n## There may be an effect on carers' health-related quality of life, but this cannot be robustly modelled\n\nThe committee recalled that people with this condition sometimes rely on help from informal carers (see section\xa03.1). The committee noted that some people would have help from district nurses (for example, with wound dressing). Also, costs for community-based care including home visits, skin and wound care and dressings were included in the model. In the first and second committee meetings, the company's base case modelled the effect of caring on the health-related quality of life of carers by applying an additional utility gain of 0.19 when a person is in the disease control health state. This was the difference between the direct estimates of carer's health-related quality of life when caring for someone in the disease control (0.56) and subsequent treatment states (0.37) from the company's vignette study. Therefore, only the additional time a person spent in the disease control state after having mogamulizumab compared with standard care contributed to improving carer's health-related quality of life. After consultation, the company submitted 2\xa0scenarios for carer utilities, in which:\n\nthe difference between carer utilities for the disease control and subsequent treatment health states was the same as the difference seen for the people in the trial (0.09)\n\nabsolute values for disease control and subsequent treatment states were used to show that the base case reflected a conservative approach.\n\nThe committee considered that the company's approach was not robust because the utility gain in the base case for carers was implausibly large compared with the expected utility gain for people with the condition. It recognised that there was a lack of detailed methodology on how to model carer utility. But it noted that the company used vignettes in the general population and it was not in line with NICE's guide to the methods of technology appraisal, which states that the EQ‑5D is the preferred measure of health-related quality of life in adults. The committee also did not consider it acceptable that the difference between carer utilities for the disease control and subsequent treatment health states would be the same as the difference seen for the people with the disease in the trial. This was because this was an unvalidated assumption, with no supporting evidence. Overall, the committee was not convinced that the company's approach to modelling carer utility values was appropriate. So it preferred to remove them from the base-case analysis, but recognised the burden placed on some carers. After the appeal, the company excluded carer utilities from its base-case analysis. Because the committee had recognised that there was a burden on some carers, the appeal panel considered that it must be clear how carer utilities were included in the decision making. The committee considered that including carer utilities in the modelling would have improved the cost-effectiveness estimates. Because it was not possible to robustly model them in this appraisal, the committee concluded it would consider them qualitatively in its decision making.\n\n# End of life\n\n## Mogamulizumab is not considered to be a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. At the first meeting, using MAVORIC data with the company's preferences, the model predicted a median survival of 21\xa0months and a mean survival of 37\xa0months in the standard care arm. The committee's preferred assumptions predicted a mean survival of between 33\xa0months and 59\xa0months in the standard care arm depending on if an IPCW or 2‑stage estimation crossover adjustment was used. The company also submitted HES data, which showed a median overall survival of around 1.3\xa0years for people who have had 1\xa0treatment. After consultation, the company submitted an updated HES analysis (see section\xa03.5) and considered that the end of life criteria had been met. The committee recognised that median life expectancy based on the new HES analysis (17.83\xa0months) was less than 24\xa0months. However, it noted that the mean extrapolated discounted and undiscounted life years in the standard care arm of the cost-effectiveness model based on the HES data, were 2.87\xa0and 3.31\xa0years respectively. The committee also considered a study by the Cutaneous Lymphoma International Consortium and the professional organisations' responses to technical engagement. After the appeal, the committee reconsidered this data and noted that the median data from the Cutaneous Lymphoma International Consortium study and the professional organisations' responses to technical engagement referred to time from diagnosis, rather than time from eligibility for second-line treatment. The committee acknowledged that time from eligibility for second-line treatment was the relevant period that should have been considered. After the appeal, the company updated the data source for overall survival in the standard care arm to the HES data. In the refined population, the HES data showed that median overall survival from time from eligibility for second-line treatment was 13\xa0months but when the HES data was used in the model, it showed that mean overall survival was 28\xa0months, when the exponential curve was chosen for both treatment arms. The committee noted that all other extrapolations of the HES data in the model led to a mean life expectancy greater than 28\xa0months. The committee remained concerned about the differences between the median overall survival results from the HES analysis and the mean results produced when it was used in the model. The company considered that the mean was skewed by the long survival of around 10% of people having allogeneic stem cell transplant after current and subsequent treatments in the HES dataset. The ERG noted that people who had allogeneic stem cell transplant were part of the same cohort for which life expectancy was estimated, so their long survival does not bias life expectancy. The clinical experts explained that the life expectancy of people with the condition is variable and both the mean and median figures could be plausible. The committee recalled that cost-effectiveness results and decisions are based on mean quality-adjusted life years (QALYs) and costs. So, the committee still considered that the best estimate of expected survival came from modelling mean life expectancy. The committee noted that NICE's guide to the methods of technology appraisal states that the appraisal committee must be satisfied that:\n\nthe assumptions used in the reference case economic modelling are plausible, objective and robust and\n\nthe estimates of the extension to life are sufficiently robust.Overall, the committee was not convinced there was robust evidence that the short life-expectancy criterion had been met. It concluded that mogamulizumab could not be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness estimates\n\n## An acceptable ICER is towards the upper end of the range normally considered cost effective\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty associated with the MAVORIC analysis, specifically:\n\nThe relative treatment effect of mogamulizumab compared with NHS standard care was uncertain because MAVORIC did not include the most appropriate comparator for NHS standard care (see section\xa03.4).\n\nThe company's preferred subgroup was limited because it included a mixed population in a single post-hoc analysis (see section\xa03.6).But it acknowledged that the HES analysis addressed some of the issues associated with MAVORIC (for example, comparator and crossover adjustment), and the rarity of the conditions means it would be hard to collect further data to reduce the uncertainty. It also recalled that including carer utilities and the costs of allogeneic stem cell transplant in the standard care arm would likely decrease the ICER. The committee noted that considering carer utilities and the costs of allogeneic stem cell transplant in the standard care arm would offset some uncertainty around the cost-effectiveness analyses. The committee therefore agreed that an ICER towards the upper end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained) would be acceptable.\n\n## The cost-effectiveness estimates are uncertain but are within the range normally considered cost effective\n\nAfter the appeal, the company's updated base-case ICER for mogamulizumab compared with standard care was £28,233 per QALY gained, including the commercial arrangement for mogamulizumab. Adjusting the baseline characteristics of the MAVORIC trial to match the refined population had a minimal impact on the ICER. The committee understood that there was a small effect on the ICERs when including the commercial arrangement for bexarotene but the exact data is confidential so cannot be reported here. The committee considered the company's base case suitable for decision making. The company's base case included:\n\nclinical-effectiveness data for overall survival for standard care from the unanchored indirect comparison using real-world data from the HES analysis and reweighted MAVORIC data\n\nthe exponential curve to extrapolate overall survival for mogamulizumab and standard care\n\nallogeneic stem cell transplant excluded after current treatment.The company's base case excluded carer health-related quality of life. The committee considered the substantial uncertainty in all the cost-effectiveness estimates when applied in an NHS setting but noted the rarity of the cancer being appraised. The committee agreed that, based on its preferred assumptions, the most plausible ICER was within the range it considered acceptable for this appraisal (see section\xa03.13). The committee concluded that mogamulizumab was cost effective for advanced mycosis fungoides after at least 2\xa0previous systemic treatments and for Sézary syndrome after at least 1\xa0previous systemic treatment.\n\n# Innovation\n\n## Benefits not captured in the model are considered in the committee's decision making\n\nThe company considered mogamulizumab to be innovative because there are limited effective treatment options for people with advanced mycosis fungoides after at least 2\xa0previous systemic treatments and for people with Sézary syndrome after at least 1\xa0previous systemic treatment. The company emphasised the importance of improved health-related quality of life for these conditions, which cause lesions that affect people's appearance. The committee recalled this, the reported benefits in improving symptoms and the burden on carers. The committee also noted that the benefits of allogeneic stem cell transplant in the standard care arm were included in the modelling, but the associated costs were not. So, the committee was willing to qualitatively consider these factors. It also noted that mogamulizumab has an innovative mechanism of action. The committee concluded that mogamulizumab is innovative and the relevant benefits associated with mogamulizumab that were not captured in the modelling were considered qualitatively in determining an acceptable ICER (see section\xa03.13)."}
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https://www.nice.org.uk/guidance/ta754
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Evidence-based recommendations on mogamulizumab (Poteligeo) for previously treated mycosis fungoides and Sézary syndrome in adults.
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cc352091cce5a753fb09bad69ce4dcb9e1681d14
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nice
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Transanal total mesorectal excision for rectal cancer
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Transanal total mesorectal excision for rectal cancer
Evidence-based recommendations on transanal total mesorectal excision for rectal cancer in adults. This involves removing the cancer through the anus or a small cut in the abdomen.
# Recommendations
Evidence on the efficacy of transanal total mesorectal excision of the rectum is adequate. Evidence on its safety is inconsistent. It also shows the potential for major safety concerns, including damage to adjacent structures and seeding of malignancy. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research, which could be randomised controlled trials or registry data, should report details of patient selection, including tumour type, use of neoadjuvant chemoradiotherapy and all complications, including malignancy dissemination.# The condition, current treatments and procedure
# The condition
The incidence of rectal cancer rises sharply with age. Symptoms include rectal bleeding and change in bowel habit, although the early stages may be asymptomatic.
# Current treatments
The management of rectal cancer is described in NICE's guideline on colorectal cancer. The main treatment is surgery. It involves resecting the affected part of the rectum with anus preservation or, when anus preservation is not technically possible, colostomy formation. Adjunctive radiotherapy and chemotherapy may also be used to reduce the risk of local recurrence and prevent metastatic disease.
# The procedure
The aim of transanal total mesorectal excision is to improve the clinical outcome of rectal resection, and to reduce length of hospital stay and morbidity after surgery. It may enable proctectomy (removal of all or part of the rectum) that would be difficult by an open or laparoscopic approach. This could be in people with a narrow pelvis or high body mass index, or where the position of the tumour is low in the rectum.
Before surgery, the patient has bowel preparation and prophylactic antibiotics. Using general anaesthesia, and with the patient in the lithotomy position, standard abdominal laparoscopic mobilisation of the left colon and upper rectum is done. After inserting an operating platform into the anus, the lower rectum including the total mesorectum is mobilised. At the start of the transanal part of the procedure, a purse-string suture is put in to close the rectal lumen. This is followed by a full thickness rectotomy. After identifying the total mesorectal excision plane, the dissection progresses proximally until it connects with the dissection from above. The specimen can be removed through the transanal platform or, if the tumour is large, through the abdomen using a small incision. Anastomosis to connect the colon and the anus can be done using sutures (hand-sewn technique) or staples, and a temporary ileostomy is usually created. When anastomosis is not possible, a permanent stoma is created.
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{'Recommendations': 'Evidence on the efficacy of transanal total mesorectal excision of the rectum is adequate. Evidence on its safety is inconsistent. It also shows the potential for major safety concerns, including damage to adjacent structures and seeding of malignancy. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research, which could be randomised controlled trials or registry data, should report details of patient selection, including tumour type, use of neoadjuvant chemoradiotherapy and all complications, including malignancy dissemination.', 'The condition, current treatments and procedure': "# The condition\n\nThe incidence of rectal cancer rises sharply with age. Symptoms include rectal bleeding and change in bowel habit, although the early stages may be asymptomatic.\n\n# Current treatments\n\nThe management of rectal cancer is described in NICE's guideline on colorectal cancer. The main treatment is surgery. It involves resecting the affected part of the rectum with anus preservation or, when anus preservation is not technically possible, colostomy formation. Adjunctive radiotherapy and chemotherapy may also be used to reduce the risk of local recurrence and prevent metastatic disease.\n\n# The procedure\n\nThe aim of transanal total mesorectal excision is to improve the clinical outcome of rectal resection, and to reduce length of hospital stay and morbidity after surgery. It may enable proctectomy (removal of all or part of the rectum) that would be difficult by an open or laparoscopic approach. This could be in people with a narrow pelvis or high body mass index, or where the position of the tumour is low in the rectum.\n\nBefore surgery, the patient has bowel preparation and prophylactic antibiotics. Using general anaesthesia, and with the patient in the lithotomy position, standard abdominal laparoscopic mobilisation of the left colon and upper rectum is done. After inserting an operating platform into the anus, the lower rectum including the total mesorectum is mobilised. At the start of the transanal part of the procedure, a purse-string suture is put in to close the rectal lumen. This is followed by a full thickness rectotomy. After identifying the total mesorectal excision plane, the dissection progresses proximally until it connects with the dissection from above. The specimen can be removed through the transanal platform or, if the tumour is large, through the abdomen using a small incision. Anastomosis to connect the colon and the anus can be done using sutures (hand-sewn technique) or staples, and a temporary ileostomy is usually created. When anastomosis is not possible, a permanent stoma is created."}
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https://www.nice.org.uk/guidance/ipg713
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Evidence-based recommendations on transanal total mesorectal excision for rectal cancer in adults. This involves removing the cancer through the anus or a small cut in the abdomen.
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0fbb423c124496c835e4152b829549f404dd9ff1
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nice
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Endobronchial nerve ablation for chronic obstructive pulmonary disease
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Endobronchial nerve ablation for chronic obstructive pulmonary disease
Evidence-based recommendations endobronchial nerve ablation for chronic obstructive pulmonary disease. This involves destroying (ablating) the nerves on the outside of the airway (endobronchial nerves) to improve breathing.
# Recommendations
Evidence on the safety and efficacy of endobronchial nerve ablation for chronic obstructive pulmonary disease (COPD) is inadequate in quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should be randomised controlled trials comparing the procedure with sham treatment. It should report details of patient selection, and short and long-term functional outcomes including lung functional outcomes, quality of life and patient-reported outcomes, incidence of exacerbations and hospital admissions, and all adverse events.# The condition, current treatments and procedure
# The condition
Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis. It's a common condition that mostly affects middle-aged and older adults. Approximately 4.5% of over 40s in the UK have diagnosed COPD. The main cause of COPD is smoking. The main symptoms are breathlessness, a persistent cough and wheezing, and frequent chest infections. COPD gradually gets worse over time and people can have sudden flare-ups (exacerbations).
# Current treatments
Although the damage to the lungs caused by COPD is permanent, treatment can help slow disease progression. Treatments include stopping smoking, pulmonary rehabilitation, inhaled beta‑2 agonists, antimuscarinic and steroid inhalers, oral medication such as bronchodilators, mucolytics and steroids, and oxygen. In a very small number of people, surgery or lung transplant may be indicated.
# The procedure
In COPD, acetylcholine released from parasympathetic airway nerve fibres mediates smooth muscle tone, reflex bronchoconstriction, mucus hyper-secretion and airway inflammation. This procedure disrupts parasympathetic signalling to the lungs and decreases neuronal release of acetylcholine. The aim is to produce permanent bronchodilation, decrease mucus production and improve breathing.
Endobronchial nerve ablation is a minimally invasive outpatient procedure carried out under general anaesthesia. A bronchoscope is used to visualise the airways and a dual-cooled radiofrequency (RF) catheter, which has a balloon and an electrode on the end, is positioned in the distal mainstem bronchus. Once in position, coolant is passed through the catheter and the balloon inflates, pressing the electrode against the airway wall. RF energy is then delivered from the electrode to ablate the parasympathetic nerves that run along the outside of the mainstem bronchus. The balloon is then deflated and rotated, and the ablation repeated until the whole circumference of the bronchus has been treated. Both main bronchi are treated during a single procedure. Most patients return home on the day of the procedure.
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{'Recommendations': 'Evidence on the safety and efficacy of endobronchial nerve ablation for chronic obstructive pulmonary disease (COPD) is inadequate in quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should be randomised controlled trials comparing the procedure with sham treatment. It should report details of patient selection, and short and long-term functional outcomes including lung functional outcomes, quality of life and patient-reported outcomes, incidence of exacerbations and hospital admissions, and all adverse events.', 'The condition, current treatments and procedure': "# The condition\n\nChronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis. It's a common condition that mostly affects middle-aged and older adults. Approximately 4.5% of over\xa040s in the UK have diagnosed COPD. The main cause of COPD is smoking. The main symptoms are breathlessness, a persistent cough and wheezing, and frequent chest infections. COPD gradually gets worse over time and people can have sudden flare-ups (exacerbations).\n\n# Current treatments\n\nAlthough the damage to the lungs caused by COPD is permanent, treatment can help slow disease progression. Treatments include stopping smoking, pulmonary rehabilitation, inhaled beta‑2 agonists, antimuscarinic and steroid inhalers, oral medication such as bronchodilators, mucolytics and steroids, and oxygen. In a very small number of people, surgery or lung transplant may be indicated.\n\n# The procedure\n\nIn COPD, acetylcholine released from parasympathetic airway nerve fibres mediates smooth muscle tone, reflex bronchoconstriction, mucus hyper-secretion and airway inflammation. This procedure disrupts parasympathetic signalling to the lungs and decreases neuronal release of acetylcholine. The aim is to produce permanent bronchodilation, decrease mucus production and improve breathing.\n\nEndobronchial nerve ablation is a minimally invasive outpatient procedure carried out under general anaesthesia. A bronchoscope is used to visualise the airways and a dual-cooled radiofrequency (RF) catheter, which has a balloon and an electrode on the end, is positioned in the distal mainstem bronchus. Once in position, coolant is passed through the catheter and the balloon inflates, pressing the electrode against the airway wall. RF\xa0energy is then delivered from the electrode to ablate the parasympathetic nerves that run along the outside of the mainstem bronchus. The balloon is then deflated and rotated, and the ablation repeated until the whole circumference of the bronchus has been treated. Both main bronchi are treated during a single procedure. Most patients return home on the day of the procedure."}
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https://www.nice.org.uk/guidance/ipg714
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Evidence-based recommendations endobronchial nerve ablation for chronic obstructive pulmonary disease. This involves destroying (ablating) the nerves on the outside of the airway (endobronchial nerves) to improve breathing.
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8ac8196fcfcc2c21d472919f86dd22b3cad0195e
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nice
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ClearGuard HD antimicrobial barrier caps for preventing haemodialysis catheter-related bloodstream infections
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ClearGuard HD antimicrobial barrier caps for preventing haemodialysis catheter-related bloodstream infections
Evidence-based recommendations on ClearGuard HD antimicrobial barrier caps for preventing haemodialysis catheter-related bloodstream infections.
# Recommendations
ClearGuard HD antimicrobial barrier caps are recommended as a cost-saving option for preventing catheter-related bloodstream infections in people with central venous catheters having haemodialysis.
Data should be collected on any long-term effect of chlorhexidine exposure, in particular in children.
Why the committee made these recommendations
ClearGuard HD caps are used with central venous catheters in haemodialysis. They are different from standard caps because they contain a rod coated in the antimicrobial chlorhexidine acetate to prevent infection. Other options for preventing infection are the Curos disinfecting cap, used with Tego needleless connectors, and antimicrobial line lock solutions.
Clinical evidence shows that using ClearGuard HD caps instead of standard caps, Tego plus Curos, or line lock solutions reduces the risk of catheter-related bloodstream infections.
Although there is not much evidence for ClearGuard HD caps in children, they are likely to have a similarly reduced risk of catheter-related bloodstream infections.
The effect of long-term exposure to chlorhexidine is not well understood, so NICE recommends collecting data on this.
Cost modelling shows that over 1 year ClearGuard HD caps are likely to be cost saving compared with standard treatments. ClearGuard HD caps are estimated to save, per person:
£351 compared with standard caps and wipes
£1,096 compared with antimicrobial line lock solution, standard caps and wipes
£568 compared with Tego needleless connector and Curos disinfecting caps.
Savings were from the lower incidence rate and associated cost of treating catheter-related bloodstream infection with ClearGuard HD caps. Therefore, ClearGuard HD caps are recommended.
By adopting this technology, the NHS in England may save around £470,000 each year. For more details, see NICE's resource impact statement and template.# The technology
# Technology
ClearGuard HD antimicrobial barrier caps (ICU Medical) are for use with central venous catheters (CVC) in haemodialysis. The cap has a rod that extends into the CVC hub. The rod and cap threads are coated in chlorhexidine acetate, a broad-spectrum antimicrobial that aims to reduce pathogenic organisms in the CVC lock and therefore reduce the risk of catheter-related bloodstream infections (CRBSI).
# Care pathway
ClearGuard HD caps are for use on CVC lines between haemodialysis sessions to reduce the risk of infections. They replace standard caps and wipes. Other options include the Curos disinfecting cap (recommended for further research by NICE) used with Tego needleless connectors, and antimicrobial line lock solutions. ClearGuard HD caps cannot be reused once removed and need to be replaced during every dialysis session. The recommended maximum use time for the cap is 3 days. The caps are not currently used in the NHS. The external assessment centre and experts do not believe that using ClearGuard HD caps would alter the current pathway and say that minimal training is needed.
# Innovative aspects
ClearGuard HD caps have a coating of chlorhexidine acetate, a broad-spectrum antimicrobial agent, on the rod and cap threads. They release chlorhexidine acetate into the catheter lock solution, which remains inside the catheter hub in between treatments.
# Intended use
ClearGuard HD antimicrobial caps are an alternative to standard caps, or caps and connectors, on CVCs, to reduce the risk of CRBSI during haemodialysis for end-stage kidney disease.
ClearGuard HD antimicrobial caps are for use by healthcare professionals trained in haemodialysis. The company and experts agree that minimal training would be needed. The caps can also be used by patients and carers doing haemodialysis at home, after they have had training in safe home haemodialysis.
# Costs
ClearGuard HD caps cost £4 per pair. Haemodialysis would normally be needed 3 times a week and the caps are replaced at each dialysis session, leading to a cost of £12 a week. The company has estimated that haemodialysis patients would need a CVC for an average of 132 days (estimated by the company based on Crowley et al. 2017, Kwak et al. 2012, and Hymes et al. 2017) until a more permanent form of vascular access is established. This results in a cost of £226 per person over this period.
Clinical experts said that the 'scrub the hub' disinfection practice is likely to continue, so alongside wipes the total cost is £247 for an average of 132 days of haemodialysis.For more details, see the website for ClearGuard HD antimicrobial barrier caps.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The main clinical evidence comprises 6 studies
The company submitted 7 studies from its literature search, including 3 full-text papers (Brunelli et al. 2018, Hymes et al. 2017 and Weiss et al. 2021) and 4 abstracts (Glennon et al. 2020, Li et al. 2019, Nitz et al. 2021 and Sibbel et al. 2020). The EAC accepted 6, excluding Nitz et al. because the intervention and outcomes did not match the scope and because it felt it did not add to the decision problem. The 3 full-text papers included a total of 10,757 participants. For full details of the clinical evidence, see section 4 of the assessment report in the supporting documentation on the NICE website.
## The 2 prospective cluster randomised controlled trials are the most relevant to the decision problem
Brunelli et al. and Hymes et al. were the most relevant to the decision problem. Both were prospective, multicentre, open-label cluster randomised controlled trials, which included 40 sites each. Outcomes varied. Brunelli et al. compared ClearGuard HD caps with Tego (needleless connectors) plus Curos (disinfecting caps). Hymes et al. compared ClearGuard HD caps with standard central venous catheter (CVC) caps.
## The other studies are observational and at high risk of bias
The remaining full-text paper (Weiss et al.) described a large retrospective analysis but was considered methodologically weak. The abstracts (Glennon et al., Li et al. and Sibbel et al.) were all retrospective analyses with limited detail and did not add much more to the decision problem. The studies had largely homogenous populations. The proportion of men ranged from 51% to 53% and mean ages were 61.1 years to 62.8 years (except for Glennon et al., which studied children).
## The pivotal trials report significantly reduced positive blood cultures
Most of the studies reported bloodstream infection rates, although they did not always use the same terminology. Positive blood cultures were the primary outcome in the randomised controlled trials. They both reported significantly lower positive blood culture rates for the ClearGuard group than for the comparator group. The incidence rate ratio (IRR) in Hymes was 0.44 (p=0.01) and in Brunelli 0.37 (p=0.001).
## Other outcome measures included hospital admissions and mortality
Rates of hospital admission were lower for the ClearGuard group in 3 studies (Brunelli et al., Hymes et al. and Sibbel et al.), although this was not significant across the studies. Not many of the studies reported length of hospital stay or rates of mortality. None of them reported intravenous antibiotic use or staff time.
## Nine adverse events are reported in MAUDE and none in the full-text papers
There are 9 records of adverse events on the US Food and Drug Administration's (FDA) MAUDE (Manufacturer and User Facility Device Experience) database. Two reported that the caps came off for 1 patient. Six reported that the caps became detached while the patients were asleep. One reported that the rod broke loose in the catheter. No patients were injured. None of the full-text papers reported adverse events. For full details of the adverse events, see section 6 of the assessment report in the supporting documentation on the NICE website.
# Cost evidence
## One abstract in the company's submission estimates costs
An abstract by Glennon et al. estimated total annual costs per patient for ClearGuard HD caps of £7,078, compared with £18,050 for antimicrobial lock solutions. This was estimated from 4 high-risk children having dialysis. The EAC noted that the authors did not do any sensitivity analysis to assess how robust the cost and rate were. It also noted that the applicability of the results to an adult setting was not certain.
## The company's model compares ClearGuard HD caps against 4 comparators
The model included a decision tree that looked at cost savings with ClearGuard HD caps against 4 comparators:
standard CVC caps plus alcohol wipes for disinfection
standard CVC caps plus antimicrobial lock solution and alcohol wipes for disinfection
Tego needleless connectors plus Curos disinfecting caps (Tego plus Curos)
Tego needleless connectors on their own, with manual decontamination of the catheter hub with alcohol wipes.The model had a 1‑year time horizon for cost and health outcomes. For full details of the cost evidence, see section 4 of the assessment report in the supporting documentation on the NICE website.
## The EAC's minor amendments to the model and parameters address mortality, comparators and disinfection protocols
The EAC agreed that the overall structure of the model, time horizon, population, most comparators, outcomes, and assumptions were acceptable and appropriate for the assessment. The EAC excluded the mortality branch of the model, saying that the cost of caps and cost of treating catheter-related bloodstream infections (CRBSI) was adequate without the need for the mortality branch. One comparator (Tego needleless connectors) was not considered appropriate by the EAC because it is a connector alone and therefore out of scope. The EAC provided additional analysis in the ClearGuard HD caps arm around disinfection protocols when using ClearGuard HD caps. This was based on discussions with clinical experts, who expected these disinfection protocols to still be used.
## Sensitivity analysis shows cost savings are from baseline incidence rate of infection with ClearGuard, comparators and the cost of treating CRBSI
The EAC recommended that all parameters not validated by clinical data should be varied up and down by 50% in the sensitivity analysis. The EAC's results were similar to the company's. The parameters that had the largest impact on cost results were:
baseline incidence rate of infection associated with the comparator
the IRR associated with ClearGuard
the average cost of treating CRBSI.
## Cost savings remain even when the CRBSI incidence rate is increased in the ClearGuard group and decreased for comparators
The company did 4 'worst case' scenario analyses, in which the base-case baseline infection rate associated with each of the 4 comparators was at the lower end of the value range. The IRR of CRBSI with ClearGuard was at the upper end of the value range. For these scenarios, based on clinical expert opinion and varying clinical estimates from published studies, the EAC recommended varying the parameters up and down by 50%, or by a range informed by the evidence (rather than up and down by the 25% suggested by the company). ClearGuard remained cost saving in all the scenarios. Another scenario reduced the cost of antimicrobial lock solution; ClearGuard remained cost saving by £418.
## Threshold analysis of baseline infections shows ClearGuard HD caps are still cost saving at infection rates that are clinically unlikely
The scenario analysis results were also supported by the EAC's threshold analysis. This reported cost-neutral break-even points for different CRBSI incidence rates per 1,000 CVC days:
with standard caps (baseline rate was 0.7)
with antimicrobial lock solution (baseline rate was 0.598)
with standard caps (baseline rate was 0.63).
## ClearGuard HD caps remain cost saving when the cost of standard caps is reduced
Experts and committee members flagged discrepancies in agency costs of standard caps compared with the cost model, which were likely to be because of volume discounts in practice. The EAC input the reported value of £0.03 for the cost of standard caps into the model. ClearGuard remained cost saving compared with:
standard caps and wipes by £351 (from £387)
standard caps, antimicrobial lock solution and wipes by £1,096 (from £1,132).
## ClearGuard HD caps are cost saving over all comparators in the EAC's updated model
The final results showed ClearGuard HD caps were cost saving compared with all the 4 comparators. The company submission reported cost savings per patient of:
£408 compared with standard caps and wipes
£1,167 compared with standard caps, antimicrobial lock solution and wipes
£590 compared with Tego needleless connector and Curos disinfecting caps.The EAC's revised base-case cost savings, with added disinfection costs in the ClearGuard HD caps arm, showed cost savings per patient of:
£387 compared with standard caps and wipes
£1,132 compared with standard caps, antimicrobial lock solution and wipes
£568 compared with Tego needleless connector and Curos disinfecting caps.# Committee discussion
# Clinical evidence overview
## Evidence shows that ClearGuard HD caps reduce the risk of catheter-related bloodstream infections
The committee noted that the literature consistently showed lower infection rates with ClearGuard compared with other options. It considered the 2 randomised controlled trials to be pivotal for decision making. While the studies had some risk of bias, the committee was reassured by the relatively large effect sizes. The way bloodstream infections were measured and reported varied across the evidence. Clinical experts said that this was a common problem in such clinical studies and also in NHS practice. The primary end point in both randomised controlled trials was positive blood cultures. The committee understood that this end point was not specifically attributable to infections arising in the central venous catheters (CVC), but nevertheless it was satisfied by the overall weight of evidence that ClearGuard HD caps are likely to reduce the risk of catheter-related bloodstream infections (CRBSI).
## The evidence is generalisable to children
A clinical expert discussed the potential benefit in children who may need a central line long term, and for whom recurrent infections could limit treatment options in the future. The clinical experts said they considered the incidence rates in the adult studies to be comparable and generalisable to children. They also highlighted some evidence of a benefit for children in the Glennon et al. study, which was in high-risk children, although this evidence is lower quality because it was a retrospective analysis with limited detail and reported as an abstract only. On balance, the committee concluded that the evidence in adults could be generalised to children.
## ClearGuard HD caps may benefit people who have haemodialysis at home
Clinical experts said that more CVCs were now being used, rather than surgical fistulas, because of the COVID‑19 pandemic. They agreed that the aim was for more people of all ages to use home dialysis. But no evidence was identified on using ClearGuard HD caps at home. The committee felt that they could benefit people having dialysis at home and was encouraged by positive feedback provided by the company from users about their usability. Clinical experts said that in their experience these patients are motivated, and so they did not see any barriers to using the caps safely and effectively at home, as long as people were trained in how to use them.
# Safety considerations
## ClearGuard HD caps are safe and compatible with central lines used in clinical practice
The committee discussed the ClearGuard HD caps' compatibility with central lines. It was satisfied that the only central line that they were incompatible with was one that is seldom used. The company confirmed that the caps had been shown to be compatible with other line lock solutions, as part of US Food and Drug Administration (FDA) benchmarking assessments, including heparin-saline, saline and citrate. The committee discussed 1 adverse event reported on the FDA's MAUDE (Manufacturer and User Facility Device Experience) database, of rod detachment. The committee was reassured by the company that the cap had been examined, and that the problem was not replicable and has not been reported before or since.
## The long-term implications for chlorhexidine allergy should be monitored
The rod and cap threads of ClearGuard HD caps are coated in chlorhexidine acetate, a broad-spectrum antimicrobial agent. Some people are allergic to chlorhexidine, although according to the clinical experts, this is unusual. The committee was satisfied that the device instructions for use clearly state it should not be used for people with known allergies to chlorhexidine. Clinical experts reported that in their experience allergy shows more commonly as a skin reaction, although people can have anaphylactic reactions to chlorhexidine. The committee was concerned that we do not yet know the long-term effects of exposure to chlorhexidine acetate, and if people could become sensitised to it. Because of this, the committee asked the company to proactively find out about adverse events and report them to the Medicines and Healthcare products Regulatory Agency (MHRA). The committee advised the company to provide a plan to monitor chlorhexidine sensitisation or allergies to address this gap in understanding for the future.
# NHS considerations overview
## The evidence is generalisable to NHS practice
The clinical evidence base was all from the US and North America. The clinical experts said that the baseline rates of catheter-related bloodstream infection in the US studies were broadly comparable to UK NHS practice. A difference between the US and UK is that high-concentrate citrate is used as a catheter lock solution for adults in the UK. But it is not approved for use in this way in the US and therefore was not included in the evidence. The committee agreed that, although citrate's effect on reducing infection rates was uncertain, it was likely to be comparable to the antimicrobial line lock solution comparator in the evidence. The committee concluded that the evidence was broadly generalisable to NHS practice and was a reasonable basis for decision-making purposes.
## No significant changes to infrastructure are needed
The clinical experts said that the 'scrub the hub' disinfection practice would continue regardless of the cap used during haemodialysis. The external assessment centre (EAC) acknowledged this in its minor amendments to the company model. The committee was satisfied that this accurately showed how the caps would be used in NHS practice. It agreed that no additional changes to NHS infrastructure would be needed to use ClearGuard HD caps in the NHS.
# Cost evidence overview
## The cost model for ClearGuard HD caps is well constructed and shows cost savings compared with all comparators
The cost model was well constructed, and the minor changes made by the EAC were appropriate and accepted by the committee. The committee concluded that the comprehensive sensitivity and scenario analyses supported cost savings compared with all comparators.
## The model's main cost drivers are the comparators' infection incidence rate and ClearGuard HD caps' infection rate ratio
The main cost savings were from reduced CRBSI incidence rate. The committee discussed the uncertainty around incidence levels across comparators but concluded that the evidence was strong enough and backed by clinical expert opinion, indicating that there were likely to be costs savings in practice.
## Sensitivity analysis adequately addresses the uncertainty around outcomes and comparators
The end points used in the pivotal clinical studies (positive blood cultures) introduced some uncertainty in the outcomes. However, the committee was satisfied that the EAC's extra sensitivity analysis adequately addressed the likely variation in incidence. There was some uncertainty around whether the model results were applicable to the NHS, when the evidence used to inform it did not include the comparator high-concentrate citrate, which is used in the UK but not in the US (see section 4.6). The clinical experts said infection rates with high-concentrate citrate were likely to be comparable to those with the antimicrobial line lock solution comparator used in the scenario analyses, which showed that even at low rates of baseline infection, ClearGuard HD caps were cost saving. The EAC's sensitivity analyses also showed cost savings at even lower rates of infection. The committee therefore concluded that the sensitivity analysis adequately addressed uncertainty around this comparator.
# Cost savings
## ClearGuard HD caps are likely to be cost saving compared with all comparators
Comprehensive scenario analyses, including 'worst case' scenarios, showed ClearGuard HD caps to be cost saving compared with all comparators. Additional threshold analysis reported that they were cost neutral at infection thresholds that clinical experts advised were clinically unlikely because they were so low. The committee was satisfied that the cost modelling evidence was robust and shows ClearGuard HD caps are cost saving compared with all comparators.
The EAC revised the base-case cost savings: it added disinfection costs in the ClearGuard HD caps arm, and reduced standard caps costs because of volume discount. This resulted in cost savings per patient of:
£351 compared with standard caps and wipes
£1,096 compared with antimicrobial line lock solution, standard caps and wipes
£568 compared with Tego needleless connectors and Curos disinfecting caps.
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{'Recommendations': "ClearGuard\xa0HD antimicrobial barrier caps are recommended as a cost-saving option for preventing catheter-related bloodstream infections in people with central venous catheters having haemodialysis.\n\nData should be collected on any long-term effect of chlorhexidine exposure, in particular in children.\n\nWhy the committee made these recommendations\n\nClearGuard\xa0HD caps are used with central venous catheters in haemodialysis. They are different from standard caps because they contain a rod coated in the antimicrobial chlorhexidine acetate to prevent infection. Other options for preventing infection are the Curos disinfecting cap, used with Tego needleless connectors, and antimicrobial line lock solutions.\n\nClinical evidence shows that using ClearGuard\xa0HD caps instead of standard caps, Tego plus Curos, or line lock solutions reduces the risk of catheter-related bloodstream infections.\n\nAlthough there is not much evidence for ClearGuard HD caps in children, they are likely to have a similarly reduced risk of catheter-related bloodstream infections.\n\nThe effect of long-term exposure to chlorhexidine is not well understood, so NICE recommends collecting data on this.\n\nCost modelling shows that over 1\xa0year ClearGuard\xa0HD caps are likely to be cost saving compared with standard treatments. ClearGuard\xa0HD caps are estimated to save, per person:\n\n£351 compared with standard caps and wipes\n\n£1,096 compared with antimicrobial line lock solution, standard caps and wipes\n\n£568 compared with Tego needleless connector and Curos disinfecting caps.\n\nSavings were from the lower incidence rate and associated cost of treating catheter-related bloodstream infection with ClearGuard\xa0HD caps. Therefore, ClearGuard\xa0HD caps are recommended.\n\nBy adopting this technology, the NHS in England may save around £470,000 each year. For more details, see NICE's resource impact statement and template.", 'The technology': "# Technology\n\nClearGuard\xa0HD antimicrobial barrier caps (ICU Medical) are for use with central venous catheters (CVC) in haemodialysis. The cap has a rod that extends into the CVC hub. The rod and cap threads are coated in chlorhexidine acetate, a broad-spectrum antimicrobial that aims to reduce pathogenic organisms in the CVC lock and therefore reduce the risk of catheter-related bloodstream infections (CRBSI).\n\n# Care pathway\n\nClearGuard\xa0HD caps are for use on CVC lines between haemodialysis sessions to reduce the risk of infections. They replace standard caps and wipes. Other options include the Curos disinfecting cap (recommended for further research by NICE) used with Tego needleless connectors, and antimicrobial line lock solutions. ClearGuard\xa0HD caps cannot be reused once removed and need to be replaced during every dialysis session. The recommended maximum use time for the cap is 3\xa0days. The caps are not currently used in the NHS. The external assessment centre and experts do not believe that using ClearGuard\xa0HD caps would alter the current pathway and say that minimal training is needed.\n\n# Innovative aspects\n\nClearGuard\xa0HD caps have a coating of chlorhexidine acetate, a broad-spectrum antimicrobial agent, on the rod and cap threads. They release chlorhexidine acetate into the catheter lock solution, which remains inside the catheter hub in between treatments.\n\n# Intended use\n\nClearGuard\xa0HD antimicrobial caps are an alternative to standard caps, or caps and connectors, on CVCs, to reduce the risk of CRBSI during haemodialysis for end-stage kidney disease.\n\nClearGuard\xa0HD antimicrobial caps are for use by healthcare professionals trained in haemodialysis. The company and experts agree that minimal training would be needed. The caps can also be used by patients and carers doing haemodialysis at home, after they have had training in safe home haemodialysis.\n\n# Costs\n\nClearGuard\xa0HD caps cost £4 per pair. Haemodialysis would normally be needed 3 times a week and the caps are replaced at each dialysis session, leading to a cost of £12 a week. The company has estimated that haemodialysis patients would need a CVC for an average of 132\xa0days (estimated by the company based on Crowley et al. 2017, Kwak et al. 2012, and Hymes et al. 2017) until a more permanent form of vascular access is established. This results in a cost of £226 per person over this period.\n\nClinical experts said that the 'scrub the hub' disinfection practice is likely to continue, so alongside wipes the total cost is £247 for an average of 132\xa0days of haemodialysis.For more details, see the website for ClearGuard HD antimicrobial barrier caps.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 6 studies\n\nThe company submitted 7 studies from its literature search, including 3 full-text papers (Brunelli et al. 2018, Hymes et al. 2017 and Weiss et al. 2021) and 4 abstracts (Glennon et al. 2020, Li et al. 2019, Nitz et al. 2021 and Sibbel et al. 2020). The EAC accepted 6, excluding Nitz et al. because the intervention and outcomes did not match the scope and because it felt it did not add to the decision problem. The 3 full-text papers included a total of 10,757 participants. For full details of the clinical evidence, see section\xa04 of the assessment report in the supporting documentation on the NICE website.\n\n## The 2 prospective cluster randomised controlled trials are the most relevant to the decision problem\n\nBrunelli et al. and Hymes et al. were the most relevant to the decision problem. Both were prospective, multicentre, open-label cluster randomised controlled trials, which included 40 sites each. Outcomes varied. Brunelli et al. compared ClearGuard\xa0HD caps with Tego (needleless connectors) plus Curos (disinfecting caps). Hymes et al. compared ClearGuard\xa0HD caps with standard central venous catheter (CVC) caps.\n\n## The other studies are observational and at high risk of bias\n\nThe remaining full-text paper (Weiss et al.) described a large retrospective analysis but was considered methodologically weak. The abstracts (Glennon et al., Li et al. and Sibbel et al.) were all retrospective analyses with limited detail and did not add much more to the decision problem. The studies had largely homogenous populations. The proportion of men ranged from 51% to 53% and mean ages were 61.1\xa0years to 62.8\xa0years (except for Glennon et al., which studied children).\n\n## The pivotal trials report significantly reduced positive blood cultures\n\nMost of the studies reported bloodstream infection rates, although they did not always use the same terminology. Positive blood cultures were the primary outcome in the randomised controlled trials. They both reported significantly lower positive blood culture rates for the ClearGuard group than for the comparator group. The incidence rate ratio (IRR) in Hymes was 0.44 (p=0.01) and in Brunelli 0.37 (p=0.001).\n\n## Other outcome measures included hospital admissions and mortality\n\nRates of hospital admission were lower for the ClearGuard group in 3\xa0studies (Brunelli et al., Hymes et al. and Sibbel et al.), although this was not significant across the studies. Not many of the studies reported length of hospital stay or rates of mortality. None of them reported intravenous antibiotic use or staff time.\n\n## Nine adverse events are reported in MAUDE and none in the full-text papers\n\nThere are 9 records of adverse events on the US Food and Drug Administration's (FDA) MAUDE (Manufacturer and User Facility Device Experience) database. Two reported that the caps came off for 1 patient. Six reported that the caps became detached while the patients were asleep. One reported that the rod broke loose in the catheter. No patients were injured. None of the full-text papers reported adverse events. For full details of the adverse events, see section\xa06 of the assessment report in the supporting documentation on the NICE website.\n\n# Cost evidence\n\n## One abstract in the company's submission estimates costs\n\nAn abstract by Glennon et al. estimated total annual costs per patient for ClearGuard\xa0HD caps of £7,078, compared with £18,050 for antimicrobial lock solutions. This was estimated from 4 high-risk children having dialysis. The EAC noted that the authors did not do any sensitivity analysis to assess how robust the cost and rate were. It also noted that the applicability of the results to an adult setting was not certain.\n\n## The company's model compares ClearGuard\xa0HD caps against 4 comparators\n\nThe model included a decision tree that looked at cost savings with ClearGuard\xa0HD caps against 4 comparators:\n\nstandard CVC caps plus alcohol wipes for disinfection\n\nstandard CVC caps plus antimicrobial lock solution and alcohol wipes for disinfection\n\nTego needleless connectors plus Curos disinfecting caps (Tego plus Curos)\n\nTego needleless connectors on their own, with manual decontamination of the catheter hub with alcohol wipes.The model had a 1‑year time horizon for cost and health outcomes. For full details of the cost evidence, see section\xa04 of the assessment report in the supporting documentation on the NICE website.\n\n## The EAC's minor amendments to the model and parameters address mortality, comparators and disinfection protocols\n\nThe EAC agreed that the overall structure of the model, time horizon, population, most comparators, outcomes, and assumptions were acceptable and appropriate for the assessment. The EAC excluded the mortality branch of the model, saying that the cost of caps and cost of treating catheter-related bloodstream infections (CRBSI) was adequate without the need for the mortality branch. One comparator (Tego needleless connectors) was not considered appropriate by the EAC because it is a connector alone and therefore out of scope. The EAC provided additional analysis in the ClearGuard\xa0HD caps arm around disinfection protocols when using ClearGuard\xa0HD caps. This was based on discussions with clinical experts, who expected these disinfection protocols to still be used.\n\n## Sensitivity analysis shows cost savings are from baseline incidence rate of infection with ClearGuard, comparators and the cost of treating CRBSI\n\nThe EAC recommended that all parameters not validated by clinical data should be varied up and down by 50% in the sensitivity analysis. The EAC's results were similar to the company's. The parameters that had the largest impact on cost results were:\n\nbaseline incidence rate of infection associated with the comparator\n\nthe IRR associated with ClearGuard\n\nthe average cost of treating CRBSI.\n\n## Cost savings remain even when the CRBSI incidence rate is increased in the ClearGuard group and decreased for comparators\n\nThe company did 4 'worst case' scenario analyses, in which the base-case baseline infection rate associated with each of the 4 comparators was at the lower end of the value range. The IRR of CRBSI with ClearGuard was at the upper end of the value range. For these scenarios, based on clinical expert opinion and varying clinical estimates from published studies, the EAC recommended varying the parameters up and down by 50%, or by a range informed by the evidence (rather than up and down by the 25% suggested by the company). ClearGuard remained cost saving in all the scenarios. Another scenario reduced the cost of antimicrobial lock solution; ClearGuard remained cost saving by £418.\n\n## Threshold analysis of baseline infections shows ClearGuard\xa0HD caps are still cost saving at infection rates that are clinically unlikely\n\nThe scenario analysis results were also supported by the EAC's threshold analysis. This reported cost-neutral break-even points for different CRBSI incidence rates per 1,000 CVC\xa0days:\n\nwith standard caps (baseline rate was 0.7)\n\nwith antimicrobial lock solution (baseline rate was 0.598)\n\nwith standard caps (baseline rate was 0.63).\n\n## ClearGuard\xa0HD caps remain cost saving when the cost of standard caps is reduced\n\nExperts and committee members flagged discrepancies in agency costs of standard caps compared with the cost model, which were likely to be because of volume discounts in practice. The EAC input the reported value of £0.03 for the cost of standard caps into the model. ClearGuard remained cost saving compared with:\n\nstandard caps and wipes by £351 (from £387)\n\nstandard caps, antimicrobial lock solution and wipes by £1,096 (from £1,132).\n\n## ClearGuard\xa0HD caps are cost saving over all comparators in the EAC's updated model\n\nThe final results showed ClearGuard\xa0HD caps were cost saving compared with all the 4 comparators. The company submission reported cost savings per patient of:\n\n£408 compared with standard caps and wipes\n\n£1,167 compared with standard caps, antimicrobial lock solution and wipes\n\n£590 compared with Tego needleless connector and Curos disinfecting caps.The EAC's revised base-case cost savings, with added disinfection costs in the ClearGuard\xa0HD caps arm, showed cost savings per patient of:\n\n£387 compared with standard caps and wipes\n\n£1,132 compared with standard caps, antimicrobial lock solution and wipes\n\n£568 compared with Tego needleless connector and Curos disinfecting caps.", 'Committee discussion': "# Clinical evidence overview\n\n## Evidence shows that ClearGuard\xa0HD caps reduce the risk of catheter-related bloodstream infections\n\nThe committee noted that the literature consistently showed lower infection rates with ClearGuard compared with other options. It considered the 2 randomised controlled trials to be pivotal for decision making. While the studies had some risk of bias, the committee was reassured by the relatively large effect sizes. The way bloodstream infections were measured and reported varied across the evidence. Clinical experts said that this was a common problem in such clinical studies and also in NHS practice. The primary end point in both randomised controlled trials was positive blood cultures. The committee understood that this end point was not specifically attributable to infections arising in the central venous catheters (CVC), but nevertheless it was satisfied by the overall weight of evidence that ClearGuard\xa0HD caps are likely to reduce the risk of catheter-related bloodstream infections (CRBSI).\n\n## The evidence is generalisable to children\n\nA clinical expert discussed the potential benefit in children who may need a central line long term, and for whom recurrent infections could limit treatment options in the future. The clinical experts said they considered the incidence rates in the adult studies to be comparable and generalisable to children. They also highlighted some evidence of a benefit for children in the Glennon et al. study, which was in high-risk children, although this evidence is lower quality because it was a retrospective analysis with limited detail and reported as an abstract only. On balance, the committee concluded that the evidence in adults could be generalised to children.\n\n## ClearGuard\xa0HD caps may benefit people who have haemodialysis at home\n\nClinical experts said that more CVCs were now being used, rather than surgical fistulas, because of the COVID‑19 pandemic. They agreed that the aim was for more people of all ages to use home dialysis. But no evidence was identified on using ClearGuard\xa0HD caps at home. The committee felt that they could benefit people having dialysis at home and was encouraged by positive feedback provided by the company from users about their usability. Clinical experts said that in their experience these patients are motivated, and so they did not see any barriers to using the caps safely and effectively at home, as long as people were trained in how to use them.\n\n# Safety considerations\n\n## ClearGuard\xa0HD caps are safe and compatible with central lines used in clinical practice\n\nThe committee discussed the ClearGuard\xa0HD caps' compatibility with central lines. It was satisfied that the only central line that they were incompatible with was one that is seldom used. The company confirmed that the caps had been shown to be compatible with other line lock solutions, as part of US Food and Drug Administration (FDA) benchmarking assessments, including heparin-saline, saline and citrate. The committee discussed 1 adverse event reported on the FDA's MAUDE (Manufacturer and User Facility Device Experience) database, of rod detachment. The committee was reassured by the company that the cap had been examined, and that the problem was not replicable and has not been reported before or since.\n\n## The long-term implications for chlorhexidine allergy should be monitored\n\nThe rod and cap threads of ClearGuard\xa0HD caps are coated in chlorhexidine acetate, a broad-spectrum antimicrobial agent. Some people are allergic to chlorhexidine, although according to the clinical experts, this is unusual. The committee was satisfied that the device instructions for use clearly state it should not be used for people with known allergies to chlorhexidine. Clinical experts reported that in their experience allergy shows more commonly as a skin reaction, although people can have anaphylactic reactions to chlorhexidine. The committee was concerned that we do not yet know the long-term effects of exposure to chlorhexidine acetate, and if people could become sensitised to it. Because of this, the committee asked the company to proactively find out about adverse events and report them to the Medicines and Healthcare products Regulatory Agency (MHRA). The committee advised the company to provide a plan to monitor chlorhexidine sensitisation or allergies to address this gap in understanding for the future.\n\n# NHS considerations overview\n\n## The evidence is generalisable to NHS practice\n\nThe clinical evidence base was all from the US and North America. The clinical experts said that the baseline rates of catheter-related bloodstream infection in the US studies were broadly comparable to UK NHS practice. A difference between the US and UK is that high-concentrate citrate is used as a catheter lock solution for adults in the UK. But it is not approved for use in this way in the US and therefore was not included in the evidence. The committee agreed that, although citrate's effect on reducing infection rates was uncertain, it was likely to be comparable to the antimicrobial line lock solution comparator in the evidence. The committee concluded that the evidence was broadly generalisable to NHS practice and was a reasonable basis for decision-making purposes.\n\n## No significant changes to infrastructure are needed\n\nThe clinical experts said that the 'scrub the hub' disinfection practice would continue regardless of the cap used during haemodialysis. The external assessment centre (EAC) acknowledged this in its minor amendments to the company model. The committee was satisfied that this accurately showed how the caps would be used in NHS practice. It agreed that no additional changes to NHS infrastructure would be needed to use ClearGuard\xa0HD caps in the NHS.\n\n# Cost evidence overview\n\n## The cost model for ClearGuard\xa0HD caps is well constructed and shows cost savings compared with all comparators\n\nThe cost model was well constructed, and the minor changes made by the EAC were appropriate and accepted by the committee. The committee concluded that the comprehensive sensitivity and scenario analyses supported cost savings compared with all comparators.\n\n## The model's main cost drivers are the comparators' infection incidence rate and ClearGuard\xa0HD caps' infection rate ratio\n\nThe main cost savings were from reduced CRBSI incidence rate. The committee discussed the uncertainty around incidence levels across comparators but concluded that the evidence was strong enough and backed by clinical expert opinion, indicating that there were likely to be costs savings in practice.\n\n## Sensitivity analysis adequately addresses the uncertainty around outcomes and comparators\n\nThe end points used in the pivotal clinical studies (positive blood cultures) introduced some uncertainty in the outcomes. However, the committee was satisfied that the EAC's extra sensitivity analysis adequately addressed the likely variation in incidence. There was some uncertainty around whether the model results were applicable to the NHS, when the evidence used to inform it did not include the comparator high-concentrate citrate, which is used in the UK but not in the US (see section\xa04.6). The clinical experts said infection rates with high-concentrate citrate were likely to be comparable to those with the antimicrobial line lock solution comparator used in the scenario analyses, which showed that even at low rates of baseline infection, ClearGuard\xa0HD caps were cost saving. The EAC's sensitivity analyses also showed cost savings at even lower rates of infection. The committee therefore concluded that the sensitivity analysis adequately addressed uncertainty around this comparator.\n\n# Cost savings\n\n## ClearGuard\xa0HD caps are likely to be cost saving compared with all comparators\n\nComprehensive scenario analyses, including 'worst case' scenarios, showed ClearGuard\xa0HD caps to be cost saving compared with all comparators. Additional threshold analysis reported that they were cost neutral at infection thresholds that clinical experts advised were clinically unlikely because they were so low. The committee was satisfied that the cost modelling evidence was robust and shows ClearGuard\xa0HD caps are cost saving compared with all comparators.\n\nThe EAC revised the base-case cost savings: it added disinfection costs in the ClearGuard\xa0HD caps arm, and reduced standard caps costs because of volume discount. This resulted in cost savings per patient of:\n\n£351 compared with standard caps and wipes\n\n£1,096 compared with antimicrobial line lock solution, standard caps and wipes\n\n£568 compared with Tego needleless connectors and Curos disinfecting caps."}
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https://www.nice.org.uk/guidance/mtg62
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Evidence-based recommendations on ClearGuard HD antimicrobial barrier caps for preventing haemodialysis catheter-related bloodstream infections.
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dd7041541f9c0070451b79f6ed2d027a11c9a8fd
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nice
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Pelvic floor dysfunction: prevention and non-surgical management
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Pelvic floor dysfunction: prevention and non-surgical management
This guideline covers the prevention, assessment and non-surgical management of pelvic floor dysfunction in women aged 12 and over. It aims to raise awareness and help women to reduce their risk of pelvic floor dysfunction. For women who have pelvic floor dysfunction, the guideline recommends interventions based on their specific symptoms.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
What is pelvic floor dysfunction?
Pelvic floor dysfunction is a condition in which the pelvic floor muscles around the bladder, anal canal, and vagina do not work properly. This guideline covers the following symptoms and disorders when they are associated with pelvic floor dysfunction:
urinary incontinence
emptying disorders of the bladder
faecal incontinence
emptying disorders of the bowel
pelvic organ prolapse
sexual dysfunction
chronic pelvic pain.
The 3 most common and definable symptoms are urinary incontinence, faecal incontinence and pelvic organ prolapse.
Who does this guideline cover?
This guideline covers young women aged 12 to 17 and women aged 18 and over. When recommendations refer to 'women' without specifying an age range, that means they cover this entire population.
# Raising awareness of pelvic floor dysfunction for all women
When producing resources on pelvic floor dysfunction, include:
the symptoms of pelvic floor dysfunction
visual aids to help identify potential causes of symptoms (for example, by showing the anatomy of pelvic organs)
when to get help
where to go for help (including self-referral to community-based multidisciplinary teams, where available)
an outline of risk factors, prevention and management options (including non-surgical management and lifestyle changes).
Consider providing information on pelvic floor dysfunction in the following formats and settings:
Formats
print, broadcast and online adverts
information given alongside over-the-counter continence products
leaflets in the community (for example, at GP surgeries, family planning clinics and exercise classes)
videos and information on social media
interactive online resources (for example, the NHS app).
Settings
as part of general exercise programmes
in leaflets on gynaecological cancer treatment or gynaecological surgery (such as hysterectomies)
as part of existing programmes, for example, cervical screening or national or local NHS health checks
contact with a healthcare practitioner with pelvic floor dysfunction knowledge
giving advice to people with contacts in the community (such as exercise and fitness instructors and teachers), so they can provide information on pelvic floor dysfunction themselves
-n community and health trust websites
information provided by healthcare charities.
Tailor information and communication about pelvic floor dysfunction for different age groups and characteristics (for example, pregnancy).
Consider covering pelvic floor dysfunction in the syllabus for healthcare and other professionals, such as trainee nurses, physiotherapists, doctors, midwives and teachers.
Local authorities should consider designing pelvic floor dysfunction information programmes for specific communities when there is evidence of healthcare inequalities (for example, in how services are provided and accessed, or rates of uptake). This can be done by:
finding more effective ways to provide information (for example, by attending community meetings)
involving members of the community as champions
using webinars to reach women who are unable to attend meetings in person.
For women using maternity services, include information on pelvic floor dysfunction, how to prevent it, the symptoms, and how to access local services:
in the booking information pack or patient portal
at all midwife consultations and reviews
at all consultations with an obstetrician
in hospital postnatal wards.
Health visitors, midwives and GPs should discuss pelvic floor dysfunction with women at each postnatal contact.
Teach young women (between 12 and 17) in education settings about pelvic floor anatomy, pelvic floor muscle exercises and how to prevent pelvic floor dysfunction.
Provide information on pelvic floor dysfunction for older women within primary and intermediate care services, and within care homes and supported living communities. This could be done:
when women ask for advice about perimenopause and menopause
as part of general health assessments
as part of comprehensive geriatric health assessments.
For guidance on tailoring communication, information and shared decision making for people using health and social care services, see the:
NICE guideline on shared decision making
NICE guideline on patient experience in adult NHS services
NICE guideline on babies, children and young people's experience of healthcare
NICE guideline on people's experience in adult social care services
NHS Accessible Information Standard (in particular, for guidance on making information accessible).
For guidance on planning and developing digital and mobile tools to provide tailored information, see the NICE guideline on behaviour change: digital and mobile health interventions.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on raising awareness of pelvic floor dysfunction for all women .
Full details of the evidence and the committee's discussion are in evidence review A: community information strategies.
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# Risk factors for pelvic floor dysfunction
When discussing the risk of pelvic floor dysfunction with women, advise them that their risk is higher with any of the characteristics in box 1.
Modifiable risk factors
A body mass index (BMI) over 25 kg/m2
Smoking
Lack of exercise
Constipation
Diabetes
Non-modifiable risk factors
Age (risk increases with increasing age)
Family history of urinary incontinence, overactive bladder or faecal incontinence
Gynaecological cancer and any treatments for this
Gynaecological surgery (such as a hysterectomy)
Fibromyalgia
Chronic respiratory disease and cough (chronic cough may increase the risk of faecal incontinence and flatus incontinence)
Related to pregnancy:
Being over 30 years when having a baby
Having given birth before their current pregnancy
Related to labour:
Assisted vaginal birth (forceps or vacuum)
A vaginal birth when the baby is lying face up (occipito-posterior)
An active second stage of labour taking more than 1 hour
Injury to the anal sphincter during birth
For pregnant women with pelvic floor dysfunction that started before or during their pregnancy, advise them that there is an increased risk that their symptoms will get worse during their pregnancy and that they may persist after this (for preventative and management strategies, see the section on preventing pelvic floor dysfunction and the section on non-surgical management of pelvic floor dysfunction.
For more detailed guidance on all the benefits and risks of vaginal and caesarean birth (including urinary incontinence, faecal incontinence and injury to the anal sphincter), see the section on benefits and risks of caesarean and vaginal birth in the NICE guideline on caesarean birth.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk factors for pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in:
evidence review B: risk factors for pelvic floor dysfunction
evidence review C: coexisting long-term conditions and pelvic floor dysfunction
evidence review D: prediction tools for pelvic floor dysfunction.
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# Preventing pelvic floor dysfunction
## Physical activity and diet
Advise women that physical activity and a healthy diet can help prevent pelvic floor dysfunction.
On levels of physical activity, advise women to follow the standard advice, as covered by:
the UK Chief Medical Officers' physical activity guidelines
the NICE guideline on physical activity: brief advice for adults in primary care
the NICE guideline on physical activity: walking and cycling.
On diet, advise women to:
have a balanced diet (following Public Health England's Eatwell Guide), and in particular to eat enough fibre, because this can improve stool consistency and prevent symptoms of faecal incontinence
ensure they have an appropriate fluid intake, increasing or decreasing it if needed.
For guidance on training to help health and social care practitioners recognise and respond to diet, physical activity and hydration needs in older people with social care needs and multiple long-term conditions, see the section on training health and social care practitioners in the NICE guideline on older people with social care needs and multiple long-term conditions.
## Weight loss, stopping smoking, managing constipation and diabetes
For guidance on weight loss, see the NICE guideline on obesity, and (if relevant) the NICE guideline on weight management before, during and after pregnancy.
Give advice on stopping smoking, using the NICE guideline on tobacco.
For guidance on managing constipation in young people, see the NICE guideline on constipation in children and young people.
For guidance on managing diabetes, see the NICE guidelines on:
type 1 diabetes in adults
type 2 diabetes in adults
diabetes (type 1 and type 2) in children and young people.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity and diet and other modifiable risk factors .
Full details of the evidence and the committee's discussion are in:
evidence review B: risk factors for pelvic floor dysfunction
evidence review E: lifestyle factors for the prevention of pelvic floor dysfunction.
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## Pelvic floor muscle training
Encourage women of all ages to do pelvic floor muscle training, and explain that it helps to prevent symptoms of pelvic floor dysfunction.
Encourage women to continue pelvic floor muscle training throughout their life, because long-term training continues to help prevent symptoms.
Encourage women who are pregnant or who have recently given birth to do pelvic floor muscle training, and explain that it helps prevent symptoms of pelvic floor dysfunction.
Consider a 3‑month programme of supervised pelvic floor muscle training:
from week 20 of pregnancy, for pregnant women who have a first-degree relative with pelvic floor dysfunction
during postnatal care, for women who have experienced any of the following risk factors during birth:
assisted vaginal birth (forceps or vacuum)
a vaginal birth when the baby is lying face up (occipito-posterior)
injury to the anal sphincter.
Before discharging women from maternity services, and during routine postnatal care, encourage them to do pelvic floor muscle training.
When designing a pelvic floor muscle training programme, see the NICE guideline on behaviour change for relevant recommendations:
recommendation 7: use proven behaviour change techniques when designing interventions
recommendation 8: ensure interventions meet individual needs.
Pelvic floor muscle training programmes should be supervised by a physiotherapist or other healthcare professional with the appropriate expertise in pelvic floor muscle training.
Supervision should involve:
assessing the woman's ability to perform a pelvic floor contraction and relaxation
tailoring the pelvic floor muscle training programme to the woman's ability to perform a pelvic floor contraction and relaxation, any discomfort felt, and her individual needs and training goals
encouraging the woman to complete the course, because this will help to prevent and manage symptoms.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pelvic floor muscle training for preventing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.
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# Communicating with and providing information to women with pelvic floor dysfunction
## Communication
Agree consultation formats (for example, in person, video or telephone) with each woman with pelvic floor dysfunction, taking into account the need for physical examinations.
When discussing pelvic floor dysfunction:
be aware of potential cultural sensitivities
be aware that women may feel embarrassed discussing their symptoms, and they may believe that healthcare professionals will also be embarrassed
take particular care around terminology:
for example, avoid using 'faeces' if a woman better understands or prefers 'poo'
be aware that women may not use the precise technical terms for parts of their pelvic anatomy
tailor information to each woman's level of understanding of anatomy and of the causes of pelvic floor dysfunction.
For general guidance on communicating with patients, see the:
section on communication in the NICE guideline on patient experience in adult NHS services
section on communication and information in the NICE guideline on babies, children and young people's experience of healthcare.
When providing information to women with pelvic floor dysfunction and cognitive impairment, ask them if they want their family, carers and other people to be involved, to support them (as appropriate) and to help reinforce and support management plans.
## Information for women with pelvic floor dysfunction
Help women with pelvic floor dysfunction to understand their condition by giving clear and concise information. This should include:
the anatomy of the pelvic floor and pelvic organs (using visual aids when helpful)
possible causes of their symptoms
management options and possible outcomes
an explanation that interventions will be focused on their symptoms, rather than on pelvic floor dysfunction in general
-ther medical conditions and treatments that can cause or exacerbate their symptoms (see risk factors for pelvic floor dysfunction).
Tailor information to each woman's age, level of understanding and circumstances, because pelvic floor dysfunction can affect women differently at different stages of life. For example:
young women (between 12 and 17)
women who are pregnant or who have given birth
women in perimenopause or postmenopause
women with comorbidities or frailty.
Consider digital information sources (for example, apps or videos) to support women with pelvic floor dysfunction (see guidance on developing digital tools in the NICE guideline on behaviour change: digital and mobile health interventions).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communicating with and providing information to women with pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in:
evidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences)
evidence review H: information provision about management of pelvic floor dysfunction (most effective ways).
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# Assessment in primary care
At initial assessment in primary care (which may include assessments by physiotherapists, bladder and bowel team members and continence advisors), take a general history from the woman about current and past symptoms or disorders associated with pelvic floor dysfunction, such as:
urinary incontinence
emptying disorders of the bladder
faecal incontinence
emptying disorders of the bowel
pelvic organ prolapse
sexual dysfunction
chronic pelvic pain.
Depending on the symptoms described, carry out a focused history, clinical examination and investigations to exclude other causes, such as:
pelvic masses
neurological disease
urinary tract infection
adverse effects of medication
diabetes
cancer (for further information, see the NICE guideline on suspected cancer: recognition and referral)
fistula
inflammatory bowel or bladder conditions
endometriosis
mobility and cognitive impairment.
Ask women who have recently given birth about symptoms of pelvic floor dysfunction during routine postnatal care, in hospital and in the community.
For women who are taking multiple medications, conduct a medication review. For guidance on how to do this, see the section on medication review in the NICE guideline on medicines optimisation.
Depending on the symptoms and the woman's preferences and circumstances, consider other clinical examinations. For example:
inspecting the woman's vulva and vagina for atrophy
asking them to bear down, to check for visible vaginal or rectal prolapse
rectal examination to check for impaction, for women who are at risk of this and who cannot give an accurate history of their symptoms (for example, women with cognitive impairments or dementia).
For more guidance on assessing urinary incontinence and pelvic organ prolapse, see the NICE guideline on urinary incontinence and pelvic organ prolapse in women. (The recommendations in this guideline may also be relevant for women under 18.)
If the woman has symptoms of faecal incontinence, follow the recommendations on baseline assessment in the NICE guideline on faecal incontinence. (The recommendations in this guideline may also be relevant for women under 18.)
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment in primary care .
Full details of the evidence and the committee's discussion are in:
evidence review I: assessment in non-specialist care
evidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).
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# Non-surgical management of pelvic floor dysfunction
## Community-based multidisciplinary teams
After initial assessment in primary care, consider a community-based multidisciplinary team approach for the management of pelvic floor dysfunction.
The community-based multidisciplinary team (or teams) should have members with competencies related to assessing and managing pelvic floor dysfunction, such as:
carrying out initial assessments (see the section on assessment in primary care)
assessments of mobility and personal care issues related to pelvic floor dysfunction
awareness of the psychosocial implications of pelvic floor dysfunction
identifying risk factors
interpreting urinalysis
conducting and interpreting bladder scans to measure post-void residual volume
conducting digital assessments of the pelvic floor and pelvic floor muscle contraction and relaxation
training women and their families and carers in behavioural interventions for pelvic floor dysfunction (such as bladder retraining)
prescribing and reviewing medications, and knowledge of interactions and side effects related to pelvic floor dysfunction
supervising a pelvic floor muscle training programme (see the section on supervising pelvic floor muscle training)
managing the use of pessaries and intravaginal devices
training and supporting other care providers to assess and manage pelvic floor dysfunction (for example, carers or care home workers)
identifying which women need referral to specialist care or other services (for young women aged 12 to 17, this may include referral to paediatric services or adolescent gynaecology services).
Discuss and agree a management plan with women who have suspected or confirmed pelvic floor dysfunction.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on community-based multidisciplinary teams .
Full details of the evidence and the committee's discussion are in evidence review R: community-based multidisciplinary teams.
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## Lifestyle changes
When discussing lifestyle changes with women who have pelvic floor dysfunction:
motivate them to make changes by focusing discussions on how this will improve their symptoms
give them regular encouragement to keep up the changes, because it may take weeks or months before they notice a benefit.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on encouraging women to make lifestyle changes .
Full details of the evidence and the committee's discussion are in evidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).
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Advise women with a body mass index (BMI) over 30 kg/m2 that weight loss can help with the following symptoms associated with pelvic floor dysfunction:
urinary incontinence
-veractive bladder
pelvic organ prolapse.
For guidance on weight loss, see the NICE guideline on obesity, and (if relevant) the NICE guideline on weight management before, during and after pregnancy.
Refer women for weight loss support following the NICE guideline on lifestyle services for weight management in overweight or obese adults and the NICE guideline on lifestyle services for weight management in overweight or obese children and young people.
Do not wait for women to lose weight before starting other pelvic floor dysfunction management options.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on weight loss .
Full details of the evidence and the committee's discussion are in evidence review J: weight loss interventions.
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For all women with pelvic floor dysfunction:
explain how a balanced diet (following Public Health England's Eatwell Guide) and appropriate fluid intake can improve stool consistency, which can help with their symptoms
follow guidance on maintaining healthy bowel habits in recommendation 1.3.2 of the NICE guideline on faecal incontinence in adults (including for women under 18 or with symptoms other than faecal incontinence).
Advise women with overactive bladder or urinary incontinence associated with pelvic floor dysfunction to:
reduce their caffeine intake
modify their fluid intake (increasing if it is too low, decreasing if it is too high).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet .
Full details of the evidence and the committee's discussion are in evidence review K: dietary factors for the management of symptoms.
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For women who are doing supervised pelvic floor muscle training and want to be physically active, advise them that supervised exercise (for example, yoga) may help with their symptoms.
Advise women with pelvic floor dysfunction that there is no evidence to say that unsupervised physical activity (such as walking or swimming) will improve or worsen their symptoms.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity .
Full details of the evidence and the committee's discussion are in evidence review L: physical activity for the management of symptoms.
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## Pelvic floor muscle training
Consider a programme of supervised pelvic floor muscle training for at least 4 months for women with symptomatic pelvic organ prolapse that does not extend greater than 1 cm beyond the hymen upon straining.
Offer a programme of supervised pelvic floor muscle training for at least 3 months to women (including pregnant women) with stress urinary incontinence or mixed urinary incontinence.
Consider a programme of supervised pelvic floor muscle training for at least 4 months for women with faecal incontinence and coexisting pelvic organ prolapse.
For women who are doing a supervised pelvic floor muscle training programme, offer the choice of group or individual sessions.
See the recommendations on supervising pelvic floor muscle training in the section on preventing pelvic floor dysfunction.
When providing a programme of pelvic floor muscle training, offer at least 1 review to assess progress during the programme, and 1 review at the end of the programme.
For women who are unable to perform an effective pelvic floor muscle contraction, consider supplementing pelvic floor muscle training with biofeedback techniques, electrical stimulation or vaginal cones.
If the programme is beneficial, advise women to continue pelvic floor muscle training after the supervised programme ends.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pelvic floor muscle training for managing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review M: pelvic floor muscle training for the management of symptoms.
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## Intravaginal devices and pessaries
Consider a trial of intravaginal devices for women with urinary incontinence, only if other non-surgical options have been unsuccessful.
Consider pessaries for women who have symptomatic pelvic organ prolapse.
Before starting treatment with a pessary for women with symptomatic pelvic organ prolapse:
discuss with the woman how a pessary could help, and explain it may not help with their urinary and bowel symptoms
explain that a pessary will only help with their pelvic organ prolapse symptoms while it is in place, and the symptoms will come back when it is removed
explain that reducing the prolapse with a pessary may cause new stress urinary incontinence.See recommendation 1.7.8 in the NICE guideline on urinary incontinence and pelvic organ prolapse for further discussions to have with women before starting treatment with a pessary.
If women using a pessary experience new stress urinary incontinence, offer them a choice of treatment for the incontinence or removal of the pessary.
For more guidance on pessaries for women with symptomatic pelvic organ prolapse, see the section on pessaries in the NICE guideline on urinary incontinence and pelvic organ prolapse.
For women who are self-managing their intravaginal device or pessary, explain how they can seek advice from a healthcare provider if they have problems.
For guidance on reviewing pessaries for women who are at risk of complications, for example because of a physical or cognitive impairment, see recommendation 1.7.9 in the NICE guideline on urinary incontinence and pelvic organ prolapse.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intravaginal devices and pessaries .
Full details of the evidence and the committee's discussion are in evidence review N: physical devices for the management of pelvic floor dysfunction.
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## Psychological interventions
Discuss the psychological impact of their symptoms with women who have pelvic floor dysfunction. Take account of this impact when developing a management plan.
For more guidance on psychological management, see the:
NICE guideline on antenatal and postnatal mental health
NICE guideline on depression in adults with a chronic physical health problem.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological interventions .
Full details of the evidence and the committee's discussion are in evidence review O: psychological therapy for women with pelvic floor dysfunction.
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## Behavioural approaches
Offer supported bladder retraining (combined with other interventions, such as pelvic floor muscle training) to women with urinary frequency, urgency or mixed incontinence.
For women with faecal incontinence, see the section on diet, bowel habit and toilet access in the NICE guideline on faecal incontinence in adults. (The recommendations in this guideline may also be relevant for women under 18.)
When choosing a behavioural intervention, take into account that prompted toileting and habit training may be particularly suitable for women with cognitive impairment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on behavioural approaches .
Full details of the evidence and the committee's discussion are in evidence review P: behavioural approaches to the management of symptoms.
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## Medicines
Do not offer vaginal diazepam to treat pelvic floor dysfunction, even for women with high muscle tone.
For guidance on medicines for urinary incontinence and faecal incontinence associated with pelvic floor dysfunction, see the NICE guideline on urinary incontinence and pelvic organ prolapse in women and the section on medication in the NICE guideline on faecal incontinence in adults. (The recommendations on medicines in these guidelines may also be relevant for women under 18.)
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on medicines .
Full details of the evidence and the committee's discussion are in evidence review Q: pharmacological management.
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# Terms used in this guideline
## Pelvic floor muscle training
Exercise to improve pelvic floor muscle strength, endurance, power, relaxation, or a combination of these. For more information, see the definition of pelvic floor muscle training in the International Continence Society and International Urogynecological Association's joint report on the terminology for the conservative and non-pharmacological management of female pelvic floor dysfunction.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## How to provide pelvic floor muscle training
What is the most effective way to provide pelvic floor muscle training (covering the type of training, the timing, and who should supervise it), to improve adherence and prevent pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.
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## Pelvic floor muscle training for preventing pelvic floor dysfunction in young women
Is pelvic floor muscle training for young women (between 12 and 17 years) effective in preventing pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.
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## Pelvic floor muscle training for preventing pelvic floor dysfunction during pregnancy for women in higher-risk groups
How effective is pelvic floor muscle training in preventing pelvic floor dysfunction during pregnancy in women who are in higher-risk groups?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.
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## Lifestyle factors to reduce the risk of pelvic floor dysfunction
What lifestyle factors reduce the risk of developing pelvic floor dysfunction (diet, reducing carbonated drink and caffeine intake)?
For a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity and diet and other modifiable risk factors .
Full details of the evidence and the committee's discussion are in evidence review E: lifestyle factors for the prevention of pelvic floor dysfunction.
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## Prediction tools
What is the effectiveness of prediction tools for identifying women who are at risk of pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review D: prediction tools for pelvic floor dysfunction.
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## Pelvic floor muscle training for preventing pelvic floor dysfunction in older women
Is pelvic floor muscle training effective in preventing pelvic floor dysfunction for older women (aged 65 and over), and women in the perimenopausal or postmenopausal phases?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.
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## Coexisting long-term conditions
What coexisting long-term conditions (for example, chronic respiratory disorders) are associated with a higher risk of pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review C: coexisting long-term conditions and pelvic floor dysfunction.
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# Other recommendations for research
## Lifestyle factors to reduce the risk of pelvic floor dysfunction
What are the long-term effects of different types, intensities and frequencies of physical activity for preventing symptoms associated with pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity and diet and other modifiable risk factors .
Full details of the evidence and the committee's discussion are in evidence review E: lifestyle factors for the prevention of pelvic floor dysfunction.
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## Universal postnatal pelvic floor muscle training for preventing pelvic floor dysfunction
Is universal postnatal pelvic floor muscle training effective in preventing pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.
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## Pelvic floor muscle training for preventing bowel symptoms associated with pelvic floor dysfunction
How effective is pelvic floor muscle training in preventing bowel symptoms associated with pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.
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## Weight loss for managing pelvic floor dysfunction
Can weight loss reduce symptoms of pelvic floor dysfunction in women who are overweight or obese?
For a short explanation of why the committee made the recommendation for research, see the rationale section on weight loss .
Full details of the evidence and the committee's discussion are in evidence review J: weight loss interventions.
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## Diet for managing pelvic floor dysfunction
What changes in diet can improve symptoms associated with pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on diet .
Full details of the evidence and the committee's discussion are in evidence review K: dietary factors for the management of symptoms.
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## Weight training to improve symptoms of pelvic floor dysfunction
How effective is weight training at improving symptoms associated with pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity .
Full details of the evidence and the committee's discussion are in evidence review L: physical activity for the management of symptoms.
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## Unsupervised physical activity to improve symptoms of pelvic floor dysfunction
How effective is unsupervised physical activity (such as walking or swimming) at improving symptoms associated with pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity .
Full details of the evidence and the committee's discussion are in evidence review L: physical activity for the management of symptoms.
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## Psychological interventions to manage symptoms of pelvic floor dysfunction
How effective are psychological interventions (either on their own or combined with other interventions) in the management of pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on psychological interventions .
Full details of the evidence and the committee's discussion are in evidence review O: psychological therapy for women with pelvic floor dysfunction.
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## Raising awareness about pelvic floor dysfunction
Are community-based strategies effective in raising awareness about the prevention of pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on raising awareness of pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review A: community information strategies.
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## Information valued by young women with pelvic floor dysfunction
What are the experiences and information needs of young women (between 12 and 17 years) with pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).
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## Effective ways of supporting women to start and continue interventions for pelvic floor dysfunction
What is the best way to support women to start and continue interventions for pelvic floor dysfunction (for example, apps, decision aids, or behavioural change techniques)?
For a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review H: information provision about management of pelvic floor dysfunction (most effective ways).
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## Effective ways of providing information to women with pelvic floor dysfunction
What are best ways to provide information about pelvic floor dysfunction to young women (between 12 and 17 years), and to groups defined by protected characteristics under the Equality Act?
For a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review H: information provision about management of pelvic floor dysfunction (most effective ways).
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## Medicines for pelvic floor dysfunction
Is vaginal oestrogen effective at treating the symptoms of pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on medicines .
Full details of the evidence and the committee's discussion are in evidence review Q: pharmacological management.
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## Community-based multidisciplinary pelvic floor dysfunction teams
What roles are needed in a community-based multidisciplinary pelvic floor dysfunction team?
For a short explanation of why the committee made the recommendation for research, see the rationale section on community-based multidisciplinary teams .
Full details of the evidence and the committee's discussion are in evidence review R: community-based multidisciplinary teams.
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## Intravaginal devices and pessaries combined with pelvic floor muscle training for managing pelvic floor dysfunction
How effective is a pessary or intravaginal device combined with pelvic floor muscle training for managing pelvic floor dysfunction, compared with pelvic floor muscle training alone?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for managing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review M: pelvic floor muscle training for the management of symptoms.
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## Virtual and in-person contact time for pelvic floor muscle training
How effective is virtual contact with a trainer, compared with in-person contact, for pelvic floor muscle training?
For a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for managing pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review M: pelvic floor muscle training for the management of symptoms.
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## Anal plug devices and rectal irrigation for the management of bowel symptoms in women with pelvic floor dysfunction
How effective are anal plug devices and rectal irrigation for bowel symptoms in women with pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on intravaginal devices and pessaries .
Full details of the evidence and the committee's discussion are in evidence review N: physical devices for the management of pelvic floor dysfunction.
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## Multiple pregnancy as an independent risk factor for pelvic floor dysfunction
Is multiple pregnancy an independent risk factor for pelvic floor dysfunction?
For a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction .
Full details of the evidence and the committee's discussion are in evidence review B: risk factors for pelvic floor dysfunction.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Raising awareness of pelvic floor dysfunction for all women
Recommendations 1.1.1 to 1.1.11
## Why the committee made the recommendations
The evidence was limited to 1 study, so most of the recommendations were based on the committee's knowledge and experience. However, this study did show that teaching pelvic floor health in school improved young women's understanding of their pelvic floor anatomy.
Improving women's knowledge of pelvic floor health is important because this increases the chance they will take action to prevent pelvic floor dysfunction (for example, through lifestyle changes and pelvic floor muscle training). The range of communication formats and strategies recommended is broad, because pelvic floor dysfunction can happen to any woman, so different strategies will be more effective for different groups of women. The committee discussed what the content of this information should be and decided that this would need to be tailored to the individual and the situation in which it is provided (for example, they noted that information provided during school lessons would likely have a different focus to information provided at a local community group). However, to ensure information is accurate and useful, it should include the topics highlighted in recommendation 1.1.1. The committee acknowledged that there can be groups of women that experience inequalities (for example, in access to services). When there is evidence of this, the committee noted that local authorities should consider designing information programmes that increase awareness of the condition with the aim of advancing equality in healthcare provision and fostering good relations with communities.
Healthcare professionals themselves need to understand enough about pelvic floor dysfunction to discuss it with women. In the committee's experience, this is not consistently taught during training, so they made a recommendation that this should be added to the syllabus for relevant professionals.
The committee believed it was particularly important to raise awareness in maternity services; this is when symptoms can first occur, when risk factors can be identified and when prevention strategies can be started. The recommendations could lead to midwives providing information about pelvic floor dysfunction many times during a woman's pregnancy. However, the committee believe this is reasonable, because it gives the midwife an opportunity to normalise the topic and time to discuss it in detail. Normalisation is important, because embarrassment often gets in the way of discussions about pelvic floor dysfunction. The committee also noted that frequent discussions would reinforce the message and improve adherence to prevention or management, which is key to their effectiveness.
Because of the sparsity of evidence, and the potential benefits of raising awareness of pelvic floor dysfunction, the committee made a recommendation for research on raising awareness about pelvic floor dysfunction.
## How the recommendations might affect practice and services
Pelvic floor dysfunction is not currently covered in the school curriculum. However, sex and relationship education is already a compulsory part of the curriculum, and pelvic floor dysfunction could be covered as part of these classes.
School nurses and nurses in other education settings could also be involved in raising awareness of pelvic floor dysfunction. There are already resources available on this topic (for example, this video on pelvic floor by NHS Highland).
Return to recommendations
# Risk factors for pelvic floor dysfunction
Recommendations 1.2.1 to 1.2.3
## Why the committee made the recommendations
Interpreting the evidence was difficult, because there was a lot of variation in how the studies were done, the way risk factors were defined, and which symptom each risk factor affected. However, the evidence did consistently reflect the committee's experience.
The evidence suggested a number of modifiable and non-modifiable risk factors. The committee recommended advising women of these, so that they are aware of their risks, and (for modifiable factors) they can take steps to reduce them. For example, the evidence showed that constipation is a risk factor for pelvic floor dysfunction (the committee believe that this is because of the straining involved). For women with constipation, there are recommendations on diet to help with constipation and reduce their risk of pelvic floor dysfunction (see recommendation 1.3.3 and recommendation 1.6.9).
Although some risk factors are non-modifiable (such as age or familial history), the committee agreed that it is still useful for women to be told about these. This is because if women know about their risks, they may be encouraged to reduce any modifiable risk factors and use preventative interventions (such as pelvic floor muscle training). Women with some of these risk factors will also be offered supervised pelvic floor muscle training (see the recommendations on pelvic floor muscle training).
For the risk factors related to vaginal birth, the committee discussed whether more information was needed in the recommendations, because these risk factors affect the decision to have a vaginal or caesarean birth. However, women consider many other factors beyond pelvic floor dysfunction when deciding on mode of birth. The committee decided not to make further recommendations on this, because the NICE guideline on caesarean section goes into much more detail on the benefits and risks of caesarean and vaginal birth.
Due to the evidence being unclear, the committee made a recommendation for research on whether multiple pregnancy is an independent risk factor for pelvic floor dysfunction.
There was evidence for a variety of physical coexisting conditions associated with pelvic floor dysfunction. There was variation in the quality of the evidence because in some studies, the inclusion criteria were not clearly described. In addition, although some conditions were shown to increase the risk of pelvic floor dysfunction, there was uncertainty around how large this increase is. Because of this, the committee did not list every condition identified in the studies. Instead, they highlighted the conditions that have a direct impact on the pelvic floor muscles, when the risk of pelvic floor dysfunction in the evidence aligns with their own experience.
For some conditions that may increase the risk of pelvic floor dysfunction (such as hypermobility, neurological disease and mental health problems), there was little evidence on their effect. In addition, there was only limited evidence on the effect of respiratory disease and chronic cough on the full range of symptoms, and this is particularly important because of the COVID‑19 pandemic. A recommendation for research on coexisting long-term conditions was made to address these evidence gaps.
There are groups of women who have an increased risk of developing pelvic floor dysfunction. There are also interventions that can help prevent pelvic floor dysfunction (see the section on physical activity and diet and the section on pelvic floor muscle training). Because of this, it would be useful to have an effective tool for predicting pelvic floor dysfunction so that women at higher risk can be prioritised for pelvic floor muscle training programmes. However, there was no evidence on the effectiveness of existing tools. The committee agreed this was an important area for further study, and made a recommendation for research on prediction tools.
## How the recommendations might affect practice
The recommendations will standardise the information and advice that is provided to women, to enable better shared decision making. There are no significant costs associated with this, because providing information is already standard practice. The costs of the time taken to give this information would be outweighed by better satisfaction with services and the potential for avoiding future pelvic floor dysfunction.
Return to recommendations
# Physical activity and diet and other modifiable risk factors
Recommendations 1.3.1 to 1.3.8
## Why the committee made the recommendations
The evidence suggested that physical activity, healthy diet and appropriate fluid intake help to prevent pelvic floor dysfunction. The quality of the evidence was low because some studies did not account for other factors that could potentially explain the findings. However, it reflected the committee's experience in clinical practice and was in line with standard UK diet and physical activity guidance.
One of the risk factors for pelvic floor dysfunction is constipation, and in the committee's experience, 1 way this can be addressed is by adjusting fluid intake. Public health guidance does not clearly define ideal levels of fluid intake, and there are differences in the fluid needs of individuals (for example, people need more fluid if they are very physically active). The committee therefore decided not to give their own definition of appropriate fluid intake.
The committee recognised that there were other modifiable risk factors: body mass index (BMI) over 25 kg/m2, smoking and diabetes, and they referenced relevant NICE guidance for management strategies for these, which would help prevent pelvic floor dysfunction.
There was only limited evidence on specific dietary factors, such as caffeine and carbonated drinks. To address this, the committee made a recommendation for research on lifestyle factors to reduce the risk of pelvic floor dysfunction.
No evidence was found on the impact of other lifestyle factors that can prevent symptoms associated with pelvic floor dysfunction (such as pelvic organ prolapse, emptying disorders of the bladder or bowel, sexual dysfunction or chronic pelvic pain syndromes). However, in the committee's experience, physical activity that involves repetitive pelvic floor loading (such as weight training) can improve pelvic floor muscle strength and so prevent symptoms. The committee agreed that more research is needed to support this, particularly in relation to the intensity of physical activity needed, so they made a recommendation for research on long-term effects of different types, intensities and frequencies of physical activity for preventing symptoms associated with pelvic floor dysfunction.
## How the recommendations might affect practice
Currently, lifestyle advice is given to women to help with the management of symptoms of pelvic floor dysfunction. However, lifestyle advice is rarely considered as part of pelvic floor dysfunction prevention, because these women are symptom free. Therefore, these recommendations will help standardise the advice women receive on preventing pelvic floor dysfunction.
Return to recommendations
# Pelvic floor muscle training for preventing pelvic floor dysfunction
Recommendations 1.3.9 to 1.3.16
## Why the committee made the recommendations
The available evidence covered women in 3 settings: community, antenatal and postnatal. It specifically addressed pelvic floor dysfunction and associated symptoms (including urinary incontinence, pelvic organ prolapse and sexual dysfunction).
In addition to the research evidence, the committee also took account of the Independent Medicines and Medical Devices Safety Review and the NHS Long Term Plan, which made recommendations on pelvic floor muscle training.
Pelvic floor muscle training was shown to prevent symptoms of pelvic floor dysfunction in all 3 settings. Evidence was not available for some symptoms (such as faecal incontinence and pelvic pain). The training was most effective in the short term. The committee noted that most studies looked at pregnant women (antenatal and postnatal). However, all healthcare professionals can provide encouragement to all women doing pelvic floor muscle training in all settings (there are already resources available on this, such as the video on pelvic floor by NHS Highland). Because there are particular obstetric risk factors associated with pelvic floor dysfunction (see the section on risk factors), pelvic floor muscle training could be particularly beneficial for pregnant women. The evidence supported this, because pelvic floor muscle training was shown to be effective in preventing pelvic floor symptoms when started during or after pregnancy.
Most of the evidence was for a narrow age range of women in their twenties or thirties. However, there was a consistent pattern of risk reduction across this group. The committee believed that this supported them in making recommendations for women of all ages.
An economic analysis showed that antenatal supervised pelvic floor muscle training is likely to be cost effective for some pregnant women:
the evidence suggested that women who have a first-degree relative with pelvic floor dysfunction are at higher risk
the committee identified 3 risk factors related to labour that they thought would increase risk.
However, there was some uncertainty about the conclusion generated from the economic analysis, which was based on evidence from only 1 study. Because of these limitations, and the costs of providing supervised pelvic floor muscle training to such a large group, the committee did not recommend routinely offering training to all of these women. The committee still recommended the training as an option, because it is likely to be cost effective for some women in these groups.
The committee did not include 'an active second stage labour taking more than 1 hour' in the recommendation on supervised pelvic floor muscle training. This is because it is quite common (so would have a high potential cost), and the evidence on this was inconsistent (some studies showed an increased risk when labour was longer than 1 hour, but others did not show increased risk when it was longer than 20 minutes).
In all the studies, pelvic floor muscle training was supervised by a trained healthcare professional. The committee agreed that this is important for ensuring that pelvic floor muscle contraction and relaxation is done correctly. In their experience, it is also important to tailor the training for each woman, to ensure that it is manageable and will meet their training goals.
There was limited evidence on long-term effectiveness, because only 2 studies had a longer follow-up period (12 months in 1 study, and 8 years in the other). However, all the studies showed that adherence decreased over time. In the committee's experience, continuing with the training is key for continued prevention of symptoms, and they agreed that low long-term adherence is likely to explain the limited evidence for long-term effectiveness. To address adherence problems, the committee made the recommendation on encouraging women to continue pelvic floor muscle training.
The committee made recommendations for research to investigate several gaps in the evidence:
Most effective ways to provide training: the studies did not give much detail on how training should be done.
Younger women: there was no evidence on training for young women (between 12 and 17).
Older women: there was only 1 study supporting training for women over 60.
Women who are pregnant and at particular risk of pelvic floor dysfunction: there was little evidence specific to women who are pregnant and have particular risk factors.
Faecal incontinence and emptying disorders of the bowel: there was no evidence on whether pelvic floor muscle training improves these symptoms (which can be particularly distressing).
The Independent Medicines and Medical Devices Safety Review recommended 'that the NHS adopts the French model for universal postnatal pelvic floor rehabilitation', to help prevent pelvic floor dysfunction. This model includes 10 sessions of routinely prescribed perineal rehabilitation sessions (pelvic floor muscle training with manual internal techniques, biofeedback and electrical stimulation) starting at least 8 weeks after birth, regardless of symptoms. The committee did not think the evidence (in particular the cost-effectiveness evidence) was strong enough to support this for all women during or after pregnancy. Instead, they identified the risk factors that put women at the greatest risk, for which pelvic floor training was most likely to be cost effective. They also made a recommendation for research on universal postnatal pelvic floor muscle training to investigate further.
## How the recommendations might affect practice
Currently, pelvic floor muscle training is rarely used for prevention, and is usually only considered and taught to women when they develop symptoms (such as urinary incontinence). There would likely be a significant resource impact if training was provided to all women with the risk factors specified in the recommendation (particularly given the size of the population who would be eligible). Some of this cost is likely to be offset by savings from preventing or delaying pelvic floor dysfunction.
Pregnant women receive information on pelvic floor muscle training. However, this is usually general advice rather than specific instructions or supervised sessions. Women are not routinely told about how pelvic floor muscle training can help prevent sexual dysfunction during and after pregnancy. The recommendations ensure that all women are getting information on the benefits of pelvic floor muscle training to prevent pelvic floor dysfunction. This will standardise practice.
Return to recommendations
# Communicating with and providing information to women with pelvic floor dysfunction
Recommendations 1.4.1 to 1.4.7
## Why the committee made the recommendations
Qualitative evidence showed that women with pelvic floor dysfunction perceived some communication styles as unhelpful. It also indicated that some women are not given enough information to understand their symptoms, diagnosis, investigations or treatment. The quality of the evidence was mixed, because of concerns about methodological limitations in the design of the studies. The committee also made recommendations based on their own experience, in areas where there was no evidence (such as video and telephone consultations).
The recommendation on asking women if they want their family, carers or other people involved is particularly important for addressing potential barriers to support for women with cognitive impairments.
Pelvic floor dysfunction is a complex condition, with particular communication issues (such as embarrassment). Based on the evidence and on their experience, the committee highlighted key issues to take into account when discussing pelvic floor dysfunction with women.
Because of the COVID‑19 pandemic, many services are being provided remotely. In the committee's experience, this has been well received by some women. A particular benefit of remote services can be reduced embarrassment (both for women and for healthcare professionals), which makes women more willing to discuss problems. However, even though this may be the case for some women, the committee acknowledged that it may be harder for the healthcare professional to identify whether symptoms may not be reported because of embarrassment during a remote consultation.
The committee made recommendations for research in areas where there was no evidence:
effective ways of providing information to young women (between 12 and 17 years) and women with protected characteristics (such as physical or learning disabilities)
effective ways of supporting women to start and continue interventions for pelvic floor dysfunction
information valued by young women with symptoms of pelvic floor dysfunction.
## How the recommendations might affect practice
Healthcare professionals already discuss pelvic floor dysfunction with women and provide information on this. However, the information given and how it is communicated can vary, and these recommendations will standardise the process. Because the symptoms of pelvic floor dysfunction are often distressing and embarrassing, communication and sensitivity are very important for all healthcare professionals to ensure good care is provided.
Services already use translation services as needed to overcome communication barriers. However, there may be an impact in areas where video consultation or digital information aids are not currently available.
Return to recommendations
# Assessment in primary care
Recommendations 1.5.1 to 1.5.7
## Why the committee made the recommendations
There are a number of signs and symptoms associated with pelvic floor dysfunction. However, there was no evidence on which assessments are needed in non-specialist care to identify these signs and symptoms. Because of this, the committee made recommendations based on their clinical expertise, highlighting the investigations they use in their practice and the most important signs and symptoms to look out for.
There was evidence that healthcare professionals may overlook symptoms of pelvic floor dysfunction in women who have recently given birth. The evidence also highlighted that there are common misconceptions about pelvic floor dysfunction during and after pregnancy, which can prevent women from seeking care early. To address this, the committee emphasised that women who have recently given birth should be asked about symptoms.
In the committee's experience, many medications can impact on symptoms of pelvic floor dysfunction. In addition, this impact is often larger for people who are taking multiple medicines. Because of this, a medication review is important.
A focused history is important for identifying the likely cause of any symptoms, because many of the symptoms of pelvic floor dysfunction can be caused by other conditions as well.
The committee highlighted some of the examinations that would be needed to clarify whether symptoms are likely to be associated with pelvic floor dysfunction or not. Because some of these are intimate examinations, they highlighted the importance of checking the woman's preferences and ensuring a private space is available.
Further assessments are described in the NICE guideline on urinary incontinence and pelvic organ prolapse in women and the section on baseline assessment in the NICE guideline on faecal incontinence. These guidelines only cover adults, but many of the initial assessments recommended are non-specialist and the committee agreed that they could be relevant for younger women (aged 12 to 17) in primary care.
## How the recommendations might affect practice
Pelvic floor dysfunction is a complex condition, and there is currently variation in how it is assessed. These recommendations will ensure consistency in the initial assessments that are done in primary care.
Return to recommendations
# Community-based multidisciplinary teams
Recommendations 1.6.1 to 1.6.3
## Why the committee made the recommendations
There was limited evidence on team-based approaches for managing pelvic floor dysfunction. However, the available evidence reflected the committee's experience in practice. They decided that the range of competencies needed could not be covered by 1 healthcare professional alone, and so a multidisciplinary team approach should be considered. Because pelvic floor dysfunction can happen to any woman, multidisciplinary teams will need a wide range of skills to be able to care for all women who need support. The committee agreed that several teams could be needed (for example, a team for pregnant women and another for older women). These teams would need to be community based, to ensure that care is accessible to all women.
Adherence and satisfaction with care are important factors in effective management of pelvic floor dysfunction, and the committee agreed that these would also be improved by community-based multidisciplinary teams.
The experience and training of multidisciplinary team members is likely to vary widely in different areas. Because of this, the committee made a recommendation on competencies, based on their own experience of the key knowledge and experience that is needed in the team to implement the other recommendations in this guideline.
The committee did not recommend including specific roles (such as specialist continence advisors) in the team, because community healthcare professionals can be trained to carry out non-specialist assessment, and because including specific specialists in every team could have substantial costs. The committee made a recommendation for research on the roles needed in community-based multidisciplinary pelvic floor dysfunction teams.
When agreeing a management plan, it is important to involve the woman with pelvic floor dysfunction, to ensure the plan takes account of her needs, preferences and goals.
## How the recommendations might affect practice
Community-based multidisciplinary teams may represent a change to current practice, because there is variation in their availability. Pelvic floor dysfunction is a common condition, and other services (such as community-based continence services) could form the basis of these teams. The committee decided that the benefits of good pelvic floor dysfunction management would outweigh potential costs associated with setting up community-based multidisciplinary teams.
There is currently variation in the competencies that community-based multidisciplinary teams have on assessing and managing pelvic floor dysfunction. There would be upfront costs for training healthcare professionals in the competencies recommended in this guideline, but these costs would be outweighed by better long-term outcomes (improved identification of symptoms and better management as a result).
Return to recommendations
# Lifestyle changes
## Encouraging women to make lifestyle changes
Recommendation 1.6.4
The evidence showed that positive communication improves patient motivation and adherence to lifestyle changes. This was also consistent with the committee's experience. It can take time for women to see a benefit from lifestyle changes, so the committee believed it was important to emphasise encouraging and motivating women in the recommendation.
All healthcare professionals communicate with women and this recommendation will raise awareness that this communication should not be framed only in a negative way but provide positive messages when appropriate.
Return to recommendation
## Weight loss
Recommendations 1.6.5 to 1.6.8
The evidence showed that in women with a BMI over 30 kg/m2, weight loss helped with urinary incontinence and overactive bladder. In the committee's experience, excess body weight exacerbates these symptoms by putting pressure on the pelvic floor muscles and organs, so weight loss will be particularly beneficial. The evidence did not show any effect from weight loss on symptoms of pelvic organ prolapse. However, the committee still believe that weight loss may be beneficial in the early stages of pelvic organ prolapse, because less weight would press on the pelvic organs and this could improve symptoms.
The committee recommended against delaying other management options until women have lost weight because:
there was no evidence on the impact of weight loss for many symptoms of pelvic floor dysfunction and
there are other interventions that could benefit women with pelvic floor dysfunction.
Because other NICE guidelines cover helping people to lose weight, the committee referred to these guidelines rather than making new recommendations on weight loss interventions.
The committee made a recommendation for research to address the lack of evidence on whether weight loss can reduce symptoms of pelvic floor dysfunction.
Weight loss referral related to pelvic floor dysfunction differs across the country. The recommendations would reduce variation and promote consistency in care.
Return to recommendations
## Diet
Recommendations 1.6.9 and 1.6.10
There was some evidence suggesting that reducing caffeine intake helps with urinary incontinence and overactive bladder, and this was supported by the committee's experience in practice.
No evidence was found on other symptoms associated with pelvic floor dysfunction. However, the committee agreed that in their experience, addressing fluid intake can help with symptoms by promoting an ideal stool consistency. Public health guidance does not clearly define ideal levels of fluid intake, and there are differences in the fluid needs of individuals (for example, people need more fluid if they are very physically active). The committee therefore decided not to give their own definition of appropriate fluid intake.
A balanced diet also reduces the risk of constipation and so would indirectly reduce the risk of pelvic floor dysfunction. This is particularly important for women with pelvic organ prolapse, faecal incontinence, emptying disorders of the bowel and chronic pelvic pain syndromes.
The committee believed that more research specific to pelvic floor dysfunction related to food rather than fluid intake is needed, and therefore made a recommendation for research on diet to address this.
These recommendations are in line with current clinical practice. Clinicians will already be familiar with the practical details of lifestyle changes that can be made to promote pelvic floor health, and lifestyle changes are a common aspect of management for symptoms of pelvic floor dysfunction.
Return to recommendations
## Physical activity
Recommendations 1.6.11 and 1.6.12
There was some evidence on urinary incontinence, overactive bladder and pelvic organ prolapse. The evidence showed that physical activity could improve these symptoms, but the physical activity programmes in these studies were supervised and included pelvic floor muscle training as part of the interventions.
The physical activity interventions covered were yoga, pilates, weight training and aerobic exercises. However, it was not clear from the studies what type of exercises were beneficial, because they were usually combined with some form of pelvic floor muscle training. Because of this, the committee did not recommend specific activities. The committee know from their own experience that women often ask whether physical activity could improve or worsen their symptoms. Because of the evidence that showed some improvement, they made a recommendation in favour of supervised exercise. 'Supervised' exercise is specified because certain exercises, if done incorrectly, can weaken the pelvic floor by increasing intra-abdominal pressure. This could worsen symptoms of pelvic floor dysfunction.
There is no evidence that unsupervised physical activity improved or worsened symptoms of pelvic floor dysfunction. The committee acknowledged that there are general health benefits associated with having an active lifestyle. Therefore, they also made a recommendation for research on unsupervised activities (in particular, common activities such as walking and swimming).
Heavy lifting has been considered a risk factor for damaging the pelvic floor by increasing intra-abdominal pressure. The NICE guideline on urinary incontinence and pelvic organ prolapse in women recommends minimising heavy lifting. However, a more recent study showed that weight training combined with pelvic floor muscle training could improve symptoms of urinary incontinence. Because there was uncertainty around the evidence and it was not entirely consistent with the committee's experience, they made a recommendation for research on weight training to investigate this further.
The recommendations cover providing information, which is part of current practice, so there should be no cost to services. These recommendations will ensure women are educated on exercises they can do to improve their symptoms and exercises that are not harmful. In addition, they will help standardise the information being provided.
Return to recommendations
# Pelvic floor muscle training for managing pelvic floor dysfunction
Recommendations 1.6.13 to 1.6.20
## Why the committee made the recommendations
The evidence showed that pelvic floor muscle training improves several symptoms of pelvic floor dysfunction (pelvic organ prolapse, stress and mixed urinary incontinence, and faecal incontinence with coexisting pelvic organ prolapse). There was greater uncertainty around the findings on faecal incontinence with coexisting pelvic organ prolapse, because there was much less evidence in this area.
For pelvic organ prolapse, the evidence showed a benefit from pelvic floor muscle training for prolapse that does not extend more than 1 cm beyond the hymen. This matched the committee's experience, because they agreed that more extensive pelvic organ prolapse would be managed in specialist care.
The recommended lengths of time for the training programmes are based on the most common time points used in the studies for assessing the benefit of training. This was 16 weeks for pelvic organ prolapse and faecal incontinence, and 3 months for urinary incontinence. The committee noted that this would give enough time to assess whether the training improved symptoms. This is also consistent with the recommendations on pelvic floor muscle training in the NICE guideline on urinary incontinence and pelvic organ prolapse in women.
In addition to the research evidence, the committee also took account of the Independent Medicines and Medical Devices Safety Review and the NHS Long Term Plan, which made recommendations on pelvic floor muscle training.
See the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction, for an explanation of the recommendations on supervising pelvic floor muscle training.
For additional therapies, such as weighted vaginal cones, biofeedback and electrical stimulation, the evidence was inconsistent. Some studies showed benefits, and others showed no effect. Some of the evidence suggested that these interventions could help women with pelvic floor muscle training by improving their ability to contract their pelvic floor muscles. In the committee's experience, effective pelvic floor contractions and relaxations are important for improving pelvic floor dysfunction symptoms and most women are able to do this as part of a supervised pelvic floor muscle training programme. However, the committee believed that supplementing a pelvic floor muscle training programme with biofeedback, electrical stimulation or vaginal cones could be cost effective in the subgroup who make little progress during supervised pelvic floor muscle training. These additional therapies are particularly likely to be cost effective if using them allows women to avoid the need for surgical intervention.
Based on their experience, the committee thought it would be important that women are advised to continue doing pelvic floor muscle training and that they have the opportunity to discuss progress in regular reviews during the initial training programme. The committee believed that reviews with a healthcare professional improve adherence, which is important for the long-term effectiveness of pelvic floor muscle training.
There was some evidence suggesting that training in a group improved adherence and symptoms, but it was not consistently found to be more effective than individual training. This was supported by the committee's experience, because some women benefit from peer support whereas others feel more motivated with one-to-one supervision. To take account of this, the committee recommended giving women a choice of group or individual training. One-to-one supervision is more expensive than group training, but the difference in cost is relatively small and so the approach favoured by each woman is likely to be cost effective.
It was unclear whether using a pessary or intravaginal device would be effective when combined with pelvic floor muscle training, so the committee made a recommendation for research on intravaginal devices and pessaries. The development of remote clinical practice during the COVID‑19 pandemic also made the committee curious about the effectiveness of virtual pelvic floor muscle training, so they recommended research into the effectiveness of virtual and in-person contact time for pelvic floor muscle training.
## How the recommendations might affect practice
The recommendations will standardise practice. Pelvic floor muscle training is a key intervention for managing the symptoms of pelvic floor dysfunction and is already widely used in the NHS. However, access to group pelvic floor muscle training classes differs across the country. Although some healthcare services may need to change practice, group pelvic floor muscle training classes are less expensive, so the committee did not anticipate a significant resource impact.
Return to recommendations
# Intravaginal devices and pessaries
Recommendations 1.6.21 to 1.6.27
## Why the committee made the recommendations
The evidence on intravaginal devices was unclear, with variance across outcomes. For example, there was no measurable reduction in urinary leakage, but women reported that their symptoms improved. However, the committee noted that a subjective improvement in symptoms was still important, because it is an indication of the woman's perception of the device's success. The committee were also aware from their experience that these devices can help to prevent urinary leakage in certain circumstances (for example, during exercise). Based on the limitations of the evidence and the potential complications, the committee recommended trialling intravaginal devices if other non-surgical options have been tried and have been unsuccessful, so that women could decide whether they were beneficial before using them long term.
This differs from recommendation 1.4.23 in the NICE guideline on urinary incontinence and pelvic organ prolapse, which recommends against the use of intravaginal devices. However, the committee noted that recommendation 1.4.23 had not been updated since 2006. Most of the evidence they reviewed for this guideline has been published since 2006. Even though the findings from the evidence were not entirely certain, they decided that these devices should not be ruled out if other non-surgical options were unsuccessful. This would provide another option that may prevent the need for more invasive treatment.
The evidence on pessaries indicated that they help with symptoms of pelvic organ prolapse while they are in position, and this is in keeping with the committee's clinical experience. However, there was a lack of long-term evidence on the effectiveness and potential complications of pessary use. Because of the uncertainty around pessaries, the committee specified particular benefits and harms to discuss with women, based on the evidence that was available and their clinical experience. This will help women to make an informed decision on whether a pessary is right for them.
In the committee's experience, women with physical or cognitive impairments may have difficulty in managing an intravaginal device or pessary and are at higher risk of complications. Because of this, these women should have regular appointments to check for complications. The committee also recommended telling women how to self-refer if they are managing the device themselves, so that they know how to get help if they are having problems or if their intravaginal device or pessary does not help.
There was a lack of evidence on the physical devices available for managing faecal incontinence (which is a particularly distressing symptom). The existing evidence consists of studies in mixed populations of men and women, so it could not be used to make recommendations for the population of this guideline. To address this, the committee made a recommendation for research on anal plug devices and rectal irrigation for managing bowel symptoms in women with pelvic floor dysfunction.
## How the recommendations might affect practice
These recommendations are in line with current practice on pessaries. There is variation in the use of intravaginal devices, but the recommendations would not involve major changes to practice because it would be an option only if other options had not been successful. Even though this may increase the general use of intravaginal devices, they are already used in some areas. They may also prevent more invasive options (such as surgery) which are more costly.
Return to recommendations
# Psychological interventions
Recommendations 1.6.28 and 1.6.29
## Why the committee made the recommendations
The evidence showed a psychological impact from the symptoms of pelvic floor dysfunction. However, the committee noted that there was a lot of uncertainty about this evidence and made recommendations based on their experience and expertise. They made a recommendation emphasising this because women with pelvic floor dysfunction often do not seek help with the psychological impact of their symptoms, and healthcare professionals do not always ask them about it.
Some therapies were shown to improve distress associated with pelvic floor dysfunction, but the studies were very small. There was also evidence that psychological therapy could help with vaginismus, but it was not clear from the studies whether the participants' symptoms were related to pelvic floor dysfunction. The committee decided that they could not recommend therapies based on this evidence.
Because other NICE guidelines cover identifying and managing mental health problems for people with a chronic health condition, the committee referenced these guidelines instead of making new recommendations on specific psychological interventions.
There was some evidence showing that psychological interventions improved attendance and adherence to pelvic floor muscle training. However, there were several limitations to this evidence:
it did not show whether the improvement in attendance and adherence was sustained in the long term
although some of the interventions improved the mental health of participants, it was not clear whether the interventions also had an impact on symptoms (which could mean that the improvement in mental health may not be sustained in the long term)
the studies were small.
These limitations meant that the committee could not make a practice recommendation. However, they do believe that better attendance and adherence to training improves the benefit of pelvic floor muscle training. Because of this, they made a recommendation for research on ways to improve adherence for women who are having this training.
## How the recommendations might affect practice
The committee agreed that there is variation in practice in how well psychological factors related to pelvic floor dysfunction are considered when planning treatment. The recommendations would not involve major changes to practice, but would standardise current good practice.
Return to recommendations
# Behavioural approaches
Recommendations 1.6.30 to 1.6.32
## Why the committee made the recommendations
There was evidence about behavioural techniques including bladder retraining and lifestyle education, provided under direct supervision by a trained healthcare professional. The studies usually included pelvic floor muscle training as part of the interventions. The symptoms covered in the studies included urinary incontinence, urinary urgency and frequency, and faecal incontinence. Evidence was not available for some symptoms (such as emptying disorders of the bladder and bowel).
The evidence was difficult to interpret because there was variation in the quality of the research and a mixture of different interventions and comparators, which made it difficult to combine results. This meant that it was not clear which aspects of interventions were directly improving the symptoms of pelvic floor dysfunction.
The evidence showed that behavioural techniques in combination with pelvic floor muscle training improved these symptoms, which was in keeping with the committee's experience in clinical practice. The committee noted that bladder retraining consists of advice about when or how frequently to go to the toilet to encourage a routine that can help prevent incontinence episodes.
There was some limited evidence suggesting that a combination of behavioural techniques and pelvic floor muscle training was associated with improved adherence and satisfaction. The committee agreed that motivation and adherence were key to long-term benefit. The committee were conscious that behavioural techniques should be tailored to the individual, because ability may differ based on other coexisting conditions (such as cognitive impairment).
## How the recommendations might affect practice
Behavioural techniques involve a wide range of techniques that can be used to change behaviour and teach women skills to reduce symptoms of pelvic floor dysfunction. These techniques are already used by most services, so the recommendations will reinforce current practice.
Bladder training can easily be provided in conjunction with a pelvic floor muscle training programme and would not add significant costs.
Return to recommendations
# Medicines
Recommendations 1.6.33 and 1.6.34
## Why the committee made the recommendations
There was limited evidence on medicines for general pelvic floor dysfunction. However, the evidence available did show that intravaginal diazepam was not effective at improving symptoms. Although this evidence was based on a small population, the committee were also concerned about the risk of dependency from diazepam use. Because of this risk and the lack of evidence for any benefit, the committee recommended against intravaginal diazepam.
Women with high muscle tone are specifically mentioned in this recommendation because this is the only group diazepam would be considered for in current practice (because diazepam relaxes muscles and relieves muscle spasms). Because the evidence showed that diazepam was not effective, the committee wanted to make sure it was not used even in this group.
The NICE guidelines on urinary incontinence and pelvic organ prolapse in women, and faecal incontinence in adults, make recommendations on medicines for symptoms that can be associated with pelvic floor dysfunction. The committee recommended following these recommendations for women with pelvic floor dysfunction, because the medicines recommended are likely to be effective even if the underlying cause of symptoms is different in the other guidelines. They also thought that some of the recommendations in this guideline may also be relevant for women under 18.
Topical intravaginal oestrogen is currently used in clinical practice for managing pelvic floor dysfunction. However, no evidence was identified for this, so the committee made a recommendation for research on vaginal oestrogen.
## How the recommendations might affect practice
The recommendation on intravaginal diazepam will not change current practice, because this is not currently used in the NHS. Because the other recommendation cross refers to other NICE guidance, it will reinforce current guidance and will not have any significant resource impact.
Return to recommendations# Context
Pelvic floor dysfunction covers a variety of symptoms. In this guideline, the following symptoms are addressed as long as they are associated with pelvic floor dysfunction: urinary incontinence, emptying disorders of the bladder, faecal incontinence, emptying disorders of the bowel, pelvic organ prolapse, sexual dysfunction and chronic pelvic pain syndromes. The 3 most common and definable conditions are urinary incontinence, faecal incontinence and pelvic organ prolapse.
Prevalence of pelvic floor dysfunction is high. For example, on examination, prolapse is present in up to 50% of women. This can have a significant impact on quality of life, reducing social engagement and ability to be physically active.
This guideline makes recommendations on common risk factors and on preventative interventions. Ideally, women who are most at risk of pelvic floor dysfunction would be identified early and offered interventions to prevent symptoms developing. This would reduce the impact on women and the NHS.
When pelvic floor dysfunction is diagnosed, there is variation in the availability of non-surgical management options, such as pelvic floor muscle training. Women have no clear and effective strategies available to prevent worsening of the condition. This guideline provides a more community-based pathway to address these problems and to reduce the number of women who develop complex symptoms that need specialist care (including surgery).
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nWhat is pelvic floor dysfunction?\n\nPelvic floor dysfunction is a condition in which the pelvic floor muscles around the bladder, anal canal, and vagina do not work properly. This guideline covers the following symptoms and disorders when they are associated with pelvic floor dysfunction:\n\nurinary incontinence\n\nemptying disorders of the bladder\n\nfaecal incontinence\n\nemptying disorders of the bowel\n\npelvic organ prolapse\n\nsexual dysfunction\n\nchronic pelvic pain.\n\nThe 3\xa0most common and definable symptoms are urinary incontinence, faecal incontinence and pelvic organ prolapse.\n\nWho does this guideline cover?\n\nThis guideline covers young women aged\xa012\xa0to\xa017 and women aged 18\xa0and over. When recommendations refer to 'women' without specifying an age range, that means they cover this entire population.\n\n# Raising awareness of pelvic floor dysfunction for all women\n\nWhen producing resources on pelvic floor dysfunction, include:\n\nthe symptoms of pelvic floor dysfunction\n\nvisual aids to help identify potential causes of symptoms (for example, by showing the anatomy of pelvic organs)\n\nwhen to get help\n\nwhere to go for help (including self-referral to community-based multidisciplinary teams, where available)\n\nan outline of risk factors, prevention and management options (including non-surgical management and lifestyle changes).\n\nConsider providing information on pelvic floor dysfunction in the following formats and settings:\n\nFormats\n\n\n\nprint, broadcast and online adverts\n\ninformation given alongside over-the-counter continence products\n\nleaflets in the community (for example, at GP surgeries, family planning clinics and exercise classes)\n\nvideos and information on social media\n\ninteractive online resources (for example, the NHS app).\n\n\n\nSettings\n\n\n\nas part of general exercise programmes\n\nin leaflets on gynaecological cancer treatment or gynaecological surgery (such as hysterectomies)\n\nas part of existing programmes, for example, cervical screening or national or local NHS health checks\n\ncontact with a healthcare practitioner with pelvic floor dysfunction knowledge\n\ngiving advice to people with contacts in the community (such as exercise and fitness instructors and teachers), so they can provide information on pelvic floor dysfunction themselves\n\non community and health trust websites\n\ninformation provided by healthcare charities.\n\n\n\nTailor information and communication about pelvic floor dysfunction for different age groups and characteristics (for example, pregnancy).\n\nConsider covering pelvic floor dysfunction in the syllabus for healthcare and other professionals, such as trainee nurses, physiotherapists, doctors, midwives and teachers.\n\nLocal authorities should consider designing pelvic floor dysfunction information programmes for specific communities when there is evidence of healthcare inequalities (for example, in how services are provided and accessed, or rates of uptake). This can be done by:\n\nfinding more effective ways to provide information (for example, by attending community meetings)\n\ninvolving members of the community as champions\n\nusing webinars to reach women who are unable to attend meetings in person.\n\nFor women using maternity services, include information on pelvic floor dysfunction, how to prevent it, the symptoms, and how to access local services:\n\nin the booking information pack or patient portal\n\nat all midwife consultations and reviews\n\nat all consultations with an obstetrician\n\nin hospital postnatal wards.\n\nHealth visitors, midwives and GPs should discuss pelvic floor dysfunction with women at each postnatal contact.\n\nTeach young women (between\xa012 and\xa017) in education settings about pelvic floor anatomy, pelvic floor muscle exercises and how to prevent pelvic floor dysfunction.\n\nProvide information on pelvic floor dysfunction for older women within primary and intermediate care services, and within care homes and supported living communities. This could be done:\n\nwhen women ask for advice about perimenopause and menopause\n\nas part of general health assessments\n\nas part of comprehensive geriatric health assessments.\n\nFor guidance on tailoring communication, information and shared decision making for people using health and social care services, see the:\n\nNICE guideline on shared decision making\n\nNICE guideline on patient experience in adult NHS services\n\nNICE guideline on babies, children and young people's experience of healthcare\n\nNICE guideline on people's experience in adult social care services\n\nNHS Accessible Information Standard (in particular, for guidance on making information accessible).\n\nFor guidance on planning and developing digital and mobile tools to provide tailored information, see the NICE guideline on behaviour change: digital and mobile health interventions.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on raising awareness of pelvic floor dysfunction for all women\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: community information strategies.\n\nLoading. Please wait.\n\n# Risk factors for pelvic floor dysfunction\n\nWhen discussing the risk of pelvic floor dysfunction with women, advise them that their risk is higher with any of the characteristics in box\xa01.\n\nModifiable risk factors\n\nA body mass index (BMI) over 25\xa0kg/m2\n\nSmoking\n\nLack of exercise\n\nConstipation\n\nDiabetes\n\nNon-modifiable risk factors\n\nAge (risk increases with increasing age)\n\nFamily history of urinary incontinence, overactive bladder or faecal incontinence\n\nGynaecological cancer and any treatments for this\n\nGynaecological surgery (such as a hysterectomy)\n\nFibromyalgia\n\nChronic respiratory disease and cough (chronic cough may increase the risk of faecal incontinence and flatus incontinence)\n\nRelated to pregnancy:\n\nBeing over 30\xa0years when having a baby\n\nHaving given birth before their current pregnancy\n\nRelated to labour:\n\nAssisted vaginal birth (forceps or vacuum)\n\nA vaginal birth when the baby is lying face up (occipito-posterior)\n\nAn active second stage of labour taking more than 1\xa0hour\n\nInjury to the anal sphincter during birth\n\nFor pregnant women with pelvic floor dysfunction that started before or during their pregnancy, advise them that there is an increased risk that their symptoms will get worse during their pregnancy and that they may persist after this (for preventative and management strategies, see the section on preventing pelvic floor dysfunction and the section on non-surgical management of pelvic floor dysfunction.\n\nFor more detailed guidance on all the benefits and risks of vaginal and caesarean birth (including urinary incontinence, faecal incontinence and injury to the anal sphincter), see the section on benefits and risks of caesarean and vaginal birth in the NICE guideline on caesarean birth.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk factors for pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0B: risk factors for pelvic floor dysfunction\n\nevidence review\xa0C: coexisting long-term conditions and pelvic floor dysfunction\n\nevidence review\xa0D: prediction tools for pelvic floor dysfunction.\n\nLoading. Please wait.\n\n# Preventing pelvic floor dysfunction\n\n## Physical activity and diet\n\nAdvise women that physical activity and a healthy diet can help prevent pelvic floor dysfunction.\n\nOn levels of physical activity, advise women to follow the standard advice, as covered by:\n\nthe UK Chief Medical Officers' physical activity guidelines\n\nthe NICE guideline on physical activity: brief advice for adults in primary care\n\nthe NICE guideline on physical activity: walking and cycling.\n\nOn diet, advise women to:\n\nhave a balanced diet (following Public Health England's Eatwell Guide), and in particular to eat enough fibre, because this can improve stool consistency and prevent symptoms of faecal incontinence\n\nensure they have an appropriate fluid intake, increasing or decreasing it if needed.\n\nFor guidance on training to help health and social care practitioners recognise and respond to diet, physical activity and hydration needs in older people with social care needs and multiple long-term conditions, see the section on training health and social care practitioners in the NICE guideline on older people with social care needs and multiple long-term conditions.\n\n## Weight loss, stopping smoking, managing constipation and diabetes\n\nFor guidance on weight loss, see the NICE guideline on obesity, and (if relevant) the NICE guideline on weight management before, during and after pregnancy.\n\nGive advice on stopping smoking, using the NICE guideline on tobacco.\n\nFor guidance on managing constipation in young people, see the NICE guideline on constipation in children and young people.\n\nFor guidance on managing diabetes, see the NICE guidelines on:\n\ntype 1 diabetes in adults\n\ntype 2 diabetes in adults\n\ndiabetes (type\xa01 and type\xa02) in children and young people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity and diet and other modifiable risk factors\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0B: risk factors for pelvic floor dysfunction\n\nevidence review\xa0E: lifestyle factors for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Pelvic floor muscle training\n\nEncourage women of all ages to do pelvic floor muscle training, and explain that it helps to prevent symptoms of pelvic floor dysfunction.\n\nEncourage women to continue pelvic floor muscle training throughout their life, because long-term training continues to help prevent symptoms.\n\nEncourage women who are pregnant or who have recently given birth to do pelvic floor muscle training, and explain that it helps prevent symptoms of pelvic floor dysfunction.\n\nConsider a 3‑month programme of supervised pelvic floor muscle training:\n\nfrom week\xa020 of pregnancy, for pregnant women who have a first-degree relative with pelvic floor dysfunction\n\nduring postnatal care, for women who have experienced any of the following risk factors during birth:\n\n\n\nassisted vaginal birth (forceps or vacuum)\n\na vaginal birth when the baby is lying face up (occipito-posterior)\n\ninjury to the anal sphincter.\n\n\n\nBefore discharging women from maternity services, and during routine postnatal care, encourage them to do pelvic floor muscle training.\n\nWhen designing a pelvic floor muscle training programme, see the NICE guideline on behaviour change for relevant recommendations:\n\nrecommendation 7: use proven behaviour change techniques when designing interventions\n\nrecommendation 8: ensure interventions meet individual needs.\n\nPelvic floor muscle training programmes should be supervised by a physiotherapist or other healthcare professional with the appropriate expertise in pelvic floor muscle training.\n\nSupervision should involve:\n\nassessing the woman's ability to perform a pelvic floor contraction and relaxation\n\ntailoring the pelvic floor muscle training programme to the woman's ability to perform a pelvic floor contraction and relaxation, any discomfort felt, and her individual needs and training goals\n\nencouraging the woman to complete the course, because this will help to prevent and manage symptoms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pelvic floor muscle training for preventing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n# Communicating with and providing information to women with pelvic floor dysfunction\n\n## Communication\n\nAgree consultation formats (for example, in person, video or telephone) with each woman with pelvic floor dysfunction, taking into account the need for physical examinations.\n\nWhen discussing pelvic floor dysfunction:\n\nbe aware of potential cultural sensitivities\n\nbe aware that women may feel embarrassed discussing their symptoms, and they may believe that healthcare professionals will also be embarrassed\n\ntake particular care around terminology:\n\n\n\nfor example, avoid using 'faeces' if a woman better understands or prefers 'poo'\n\nbe aware that women may not use the precise technical terms for parts of their pelvic anatomy\n\n\n\ntailor information to each woman's level of understanding of anatomy and of the causes of pelvic floor dysfunction.\n\nFor general guidance on communicating with patients, see the:\n\nsection on communication in the NICE guideline on patient experience in adult NHS services\n\nsection on communication and information in the NICE guideline on babies, children and young people's experience of healthcare.\n\nWhen providing information to women with pelvic floor dysfunction and cognitive impairment, ask them if they want their family, carers and other people to be involved, to support them (as appropriate) and to help reinforce and support management plans.\n\n## Information for women with pelvic floor dysfunction\n\nHelp women with pelvic floor dysfunction to understand their condition by giving clear and concise information. This should include:\n\nthe anatomy of the pelvic floor and pelvic organs (using visual aids when helpful)\n\npossible causes of their symptoms\n\nmanagement options and possible outcomes\n\nan explanation that interventions will be focused on their symptoms, rather than on pelvic floor dysfunction in general\n\nother medical conditions and treatments that can cause or exacerbate their symptoms (see risk factors for pelvic floor dysfunction).\n\nTailor information to each woman's age, level of understanding and circumstances, because pelvic floor dysfunction can affect women differently at different stages of life. For example:\n\nyoung women (between\xa012 and\xa017)\n\nwomen who are pregnant or who have given birth\n\nwomen in perimenopause or postmenopause\n\nwomen with comorbidities or frailty.\n\nConsider digital information sources (for example, apps or videos) to support women with pelvic floor dysfunction (see guidance on developing digital tools in the NICE guideline on behaviour change: digital and mobile health interventions).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on communicating with and providing information to women with pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: information provision related to the management of pelvic floor dysfunction (people's views and experiences)\n\nevidence review\xa0H: information provision about management of pelvic floor dysfunction (most effective ways).\n\nLoading. Please wait.\n\n# Assessment in primary care\n\nAt initial assessment in primary care (which may include assessments by physiotherapists, bladder and bowel team members and continence advisors), take a general history from the woman about current and past symptoms or disorders associated with pelvic floor dysfunction, such as:\n\nurinary incontinence\n\nemptying disorders of the bladder\n\nfaecal incontinence\n\nemptying disorders of the bowel\n\npelvic organ prolapse\n\nsexual dysfunction\n\nchronic pelvic pain.\n\nDepending on the symptoms described, carry out a focused history, clinical examination and investigations to exclude other causes, such as:\n\npelvic masses\n\nneurological disease\n\nurinary tract infection\n\nadverse effects of medication\n\ndiabetes\n\ncancer (for further information, see the NICE guideline on suspected cancer: recognition and referral)\n\nfistula\n\ninflammatory bowel or bladder conditions\n\nendometriosis\n\nmobility and cognitive impairment.\n\nAsk women who have recently given birth about symptoms of pelvic floor dysfunction during routine postnatal care, in hospital and in the community.\n\nFor women who are taking multiple medications, conduct a medication review. For guidance on how to do this, see the section on medication review in the NICE guideline on medicines optimisation.\n\nDepending on the symptoms and the woman's preferences and circumstances, consider other clinical examinations. For example:\n\ninspecting the woman's vulva and vagina for atrophy\n\nasking them to bear down, to check for visible vaginal or rectal prolapse\n\nrectal examination to check for impaction, for women who are at risk of this and who cannot give an accurate history of their symptoms (for example, women with cognitive impairments or dementia).\n\nFor more guidance on assessing urinary incontinence and pelvic organ prolapse, see the NICE guideline on urinary incontinence and pelvic organ prolapse in women. (The recommendations in this guideline may also be relevant for women under\xa018.)\n\nIf the woman has symptoms of faecal incontinence, follow the recommendations on baseline assessment in the NICE guideline on faecal incontinence. (The recommendations in this guideline may also be relevant for women under\xa018.)\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment in primary care\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0I: assessment in non-specialist care\n\nevidence review\xa0G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).\n\nLoading. Please wait.\n\n# Non-surgical management of pelvic floor dysfunction\n\n## Community-based multidisciplinary teams\n\nAfter initial assessment in primary care, consider a community-based multidisciplinary team approach for the management of pelvic floor dysfunction.\n\nThe community-based multidisciplinary team (or teams) should have members with competencies related to assessing and managing pelvic floor dysfunction, such as:\n\ncarrying out initial assessments (see the section on assessment in primary care)\n\nassessments of mobility and personal care issues related to pelvic floor dysfunction\n\nawareness of the psychosocial implications of pelvic floor dysfunction\n\nidentifying risk factors\n\ninterpreting urinalysis\n\nconducting and interpreting bladder scans to measure post-void residual volume\n\nconducting digital assessments of the pelvic floor and pelvic floor muscle contraction and relaxation\n\ntraining women and their families and carers in behavioural interventions for pelvic floor dysfunction (such as bladder retraining)\n\nprescribing and reviewing medications, and knowledge of interactions and side effects related to pelvic floor dysfunction\n\nsupervising a pelvic floor muscle training programme (see the section on supervising pelvic floor muscle training)\n\nmanaging the use of pessaries and intravaginal devices\n\ntraining and supporting other care providers to assess and manage pelvic floor dysfunction (for example, carers or care home workers)\n\nidentifying which women need referral to specialist care or other services (for young women aged\xa012\xa0to 17, this may include referral to paediatric services or adolescent gynaecology services).\n\nDiscuss and agree a management plan with women who have suspected or confirmed pelvic floor dysfunction.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on community-based multidisciplinary teams\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: community-based multidisciplinary teams.\n\nLoading. Please wait.\n\n## Lifestyle changes\n\nWhen discussing lifestyle changes with women who have pelvic floor dysfunction:\n\nmotivate them to make changes by focusing discussions on how this will improve their symptoms\n\ngive them regular encouragement to keep up the changes, because it may take weeks or months before they notice a benefit.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on encouraging women to make lifestyle changes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).\n\nLoading. Please wait.\n\nAdvise women with a body mass index (BMI) over 30\xa0kg/m2 that weight loss can help with the following symptoms associated with pelvic floor dysfunction:\n\nurinary incontinence\n\noveractive bladder\n\npelvic organ prolapse.\n\nFor guidance on weight loss, see the NICE guideline on obesity, and (if relevant) the NICE guideline on weight management before, during and after pregnancy.\n\nRefer women for weight loss support following the NICE guideline on lifestyle services for weight management in overweight or obese adults and the NICE guideline on lifestyle services for weight management in overweight or obese children and young people.\n\nDo not wait for women to lose weight before starting other pelvic floor dysfunction management options.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on weight loss\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: weight loss interventions.\n\nLoading. Please wait.\n\nFor all women with pelvic floor dysfunction:\n\nexplain how a balanced diet (following Public Health England's Eatwell Guide) and appropriate fluid intake can improve stool consistency, which can help with their symptoms\n\nfollow guidance on maintaining healthy bowel habits in recommendation 1.3.2 of the NICE guideline on faecal incontinence in adults (including for women under\xa018 or with symptoms other than faecal incontinence).\n\nAdvise women with overactive bladder or urinary incontinence associated with pelvic floor dysfunction to:\n\nreduce their caffeine intake\n\nmodify their fluid intake (increasing if it is too low, decreasing if it is too high).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diet\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: dietary factors for the management of symptoms.\n\nLoading. Please wait.\n\nFor women who are doing supervised pelvic floor muscle training and want to be physically active, advise them that supervised exercise (for example, yoga) may help with their symptoms.\n\nAdvise women with pelvic floor dysfunction that there is no evidence to say that unsupervised physical activity (such as walking or swimming) will improve or worsen their symptoms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical activity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: physical activity for the management of symptoms.\n\nLoading. Please wait.\n\n## Pelvic floor muscle training\n\nConsider a programme of supervised pelvic floor muscle training for at least 4\xa0months for women with symptomatic pelvic organ prolapse that does not extend greater than 1\xa0cm beyond the hymen upon straining.\n\nOffer a programme of supervised pelvic floor muscle training for at least 3\xa0months to women (including pregnant women) with stress urinary incontinence or mixed urinary incontinence.\n\nConsider a programme of supervised pelvic floor muscle training for at least 4\xa0months for women with faecal incontinence and coexisting pelvic organ prolapse.\n\nFor women who are doing a supervised pelvic floor muscle training programme, offer the choice of group or individual sessions.\n\nSee the recommendations on supervising pelvic floor muscle training in the section on preventing pelvic floor dysfunction.\n\nWhen providing a programme of pelvic floor muscle training, offer at least 1\xa0review to assess progress during the programme, and 1\xa0review at the end of the programme.\n\nFor women who are unable to perform an effective pelvic floor muscle contraction, consider supplementing pelvic floor muscle training with biofeedback techniques, electrical stimulation or vaginal cones.\n\nIf the programme is beneficial, advise women to continue pelvic floor muscle training after the supervised programme ends.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pelvic floor muscle training for managing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: pelvic floor muscle training for the management of symptoms.\n\nLoading. Please wait.\n\n## Intravaginal devices and pessaries\n\nConsider a trial of intravaginal devices for women with urinary incontinence, only if other non-surgical options have been unsuccessful.\n\nConsider pessaries for women who have symptomatic pelvic organ prolapse.\n\nBefore starting treatment with a pessary for women with symptomatic pelvic organ prolapse:\n\ndiscuss with the woman how a pessary could help, and explain it may not help with their urinary and bowel symptoms\n\nexplain that a pessary will only help with their pelvic organ prolapse symptoms while it is in place, and the symptoms will come back when it is removed\n\nexplain that reducing the prolapse with a pessary may cause new stress urinary incontinence.See recommendation 1.7.8 in the NICE guideline on urinary incontinence and pelvic organ prolapse for further discussions to have with women before starting treatment with a pessary.\n\nIf women using a pessary experience new stress urinary incontinence, offer them a choice of treatment for the incontinence or removal of the pessary.\n\nFor more guidance on pessaries for women with symptomatic pelvic organ prolapse, see the section on pessaries in the NICE guideline on urinary incontinence and pelvic organ prolapse.\n\nFor women who are self-managing their intravaginal device or pessary, explain how they can seek advice from a healthcare provider if they have problems.\n\nFor guidance on reviewing pessaries for women who are at risk of complications, for example because of a physical or cognitive impairment, see recommendation 1.7.9 in the NICE guideline on urinary incontinence and pelvic organ prolapse.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on intravaginal devices and pessaries\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: physical devices for the management of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Psychological interventions\n\nDiscuss the psychological impact of their symptoms with women who have pelvic floor dysfunction. Take account of this impact when developing a management plan.\n\nFor more guidance on psychological management, see the:\n\nNICE guideline on antenatal and postnatal mental health\n\nNICE guideline on depression in adults with a chronic physical health problem.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on psychological interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: psychological therapy for women with pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Behavioural approaches\n\nOffer supported bladder retraining (combined with other interventions, such as pelvic floor muscle training) to women with urinary frequency, urgency or mixed incontinence.\n\nFor women with faecal incontinence, see the section on diet, bowel habit and toilet access in the NICE guideline on faecal incontinence in adults. (The recommendations in this guideline may also be relevant for women under\xa018.)\n\nWhen choosing a behavioural intervention, take into account that prompted toileting and habit training may be particularly suitable for women with cognitive impairment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on behavioural approaches\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0P: behavioural approaches to the management of symptoms.\n\nLoading. Please wait.\n\n## Medicines\n\nDo not offer vaginal diazepam to treat pelvic floor dysfunction, even for women with high muscle tone.\n\nFor guidance on medicines for urinary incontinence and faecal incontinence associated with pelvic floor dysfunction, see the NICE guideline on urinary incontinence and pelvic organ prolapse in women and the section on medication in the NICE guideline on faecal incontinence in adults. (The recommendations on medicines in these guidelines may also be relevant for women under\xa018.)\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on medicines\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0Q: pharmacological management.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\n## Pelvic floor muscle training\n\nExercise to improve pelvic floor muscle strength, endurance, power, relaxation, or a combination of these. For more information, see the definition of pelvic floor muscle training in the International Continence Society and International Urogynecological Association's joint report on the terminology for the conservative and non-pharmacological management of female pelvic floor dysfunction.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## How to provide pelvic floor muscle training\n\nWhat is the most effective way to provide pelvic floor muscle training (covering the type of training, the timing, and who should supervise it), to improve adherence and prevent pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing pelvic floor dysfunction in young women\n\nIs pelvic floor muscle training for young women (between 12\xa0and 17\xa0years) effective in preventing pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing pelvic floor dysfunction during pregnancy for women in higher-risk groups\n\nHow effective is pelvic floor muscle training in preventing pelvic floor dysfunction during pregnancy in women who are in higher-risk groups?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Lifestyle factors to reduce the risk of pelvic floor dysfunction\n\nWhat lifestyle factors reduce the risk of developing pelvic floor dysfunction (diet, reducing carbonated drink and caffeine intake)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity and diet and other modifiable risk factors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: lifestyle factors for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Prediction tools\n\nWhat is the effectiveness of prediction tools for identifying women who are at risk of pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: prediction tools for pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing pelvic floor dysfunction in older women\n\nIs pelvic floor muscle training effective in preventing pelvic floor dysfunction for older women (aged 65\xa0and over), and women in the perimenopausal or postmenopausal phases?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Coexisting long-term conditions\n\nWhat coexisting long-term conditions (for example, chronic respiratory disorders) are associated with a higher risk of pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: coexisting long-term conditions and pelvic floor dysfunction.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Lifestyle factors to reduce the risk of pelvic floor dysfunction\n\nWhat are the long-term effects of different types, intensities and frequencies of physical activity for preventing symptoms associated with pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity and diet and other modifiable risk factors\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: lifestyle factors for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Universal postnatal pelvic floor muscle training for preventing pelvic floor dysfunction\n\nIs universal postnatal pelvic floor muscle training effective in preventing pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Pelvic floor muscle training for preventing bowel symptoms associated with pelvic floor dysfunction\n\nHow effective is pelvic floor muscle training in preventing bowel symptoms associated with pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pelvic floor muscle training for the prevention of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Weight loss for managing pelvic floor dysfunction\n\nCan weight loss reduce symptoms of pelvic floor dysfunction in women who are overweight or obese?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on weight loss\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: weight loss interventions.\n\nLoading. Please wait.\n\n## Diet for managing pelvic floor dysfunction\n\nWhat changes in diet can improve symptoms associated with pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on diet\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: dietary factors for the management of symptoms.\n\nLoading. Please wait.\n\n## Weight training to improve symptoms of pelvic floor dysfunction\n\nHow effective is weight training at improving symptoms associated with pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: physical activity for the management of symptoms.\n\nLoading. Please wait.\n\n## Unsupervised physical activity to improve symptoms of pelvic floor dysfunction\n\nHow effective is unsupervised physical activity (such as walking or swimming) at improving symptoms associated with pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on physical activity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: physical activity for the management of symptoms.\n\nLoading. Please wait.\n\n## Psychological interventions to manage symptoms of pelvic floor dysfunction\n\nHow effective are psychological interventions (either on their own or combined with other interventions) in the management of pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on psychological interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0O: psychological therapy for women with pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Raising awareness about pelvic floor dysfunction\n\nAre community-based strategies effective in raising awareness about the prevention of pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on raising awareness of pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: community information strategies.\n\nLoading. Please wait.\n\n## Information valued by young women with pelvic floor dysfunction\n\nWhat are the experiences and information needs of young women (between 12\xa0and 17\xa0years) with pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: information provision related to the management of pelvic floor dysfunction (people's views and experiences).\n\nLoading. Please wait.\n\n## Effective ways of supporting women to start and continue interventions for pelvic floor dysfunction\n\nWhat is the best way to support women to start and continue interventions for pelvic floor dysfunction (for example, apps, decision aids, or behavioural change techniques)?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: information provision about management of pelvic floor dysfunction (most effective ways).\n\nLoading. Please wait.\n\n## Effective ways of providing information to women with pelvic floor dysfunction\n\nWhat are best ways to provide information about pelvic floor dysfunction to young women (between 12\xa0and 17\xa0years), and to groups defined by protected characteristics under the Equality Act?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on communicating with and providing information to women with pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: information provision about management of pelvic floor dysfunction (most effective ways).\n\nLoading. Please wait.\n\n## Medicines for pelvic floor dysfunction\n\nIs vaginal oestrogen effective at treating the symptoms of pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on medicines\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0Q: pharmacological management.\n\nLoading. Please wait.\n\n## Community-based multidisciplinary pelvic floor dysfunction teams\n\nWhat roles are needed in a community-based multidisciplinary pelvic floor dysfunction team?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on community-based multidisciplinary teams\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0R: community-based multidisciplinary teams.\n\nLoading. Please wait.\n\n## Intravaginal devices and pessaries combined with pelvic floor muscle training for managing pelvic floor dysfunction\n\nHow effective is a pessary or intravaginal device combined with pelvic floor muscle training for managing pelvic floor dysfunction, compared with pelvic floor muscle training alone?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for managing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: pelvic floor muscle training for the management of symptoms.\n\nLoading. Please wait.\n\n## Virtual and in-person contact time for pelvic floor muscle training\n\nHow effective is virtual contact with a trainer, compared with in-person contact, for pelvic floor muscle training?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on pelvic floor muscle training for managing pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: pelvic floor muscle training for the management of symptoms.\n\nLoading. Please wait.\n\n## Anal plug devices and rectal irrigation for the management of bowel symptoms in women with pelvic floor dysfunction\n\nHow effective are anal plug devices and rectal irrigation for bowel symptoms in women with pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on intravaginal devices and pessaries\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: physical devices for the management of pelvic floor dysfunction.\n\nLoading. Please wait.\n\n## Multiple pregnancy as an independent risk factor for pelvic floor dysfunction\n\nIs multiple pregnancy an independent risk factor for pelvic floor dysfunction?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on risk factors for pelvic floor dysfunction\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: risk factors for pelvic floor dysfunction.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Raising awareness of pelvic floor dysfunction for all women\n\nRecommendations 1.1.1 to 1.1.11\n\n## Why the committee made the recommendations\n\nThe evidence was limited to 1\xa0study, so most of the recommendations were based on the committee's knowledge and experience. However, this study did show that teaching pelvic floor health in school improved young women's understanding of their pelvic floor anatomy.\n\nImproving women's knowledge of pelvic floor health is important because this increases the chance they will take action to prevent pelvic floor dysfunction (for example, through lifestyle changes and pelvic floor muscle training). The range of communication formats and strategies recommended is broad, because pelvic floor dysfunction can happen to any woman, so different strategies will be more effective for different groups of women. The committee discussed what the content of this information should be and decided that this would need to be tailored to the individual and the situation in which it is provided (for example, they noted that information provided during school lessons would likely have a different focus to information provided at a local community group). However, to ensure information is accurate and useful, it should include the topics highlighted in recommendation 1.1.1. The committee acknowledged that there can be groups of women that experience inequalities (for example, in access to services). When there is evidence of this, the committee noted that local authorities should consider designing information programmes that increase awareness of the condition with the aim of advancing equality in healthcare provision and fostering good relations with communities.\n\nHealthcare professionals themselves need to understand enough about pelvic floor dysfunction to discuss it with women. In the committee's experience, this is not consistently taught during training, so they made a recommendation that this should be added to the syllabus for relevant professionals.\n\nThe committee believed it was particularly important to raise awareness in maternity services; this is when symptoms can first occur, when risk factors can be identified and when prevention strategies can be started. The recommendations could lead to midwives providing information about pelvic floor dysfunction many times during a woman's pregnancy. However, the committee believe this is reasonable, because it gives the midwife an opportunity to normalise the topic and time to discuss it in detail. Normalisation is important, because embarrassment often gets in the way of discussions about pelvic floor dysfunction. The committee also noted that frequent discussions would reinforce the message and improve adherence to prevention or management, which is key to their effectiveness.\n\nBecause of the sparsity of evidence, and the potential benefits of raising awareness of pelvic floor dysfunction, the committee made a recommendation for research on raising awareness about pelvic floor dysfunction.\n\n## How the recommendations might affect practice and services\n\nPelvic floor dysfunction is not currently covered in the school curriculum. However, sex and relationship education is already a compulsory part of the curriculum, and pelvic floor dysfunction could be covered as part of these classes.\n\nSchool nurses and nurses in other education settings could also be involved in raising awareness of pelvic floor dysfunction. There are already resources available on this topic (for example, this video on pelvic floor by NHS Highland).\n\nReturn to recommendations\n\n# Risk factors for pelvic floor dysfunction\n\nRecommendations 1.2.1 to 1.2.3\n\n## Why the committee made the recommendations\n\nInterpreting the evidence was difficult, because there was a lot of variation in how the studies were done, the way risk factors were defined, and which symptom each risk factor affected. However, the evidence did consistently reflect the committee's experience.\n\nThe evidence suggested a number of modifiable and non-modifiable risk factors. The committee recommended advising women of these, so that they are aware of their risks, and (for modifiable factors) they can take steps to reduce them. For example, the evidence showed that constipation is a risk factor for pelvic floor dysfunction (the committee believe that this is because of the straining involved). For women with constipation, there are recommendations on diet to help with constipation and reduce their risk of pelvic floor dysfunction (see recommendation 1.3.3 and recommendation\xa01.6.9).\n\nAlthough some risk factors are non-modifiable (such as age or familial history), the committee agreed that it is still useful for women to be told about these. This is because if women know about their risks, they may be encouraged to reduce any modifiable risk factors and use preventative interventions (such as pelvic floor muscle training). Women with some of these risk factors will also be offered supervised pelvic floor muscle training (see the recommendations on pelvic floor muscle training).\n\nFor the risk factors related to vaginal birth, the committee discussed whether more information was needed in the recommendations, because these risk factors affect the decision to have a vaginal or caesarean birth. However, women consider many other factors beyond pelvic floor dysfunction when deciding on mode of birth. The committee decided not to make further recommendations on this, because the NICE guideline on caesarean section goes into much more detail on the benefits and risks of caesarean and vaginal birth.\n\nDue to the evidence being unclear, the committee made a recommendation for research on whether multiple pregnancy is an independent risk factor for pelvic floor dysfunction.\n\nThere was evidence for a variety of physical coexisting conditions associated with pelvic floor dysfunction. There was variation in the quality of the evidence because in some studies, the inclusion criteria were not clearly described. In addition, although some conditions were shown to increase the risk of pelvic floor dysfunction, there was uncertainty around how large this increase is. Because of this, the committee did not list every condition identified in the studies. Instead, they highlighted the conditions that have a direct impact on the pelvic floor muscles, when the risk of pelvic floor dysfunction in the evidence aligns with their own experience.\n\nFor some conditions that may increase the risk of pelvic floor dysfunction (such as hypermobility, neurological disease and mental health problems), there was little evidence on their effect. In addition, there was only limited evidence on the effect of respiratory disease and chronic cough on the full range of symptoms, and this is particularly important because of the COVID‑19 pandemic. A recommendation for research on coexisting long-term conditions was made to address these evidence gaps.\n\nThere are groups of women who have an increased risk of developing pelvic floor dysfunction. There are also interventions that can help prevent pelvic floor dysfunction (see the section on physical activity and diet and the section on pelvic floor muscle training). Because of this, it would be useful to have an effective tool for predicting pelvic floor dysfunction so that women at higher risk can be prioritised for pelvic floor muscle training programmes. However, there was no evidence on the effectiveness of existing tools. The committee agreed this was an important area for further study, and made a recommendation for research on prediction tools.\n\n## How the recommendations might affect practice\n\nThe recommendations will standardise the information and advice that is provided to women, to enable better shared decision making. There are no significant costs associated with this, because providing information is already standard practice. The costs of the time taken to give this information would be outweighed by better satisfaction with services and the potential for avoiding future pelvic floor dysfunction.\n\nReturn to recommendations\n\n# Physical activity and diet and other modifiable risk factors\n\nRecommendations 1.3.1 to 1.3.8\n\n## Why the committee made the recommendations\n\nThe evidence suggested that physical activity, healthy diet and appropriate fluid intake help to prevent pelvic floor dysfunction. The quality of the evidence was low because some studies did not account for other factors that could potentially explain the findings. However, it reflected the committee's experience in clinical practice and was in line with standard UK diet and physical activity guidance.\n\nOne of the risk factors for pelvic floor dysfunction is constipation, and in the committee's experience, 1\xa0way this can be addressed is by adjusting fluid intake. Public health guidance does not clearly define ideal levels of fluid intake, and there are differences in the fluid needs of individuals (for example, people need more fluid if they are very physically active). The committee therefore decided not to give their own definition of appropriate fluid intake.\n\nThe committee recognised that there were other modifiable risk factors: body mass index (BMI) over 25\xa0kg/m2, smoking and diabetes, and they referenced relevant NICE guidance for management strategies for these, which would help prevent pelvic floor dysfunction.\n\nThere was only limited evidence on specific dietary factors, such as caffeine and carbonated drinks. To address this, the committee made a recommendation for research on lifestyle factors to reduce the risk of pelvic floor dysfunction.\n\nNo evidence was found on the impact of other lifestyle factors that can prevent symptoms associated with pelvic floor dysfunction (such as pelvic organ prolapse, emptying disorders of the bladder or bowel, sexual dysfunction or chronic pelvic pain syndromes). However, in the committee's experience, physical activity that involves repetitive pelvic floor loading (such as weight training) can improve pelvic floor muscle strength and so prevent symptoms. The committee agreed that more research is needed to support this, particularly in relation to the intensity of physical activity needed, so they made a recommendation for research on long-term effects of different types, intensities and frequencies of physical activity for preventing symptoms associated with pelvic floor dysfunction.\n\n## How the recommendations might affect practice\n\nCurrently, lifestyle advice is given to women to help with the management of symptoms of pelvic floor dysfunction. However, lifestyle advice is rarely considered as part of pelvic floor dysfunction prevention, because these women are symptom free. Therefore, these recommendations will help standardise the advice women receive on preventing pelvic floor dysfunction.\n\nReturn to recommendations\n\n# Pelvic floor muscle training for preventing pelvic floor dysfunction\n\nRecommendations 1.3.9 to 1.3.16\n\n## Why the committee made the recommendations\n\nThe available evidence covered women in 3\xa0settings: community, antenatal and postnatal. It specifically addressed pelvic floor dysfunction and associated symptoms (including urinary incontinence, pelvic organ prolapse and sexual dysfunction).\n\nIn addition to the research evidence, the committee also took account of the Independent Medicines and Medical Devices Safety Review and the NHS Long Term Plan, which made recommendations on pelvic floor muscle training.\n\nPelvic floor muscle training was shown to prevent symptoms of pelvic floor dysfunction in all 3\xa0settings. Evidence was not available for some symptoms (such as faecal incontinence and pelvic pain). The training was most effective in the short term. The committee noted that most studies looked at pregnant women (antenatal and postnatal). However, all healthcare professionals can provide encouragement to all women doing pelvic floor muscle training in all settings (there are already resources available on this, such as the video on pelvic floor by NHS Highland). Because there are particular obstetric risk factors associated with pelvic floor dysfunction (see the section on risk factors), pelvic floor muscle training could be particularly beneficial for pregnant women. The evidence supported this, because pelvic floor muscle training was shown to be effective in preventing pelvic floor symptoms when started during or after pregnancy.\n\nMost of the evidence was for a narrow age range of women in their twenties or thirties. However, there was a consistent pattern of risk reduction across this group. The committee believed that this supported them in making recommendations for women of all ages.\n\nAn economic analysis showed that antenatal supervised pelvic floor muscle training is likely to be cost effective for some pregnant women:\n\nthe evidence suggested that women who have a first-degree relative with pelvic floor dysfunction are at higher risk\n\nthe committee identified 3\xa0risk factors related to labour that they thought would increase risk.\n\nHowever, there was some uncertainty about the conclusion generated from the economic analysis, which was based on evidence from only 1\xa0study. Because of these limitations, and the costs of providing supervised pelvic floor muscle training to such a large group, the committee did not recommend routinely offering training to all of these women. The committee still recommended the training as an option, because it is likely to be cost effective for some women in these groups.\n\nThe committee did not include 'an active second stage labour taking more than 1\xa0hour' in the recommendation on supervised pelvic floor muscle training. This is because it is quite common (so would have a high potential cost), and the evidence on this was inconsistent (some studies showed an increased risk when labour was longer than 1\xa0hour, but others did not show increased risk when it was longer than 20\xa0minutes).\n\nIn all the studies, pelvic floor muscle training was supervised by a trained healthcare professional. The committee agreed that this is important for ensuring that pelvic floor muscle contraction and relaxation is done correctly. In their experience, it is also important to tailor the training for each woman, to ensure that it is manageable and will meet their training goals.\n\nThere was limited evidence on long-term effectiveness, because only 2\xa0studies had a longer follow-up period (12\xa0months in 1\xa0study, and 8\xa0years in the other). However, all the studies showed that adherence decreased over time. In the committee's experience, continuing with the training is key for continued prevention of symptoms, and they agreed that low long-term adherence is likely to explain the limited evidence for long-term effectiveness. To address adherence problems, the committee made the recommendation on encouraging women to continue pelvic floor muscle training.\n\nThe committee made recommendations for research to investigate several gaps in the evidence:\n\nMost effective ways to provide training: the studies did not give much detail on how training should be done.\n\nYounger women: there was no evidence on training for young women (between 12\xa0and\xa017).\n\nOlder women: there was only 1\xa0study supporting training for women over\xa060.\n\nWomen who are pregnant and at particular risk of pelvic floor dysfunction: there was little evidence specific to women who are pregnant and have particular risk factors.\n\nFaecal incontinence and emptying disorders of the bowel: there was no evidence on whether pelvic floor muscle training improves these symptoms (which can be particularly distressing).\n\nThe Independent Medicines and Medical Devices Safety Review recommended 'that the NHS adopts the French model for universal postnatal pelvic floor rehabilitation', to help prevent pelvic floor dysfunction. This model includes 10\xa0sessions of routinely prescribed perineal rehabilitation sessions (pelvic floor muscle training with manual internal techniques, biofeedback and electrical stimulation) starting at least 8\xa0weeks after birth, regardless of symptoms. The committee did not think the evidence (in particular the cost-effectiveness evidence) was strong enough to support this for all women during or after pregnancy. Instead, they identified the risk factors that put women at the greatest risk, for which pelvic floor training was most likely to be cost effective. They also made a recommendation for research on universal postnatal pelvic floor muscle training to investigate further.\n\n## How the recommendations might affect practice\n\nCurrently, pelvic floor muscle training is rarely used for prevention, and is usually only considered and taught to women when they develop symptoms (such as urinary incontinence). There would likely be a significant resource impact if training was provided to all women with the risk factors specified in the recommendation (particularly given the size of the population who would be eligible). Some of this cost is likely to be offset by savings from preventing or delaying pelvic floor dysfunction.\n\nPregnant women receive information on pelvic floor muscle training. However, this is usually general advice rather than specific instructions or supervised sessions. Women are not routinely told about how pelvic floor muscle training can help prevent sexual dysfunction during and after pregnancy. The recommendations ensure that all women are getting information on the benefits of pelvic floor muscle training to prevent pelvic floor dysfunction. This will standardise practice.\n\nReturn to recommendations\n\n# Communicating with and providing information to women with pelvic floor dysfunction\n\nRecommendations 1.4.1 to 1.4.7\n\n## Why the committee made the recommendations\n\nQualitative evidence showed that women with pelvic floor dysfunction perceived some communication styles as unhelpful. It also indicated that some women are not given enough information to understand their symptoms, diagnosis, investigations or treatment. The quality of the evidence was mixed, because of concerns about methodological limitations in the design of the studies. The committee also made recommendations based on their own experience, in areas where there was no evidence (such as video and telephone consultations).\n\nThe recommendation on asking women if they want their family, carers or other people involved is particularly important for addressing potential barriers to support for women with cognitive impairments.\n\nPelvic floor dysfunction is a complex condition, with particular communication issues (such as embarrassment). Based on the evidence and on their experience, the committee highlighted key issues to take into account when discussing pelvic floor dysfunction with women.\n\nBecause of the COVID‑19 pandemic, many services are being provided remotely. In the committee's experience, this has been well received by some women. A particular benefit of remote services can be reduced embarrassment (both for women and for healthcare professionals), which makes women more willing to discuss problems. However, even though this may be the case for some women, the committee acknowledged that it may be harder for the healthcare professional to identify whether symptoms may not be reported because of embarrassment during a remote consultation.\n\nThe committee made recommendations for research in areas where there was no evidence:\n\neffective ways of providing information to young women (between 12\xa0and 17\xa0years) and women with protected characteristics (such as physical or learning disabilities)\n\neffective ways of supporting women to start and continue interventions for pelvic floor dysfunction\n\ninformation valued by young women with symptoms of pelvic floor dysfunction.\n\n## How the recommendations might affect practice\n\nHealthcare professionals already discuss pelvic floor dysfunction with women and provide information on this. However, the information given and how it is communicated can vary, and these recommendations will standardise the process. Because the symptoms of pelvic floor dysfunction are often distressing and embarrassing, communication and sensitivity are very important for all healthcare professionals to ensure good care is provided.\n\nServices already use translation services as needed to overcome communication barriers. However, there may be an impact in areas where video consultation or digital information aids are not currently available.\n\nReturn to recommendations\n\n# Assessment in primary care\n\nRecommendations 1.5.1 to 1.5.7\n\n## Why the committee made the recommendations\n\nThere are a number of signs and symptoms associated with pelvic floor dysfunction. However, there was no evidence on which assessments are needed in non-specialist care to identify these signs and symptoms. Because of this, the committee made recommendations based on their clinical expertise, highlighting the investigations they use in their practice and the most important signs and symptoms to look out for.\n\nThere was evidence that healthcare professionals may overlook symptoms of pelvic floor dysfunction in women who have recently given birth. The evidence also highlighted that there are common misconceptions about pelvic floor dysfunction during and after pregnancy, which can prevent women from seeking care early. To address this, the committee emphasised that women who have recently given birth should be asked about symptoms.\n\nIn the committee's experience, many medications can impact on symptoms of pelvic floor dysfunction. In addition, this impact is often larger for people who are taking multiple medicines. Because of this, a medication review is important.\n\nA focused history is important for identifying the likely cause of any symptoms, because many of the symptoms of pelvic floor dysfunction can be caused by other conditions as well.\n\nThe committee highlighted some of the examinations that would be needed to clarify whether symptoms are likely to be associated with pelvic floor dysfunction or not. Because some of these are intimate examinations, they highlighted the importance of checking the woman's preferences and ensuring a private space is available.\n\nFurther assessments are described in the NICE guideline on urinary incontinence and pelvic organ prolapse in women and the section on baseline assessment in the NICE guideline on faecal incontinence. These guidelines only cover adults, but many of the initial assessments recommended are non-specialist and the committee agreed that they could be relevant for younger women (aged\xa012\xa0to\xa017) in primary care.\n\n## How the recommendations might affect practice\n\nPelvic floor dysfunction is a complex condition, and there is currently variation in how it is assessed. These recommendations will ensure consistency in the initial assessments that are done in primary care.\n\nReturn to recommendations\n\n# Community-based multidisciplinary teams\n\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\n\nThere was limited evidence on team-based approaches for managing pelvic floor dysfunction. However, the available evidence reflected the committee's experience in practice. They decided that the range of competencies needed could not be covered by 1\xa0healthcare professional alone, and so a multidisciplinary team approach should be considered. Because pelvic floor dysfunction can happen to any woman, multidisciplinary teams will need a wide range of skills to be able to care for all women who need support. The committee agreed that several teams could be needed (for example, a team for pregnant women and another for older women). These teams would need to be community based, to ensure that care is accessible to all women.\n\nAdherence and satisfaction with care are important factors in effective management of pelvic floor dysfunction, and the committee agreed that these would also be improved by community-based multidisciplinary teams.\n\nThe experience and training of multidisciplinary team members is likely to vary widely in different areas. Because of this, the committee made a recommendation on competencies, based on their own experience of the key knowledge and experience that is needed in the team to implement the other recommendations in this guideline.\n\nThe committee did not recommend including specific roles (such as specialist continence advisors) in the team, because community healthcare professionals can be trained to carry out non-specialist assessment, and because including specific specialists in every team could have substantial costs. The committee made a recommendation for research on the roles needed in community-based multidisciplinary pelvic floor dysfunction teams.\n\nWhen agreeing a management plan, it is important to involve the woman with pelvic floor dysfunction, to ensure the plan takes account of her needs, preferences and goals.\n\n## How the recommendations might affect practice\n\nCommunity-based multidisciplinary teams may represent a change to current practice, because there is variation in their availability. Pelvic floor dysfunction is a common condition, and other services (such as community-based continence services) could form the basis of these teams. The committee decided that the benefits of good pelvic floor dysfunction management would outweigh potential costs associated with setting up community-based multidisciplinary teams.\n\nThere is currently variation in the competencies that community-based multidisciplinary teams have on assessing and managing pelvic floor dysfunction. There would be upfront costs for training healthcare professionals in the competencies recommended in this guideline, but these costs would be outweighed by better long-term outcomes (improved identification of symptoms and better management as a result).\n\nReturn to recommendations\n\n# Lifestyle changes\n\n## Encouraging women to make lifestyle changes\n\nRecommendation 1.6.4\n\nThe evidence showed that positive communication improves patient motivation and adherence to lifestyle changes. This was also consistent with the committee's experience. It can take time for women to see a benefit from lifestyle changes, so the committee believed it was important to emphasise encouraging and motivating women in the recommendation.\n\nAll healthcare professionals communicate with women and this recommendation will raise awareness that this communication should not be framed only in a negative way but provide positive messages when appropriate.\n\nReturn to recommendation\n\n## Weight loss\n\nRecommendations 1.6.5 to 1.6.8\n\nThe evidence showed that in women with a BMI over 30\xa0kg/m2, weight loss helped with urinary incontinence and overactive bladder. In the committee's experience, excess body weight exacerbates these symptoms by putting pressure on the pelvic floor muscles and organs, so weight loss will be particularly beneficial. The evidence did not show any effect from weight loss on symptoms of pelvic organ prolapse. However, the committee still believe that weight loss may be beneficial in the early stages of pelvic organ prolapse, because less weight would press on the pelvic organs and this could improve symptoms.\n\nThe committee recommended against delaying other management options until women have lost weight because:\n\nthere was no evidence on the impact of weight loss for many symptoms of pelvic floor dysfunction and\n\nthere are other interventions that could benefit women with pelvic floor dysfunction.\n\nBecause other NICE guidelines cover helping people to lose weight, the committee referred to these guidelines rather than making new recommendations on weight loss interventions.\n\nThe committee made a recommendation for research to address the lack of evidence on whether weight loss can reduce symptoms of pelvic floor dysfunction.\n\nWeight loss referral related to pelvic floor dysfunction differs across the country. The recommendations would reduce variation and promote consistency in care.\n\nReturn to recommendations\n\n## Diet\n\nRecommendations 1.6.9 and 1.6.10\n\nThere was some evidence suggesting that reducing caffeine intake helps with urinary incontinence and overactive bladder, and this was supported by the committee's experience in practice.\n\nNo evidence was found on other symptoms associated with pelvic floor dysfunction. However, the committee agreed that in their experience, addressing fluid intake can help with symptoms by promoting an ideal stool consistency. Public health guidance does not clearly define ideal levels of fluid intake, and there are differences in the fluid needs of individuals (for example, people need more fluid if they are very physically active). The committee therefore decided not to give their own definition of appropriate fluid intake.\n\nA balanced diet also reduces the risk of constipation and so would indirectly reduce the risk of pelvic floor dysfunction. This is particularly important for women with pelvic organ prolapse, faecal incontinence, emptying disorders of the bowel and chronic pelvic pain syndromes.\n\nThe committee believed that more research specific to pelvic floor dysfunction related to food rather than fluid intake is needed, and therefore made a recommendation for research on diet to address this.\n\nThese recommendations are in line with current clinical practice. Clinicians will already be familiar with the practical details of lifestyle changes that can be made to promote pelvic floor health, and lifestyle changes are a common aspect of management for symptoms of pelvic floor dysfunction.\n\nReturn to recommendations\n\n## Physical activity\n\nRecommendations 1.6.11 and 1.6.12\n\nThere was some evidence on urinary incontinence, overactive bladder and pelvic organ prolapse. The evidence showed that physical activity could improve these symptoms, but the physical activity programmes in these studies were supervised and included pelvic floor muscle training as part of the interventions.\n\nThe physical activity interventions covered were yoga, pilates, weight training and aerobic exercises. However, it was not clear from the studies what type of exercises were beneficial, because they were usually combined with some form of pelvic floor muscle training. Because of this, the committee did not recommend specific activities. The committee know from their own experience that women often ask whether physical activity could improve or worsen their symptoms. Because of the evidence that showed some improvement, they made a recommendation in favour of supervised exercise. 'Supervised' exercise is specified because certain exercises, if done incorrectly, can weaken the pelvic floor by increasing intra-abdominal pressure. This could worsen symptoms of pelvic floor dysfunction.\n\nThere is no evidence that unsupervised physical activity improved or worsened symptoms of pelvic floor dysfunction. The committee acknowledged that there are general health benefits associated with having an active lifestyle. Therefore, they also made a recommendation for research on unsupervised activities (in particular, common activities such as walking and swimming).\n\nHeavy lifting has been considered a risk factor for damaging the pelvic floor by increasing intra-abdominal pressure. The NICE guideline on urinary incontinence and pelvic organ prolapse in women recommends minimising heavy lifting. However, a more recent study showed that weight training combined with pelvic floor muscle training could improve symptoms of urinary incontinence. Because there was uncertainty around the evidence and it was not entirely consistent with the committee's experience, they made a recommendation for research on weight training to investigate this further.\n\nThe recommendations cover providing information, which is part of current practice, so there should be no cost to services. These recommendations will ensure women are educated on exercises they can do to improve their symptoms and exercises that are not harmful. In addition, they will help standardise the information being provided.\n\nReturn to recommendations\n\n# Pelvic floor muscle training for managing pelvic floor dysfunction\n\nRecommendations 1.6.13 to 1.6.20\n\n## Why the committee made the recommendations\n\nThe evidence showed that pelvic floor muscle training improves several symptoms of pelvic floor dysfunction (pelvic organ prolapse, stress and mixed urinary incontinence, and faecal incontinence with coexisting pelvic organ prolapse). There was greater uncertainty around the findings on faecal incontinence with coexisting pelvic organ prolapse, because there was much less evidence in this area.\n\nFor pelvic organ prolapse, the evidence showed a benefit from pelvic floor muscle training for prolapse that does not extend more than 1\xa0cm beyond the hymen. This matched the committee's experience, because they agreed that more extensive pelvic organ prolapse would be managed in specialist care.\n\nThe recommended lengths of time for the training programmes are based on the most common time points used in the studies for assessing the benefit of training. This was 16\xa0weeks for pelvic organ prolapse and faecal incontinence, and 3\xa0months for urinary incontinence. The committee noted that this would give enough time to assess whether the training improved symptoms. This is also consistent with the recommendations on pelvic floor muscle training in the NICE guideline on urinary incontinence and pelvic organ prolapse in women.\n\nIn addition to the research evidence, the committee also took account of the Independent Medicines and Medical Devices Safety Review and the NHS Long Term Plan, which made recommendations on pelvic floor muscle training.\n\nSee the rationale section on pelvic floor muscle training for preventing pelvic floor dysfunction, for an explanation of the recommendations on supervising pelvic floor muscle training.\n\nFor additional therapies, such as weighted vaginal cones, biofeedback and electrical stimulation, the evidence was inconsistent. Some studies showed benefits, and others showed no effect. Some of the evidence suggested that these interventions could help women with pelvic floor muscle training by improving their ability to contract their pelvic floor muscles. In the committee's experience, effective pelvic floor contractions and relaxations are important for improving pelvic floor dysfunction symptoms and most women are able to do this as part of a supervised pelvic floor muscle training programme. However, the committee believed that supplementing a pelvic floor muscle training programme with biofeedback, electrical stimulation or vaginal cones could be cost effective in the subgroup who make little progress during supervised pelvic floor muscle training. These additional therapies are particularly likely to be cost effective if using them allows women to avoid the need for surgical intervention.\n\nBased on their experience, the committee thought it would be important that women are advised to continue doing pelvic floor muscle training and that they have the opportunity to discuss progress in regular reviews during the initial training programme. The committee believed that reviews with a healthcare professional improve adherence, which is important for the long-term effectiveness of pelvic floor muscle training.\n\nThere was some evidence suggesting that training in a group improved adherence and symptoms, but it was not consistently found to be more effective than individual training. This was supported by the committee's experience, because some women benefit from peer support whereas others feel more motivated with one-to-one supervision. To take account of this, the committee recommended giving women a choice of group or individual training. One-to-one supervision is more expensive than group training, but the difference in cost is relatively small and so the approach favoured by each woman is likely to be cost effective.\n\nIt was unclear whether using a pessary or intravaginal device would be effective when combined with pelvic floor muscle training, so the committee made a recommendation for research on intravaginal devices and pessaries. The development of remote clinical practice during the COVID‑19 pandemic also made the committee curious about the effectiveness of virtual pelvic floor muscle training, so they recommended research into the effectiveness of virtual and in-person contact time for pelvic floor muscle training.\n\n## How the recommendations might affect practice\n\nThe recommendations will standardise practice. Pelvic floor muscle training is a key intervention for managing the symptoms of pelvic floor dysfunction and is already widely used in the NHS. However, access to group pelvic floor muscle training classes differs across the country. Although some healthcare services may need to change practice, group pelvic floor muscle training classes are less expensive, so the committee did not anticipate a significant resource impact.\n\nReturn to recommendations\n\n# Intravaginal devices and pessaries\n\nRecommendations 1.6.21 to 1.6.27\n\n## Why the committee made the recommendations\n\nThe evidence on intravaginal devices was unclear, with variance across outcomes. For example, there was no measurable reduction in urinary leakage, but women reported that their symptoms improved. However, the committee noted that a subjective improvement in symptoms was still important, because it is an indication of the woman's perception of the device's success. The committee were also aware from their experience that these devices can help to prevent urinary leakage in certain circumstances (for example, during exercise). Based on the limitations of the evidence and the potential complications, the committee recommended trialling intravaginal devices if other non-surgical options have been tried and have been unsuccessful, so that women could decide whether they were beneficial before using them long term.\n\nThis differs from recommendation 1.4.23 in the NICE guideline on urinary incontinence and pelvic organ prolapse, which recommends against the use of intravaginal devices. However, the committee noted that recommendation 1.4.23 had not been updated since 2006. Most of the evidence they reviewed for this guideline has been published since 2006. Even though the findings from the evidence were not entirely certain, they decided that these devices should not be ruled out if other non-surgical options were unsuccessful. This would provide another option that may prevent the need for more invasive treatment.\n\nThe evidence on pessaries indicated that they help with symptoms of pelvic organ prolapse while they are in position, and this is in keeping with the committee's clinical experience. However, there was a lack of long-term evidence on the effectiveness and potential complications of pessary use. Because of the uncertainty around pessaries, the committee specified particular benefits and harms to discuss with women, based on the evidence that was available and their clinical experience. This will help women to make an informed decision on whether a pessary is right for them.\n\nIn the committee's experience, women with physical or cognitive impairments may have difficulty in managing an intravaginal device or pessary and are at higher risk of complications. Because of this, these women should have regular appointments to check for complications. The committee also recommended telling women how to self-refer if they are managing the device themselves, so that they know how to get help if they are having problems or if their intravaginal device or pessary does not help.\n\nThere was a lack of evidence on the physical devices available for managing faecal incontinence (which is a particularly distressing symptom). The existing evidence consists of studies in mixed populations of men and women, so it could not be used to make recommendations for the population of this guideline. To address this, the committee made a recommendation for research on anal plug devices and rectal irrigation for managing bowel symptoms in women with pelvic floor dysfunction.\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with current practice on pessaries. There is variation in the use of intravaginal devices, but the recommendations would not involve major changes to practice because it would be an option only if other options had not been successful. Even though this may increase the general use of intravaginal devices, they are already used in some areas. They may also prevent more invasive options (such as surgery) which are more costly.\n\nReturn to recommendations\n\n# Psychological interventions\n\nRecommendations 1.6.28 and 1.6.29\n\n## Why the committee made the recommendations\n\nThe evidence showed a psychological impact from the symptoms of pelvic floor dysfunction. However, the committee noted that there was a lot of uncertainty about this evidence and made recommendations based on their experience and expertise. They made a recommendation emphasising this because women with pelvic floor dysfunction often do not seek help with the psychological impact of their symptoms, and healthcare professionals do not always ask them about it.\n\nSome therapies were shown to improve distress associated with pelvic floor dysfunction, but the studies were very small. There was also evidence that psychological therapy could help with vaginismus, but it was not clear from the studies whether the participants' symptoms were related to pelvic floor dysfunction. The committee decided that they could not recommend therapies based on this evidence.\n\nBecause other NICE guidelines cover identifying and managing mental health problems for people with a chronic health condition, the committee referenced these guidelines instead of making new recommendations on specific psychological interventions.\n\nThere was some evidence showing that psychological interventions improved attendance and adherence to pelvic floor muscle training. However, there were several limitations to this evidence:\n\nit did not show whether the improvement in attendance and adherence was sustained in the long term\n\nalthough some of the interventions improved the mental health of participants, it was not clear whether the interventions also had an impact on symptoms (which could mean that the improvement in mental health may not be sustained in the long term)\n\nthe studies were small.\n\nThese limitations meant that the committee could not make a practice recommendation. However, they do believe that better attendance and adherence to training improves the benefit of pelvic floor muscle training. Because of this, they made a recommendation for research on ways to improve adherence for women who are having this training.\n\n## How the recommendations might affect practice\n\nThe committee agreed that there is variation in practice in how well psychological factors related to pelvic floor dysfunction are considered when planning treatment. The recommendations would not involve major changes to practice, but would standardise current good practice.\n\nReturn to recommendations\n\n# Behavioural approaches\n\nRecommendations 1.6.30 to 1.6.32\n\n## Why the committee made the recommendations\n\nThere was evidence about behavioural techniques including bladder retraining and lifestyle education, provided under direct supervision by a trained healthcare professional. The studies usually included pelvic floor muscle training as part of the interventions. The symptoms covered in the studies included urinary incontinence, urinary urgency and frequency, and faecal incontinence. Evidence was not available for some symptoms (such as emptying disorders of the bladder and bowel).\n\nThe evidence was difficult to interpret because there was variation in the quality of the research and a mixture of different interventions and comparators, which made it difficult to combine results. This meant that it was not clear which aspects of interventions were directly improving the symptoms of pelvic floor dysfunction.\n\nThe evidence showed that behavioural techniques in combination with pelvic floor muscle training improved these symptoms, which was in keeping with the committee's experience in clinical practice. The committee noted that bladder retraining consists of advice about when or how frequently to go to the toilet to encourage a routine that can help prevent incontinence episodes.\n\nThere was some limited evidence suggesting that a combination of behavioural techniques and pelvic floor muscle training was associated with improved adherence and satisfaction. The committee agreed that motivation and adherence were key to long-term benefit. The committee were conscious that behavioural techniques should be tailored to the individual, because ability may differ based on other coexisting conditions (such as cognitive impairment).\n\n## How the recommendations might affect practice\n\nBehavioural techniques involve a wide range of techniques that can be used to change behaviour and teach women skills to reduce symptoms of pelvic floor dysfunction. These techniques are already used by most services, so the recommendations will reinforce current practice.\n\nBladder training can easily be provided in conjunction with a pelvic floor muscle training programme and would not add significant costs.\n\nReturn to recommendations\n\n# Medicines\n\nRecommendations 1.6.33 and 1.6.34\n\n## Why the committee made the recommendations\n\nThere was limited evidence on medicines for general pelvic floor dysfunction. However, the evidence available did show that intravaginal diazepam was not effective at improving symptoms. Although this evidence was based on a small population, the committee were also concerned about the risk of dependency from diazepam use. Because of this risk and the lack of evidence for any benefit, the committee recommended against intravaginal diazepam.\n\nWomen with high muscle tone are specifically mentioned in this recommendation because this is the only group diazepam would be considered for in current practice (because diazepam relaxes muscles and relieves muscle spasms). Because the evidence showed that diazepam was not effective, the committee wanted to make sure it was not used even in this group.\n\nThe NICE guidelines on urinary incontinence and pelvic organ prolapse in women, and faecal incontinence in adults, make recommendations on medicines for symptoms that can be associated with pelvic floor dysfunction. The committee recommended following these recommendations for women with pelvic floor dysfunction, because the medicines recommended are likely to be effective even if the underlying cause of symptoms is different in the other guidelines. They also thought that some of the recommendations in this guideline may also be relevant for women under\xa018.\n\nTopical intravaginal oestrogen is currently used in clinical practice for managing pelvic floor dysfunction. However, no evidence was identified for this, so the committee made a recommendation for research on vaginal oestrogen.\n\n## How the recommendations might affect practice\n\nThe recommendation on intravaginal diazepam will not change current practice, because this is not currently used in the NHS. Because the other recommendation cross refers to other NICE guidance, it will reinforce current guidance and will not have any significant resource impact.\n\nReturn to recommendations", 'Context': 'Pelvic floor dysfunction covers a variety of symptoms. In this guideline, the following symptoms are addressed as long as they are associated with pelvic floor dysfunction: urinary incontinence, emptying disorders of the bladder, faecal incontinence, emptying disorders of the bowel, pelvic organ prolapse, sexual dysfunction and chronic pelvic pain syndromes. The 3\xa0most common and definable conditions are urinary incontinence, faecal incontinence and pelvic organ prolapse.\n\nPrevalence of pelvic floor dysfunction is high. For example, on examination, prolapse is present in up to 50% of women. This can have a significant impact on quality of life, reducing social engagement and ability to be physically active.\n\nThis guideline makes recommendations on common risk factors and on preventative interventions. Ideally, women who are most at risk of pelvic floor dysfunction would be identified early and offered interventions to prevent symptoms developing. This would reduce the impact on women and the NHS.\n\nWhen pelvic floor dysfunction is diagnosed, there is variation in the availability of non-surgical management options, such as pelvic floor muscle training. Women have no clear and effective strategies available to prevent worsening of the condition. This guideline provides a more community-based pathway to address these problems and to reduce the number of women who develop complex symptoms that need specialist care (including surgery).'}
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https://www.nice.org.uk/guidance/ng210
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This guideline covers the prevention, assessment and non-surgical management of pelvic floor dysfunction in women aged 12 and over. It aims to raise awareness and help women to reduce their risk of pelvic floor dysfunction. For women who have pelvic floor dysfunction, the guideline recommends interventions based on their specific symptoms.
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b40e7f84ba9b9a6c0b918efb496796eaa4787813
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nice
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Dupilumab for treating severe asthma with type 2 inflammation
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Dupilumab for treating severe asthma with type 2 inflammation
Evidence-based recommendations on dupilumab (Dupixent) for treating severe asthma with type 2 inflammation that is inadequately controlled in people 12 years and over.
# Recommendations
Dupilumab as add-on maintenance therapy is recommended as an option for treating severe asthma with type 2 inflammation that is inadequately controlled in people 12 years and over, despite maintenance therapy with high-dose inhaled corticosteroids and another maintenance treatment, only if:
the dosage used is 400 mg initially and then 200 mg subcutaneously every other week
the person has agreed to and follows an optimised standard treatment plan
the person has a blood eosinophil count of 150 cells per microlitre or more and fractional exhaled nitric oxide of 25 parts per billion or more, and has had at least 4 or more exacerbations in the previous 12 months
the person is not eligible for mepolizumab, reslizumab or benralizumab, or has asthma that has not responded adequately to these biological therapies
the company provides dupilumab according to the commercial arrangement.
Stop dupilumab if the rate of severe asthma exacerbations has not been reduced by at least a 50% after 12 months.
These recommendations are not intended to affect treatment with dupilumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by them, their clinician, and their parents or carers.
Why the committee made these recommendations
Severe asthma is usually treated with inhaled corticosteroids plus another drug, such as a long-acting beta-agonist. Oral corticosteroids may also be needed to prevent exacerbations (asthma attacks), but they can cause long-term adverse effects. Also, these treatments may not work well enough for severe asthma with type 2 inflammation, which can be difficult to control.
Clinical trial results show that adding dupilumab to standard asthma treatment is more effective than placebo plus standard treatment at reducing the frequency of severe exacerbations, and the use of oral corticosteroids in people with severe asthma with type 2 inflammation.
The company proposes dupilumab 200 mg for very severe asthma with type 2 inflammation in people not eligible for mepolizumab, reslizumab or benralizumab, or whose asthma has not adequately responded to these biological treatments. This is a narrower population than that in the marketing authorisation. It represents people with the highest unmet need and people only eligible for standard care. Dupilumab could be a valuable treatment option in these people because, without it, they will need regular oral corticosteroids.
The cost-effectiveness estimates for dupilumab plus standard care are at the higher end of what NICE usually considers an acceptable use of NHS resources. But there is an unmet need for people with very severe asthma with type 2 inflammation and dupilumab represents an additional treatment option before oral corticosteroids. Also, the benefits associated with avoiding oral corticosteroids to people with this type of asthma and to the NHS may not have been fully captured in the cost-effectiveness estimates. So, dupilumab (200 mg) is recommended for treating inadequately controlled very severe asthma with type 2 inflammation.# Information about dupilumab
# Marketing authorisation indication
Dupilumab (Dupixent, Sanofi) has a marketing authorisation 'in adults and adolescents 12 years and older as an add-on maintenance treatment for severe asthma with type 2 inflammation characterised by raised blood eosinophils and/or raised FeNO who are inadequately controlled with high dose ICS plus another medicinal product for maintenance treatment'. The definition of type 2 inflammation is as in the Global Initiative for Asthma guideline.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of dupilumab is £1,264.89 for 2 prefilled syringes 200 mg per 1.44 ml (excluding VAT; BNF online accessed November 2020).
The company has a commercial arrangement. This makes dupilumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Sanofi Genzyme, a review of this submission by the evidence review group (ERG), NICE's technical report and responses from stakeholders. See the committee papers for full details of the evidence.
# New treatment option
## An additional treatment option that lowers the risk of exacerbations and may reduce the need for oral corticosteroids would be welcome
Severe asthma is a distressing and socially isolating condition. The patient expert explained that exacerbations can happen without warning, be life threatening, cause fear and result in hospitalisation. They further explained that people are often unable to work or start a family, and may need help with day-to-day activities because of their symptoms. The clinical expert explained that, in addition to optimised inhaled treatment, standard treatment for severe asthma is oral systemic corticosteroids or, if the person has eosinophilic asthma, and depending on the blood eosinophil count, NICE recommended interleukin 5 inhibitor biologicals benralizumab, mepolizumab and reslizumab. Dupilumab is the only licensed treatment for severe asthma with type 2 inflammation. Although asthma can respond to systemic corticosteroids, the treatment can be associated with long-term complications (such as diabetes mellitus, weight gain, bone loss, immunosuppression and a negative effect on mental health). The patient expert explained that people with severe asthma with type 2 inflammation would welcome treatment options that replace the need for corticosteroids. The clinical expert explained that a blood eosinophil count and fractional exhaled nitric oxide (FeNO) are used to help define subtypes of severe asthma and help predict the people with severe asthma who are at the highest risk of a future exacerbation. In people with severe asthma with type 2 inflammation, if their condition does not respond to interleukin‑5 inhibitors it may respond to interleukin‑13 inhibitors such as dupilumab. The committee concluded that there is a need for new treatments with a different mode of action for people with severe asthma with type 2 inflammation whose asthma does not respond with current standard care, and for people not eligible for current NICE recommended biologicals.
# Clinical management
## Severe asthma with type 2 inflammation is a subtype of asthma
Severe asthma with type 2 inflammation is associated with allergy, higher risk of exacerbations, hospitalisation and dependency on oral corticosteroids, and increased risk of dying than in people with severe asthma without type 2 inflammation. The Global Initiative for Asthma (GINA) guideline on difficult to treat severe asthma (2021) lists 5 criteria in its definition of severe asthma with type 2 inflammation that are prognostics markers:
a blood eosinophil count of 150 cells per microlitre or more
FeNO of 20 parts per billion or more
sputum eosinophils of 2% or more
asthma that is clinically allergen driven
the need for maintenance oral corticosteroids.GINA suggests that 1 or more criteria can be used to make a diagnosis. The clinical expert explained that raised blood eosinophils and FeNO are predictors for future exacerbations. The committee concluded that this subtype of severe asthma can be characterised as type 2 inflammation.
## Blood eosinophil count and FeNO are common biomarkers for diagnosis
The clinical expert explained that blood eosinophil counts and FeNO levels are routinely measured in clinical practice. They also explained that, while blood eosinophils counts are raised in both eosinophilic asthma and asthma with type 2 inflammation, raised FeNO is more specific to type 2 inflammation. The committee noted the response of stakeholders during technical engagement that a blood eosinophil count of 150 cells per microlitre or more, FeNO of 20 parts per billion or more, or both, could be used for identifying people with type 2 inflammation. The committee acknowledged the complexity of diagnosing asthma subtypes, and the potential for overlap or misclassification between them, despite the use of blood eosinophil counts and FeNO levels.
## Dupilumab as add-on treatment is an option for managing uncontrolled severe asthma with type 2 inflammation
The clinical expert explained that treatment for asthma in clinical practice follows the NICE guideline on diagnosis, monitoring and chronic asthma management and the GINA 2021 guideline (which includes the use of biologicals). If the asthma is still uncontrolled despite optimised inhaled therapy that includes corticosteroids, then low-dose oral corticosteroids or biologicals are added. The clinical and patient experts explained that biologicals are preferred over oral corticosteroids because they have fewer debilitating adverse effects. The choice of biological depends on the subtype of asthma. For severe eosinophilic asthma, according to NICE technology appraisal guidance for benralizumab, mepolizumab and reslizumab, the treatment of choice depends on the blood eosinophil count (300 cells per microlitre or more, or 400 cells per microlitre or more) and the number of exacerbations (3 or 4, or more) or the use of systemic corticosteroids. Omalizumab is another biological recommended by NICE and used for treating severe persistent allergic asthma. However, it is not used for eosinophilic asthma (see section 3.6). There are currently no NICE recommended biologicals for treating severe asthma with type 2 inflammation. The committee concluded that dupilumab as add-on treatment is an option for managing uncontrolled severe asthma with type 2 inflammation.
# Populations
## The company's updated population is suitable for decision making
There are several subgroups to consider when deciding which population to use for decision making. At the first appraisal committee meeting, the committee considered whether the population would need to have a raised eosinophil count, raised FeNO or both based on the 'and/or' wording in the marketing authorisation and GINA recommendations for these biomarkers. The committee also acknowledged that there are subgroups on or off maintenance oral corticosteroids, or both (mixed proportions on and off oral corticosteroids), and populations eligible or not eligible for biologicals. In addition, it acknowledged the overlap between the populations in the marketing authorisation, trials and company decision problem at the first committee meeting:
The marketing authorisation population is broad, consisting of people with uncontrolled severe asthma with type 2 inflammation on high-dose inhaled corticosteroids plus 1 maintenance treatment and with a blood eosinophil count and FeNO as described by GINA.
The clinical trials (DRI12544, QUEST and VENTURE) recruited people with 1 or more exacerbations in the previous 12 months and no restrictions on blood eosinophils and FeNO.The company's decision problem (base case) was in a subpopulation of people not eligible for mepolizumab, reslizumab or benralizumab or whose asthma had not responded to these biological therapies based on a post hoc analysis of the QUEST data. They were 12 years and older and had blood eosinophils counts of 150 cells per microlitre or more, FeNO of 25 parts per billion or more, and at least 4 exacerbations in the previous 12 months. The company considered that this narrower population represented people with the highest unmet need and could be split into 3 subgroups: young people aged 12 years to 17 years, adults not eligible for mepolizumab, reslizumab or benralizumab (a blood eosinophil count 150 cells per microlitre to 299 cells per microlitre) and adults whose asthma had not responded to these biological therapies (blood eosinophil count of 300 cells per microlitre and more). The committee noted that the comparator for the updated population was standard care and other biologicals were only recommended for adults in NICE guidance. The committee concluded that the updated population was suitable for decision making.
# Comparators
## Standard care is the appropriate comparator in the updated population
The clinical trial population in QUEST included people with differing asthma severity (defined by eosinophil level, FeNO and the number of exacerbations in the previous 12 months). These populations therefore included people who would be offered different treatment options in the NHS:
People with a blood eosinophil count of 300 cells per microlitre or more who have had at least 4 exacerbations in the previous 12 months, or who are taking oral corticosteroids, can have mepolizumab or benralizumab.
People with a blood eosinophil count of 400 cells per microlitre or more who have had at least 3 exacerbations in the previous 12 months can have reslizumab, mepolizumab or benralizumab.
People not eligible for biologicals are offered standard care, defined as:
a blood eosinophil count of between 150 and 299 cells per microlitre and 4 or more exacerbations in the previous 12 months (not eligible for mepolizumab or benralizumab)
a blood eosinophil count of between 150 and 399 cells per microlitre and 3 or more exacerbations in the previous 12 months (not eligible for reslizumab or benralizumab)
a blood eosinophil count of less than 150 cells per microlitre and FeNO of 25 parts per billion or more (not eligible for any other biological)
People whose asthma had not responded to biological therapy are offered standard care.The committee concluded that standard care was an appropriate comparator in the company's population, that is, people who are not eligible for mepolizumab, reslizumab or benralizumab or people whose asthma has not responded to these biological therapies.
# Clinical evidence
## The population in QUEST is generalisable to people seen in NHS clinical practice
The clinical evidence for the company's population came from a double-blind placebo-controlled randomised trial, QUEST. This trial compared dupilumab with placebo in 948 people 12 years and over with persistent asthma who had 1 or more exacerbations in the previous 12 months. It included people with moderate to severe asthma, who were not on maintenance oral corticosteroids. It was conducted globally and included people from the UK. QUEST's population was based on the use of moderate-to-high doses of inhaled corticosteroids. This was because it included people from countries such as the US and Japan where, according to the clinical expert, there is a reluctance to use high-dose inhaled corticosteroids. The committee concluded that QUEST was broadly generalisable to NHS practice and appropriate for decision making.
## Dupilumab is more clinically effective than standard care in the clinical trial population
All primary outcomes were reported for the intention-to-treat population in all 3 trials. In QUEST, the coprimary outcome was annualised rate of severe exacerbations and change from baseline in the forced expiratory volume in 1 second (FEV1) at 12 weeks. There was a 47.7% (95% confidence interval 33.8% to 58.7%, p<0.0001) lower rate of severe exacerbations in the dupilumab group compared with placebo. There was an increase in FEV1 at 12 weeks when dupilumab was compared with placebo in QUEST (least squares mean difference 0.20 litre, 95% CI 0.11 to 0.28, p<0.0001). The committee concluded that dupilumab was more clinically effective than standard care in the clinical trial population.
## Dupilumab is clinically effective in the company's population, but estimates are based on a small population
The company proposed dupilumab in a small post hoc population of people from QUEST:
with a blood eosinophil count of 150 cells per microlitre or more, FeNO of 25 parts per billion or more and 4 or more exacerbations in the previous 12 months
who are not eligible for mepolizumab, reslizumab or benralizumab or have had biological therapy.It explained that dupilumab reduced the rate of severe exacerbations when compared with placebo within this subpopulation but was based on small post hoc subgroups. The relative risk ratios are considered confidential by the company so cannot be reported here. The committee noted that dupilumab was clinically effective as an addition to standard care in people who had not had biological therapy and had a blood eosinophil count of at least 150 cells per microlitre, FeNO of 25 parts per billion or more, and 4 or more exacerbations in the previous 12 months. The committee concluded that the clinical-effectiveness evidence for dupilumab in the company's population was limited and based on a small number of people.
## QUEST subgroup analyses support dupilumab's efficacy in the company's populations
The company presented additional subgroup analyses from QUEST on different severities of asthma based on exacerbation level in the previous 12 months, and blood eosinophil and FeNo levels. It did this to support its definition of the population with the highest unmet need. One analysis of the dupilumab's clinical effectiveness showed that, in people randomised to placebo, the adjusted annualised severe exacerbation rate increased with an increasing number of exacerbations in the 12 months before QUEST baseline from 0.871 in people with 1 or more exacerbations to more than 2.563 in those with 4 or more exacerbations. There was also a statistically significant reduction in the adjusted annualised severe exacerbation rate with dupilumab, ranging from a 48% (0.456) reduction compared with placebo in the 1 or more exacerbation group to a 77% (0.571) reduction compared with placebo in the 4 or more exacerbations group. Another analysis assessed adjusted annualised severe exacerbation rate by baseline levels of blood eosinophil count and FeNO. In this, the subgroup with a blood eosinophil count of 150 cells per microlitre or more and FeNO of 20 parts per billion or more (48% of the QUEST population) had the highest adjusted annualised exacerbation rate in people randomised to placebo and the most pronounced treatment effect (66%, p<0.001 rate reduction compared with placebo). The ERG agreed that a raised blood eosinophil count of 150 cells per microlitre or more and FeNO of 20 parts per billion or more represented the group with the highest baseline exacerbation rate and response to dupilumab. The committee considered the additional company analyses were sufficient to support the company's definition of severe asthma with type 2 inflammation, that is, 4 exacerbations or more, a blood eosinophil count of 150 cells per microlitre or more, and FeNO of 20 parts per billion or more. The committee concluded that adding dupilumab to standard care is clinically effective in people with the highest unmet need defined by a blood eosinophil count of 150 cells per microlitre or more and FeNO of 25 parts per billion or more and 4 or more exacerbations in the previous 12 months.
## The proportion of people who have had biological therapy whose asthma will respond to dupilumab is uncertain
The committee had concerns about the company's assumption of equal efficacy with dupilumab in people who have and have not had a biological therapy. In response to its second appraisal consultation document, the company presented real-world evidence on the clinical effectiveness of dupilumab from the UK, Europe and US for people who had mepolizumab, reslizumab or benralizumab. The committee noted that the company's real-world evidence from the UK showed a similar response in people who had and had not had biological therapy. The details of the company's observational evidence are confidential so cannot be reported here. The company's real-world evidence from Europe and the US showed that dupilumab improved asthma control and reduced asthma exacerbations in people with severe asthma who had mepolizumab, reslizumab or benralizumab. The ERG noted several differences in the observational studies from the EU. People had had the 300 mg dose of dupilumab, which is only recommended in people on oral corticosteroids. Also, a high proportion of people had oral corticosteroids compared with people in QUEST who had 200 mg dupilumab. The committee noted that, based on limited retrospective studies with small sizes, dupilumab was effective in improving asthma control and reducing exacerbations in people with severe asthma who had mepolizumab, reslizumab or benralizumab. The committee concluded that dupilumab is likely to be effective in some people whose asthma has not responded to mepolizumab, reslizumab or benralizumab. However, it concluded that the proportion of people who have had mepolizumab, reslizumab or benralizumab whose asthma will respond to dupilumab is uncertain.
# The company's economic model
## The model structure is appropriate for decision making
The company submitted a 4‑state Markov model comparing dupilumab with standard care in people with severe asthma and type 2 inflammation. The model consisted of 4 live health states: uncontrolled asthma; controlled asthma; moderate exacerbation; and severe exacerbation. In addition, the model included states for asthma-related deaths and death from other causes. Response to treatment was defined as a 50% or greater reduction in the annual exacerbation rate, which was assessed at 52 weeks. People whose asthma responded continued on dupilumab and those whose asthma did not respond were transferred to standard care. The company derived the efficacy and clinical parameters in the model from QUEST. The committee concluded that the model structure was appropriate for decision making.
## The evidence for the company's population is limited because it is based on clinical-effectiveness estimates from small sample sizes
The committee noted that the company's population included young people aged 12 years to 17 years, adults not eligible for mepolizumab, reslizumab or benralizumab (blood eosinophil count of 150 cells per microlitre to 299 cells per microlitre) and adults who had biological therapy but whose asthma had not responded (a blood eosinophil count of 300 cells per microlitre or more). The committee noted that the clinical-effectiveness evidence available for the company's populations was limited because the number of people included in QUEST was small (see section 3.11). The trial only included 2 people corresponding to the young-people subgroup and 14 people corresponding to the subgroup of adults not eligible for biologicals. Also, the QUEST protocol excluded people who had had biological therapy but 1 person was included who had had a biological. The ERG noted that the estimates of transition probabilities for the company's population were highly uncertain because of the small sample sizes. The company assumed that clinical effectiveness was the same for each subgroup based on trial estimates for the company's population. The company provided clinical expert opinion that switching from other biologicals (the interleukin‑5 inhibitors: mepolizumab, reslizumab, benralizumab) to dupilumab (a interleukin‑4/13 inhibitor) was acceptable because the mechanisms of action were different enough. The committee considered that the assumption of equal efficacy of dupilumab regardless of whether people had mepolizumab, reslizumab or benralizumab was uncertain. This was because it considered assuming that the response rate would be as good in people not eligible for mepolizumab, reslizumab or benralizumab was optimistic. In response to its second appraisal consultation document, the company provided additional data on the effectiveness of dupilumab in people with asthma that had not responded to mepolizumab, reslizumab or benralizumab. The committee concluded that, because the evidence for dupilumab's clinical effectiveness in the company's population was based on a small number of people, it was limited.
# Clinical inputs to the model
## The company's updated base case does not include a multiplier for long-term severe exacerbation rates
The committee noted that asthma-related mortality often drives cost effectiveness in asthma models. The annual severe exacerbation rate (2.39 exacerbations per year) in the placebo arm of QUEST was lower than that seen in clinical practice in the year before trial enrolment (4.46 exacerbations per year). The company's model after technical engagement used the exacerbation rates from QUEST and VENTURE in the first year of the model. Also, it increased the number of severe exacerbations in subsequent years for both dupilumab and standard care by applying a multiplier. The ERG considered the trial to be the best source of exacerbation data. It did not include an exacerbation multiplier in its base-case model, which resulted in higher incremental cost-effectiveness ratios (ICERs). The company provided evidence on severe exacerbation rates from 3 cohorts with severe asthma: WATCH (Wessex Asthma Cohort of Difficult Asthma), U‑BIOPRED (Unbiased Biomarkers in Prediction of respiratory disease outcomes) and the Sanofi Real World Evidence (RWE) study. It also accepted the committee's and ERG's concerns about the uncertainty of using a multiplier. The exacerbation rates in the company's updated base-case model were taken from QUEST for the duration of the model without an exacerbation multiplier. The committee concluded that the updated base-case model without the exacerbation multiplier was appropriate.
## Real-world evidence is an appropriate source of data to inform the treating severe exacerbations setting
The company assigned different mortality rates to severe exacerbations treated in hospital emergency care, inpatients and general practice based on the UK Difficult Asthma Registry data (O'Neill et al. 2015). In QUEST, 6.7% of severe exacerbations were treated in hospitals (3.0% in emergency care, 3.7% in inpatients and 93.3% in general practice). In the UK Difficult Asthma Registry data, this was 26.5% (7.8% in emergency care, 18.7% in inpatients and 74.0% in general practice), which it thought was a more appropriate estimate of resource use in the NHS. The ERG base-case model used the QUEST data for the setting of severe exacerbations. The clinical expert explained that the number of people treated in hospitals in clinical practice is likely to be higher than that seen in QUEST. This was because people in trials are well monitored on optimised treatment, more motivated and adhere better to treatment. The committee requested further exploration of different sources of data to inform the setting of treating exacerbations to inform the model. The company then submitted data on the setting of treating severe exacerbation rates from 3 different sources (WATCH, U‑BIOPRED and the Sanofi RWE study). The definition of severe exacerbation in the Sanofi RWE study was based on case notes from severe asthma centres in the NHS to match the definition in QUEST. The data for setting exacerbations from the Sanofi RWE study was used in the company's updated model. The ERG considered the Sanofi RWE study to be of reasonable quality and that it produced results consistent with other sources. The committee concluded that the Sanofi RWE study on the setting of severe exacerbations was appropriate for use in the company's base case.
## The company's mortality estimates are appropriate for decision making but uncertain
The company's original model (using the confidential exacerbation multiplier) predicted 20% mortality over 10 years in the standard care arm. The committee questioned the clinical plausibility of this estimate because it seemed high compared with the estimated 1,300 asthma-related deaths a year in the UK. The higher death rate was because of interaction between the exacerbation multiplier (see section 3.14) and using registry data to inform the setting of treating exacerbations (see section 3.15). The committee noted that the model did not offer plausible estimates and asked that additional analyses presented by the company:
include 10‑year mortality rates for dupilumab and standard care and
show the flow of patients through different health states in the model for the purposes of model validation.The company updated its model and removed the exacerbation multiplier (see section 3.15), which reduced 10‑year mortality with standard care to 16.7%. The ERG considered that this still probably overestimated mortality, but that the plausibility of model survival projections was difficult to judge without UK data. The committee was concerned that mortality could have been overestimated because asthma-related mortality was one of the drivers of the model. It also noted that alternative methods had been used in NICE's technology appraisal guidance on benralizumab for treating severe eosinophilic asthma to adjust for high mortality. So, at its second meeting, the committee concluded that the mortality rates were still uncertain. It asked the company to explore alternative scenarios to assess the effect of mortality on the ICER. To address the committee's concern, the company explained that the modelled mortality rates (73 years for standard care and 75 years with dupilumab) were consistent with published literature. It provided data from a French asthma study. When it adjusted its model to a mean starting age of 61 years, the mortality was 7.1% at 3 years compared with a modelled output of 7.6% at 3 years. The ERG did not consider this to reduce the uncertainty about whether the modelled mortality was overestimated for current UK clinical practice. This was because of differences in the population, treatments and setting. The company also applied a correction to the case fatality rate (1.81% rather than 0.85%) for people aged 55 years to 64 years admitted to hospital with a severe asthma exacerbation. The ERG noted that this increased the ICER from £28,156 to £28,929 per quality-adjusted life year (QALY) gained. The committee noted that this correction was not in the company's base case. To further address committee concerns, the company presented a scenario using NICE's technology appraisal guidance on mepolizumab for treating severe refractory eosinophilic asthma exacerbation settings. The committee noted that this only reduced the ICER to £27,257 per QALY gained. It appreciated the company's attempt to explore uncertainty. It concluded that the company's mortality estimates were appropriate for decision making and that the mortality rates were still uncertain.
# Cost-effectiveness estimates
## The company's updated base-case ICER is £28,156 per QALY gained for dupilumab compared with standard care
At consultation, the company updated the confidential discount for dupilumab and provided additional evidence for dupilumab's efficacy. It also explored scenarios for the uncertainties identified by the committee, including:
varying the 1‑year response rate for dupilumab
varying the relative risks of severe exacerbations for dupilumab compared with standard care alone
using settings of exacerbation from NICE's technology appraisal guidance on mepolizumab for treating severe refractory eosinophilic asthma
using a lower mortality estimate for people aged 55 years to 64 years who were hospitalised.The company's revised base-case deterministic ICER for dupilumab compared with standard care was £28,156 per QALY gained in people with a blood eosinophil count of 150 cells per microlitre or more and FeNo of 25 parts per billion or more, who have had at least 4 or more exacerbations in the previous 12 months, and who are not eligible for mepolizumab, reslizumab or benralizumab or whose asthma has not responded adequately to these biological therapies. The committee was aware that all the explored scenarios had minimal effect on the cost-effectiveness results. It noted, however, that the base-case model should have included the mortality correction (see section 3.16), which increased the ICER to £28,929 per QALY gained. The committee noted that this was at the higher end of what NICE usually considers a cost-effective use of NHS resources. However, it considered dupilumab to be innovative as an additional treatment for people with severe asthma with type 2 inflammation and a high unmet need. It also noted that the model did not take into account the costs and disutilities associated with long-term oral corticosteroid use (that is, obesity, diabetes, osteoporosis, cataracts, hypertension, adrenal suppression, anxiety and depression). Also, some people with comorbidities such as nasal polyps and atopic dermatitis would get additional benefits from dupilumab. The committee considered dupilumab to be a step change for people with severe asthma with type 2 inflammation. Therefore, it concluded that the ICER of £28,929 per QALY was likely to represent the upper estimate of the cost effectiveness of dupilumab.
# Other factors
## Additional benefits in people with nasal polyps or atopic dermatitis may not be adequately captured in the QALY calculation
The committee recognised that there is an unmet need for people with severe asthma with type 2 inflammation. It also heard that dupilumab is effective in people with comorbidities (such as nasal polyps and atopic dermatitis). It concluded that these additional benefits of dupilumab had not been adequately captured in the QALY calculation and took them into consideration in its decision making.
## There is limited data available on dupilumab for young people
Dupilumab is licensed in people 12 years and over. The company provided an analysis for the subgroup of people aged 12 years to 17 years. The committee noted that QUEST only included 2 people under 18 years that met the criteria for the base-case population. There is an unmet need in this population with uncontrolled severe asthma with type 2 inflammation. Mepolizumab is the only other biological that is licensed for treating severe refractory eosinophilic asthma in children (6 years or over). However, NICE's technology appraisal guidance on mepolizumab only recommends it for use in adults. No other biologicals are recommended by NICE for severe asthma in people under 18 years. The committee concluded that there is limited data available for dupilumab in young people and acknowledged this during decision making.
## There are no equality issues relevant to the recommendations
No equality or social value judgement issues were identified.
# Conclusion
## Dupilumab is recommended for treating severe asthma with type 2 inflammation
The committee acknowledged that dupilumab is effective for preventing exacerbations in people with severe asthma with type 2 inflammation compared with standard care. The cost-effectiveness estimates for dupilumab are within what NICE usually considers a cost-effective use of NHS resources. The committee identified several uncertainties in the modelling assumptions, particularly about estimates of mortality and response rates in adults whose asthma did not respond to biological therapy. These uncertainties resulted in uncertainty about the true cost effectiveness of dupilumab. To address the committee's concerns, the company presented further analyses to support the population with a high unmet need and further increased the discount for the 200 mg dose of dupilumab (see section 3.17). The committee noted that all scenarios presented by the company had minimal effect on the cost-effectiveness results and considered the ICER of £28,929 per QALY a plausible estimate of cost effectiveness. It also noted that the additional benefits of dupilumab may not have been fully captured in the QALY calculation. Therefore, it recommended dupilumab as a cost-effective treatment for use in the NHS for treating severe asthma with type 2 inflammation that is inadequately controlled in people 12 years and older, despite maintenance therapy with high-dose inhaled corticosteroids and another maintenance treatment, only if:
the dosage used is 400 mg initially and then 200 mg subcutaneously every other week
the person has agreed to and follows an optimised standard treatment plan
the person has a blood eosinophil count of 150 cells per microlitre or more and FeNo of 25 parts per billion or more, and has had at least 4 or more exacerbations in the previous 12 months
the person is not eligible for mepolizumab, reslizumab or benralizumab, or the asthma has not responded adequately to these biological therapies.
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{'Recommendations': 'Dupilumab as add-on maintenance therapy is recommended as an option for treating severe asthma with type\xa02 inflammation that is inadequately controlled in people 12\xa0years and over, despite maintenance therapy with high-dose inhaled corticosteroids and another maintenance treatment, only if:\n\nthe dosage used is 400\xa0mg initially and then 200\xa0mg subcutaneously every other week\n\nthe person has agreed to and follows an optimised standard treatment plan\n\nthe person has a blood eosinophil count of 150\xa0cells per microlitre or more and fractional exhaled nitric oxide of 25\xa0parts per billion or more, and has had at least 4\xa0or more exacerbations in the previous 12\xa0months\n\nthe person is not eligible for mepolizumab, reslizumab or benralizumab, or has asthma that has not responded adequately to these biological therapies\n\nthe company provides dupilumab according to the commercial arrangement.\n\nStop dupilumab if the rate of severe asthma exacerbations has not been reduced by at least a 50% after 12\xa0months.\n\nThese recommendations are not intended to affect treatment with dupilumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by them, their clinician, and their parents or carers.\n\nWhy the committee made these recommendations\n\nSevere asthma is usually treated with inhaled corticosteroids plus another drug, such as a long-acting beta-agonist. Oral corticosteroids may also be needed to prevent exacerbations (asthma attacks), but they can cause long-term adverse effects. Also, these treatments may not work well enough for severe asthma with type\xa02 inflammation, which can be difficult to control.\n\nClinical trial results show that adding dupilumab to standard asthma treatment is more effective than placebo plus standard treatment at reducing the frequency of severe exacerbations, and the use of oral corticosteroids in people with severe asthma with type\xa02 inflammation.\n\nThe company proposes dupilumab 200\xa0mg for very severe asthma with type\xa02 inflammation in people not eligible for mepolizumab, reslizumab or benralizumab, or whose asthma has not adequately responded to these biological treatments. This is a narrower population than that in the marketing authorisation. It represents people with the highest unmet need and people only eligible for standard care. Dupilumab could be a valuable treatment option in these people because, without it, they will need regular oral corticosteroids.\n\nThe cost-effectiveness estimates for dupilumab plus standard care are at the higher end of what NICE usually considers an acceptable use of NHS resources. But there is an unmet need for people with very severe asthma with type\xa02 inflammation and dupilumab represents an additional treatment option before oral corticosteroids. Also, the benefits associated with avoiding oral corticosteroids to people with this type of asthma and to the NHS may not have been fully captured in the cost-effectiveness estimates. So, dupilumab (200\xa0mg) is recommended for treating inadequately controlled very severe asthma with type\xa02 inflammation.', 'Information about dupilumab': "# Marketing authorisation indication\n\nDupilumab (Dupixent, Sanofi) has a marketing authorisation 'in adults and adolescents 12\xa0years and older as an add-on maintenance treatment for severe asthma with type\xa02 inflammation characterised by raised blood eosinophils and/or raised FeNO [fractional exhaled nitric oxide] who are inadequately controlled with high dose ICS [inhaled corticosteroid] plus another medicinal product for maintenance treatment'. The definition of type 2 inflammation is as in the Global Initiative for Asthma guideline.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of dupilumab is £1,264.89 for 2\xa0prefilled syringes 200\xa0mg per 1.44\xa0ml (excluding VAT; BNF online accessed November\xa02020).\n\nThe company has a commercial arrangement. This makes dupilumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Sanofi Genzyme, a review of this submission by the evidence review group (ERG), NICE's technical report and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## An additional treatment option that lowers the risk of exacerbations and may reduce the need for oral corticosteroids would be welcome\n\nSevere asthma is a distressing and socially isolating condition. The patient expert explained that exacerbations can happen without warning, be life threatening, cause fear and result in hospitalisation. They further explained that people are often unable to work or start a family, and may need help with day-to-day activities because of their symptoms. The clinical expert explained that, in addition to optimised inhaled treatment, standard treatment for severe asthma is oral systemic corticosteroids or, if the person has eosinophilic asthma, and depending on the blood eosinophil count, NICE recommended interleukin 5 inhibitor biologicals benralizumab, mepolizumab and reslizumab. Dupilumab is the only licensed treatment for severe asthma with type\xa02 inflammation. Although asthma can respond to systemic corticosteroids, the treatment can be associated with long-term complications (such as diabetes mellitus, weight gain, bone loss, immunosuppression and a negative effect on mental health). The patient expert explained that people with severe asthma with type\xa02 inflammation would welcome treatment options that replace the need for corticosteroids. The clinical expert explained that a blood eosinophil count and fractional exhaled nitric oxide (FeNO) are used to help define subtypes of severe asthma and help predict the people with severe asthma who are at the highest risk of a future exacerbation. In people with severe asthma with type\xa02 inflammation, if their condition does not respond to interleukin‑5 inhibitors it may respond to interleukin‑13 inhibitors such as dupilumab. The committee concluded that there is a need for new treatments with a different mode of action for people with severe asthma with type\xa02 inflammation whose asthma does not respond with current standard care, and for people not eligible for current NICE recommended biologicals.\n\n# Clinical management\n\n## Severe asthma with type\xa02 inflammation is a subtype of asthma\n\nSevere asthma with type\xa02 inflammation is associated with allergy, higher risk of exacerbations, hospitalisation and dependency on oral corticosteroids, and increased risk of dying than in people with severe asthma without type\xa02 inflammation. The Global Initiative for Asthma (GINA) guideline on difficult to treat severe asthma (2021) lists 5\xa0criteria in its definition of severe asthma with type\xa02 inflammation that are prognostics markers:\n\na blood eosinophil count of 150\xa0cells per microlitre or more\n\nFeNO of 20\xa0parts per billion or more\n\nsputum eosinophils of 2% or more\n\nasthma that is clinically allergen driven\n\nthe need for maintenance oral corticosteroids.GINA suggests that 1\xa0or more criteria can be used to make a diagnosis. The clinical expert explained that raised blood eosinophils and FeNO are predictors for future exacerbations. The committee concluded that this subtype of severe asthma can be characterised as type\xa02 inflammation.\n\n## Blood eosinophil count and FeNO are common biomarkers for diagnosis\n\nThe clinical expert explained that blood eosinophil counts and FeNO levels are routinely measured in clinical practice. They also explained that, while blood eosinophils counts are raised in both eosinophilic asthma and asthma with type\xa02 inflammation, raised FeNO is more specific to type\xa02 inflammation. The committee noted the response of stakeholders during technical engagement that a blood eosinophil count of 150\xa0cells per microlitre or more, FeNO of 20\xa0parts per billion or more, or both, could be used for identifying people with type\xa02 inflammation. The committee acknowledged the complexity of diagnosing asthma subtypes, and the potential for overlap or misclassification between them, despite the use of blood eosinophil counts and FeNO levels.\n\n## Dupilumab as add-on treatment is an option for managing uncontrolled severe asthma with type\xa02 inflammation\n\nThe clinical expert explained that treatment for asthma in clinical practice follows the NICE guideline on diagnosis, monitoring and chronic asthma management and the GINA 2021 guideline (which includes the use of biologicals). If the asthma is still uncontrolled despite optimised inhaled therapy that includes corticosteroids, then low-dose oral corticosteroids or biologicals are added. The clinical and patient experts explained that biologicals are preferred over oral corticosteroids because they have fewer debilitating adverse effects. The choice of biological depends on the subtype of asthma. For severe eosinophilic asthma, according to NICE technology appraisal guidance for benralizumab, mepolizumab and reslizumab, the treatment of choice depends on the blood eosinophil count (300\xa0cells per microlitre or more, or 400\xa0cells per microlitre or more) and the number of exacerbations (3\xa0or\xa04, or more) or the use of systemic corticosteroids. Omalizumab is another biological recommended by NICE and used for treating severe persistent allergic asthma. However, it is not used for eosinophilic asthma (see section\xa03.6). There are currently no NICE recommended biologicals for treating severe asthma with type\xa02 inflammation. The committee concluded that dupilumab as add-on treatment is an option for managing uncontrolled severe asthma with type\xa02 inflammation.\n\n# Populations\n\n## The company's updated population is suitable for decision making\n\nThere are several subgroups to consider when deciding which population to use for decision making. At the first appraisal committee meeting, the committee considered whether the population would need to have a raised eosinophil count, raised FeNO or both based on the 'and/or' wording in the marketing authorisation and GINA recommendations for these biomarkers. The committee also acknowledged that there are subgroups on or off maintenance oral corticosteroids, or both (mixed proportions on and off oral corticosteroids), and populations eligible or not eligible for biologicals. In addition, it acknowledged the overlap between the populations in the marketing authorisation, trials and company decision problem at the first committee meeting:\n\nThe marketing authorisation population is broad, consisting of people with uncontrolled severe asthma with type\xa02 inflammation on high-dose inhaled corticosteroids plus 1\xa0maintenance treatment and with a blood eosinophil count and FeNO as described by GINA.\n\nThe clinical trials (DRI12544, QUEST and VENTURE) recruited people with 1\xa0or more exacerbations in the previous 12\xa0months and no restrictions on blood eosinophils and FeNO.The company's decision problem (base case) was in a subpopulation of people not eligible for mepolizumab, reslizumab or benralizumab or whose asthma had not responded to these biological therapies based on a post hoc analysis of the QUEST data. They were 12\xa0years and older and had blood eosinophils counts of 150\xa0cells per microlitre or more, FeNO of 25\xa0parts per billion or more, and at least 4\xa0exacerbations in the previous 12\xa0months. The company considered that this narrower population represented people with the highest unmet need and could be split into 3\xa0subgroups: young people aged 12\xa0years to 17\xa0years, adults not eligible for mepolizumab, reslizumab or benralizumab (a blood eosinophil count 150\xa0cells per microlitre to 299\xa0cells per microlitre) and adults whose asthma had not responded to these biological therapies (blood eosinophil count of 300\xa0cells per microlitre and more). The committee noted that the comparator for the updated population was standard care and other biologicals were only recommended for adults in NICE guidance. The committee concluded that the updated population was suitable for decision making.\n\n# Comparators\n\n## Standard care is the appropriate comparator in the updated population\n\nThe clinical trial population in QUEST included people with differing asthma severity (defined by eosinophil level, FeNO and the number of exacerbations in the previous 12\xa0months). These populations therefore included people who would be offered different treatment options in the NHS:\n\nPeople with a blood eosinophil count of 300\xa0cells per microlitre or more who have had at least 4\xa0exacerbations in the previous 12\xa0months, or who are taking oral corticosteroids, can have mepolizumab or benralizumab.\n\nPeople with a blood eosinophil count of 400\xa0cells per microlitre or more who have had at least 3\xa0exacerbations in the previous 12\xa0months can have reslizumab, mepolizumab or benralizumab.\n\nPeople not eligible for biologicals are offered standard care, defined as:\n\n\n\na blood eosinophil count of between 150\xa0and 299\xa0cells per microlitre and 4\xa0or more exacerbations in the previous 12\xa0months (not eligible for mepolizumab or benralizumab)\n\na blood eosinophil count of between 150\xa0and 399\xa0cells per microlitre and 3\xa0or more exacerbations in the previous 12\xa0months (not eligible for reslizumab or benralizumab)\n\na blood eosinophil count of less than 150\xa0cells per microlitre and FeNO of 25\xa0parts per billion or more (not eligible for any other biological)\n\n\n\nPeople whose asthma had not responded to biological therapy are offered standard care.The committee concluded that standard care was an appropriate comparator in the company's population, that is, people who are not eligible for mepolizumab, reslizumab or benralizumab or people whose asthma has not responded to these biological therapies.\n\n# Clinical evidence\n\n## The population in QUEST is generalisable to people seen in NHS clinical practice\n\nThe clinical evidence for the company's population came from a double-blind placebo-controlled randomised trial, QUEST. This trial compared dupilumab with placebo in 948\xa0people 12\xa0years and over with persistent asthma who had 1\xa0or more exacerbations in the previous 12\xa0months. It included people with moderate to severe asthma, who were not on maintenance oral corticosteroids. It was conducted globally and included people from the UK. QUEST's population was based on the use of moderate-to-high doses of inhaled corticosteroids. This was because it included people from countries such as the US and Japan where, according to the clinical expert, there is a reluctance to use high-dose inhaled corticosteroids. The committee concluded that QUEST was broadly generalisable to NHS practice and appropriate for decision making.\n\n## Dupilumab is more clinically effective than standard care in the clinical trial population\n\nAll primary outcomes were reported for the intention-to-treat population in all 3\xa0trials. In QUEST, the coprimary outcome was annualised rate of severe exacerbations and change from baseline in the forced expiratory volume in 1\xa0second (FEV1) at 12\xa0weeks. There was a 47.7% (95% confidence interval [CI] 33.8%\xa0to\xa058.7%, p<0.0001) lower rate of severe exacerbations in the dupilumab group compared with placebo. There was an increase in FEV1 at 12\xa0weeks when dupilumab was compared with placebo in QUEST (least squares mean difference 0.20\xa0litre, 95%\xa0CI 0.11\xa0to\xa00.28, p<0.0001). The committee concluded that dupilumab was more clinically effective than standard care in the clinical trial population.\n\n## Dupilumab is clinically effective in the company's population, but estimates are based on a small population\n\nThe company proposed dupilumab in a small post hoc population of people from QUEST:\n\nwith a blood eosinophil count of 150\xa0cells per microlitre or more, FeNO of 25\xa0parts per billion or more and 4\xa0or more exacerbations in the previous 12\xa0months\n\nwho are not eligible for mepolizumab, reslizumab or benralizumab or have had biological therapy.It explained that dupilumab reduced the rate of severe exacerbations when compared with placebo within this subpopulation but was based on small post hoc subgroups. The relative risk ratios are considered confidential by the company so cannot be reported here. The committee noted that dupilumab was clinically effective as an addition to standard care in people who had not had biological therapy and had a blood eosinophil count of at least 150\xa0cells per microlitre, FeNO of 25\xa0parts per billion or more, and 4\xa0or more exacerbations in the previous 12\xa0months. The committee concluded that the clinical-effectiveness evidence for dupilumab in the company's population was limited and based on a small number of people.\n\n## QUEST subgroup analyses support dupilumab's efficacy in the company's populations\n\nThe company presented additional subgroup analyses from QUEST on different severities of asthma based on exacerbation level in the previous 12\xa0months, and blood eosinophil and FeNo levels. It did this to support its definition of the population with the highest unmet need. One analysis of the dupilumab's clinical effectiveness showed that, in people randomised to placebo, the adjusted annualised severe exacerbation rate increased with an increasing number of exacerbations in the 12\xa0months before QUEST baseline from 0.871 in people with 1\xa0or more exacerbations to more than 2.563 in those with 4\xa0or more exacerbations. There was also a statistically significant reduction in the adjusted annualised severe exacerbation rate with dupilumab, ranging from a 48% (0.456) reduction compared with placebo in the 1\xa0or more exacerbation group to a 77% (0.571) reduction compared with placebo in the 4\xa0or more exacerbations group. Another analysis assessed adjusted annualised severe exacerbation rate by baseline levels of blood eosinophil count and FeNO. In this, the subgroup with a blood eosinophil count of 150\xa0cells per microlitre or more and FeNO of 20\xa0parts per billion or more (48% of the QUEST population) had the highest adjusted annualised exacerbation rate in people randomised to placebo and the most pronounced treatment effect (66%, p<0.001 rate reduction compared with placebo). The ERG agreed that a raised blood eosinophil count of 150\xa0cells per microlitre or more and FeNO of 20\xa0parts per billion or more represented the group with the highest baseline exacerbation rate and response to dupilumab. The committee considered the additional company analyses were sufficient to support the company's definition of severe asthma with type\xa02 inflammation, that is, 4\xa0exacerbations or more, a blood eosinophil count of 150\xa0cells per microlitre or more, and FeNO of 20\xa0parts per billion or more. The committee concluded that adding dupilumab to standard care is clinically effective in people with the highest unmet need defined by a blood eosinophil count of 150\xa0cells per microlitre or more and FeNO of 25\xa0parts per billion or more and 4\xa0or more exacerbations in the previous 12\xa0months.\n\n## The proportion of people who have had biological therapy whose asthma will respond to dupilumab is uncertain\n\nThe committee had concerns about the company's assumption of equal efficacy with dupilumab in people who have and have not had a biological therapy. In response to its second appraisal consultation document, the company presented real-world evidence on the clinical effectiveness of dupilumab from the UK, Europe and US for people who had mepolizumab, reslizumab or benralizumab. The committee noted that the company's real-world evidence from the UK showed a similar response in people who had and had not had biological therapy. The details of the company's observational evidence are confidential so cannot be reported here. The company's real-world evidence from Europe and the US showed that dupilumab improved asthma control and reduced asthma exacerbations in people with severe asthma who had mepolizumab, reslizumab or benralizumab. The ERG noted several differences in the observational studies from the EU. People had had the 300\xa0mg dose of dupilumab, which is only recommended in people on oral corticosteroids. Also, a high proportion of people had oral corticosteroids compared with people in QUEST who had 200\xa0mg dupilumab. The committee noted that, based on limited retrospective studies with small sizes, dupilumab was effective in improving asthma control and reducing exacerbations in people with severe asthma who had mepolizumab, reslizumab or benralizumab. The committee concluded that dupilumab is likely to be effective in some people whose asthma has not responded to mepolizumab, reslizumab or benralizumab. However, it concluded that the proportion of people who have had mepolizumab, reslizumab or benralizumab whose asthma will respond to dupilumab is uncertain.\n\n# The company's economic model\n\n## The model structure is appropriate for decision making\n\nThe company submitted a 4‑state Markov model comparing dupilumab with standard care in people with severe asthma and type\xa02 inflammation. The model consisted of 4\xa0live health states: uncontrolled asthma; controlled asthma; moderate exacerbation; and severe exacerbation. In addition, the model included states for asthma-related deaths and death from other causes. Response to treatment was defined as a 50% or greater reduction in the annual exacerbation rate, which was assessed at 52\xa0weeks. People whose asthma responded continued on dupilumab and those whose asthma did not respond were transferred to standard care. The company derived the efficacy and clinical parameters in the model from QUEST. The committee concluded that the model structure was appropriate for decision making.\n\n## The evidence for the company's population is limited because it is based on clinical-effectiveness estimates from small sample sizes\n\nThe committee noted that the company's population included young people aged 12\xa0years to 17\xa0years, adults not eligible for mepolizumab, reslizumab or benralizumab (blood eosinophil count of 150\xa0cells per microlitre to 299\xa0cells per microlitre) and adults who had biological therapy but whose asthma had not responded (a blood eosinophil count of 300\xa0cells per microlitre or more). The committee noted that the clinical-effectiveness evidence available for the company's populations was limited because the number of people included in QUEST was small (see section\xa03.11). The trial only included 2\xa0people corresponding to the young-people subgroup and 14\xa0people corresponding to the subgroup of adults not eligible for biologicals. Also, the QUEST protocol excluded people who had had biological therapy but 1\xa0person was included who had had a biological. The ERG noted that the estimates of transition probabilities for the company's population were highly uncertain because of the small sample sizes. The company assumed that clinical effectiveness was the same for each subgroup based on trial estimates for the company's population. The company provided clinical expert opinion that switching from other biologicals (the interleukin‑5 inhibitors: mepolizumab, reslizumab, benralizumab) to dupilumab (a interleukin‑4/13 inhibitor) was acceptable because the mechanisms of action were different enough. The committee considered that the assumption of equal efficacy of dupilumab regardless of whether people had mepolizumab, reslizumab or benralizumab was uncertain. This was because it considered assuming that the response rate would be as good in people not eligible for mepolizumab, reslizumab or benralizumab was optimistic. In response to its second appraisal consultation document, the company provided additional data on the effectiveness of dupilumab in people with asthma that had not responded to mepolizumab, reslizumab or benralizumab. The committee concluded that, because the evidence for dupilumab's clinical effectiveness in the company's population was based on a small number of people, it was limited.\n\n# Clinical inputs to the model\n\n## The company's updated base case does not include a multiplier for long-term severe exacerbation rates\n\nThe committee noted that asthma-related mortality often drives cost effectiveness in asthma models. The annual severe exacerbation rate (2.39\xa0exacerbations per year) in the placebo arm of QUEST was lower than that seen in clinical practice in the year before trial enrolment (4.46\xa0exacerbations per year). The company's model after technical engagement used the exacerbation rates from QUEST and VENTURE in the first year of the model. Also, it increased the number of severe exacerbations in subsequent years for both dupilumab and standard care by applying a multiplier. The ERG considered the trial to be the best source of exacerbation data. It did not include an exacerbation multiplier in its base-case model, which resulted in higher incremental cost-effectiveness ratios (ICERs). The company provided evidence on severe exacerbation rates from 3\xa0cohorts with severe asthma: WATCH (Wessex Asthma Cohort of Difficult Asthma), U‑BIOPRED (Unbiased Biomarkers in Prediction of respiratory disease outcomes) and the Sanofi Real World Evidence (RWE) study. It also accepted the committee's and ERG's concerns about the uncertainty of using a multiplier. The exacerbation rates in the company's updated base-case model were taken from QUEST for the duration of the model without an exacerbation multiplier. The committee concluded that the updated base-case model without the exacerbation multiplier was appropriate.\n\n## Real-world evidence is an appropriate source of data to inform the treating severe exacerbations setting\n\nThe company assigned different mortality rates to severe exacerbations treated in hospital emergency care, inpatients and general practice based on the UK Difficult Asthma Registry data (O'Neill et al. 2015). In QUEST, 6.7% of severe exacerbations were treated in hospitals (3.0% in emergency care, 3.7% in inpatients and 93.3% in general practice). In the UK Difficult Asthma Registry data, this was 26.5% (7.8% in emergency care, 18.7% in inpatients and 74.0% in general practice), which it thought was a more appropriate estimate of resource use in the NHS. The ERG base-case model used the QUEST data for the setting of severe exacerbations. The clinical expert explained that the number of people treated in hospitals in clinical practice is likely to be higher than that seen in QUEST. This was because people in trials are well monitored on optimised treatment, more motivated and adhere better to treatment. The committee requested further exploration of different sources of data to inform the setting of treating exacerbations to inform the model. The company then submitted data on the setting of treating severe exacerbation rates from 3\xa0different sources (WATCH, U‑BIOPRED and the Sanofi RWE study). The definition of severe exacerbation in the Sanofi RWE study was based on case notes from severe asthma centres in the NHS to match the definition in QUEST. The data for setting exacerbations from the Sanofi RWE study was used in the company's updated model. The ERG considered the Sanofi RWE study to be of reasonable quality and that it produced results consistent with other sources. The committee concluded that the Sanofi RWE study on the setting of severe exacerbations was appropriate for use in the company's base case.\n\n## The company's mortality estimates are appropriate for decision making but uncertain\n\nThe company's original model (using the confidential exacerbation multiplier) predicted 20% mortality over 10\xa0years in the standard care arm. The committee questioned the clinical plausibility of this estimate because it seemed high compared with the estimated 1,300 asthma-related deaths a year in the UK. The higher death rate was because of interaction between the exacerbation multiplier (see section\xa03.14) and using registry data to inform the setting of treating exacerbations (see section\xa03.15). The committee noted that the model did not offer plausible estimates and asked that additional analyses presented by the company:\n\ninclude 10‑year mortality rates for dupilumab and standard care and\n\nshow the flow of patients through different health states in the model for the purposes of model validation.The company updated its model and removed the exacerbation multiplier (see section\xa03.15), which reduced 10‑year mortality with standard care to 16.7%. The ERG considered that this still probably overestimated mortality, but that the plausibility of model survival projections was difficult to judge without UK data. The committee was concerned that mortality could have been overestimated because asthma-related mortality was one of the drivers of the model. It also noted that alternative methods had been used in NICE's technology appraisal guidance on benralizumab for treating severe eosinophilic asthma to adjust for high mortality. So, at its second meeting, the committee concluded that the mortality rates were still uncertain. It asked the company to explore alternative scenarios to assess the effect of mortality on the ICER. To address the committee's concern, the company explained that the modelled mortality rates (73\xa0years for standard care and 75\xa0years with dupilumab) were consistent with published literature. It provided data from a French asthma study. When it adjusted its model to a mean starting age of 61\xa0years, the mortality was 7.1% at 3\xa0years compared with a modelled output of 7.6% at 3\xa0years. The ERG did not consider this to reduce the uncertainty about whether the modelled mortality was overestimated for current UK clinical practice. This was because of differences in the population, treatments and setting. The company also applied a correction to the case fatality rate (1.81% rather than 0.85%) for people aged 55\xa0years to 64\xa0years admitted to hospital with a severe asthma exacerbation. The ERG noted that this increased the ICER from £28,156 to £28,929 per quality-adjusted life year (QALY) gained. The committee noted that this correction was not in the company's base case. To further address committee concerns, the company presented a scenario using NICE's technology appraisal guidance on mepolizumab for treating severe refractory eosinophilic asthma exacerbation settings. The committee noted that this only reduced the ICER to £27,257 per QALY gained. It appreciated the company's attempt to explore uncertainty. It concluded that the company's mortality estimates were appropriate for decision making and that the mortality rates were still uncertain.\n\n# Cost-effectiveness estimates\n\n## The company's updated base-case ICER is £28,156 per QALY gained for dupilumab compared with standard care\n\nAt consultation, the company updated the confidential discount for dupilumab and provided additional evidence for dupilumab's efficacy. It also explored scenarios for the uncertainties identified by the committee, including:\n\nvarying the 1‑year response rate for dupilumab\n\nvarying the relative risks of severe exacerbations for dupilumab compared with standard care alone\n\nusing settings of exacerbation from NICE's technology appraisal guidance on mepolizumab for treating severe refractory eosinophilic asthma\n\nusing a lower mortality estimate for people aged 55\xa0years to 64\xa0years who were hospitalised.The company's revised base-case deterministic ICER for dupilumab compared with standard care was £28,156 per QALY gained in people with a blood eosinophil count of 150\xa0cells per microlitre or more and FeNo of 25\xa0parts per billion or more, who have had at least 4\xa0or more exacerbations in the previous 12\xa0months, and who are not eligible for mepolizumab, reslizumab or benralizumab or whose asthma has not responded adequately to these biological therapies. The committee was aware that all the explored scenarios had minimal effect on the cost-effectiveness results. It noted, however, that the base-case model should have included the mortality correction (see section\xa03.16), which increased the ICER to £28,929 per QALY gained. The committee noted that this was at the higher end of what NICE usually considers a cost-effective use of NHS resources. However, it considered dupilumab to be innovative as an additional treatment for people with severe asthma with type\xa02 inflammation and a high unmet need. It also noted that the model did not take into account the costs and disutilities associated with long-term oral corticosteroid use (that is, obesity, diabetes, osteoporosis, cataracts, hypertension, adrenal suppression, anxiety and depression). Also, some people with comorbidities such as nasal polyps and atopic dermatitis would get additional benefits from dupilumab. The committee considered dupilumab to be a step change for people with severe asthma with type\xa02 inflammation. Therefore, it concluded that the ICER of £28,929 per QALY was likely to represent the upper estimate of the cost effectiveness of dupilumab.\n\n# Other factors\n\n## Additional benefits in people with nasal polyps or atopic dermatitis may not be adequately captured in the QALY calculation\n\nThe committee recognised that there is an unmet need for people with severe asthma with type\xa02 inflammation. It also heard that dupilumab is effective in people with comorbidities (such as nasal polyps and atopic dermatitis). It concluded that these additional benefits of dupilumab had not been adequately captured in the QALY calculation and took them into consideration in its decision making.\n\n## There is limited data available on dupilumab for young people\n\nDupilumab is licensed in people 12\xa0years and over. The company provided an analysis for the subgroup of people aged 12\xa0years to 17\xa0years. The committee noted that QUEST only included 2\xa0people under 18\xa0years that met the criteria for the base-case population. There is an unmet need in this population with uncontrolled severe asthma with type\xa02 inflammation. Mepolizumab is the only other biological that is licensed for treating severe refractory eosinophilic asthma in children (6\xa0years or over). However, NICE's technology appraisal guidance on mepolizumab only recommends it for use in adults. No other biologicals are recommended by NICE for severe asthma in people under 18\xa0years. The committee concluded that there is limited data available for dupilumab in young people and acknowledged this during decision making.\n\n## There are no equality issues relevant to the recommendations\n\nNo equality or social value judgement issues were identified.\n\n# Conclusion\n\n## Dupilumab is recommended for treating severe asthma with type\xa02 inflammation\n\nThe committee acknowledged that dupilumab is effective for preventing exacerbations in people with severe asthma with type\xa02 inflammation compared with standard care. The cost-effectiveness estimates for dupilumab are within what NICE usually considers a cost-effective use of NHS resources. The committee identified several uncertainties in the modelling assumptions, particularly about estimates of mortality and response rates in adults whose asthma did not respond to biological therapy. These uncertainties resulted in uncertainty about the true cost effectiveness of dupilumab. To address the committee's concerns, the company presented further analyses to support the population with a high unmet need and further increased the discount for the 200\xa0mg dose of dupilumab (see section\xa03.17). The committee noted that all scenarios presented by the company had minimal effect on the cost-effectiveness results and considered the ICER of £28,929 per QALY a plausible estimate of cost effectiveness. It also noted that the additional benefits of dupilumab may not have been fully captured in the QALY calculation. Therefore, it recommended dupilumab as a cost-effective treatment for use in the NHS for treating severe asthma with type\xa02 inflammation that is inadequately controlled in people 12\xa0years and older, despite maintenance therapy with high-dose inhaled corticosteroids and another maintenance treatment, only if:\n\nthe dosage used is 400\xa0mg initially and then 200\xa0mg subcutaneously every other week\n\nthe person has agreed to and follows an optimised standard treatment plan\n\nthe person has a blood eosinophil count of 150\xa0cells per microlitre or more and FeNo of 25\xa0parts per billion or more, and has had at least 4\xa0or more exacerbations in the previous 12\xa0months\n\nthe person is not eligible for mepolizumab, reslizumab or benralizumab, or the asthma has not responded adequately to these biological therapies."}
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https://www.nice.org.uk/guidance/ta751
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Evidence-based recommendations on dupilumab (Dupixent) for treating severe asthma with type 2 inflammation that is inadequately controlled in people 12 years and over.
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98f5b64af1feda7ff3f29c33e2307265eb43face
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nice
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Mexiletine for treating the symptoms of myotonia in non-dystrophic myotonic disorders
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Mexiletine for treating the symptoms of myotonia in non-dystrophic myotonic disorders
Evidence-based recommendations on mexiletine (Namuscla) for treating the symptoms of myotonia in adults with non-dystrophic myotonic disorders.
# Recommendations
Mexiletine (Namuscla) is recommended, within its marketing authorisation, as an option for treating the symptoms of myotonia in adults with non-dystrophic myotonic disorders. It is recommended only if the company provides mexiletine (Namuscla) according to the commercial arrangement.
Why the committee made these recommendations
Treatments for the symptoms of myotonia in adults with non-dystrophic myotonic disorders already include imported mexiletine (which is not licensed in the UK). Other sodium channel blockers are used if mexiletine is not suitable. NICE's remit for this appraisal is to appraise Namuscla, the only brand of mexiletine with a UK marketing authorisation.
Clinical trial evidence suggests that mexiletine is better than placebo at reducing the symptoms of myotonia. But the trial did not compare mexiletine with other sodium channel blockers. Also, a higher dose of mexiletine was used in the clinical trial than people would normally have in the NHS.
The economic model does not compare mexiletine with other sodium channel blockers that are used in the NHS. Because of this, mexiletine's clinical benefit compared with these medicines is uncertain. However, the cost-effectiveness estimates for mexiletine compared with best supportive care are within the range that NICE considers a cost-effective use of NHS resources. It is uncertain if they would exceed this range when compared with other sodium channel blockers. Therefore, mexiletine (Namuscla) is recommended.# Information about mexiletine
# Marketing authorisation indication
Mexiletine (Namuscla, Lupin) is indicated 'for the symptomatic treatment of myotonia in adult patients with non-dystrophic myotonic disorders'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £5,000 per 100×167 mg capsules (excluding VAT; BNF online, accessed September 2021). The company has a commercial arrangement. This makes mexiletine (Namuscla) available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Lupin, a review of this submission by the evidence review group (ERG), NICE's technical report, responses from stakeholders, and consultation comments from stakeholders, experts and members of the public. See the committee papers for full details of the evidence.
# Disease background and current clinical management
## Non-dystrophic myotonia can affect the quality of life of patients and carers
Non-dystrophic myotonia (NDM) refers to a group of rare genetic disorders affecting skeletal muscle chloride or sodium ion channels. The most common symptom is myotonia, which is a delay in muscle relaxation and can lead to muscle locking and stiffness. The patient expert explained the constant effect of myotonia on quality of life for people with the condition and their carers. It can cause general muscular discomfort and pain, lack of sleep and major falls because muscle locking can cause falls and also limit the ability to break a fall. The patient expert highlighted that this leads to avoiding stairs where possible. It can also cause embarrassment for people with NDM because slurring speech and facial locking after sneezing can be misunderstood by other people. The patient organisation emphasised the invisible nature of the disease because of its rarity. The patient expert also noted constant worry about triggers (such as cold weather) that could affect myotonic episodes. The clinical experts explained that symptom severity varies between people, and can also vary over time for each individual (for example, it can affect different parts of the body). Some people need constant treatment and others choose episodic management, for instance, during cold weather. If the disease is not managed, the patient expert explained that care is sometimes needed for tasks such as climbing stairs, lifting or bathing.
## Current clinical management involves using mexiletine and other sodium channel blockers
Current clinical management of NDM includes muscle warming routines, specialist physiotherapy and avoidance of triggers. However, the clinical experts stated that pharmacological management should be offered to any person with NDM who is seeking treatment because it is affecting their daily lives. Sodium channel blockers (such as mexiletine, carbamazepine, acetazolamide, flecainide and phenytoin) have been used off label for many years to treat NDM. Off-label imported mexiletine was used most because benefits can be seen very quickly. The clinical experts explained that a recent randomised controlled trial showed evidence of efficacy of another sodium channel blocker, lamotrigine, which is also sometimes used if mexiletine is contraindicated, not effective or not tolerated. The patient expert explained that using mexiletine addressed most of the symptoms of NDM with near-normal muscle function and manageable side effects. The committee concluded that mexiletine is currently the preferred, established treatment for NDM and other options are available when mexiletine is not suitable.
## The company should compare mexiletine with other sodium channel blockers
The committee was aware that the remit for this appraisal was to appraise mexiletine (Namuscla) within its licensed indication for NDM. It understood that it would make recommendations within the terms of the marketing authorisation, as published in the manufacturer's summary of product characteristics. It noted that the comparator in the scope for this appraisal was established clinical management without mexiletine, including but not limited to lamotrigine and best supportive care. The company considered that mexiletine (Namuscla) is now the only licensed treatment for NDM and therefore compared mexiletine with placebo to represent best supportive care. The company also indicated that lamotrigine is not established in clinical practice because few people take it. The company explained that lamotrigine has a longer titration period than mexiletine, with intensive monitoring to reach higher doses if needed. It also believed that pain and fatigue are influenced by the placebo effect, and other sodium channel blockers would have no additional benefit to placebo as implemented in their comparison with best supportive care. The committee recalled comments from the evidence submissions that clinicians in England had used lamotrigine with success in people whose disease did not respond to mexiletine or who could not have mexiletine because of cardiac arrythmias. At consultation, the Association of British Neurologists (ABN) believed it was not reasonable to consider other sodium channel blockers as comparators. The ABN commented that lamotrigine is rarely used because they suggested it was not as effective as mexiletine and has a high discontinuation rate. But it noted that there is a direct comparator trial being set up. The committee considered that established clinical management without mexiletine cannot currently be observed in the NHS because mexiletine is already established in clinical practice with off-label use and, more recently, an interim access agreement for the licensed treatment (Namuscla). Therefore, the committee deemed the most appropriate comparison to be with what people currently taking mexiletine would have if mexiletine was not available. The clinical experts stated that if mexiletine was not available, patients would have another sodium channel blocker. The patient organisation representative and patient expert at the first committee meeting agreed with this. The committee concluded that comparing mexiletine with best supportive care was not appropriate because people would be offered other active treatments such as lamotrigine or other sodium channel blockers if mexiletine was not available, and that other active treatments would likely be more effective than best supportive care.
# Clinical evidence
## The main clinical-effectiveness evidence comes from the MYOMEX trial, with supporting evidence from other studies
The main clinical evidence for mexiletine comes from MYOMEX, a randomised crossover trial of 26 patients with NDM comparing mexiletine with placebo. The primary outcome was muscle stiffness as measured by visual analogue scale, but the efficacy evidence used in the economic model was a secondary outcome measure, the Individualised Neuromuscular Quality of Life (INQoL) questionnaire (see section 3.10). Supporting evidence came from 3 other studies:
Suetterlin et al. (2015) – a retrospective review of 63 UK patients with NDM taking mexiletine for 6 months or more
Statland et al. (2012) – a randomised crossover trial of 59 patients comparing mexiletine with placebo
Stunnenberg et al. (2015) – an aggregated study of patients individually randomised to mexiletine or placebo in a crossover design for 30 patients with NDM in the Dutch neuromuscular database.These trials were used as supporting clinical evidence and used to inform some economic model parameters and scenario analyses. The committee concluded that all the evidence, combined with the statements that mexiletine has been standard practice for over 15 years, suggest mexiletine is effective for relieving myotonia symptoms. However, the committee also noted that there were no comparisons of mexiletine with an active comparator.
## MYOMEX is broadly generalisable to NHS clinical practice
MYOMEX included people aged between 18 and 65 with genetically confirmed NDM and with myotonic symptoms severe enough to justify treatment. The severity of symptoms was evaluated by whether it affected more than 1 segment of the body and if it impacted on 3 or more daily activities. The clinical experts explained that there are no formal methods of assessing severity of NDM because of the large amount of heterogeneity between patient symptoms and needs (see section 3.1). However, they considered that the severity inclusion criteria would be broadly generalisable to NHS clinical practice. The company noted that the small number of people aged over 65 who have treatment for NDM would not have different treatment to those under 65, therefore it does not consider the age criteria to be a limitation. The committee concluded that MYOMEX was broadly generalisable but noted the limitations of the inclusion criteria.
## There are significant limitations with the design of the MYOMEX trial
A large proportion of patients in MYOMEX had previously had mexiletine. The clinical expert stated that this would be expected because there are few people with NDM who have not had mexiletine because it is a rare condition and mexiletine is routinely offered as a first treatment option. The ERG noted, and the clinical expert agreed, that the recognisable side effects of mexiletine could have effectively unblinded patients to which treatment they had. This is supported by the Statland et al. study in which around 80% of patients correctly guessed which treatment they had. The ERG considered that unblinding could potentially bias results because most of the outcomes are patient reported. Additionally, the ERG noted that there was potential for a carry-over effect between the 2 phases of the crossover trial if there was not enough time between the phases (the washout period). People in the MYOMEX trial had a 4‑ to 8‑day washout period and the company presented analysis that there was no statistical evidence of a carry-over effect and the ERG noted that data from the first phase only also showed similar changes in muscle stiffness to both phases combined. However, the ERG noted the Statland et al. trial had at least a 7‑day washout period and there was a statistically significant carry-over effect. The committee noted that MYOMEX included few patients and it was uncertain if the trial was powered to detect a carry-over effect. It also noted that MYOMEX had a short duration of only 18 days in each phase, so there is uncertainty in how effectiveness is maintained over a lifetime of treatment. At consultation, the company said that no risk of bias was found in the MYOMEX trial but did not provide evidence on this. The committee concluded that potential for unblinding and carry-over effects, short trial duration and few patients contribute substantial uncertainty to the MYOMEX results.
## The dose and dosing schedule of mexiletine in MYOMEX does not match how it is used in clinical practice
Namuscla is a new formulation of mexiletine that uses different dose measurements to previous off‑label use (a 167 mg capsule of Namuscla formulation is equivalent to 200 mg of imported mexiletine). However, all the clinical evidence uses the imported formulation of mexiletine. The daily dose in the MYOMEX trial started at 200 mg for 3 days, at which point all patients had a dose titration up to 400 mg for a further 3 days and then a final titration to 600 mg for 12 days, at which point efficacy was assessed. The summary of product characteristics for Namuscla states that the dosing schedule is based on clinical response and can be increased after at least 1 week of treatment in 167 mg (200 mg imported mexiletine dose equivalent) increments to a maximum dose of 500 mg (600 mg equivalent). The clinical experts stated that the rapid forced dose titration to 600 mg in MYOMEX does not represent current clinical management and is not in line with the summary of product characteristics. Currently, some people have dose titration in smaller off‑label 100 mg dose increments at a more cautious rate of titration to avoid gastric side effects of mexiletine. Some people who are experienced with mexiletine use could have a faster rate of titration, but the clinical experts considered that this would not be as fast as in MYOMEX. The committee considered that because of the short duration of the MYOMEX trial, some adverse events might not have been reported. In clinical practice, such adverse events could take much longer than the MYOMEX trial duration to emerge. The clinical experts stated that most patients currently have between 300 mg and 400 mg of imported mexiletine but patients with more severe symptoms, or patients with specific subgroups of myotonia that need greater doses, can have 600 mg doses or greater. The company considered the average daily dose of 417 mg in the Suetterlin et al. retrospective review to be the most accurate dose for modelling, and therefore included 15 capsules a week (equivalent to a daily dose of 429 mg) in its base case. The committee noted the difference between this dose and the 600 mg dose that was used at the point of assessment of efficacy in MYOMEX. It considered that it is not usually appropriate to separate the costs and benefits of treatments. The company stated that people in MYOMEX had the opportunity to immediately continue treatment with mexiletine at a dosage adapted to their clinical response and tolerance to the drug, after the initial titration to 600 mg. The company explained that the average dose used in clinical practice at the largest treating centre in the UK was 300 mg to 400 mg, with 600 mg not usually needed to reach maximum quality-of-life improvements. The company stated that the experts it consulted with had estimated that 400 mg was the average dose in clinical practice. The committee decided it was appropriate to consider the costs of the 429 mg dose (informed by Suetterlin et al. and clinical expert opinion on current practice). However, it also considered a scenario with the costs of the 600 mg dose (as was seen in MYOMEX), because it was mindful that efficacy estimates in the trial were taken once treatment had been titrated up to the 600 mg daily dose, so there would be uncertainty around the clinical-effectiveness results. The committee concluded that the dose and dosing schedule in MYOMEX does not reflect how mexiletine is currently used or would be used in clinical practice, so the cost of mexiletine is uncertain.
# The company's economic model
## The company's economic model does not represent clinical practice
The company's economic model has a simple structure with 3 states: 'alive on treatment', 'alive with no treatment' and 'death'. The transition between alive on treatment and alive with no treatment is based on the discontinuation rate of the Suetterlin et al. study, and the transitions to death are based on general population mortality. The ERG considered that the model was simplistic and did not represent conventional health states such as disease severity or disease progression. However, in the absence of more data on the natural history of the disease, it was adequate for a comparison with best supportive care. The ERG also provided an indicative comparison with lamotrigine. It considered an indirect treatment comparison was not possible so provided analysis that varied the expected utility value of lamotrigine between best supportive care and mexiletine. The committee considered that 'alive with no treatment' would not happen in clinical practice because other treatments are available and would be used (see section 3.3). This would affect both how the comparator arm is created in the model and the subsequent treatments after stopping mexiletine. The committee also noted that not everyone's disease in clinical practice would be expected to respond to treatment with mexiletine; MYOMEX and the Suetterlin et al. study selected patients whose disease would be more likely to respond (see section 3.6). The committee concluded that the economic model does not reflect what would happen in clinical practice.
## The natural history of the disease is not well characterised
The company considered that the disease progresses over time based on testimony that symptoms worsen after diagnosis. Therefore, it included a 15% reduction in quality of life after a modelled 'progression' event in the model. This event was modelled to happen at a faster rate for people who had not had treatment; the rate was estimated based on clinical opinion elicited through a Delphi panel. The clinical experts stated that there is no long-term evidence on the natural history of the disease and that treatment is only aimed at relieving symptoms. It is not disease modifying. However, some patients may experience muscle weakening later in life, which may be affected by treatment status. The ERG considered that the implementation of any disease progression in the model and its impact on quality of life was very uncertain. A single decrease in quality of life is not likely to reflect the natural history of the condition and the appropriateness of a 15% reduction in addition to differences seen in the trial was not justified by the evidence. The ERG removed this assumption in its base case with minimal effect on the incremental cost-effectiveness ratio (ICER). The committee considered that the natural history of the disease is uncertain and likely to be dependent on each patient's needs and preferences. It also considered that if an effect existed, the evidence for a differential rate of progression was not robust and the size of the effect on quality of life was not supported by any evidence. The committee concluded that there was no evidence of a worsening of disease for people having best supportive care and because mexiletine only treats the symptoms of the disease, it agreed with the ERG's removal of this assumption. At consultation, the company removed any disease progression assumptions from its analyses.
# Health-related quality of life
## Generic quality-of-life instruments can measure health-related quality of life in people with NDM
MYOMEX measured only the condition-specific INQoL tool as a quality-of-life measurement. The company considered that the suitability of generic quality-of-life measurement tools such as EuroQoL 5 dimensions (EQ‑5D‑3L) to effectively capture the quality-of-life implications of muscle locking in NDM is unknown. Therefore, the company used INQoL data conceptually mapped to EQ‑5D‑3L utility values using company valuation studies in its base case. The ERG considered that the company did not show that generic measures of quality of life are unable to measure health-related quality of life of people with NDM. It considers generic instruments can be advantageous for capturing broader aspects of health, including comorbidities and adverse events. At the request of the NICE technical team, the ERG provided SF‑36 data from the Statland et al. trial mapped to EQ‑5D‑3L utilities as a scenario analysis. The committee noted that generic quality-of-life instruments are included in the NICE reference case to achieve consistency in decision making across different diseases. The committee considered that domains such as physical function and activity in the SF‑36 matched issues described by the patient expert. It considered that generic quality-of-life instruments can measure health-related quality of life of people with NDM, particularly through domains such as mobility, usual activities and pain. However, it recognised that some elements of muscle locking may be more difficult to capture. It concluded that the generic SF‑36 data from the Statland et al. trial could be included in its considerations.
## The utility values derived from the company's discrete choice valuation experiment are implausible
The company required a valuation study to map INQoL measurements from MYOMEX to EQ‑5D‑3L utility values (see section 3.10). The company commissioned a discrete choice experiment (DCE), which compared 2 hypothetical health states drawn from the INQoL questionnaire. The ERG noted several problems with the DCE valuation studies:
A lack of clear ordering preference in the language used to describe health states (monotonicity), for example the difference between 'some' and 'moderate' problems may not be clear to people taking part.
Many logical inconsistencies, some of which could not be explained by lack of clear ordering. This suggests lack of understanding or attention to the task.
Lack of adequate quality-control checks (other than whether the task was completed).
Eight attributes of the INQoL were varied at the same time, which may have been too complex for people taking part.Conceptual mapping to EQ‑5D‑3L introduces several problems including issues with anchoring the valuation model to the appropriate top and bottom EQ‑5D‑3L health state. The company chose a scenario that assumed the worst health state in the INQoL was equivalent or 'anchored' to the worst state in the EQ‑5D‑3L but also provided a scenario with different anchoring assumptions. The ERG considered that the utility values derived from each of the scenarios were substantially different, which showed considerable uncertainty with the conceptual mapping method. The committee saw the individual patient utility values for MYOMEX patients derived from the DCE study and considered the range of utility values to be implausible and some patients to have implausibly low utility. The clinical experts agreed that some of the utility values were implausibly low and did not represent the patient population seen in clinical practice. The committee concluded that the utility values and modelled treatment effect derived from the DCE were implausible and considered other valuation methods.
## The utility values derived from the company's vignette valuation study and from the Statland et al. study are uncertain
The company also provided a vignette time trade‑off study that asked people taking part to compare living in a hypothetical health state drawn from the INQoL for 10 years compared with 10 minus a given number of years in perfect health. The ERG considered that the vignette study had many of the same problems as the DCE study (see section 3.11) but also had potential issues with the study design, such as lack of warm up exercises for the complex task and lack of explanation for some of the health states. The ERG preferred the vignette study because it avoided issues with conceptual mapping and produced a more plausible treatment effect. The committee agreed that the utility values derived from the vignette study were more plausible. The ERG also presented utility values derived from SF‑36 data in the Statland et al. trial (see section 3.10), which produced a treatment effect much lower than any of the company valuation studies. The ERG considered this to be validation that the vignette study should be considered but cautioned that the algorithm to map SF‑36 to EQ‑5D‑3L utilities can underestimate severe health states. The ERG also considered the data from Statland et al. publication to be limited because only the reported mean values could be used and some data was missing for the crossover periods. The committee noted that section 5.3.9 of NICE's guide to the methods of technology appraisal 2013 states that when mapping to EQ‑5D, the mapping function chosen should be based on data sets containing both health-related quality-of-life measures. The committee considered this was only available for the SF‑36 data and it had not been justified that SF‑36 instrument could not measure quality of life of people with NDM (see section 3.10). The committee noted that all utility values presented were not compared with other sodium channel blockers and were therefore not the comparison of interest (see section 3.3). However, for the comparison with best supportive care, it considered that both sets of utility data presented were highly uncertain. The committee concluded that both sets of utility values could be considered with caution.
## The company's hybrid model cannot overcome the problems with the discrete choice experiment
At consultation, the company provided analyses using a new hybrid model approach, combining data from the DCE and the vignette study. The ERG considered that the hybrid modelling had been well conducted, and that linking data from the 2 studies resolved the anchoring issues for the DCE. But it explained that reanalysis of data taken from the DCE would not be able to resolve the DCE's design issues. The ERG still preferred the vignette approach for utility valuation. Many of the treatment effect utility values are considered confidential so cannot be shown here. The Statland et al. mapping gave a treatment effect of 0.1, whereas the vignette approach gave a value greater than this. The company's preferred hybrid model resulted in an even larger treatment effect than both the Statland et al. mapping and the vignette approach. The committee considered that the treatment effect from the Statland et al. mapping would be an underestimate (because the algorithm used reduces extreme values), giving an unrealistic difference in the utilities on and off treatment. In the absence of a burden of disease study, the committee considered both the vignette approach and the Statland et al. mapping in their decision making, and agreed that the utility increase from mexiletine would be somewhere between the values generated by these 2 approaches. The committee considered there was a high level of uncertainty associated with these 2 utility valuation approaches.
## The reduction in quality of life for carers of people with NDM should be removed as an assumption
At technical engagement, the company considered there to be a case for including carer disutility in the appraisal because carers would also expect to have a reduction in quality of life without treatment. The company included a carer disutility as published in NICE's highly specialised technologies guidance on ataluren for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene of 0.11 for an estimated 20% of patients with severe NDM. The ERG considered it could be appropriate to apply a carer disutility for patients who had no treatment, but it was uncertain how many people have severe enough symptoms to need care. It also noted that the disutility from NICE's guidance on ataluren for treating Duchenne muscular dystrophy is for non-ambulatory patients with progressive loss of motor function in the upper body, but no patients in MYOMEX needed to use wheelchairs or walking aids to complete a walking test of 3 to 5 metres. The clinical expert stated that non-ambulatory patients with NDM are very rare, having only ever seen 1 patient who needed to use a wheelchair. The committee considered that patients not having mexiletine would have another treatment (see section 3.3), and therefore the carer disutility would have been overestimated. The committee noted comments from the consultation that people with the condition and their carers had a better quality of life because of mexiletine, and carers would face a lifetime of caring without it. The company had planned to present results from a carer study, but this had ethical approval delays. Instead, it provided a scenario using carer disutility for carers of people with multiple sclerosis as a proxy. The ERG thought the resulting disutility could be an overestimate and noted that this scenario also includes carers of non-ambulatory people, with substantial uncertainties unresolved. The committee acknowledged the impact of caring for someone with NDM has, but that there was no appropriate data available to do a relevant scenario analysis. It concluded that it had not seen enough evidence to justify including consideration of carer quality of life, and that inclusion of this assumption is highly uncertain and should be removed.
# Resource use
## The costs of resource use for people with NDM who are not having treatment is likely to be overestimated
The company considered that people who do not have treatment would use 3 times the number of resources as somebody having mexiletine. This includes increased costs for admissions for falls, physiotherapy and other therapies. The company validated this multiplier using estimation from an advisory board. The ERG considered the justification behind the advisory board findings to be incorrect because it used both the estimated frequency of resource use and the estimated number of people using the resource when only the frequency of resource use is needed for use in the model. The ERG therefore used only the frequency of resource use multiplier in its base case. The committee considered that this change had minimal effect on the ICER. It also noted that any comparison with best supportive care would overestimate the difference in resource use because many people would have other active treatments such as lamotrigine or other sodium channel blockers (see section 3.3). The committee concluded that the ERG amendments were likely to be appropriate for any comparison with best supportive care but would not reflect what would happen in clinical practice.
# Cost-effectiveness estimate
## Because of the uncertainty an acceptable ICER is £20,000 per QALY gained
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically:
Impact from differing cost and potential difference in effectiveness of mexiletine because of the different options for the average dose (429 mg, 600 mg) preferred by the company and the ERG.
Problems with the MYOMEX clinical trial, including potential carry-over effects and unintentional blinding, short trial duration and a small number of patients.
Unknown true treatment effect in terms of utility from mexiletine treatment.Therefore, it agreed that an acceptable ICER would be around £20,000 per QALY gained.
## Mexiletine is cost effective for people with NDM
Both the company's and ERG's base case after consultation included removing the disease progression assumptions (see section 3.9). But the ERG base case used the vignette valuation study (see section 3.12), 600 mg mexiletine dose for the costs and benefits of treatment (see section 3.7), reduction of the resource use multiplier (see section 3.15) and removed carer disutility because of the uncertainty around symptom severity and need for care (see section 3.14). The committee-preferred assumptions differed from the revised ERG base-case assumptions for the comparison with best supportive care. It considered that:
It is appropriate to consider the costs of the 429 mg dose in line with clinical practice. However, this is associated with uncertainty because the mexiletine efficacy data has been derived from the 600 mg equivalent dose (see section 3.7).
It is appropriate to explore scenarios using utilities derived from SF‑36 data in the Statland et al. trial because it has the advantage of being a generic health-related quality-of-life measurement, as well as to consider those produced by the ERG-preferred vignette approach. However, the committee noted that there is substantial uncertainty in the utility values. (see section 3.12 and section 3.13).Using the vignette approach and the scenario with the 429 mg dose, the ICER was £19,039 per QALY gained for mexiletine (Namuscla) compared with best supportive care. When the 600 mg dose was used, the ICER exceeded £30,000 per QALY. The committee considered that comparison with best supportive care was not appropriate (see section 3.3) and the indicative ERG analysis comparison with lamotrigine (see section 3.8) suggests this would increase the ICER if lamotrigine's treatment effect was greater than placebo. It accepted that if the utility gain associated with an active comparator was very modest, the ICER would remain below £20,000 per QALY gained. The committee recognised the serious limitations in the cost-effectiveness modelling. However, it also acknowledged that the evidence base is necessarily weaker for some technologies, such as those used to treat rare diseases. On balance, and taking into consideration the likelihood of decision error and its consequences, the committee concluded that mexiletine (Namuscla) was a cost-effective use of NHS resources and recommended it for routine commissioning.
# Equalities considerations
## There are no equality issues that can be addressed by the committee
The committee noted that disability is a protected characteristic and that people with NDM have a disability that could make travel to regional neurology centres for treatment more difficult. The committee noted that any equalities issue relating to geographical access to treatment with NDM would already be realised because mexiletine is current standard practice. However, the committee concluded that this potential equality issue could not be addressed in the guidance recommendations.
At consultation, it was noted that there are possible sex-based differences in alternative treatment suitability. For example, an increased risk of major birth defects in pregnancy have been seen with phenytoin, and changes in the body during pregnancy may affect lamotrigine levels or therapeutic effect. However, the committee noted that mexiletine should be avoided during pregnancy. It concluded that this potential equality issue could not be addressed in the guidance recommendations.
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{'Recommendations': "Mexiletine (Namuscla) is recommended, within its marketing authorisation, as an option for treating the symptoms of myotonia in adults with non-dystrophic myotonic disorders. It is recommended only if the company provides mexiletine (Namuscla) according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nTreatments for the symptoms of myotonia in adults with non-dystrophic myotonic disorders already include imported mexiletine (which is not licensed in the UK). Other sodium channel blockers are used if mexiletine is not suitable. NICE's remit for this appraisal is to appraise Namuscla, the only brand of mexiletine with a UK marketing authorisation.\n\nClinical trial evidence suggests that mexiletine is better than placebo at reducing the symptoms of myotonia. But the trial did not compare mexiletine with other sodium channel blockers. Also, a higher dose of mexiletine was used in the clinical trial than people would normally have in the NHS.\n\nThe economic model does not compare mexiletine with other sodium channel blockers that are used in the NHS. Because of this, mexiletine's clinical benefit compared with these medicines is uncertain. However, the cost-effectiveness estimates for mexiletine compared with best supportive care are within the range that NICE considers a cost-effective use of NHS resources. It is uncertain if they would exceed this range when compared with other sodium channel blockers. Therefore, mexiletine (Namuscla) is recommended.", 'Information about mexiletine': "# Marketing authorisation indication\n\nMexiletine (Namuscla, Lupin) is indicated 'for the symptomatic treatment of myotonia in adult patients with non-dystrophic myotonic disorders'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £5,000 per 100×167\xa0mg capsules (excluding VAT; BNF online, accessed September 2021). The company has a commercial arrangement. This makes mexiletine (Namuscla) available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Lupin, a review of this submission by the evidence review group (ERG), NICE's technical report, responses from stakeholders, and consultation comments from stakeholders, experts and members of the public. See the committee papers for full details of the evidence.\n\n# Disease background and current clinical management\n\n## Non-dystrophic myotonia can affect the quality of life of patients and carers\n\nNon-dystrophic myotonia (NDM) refers to a group of rare genetic disorders affecting skeletal muscle chloride or sodium ion channels. The most common symptom is myotonia, which is a delay in muscle relaxation and can lead to muscle locking and stiffness. The patient expert explained the constant effect of myotonia on quality of life for people with the condition and their carers. It can cause general muscular discomfort and pain, lack of sleep and major falls because muscle locking can cause falls and also limit the ability to break a fall. The patient expert highlighted that this leads to avoiding stairs where possible. It can also cause embarrassment for people with NDM because slurring speech and facial locking after sneezing can be misunderstood by other people. The patient organisation emphasised the invisible nature of the disease because of its rarity. The patient expert also noted constant worry about triggers (such as cold weather) that could affect myotonic episodes. The clinical experts explained that symptom severity varies between people, and can also vary over time for each individual (for example, it can affect different parts of the body). Some people need constant treatment and others choose episodic management, for instance, during cold weather. If the disease is not managed, the patient expert explained that care is sometimes needed for tasks such as climbing stairs, lifting or bathing.\n\n## Current clinical management involves using mexiletine and other sodium channel blockers\n\nCurrent clinical management of NDM includes muscle warming routines, specialist physiotherapy and avoidance of triggers. However, the clinical experts stated that pharmacological management should be offered to any person with NDM who is seeking treatment because it is affecting their daily lives. Sodium channel blockers (such as mexiletine, carbamazepine, acetazolamide, flecainide and phenytoin) have been used off label for many years to treat NDM. Off-label imported mexiletine was used most because benefits can be seen very quickly. The clinical experts explained that a recent randomised controlled trial showed evidence of efficacy of another sodium channel blocker, lamotrigine, which is also sometimes used if mexiletine is contraindicated, not effective or not tolerated. The patient expert explained that using mexiletine addressed most of the symptoms of NDM with near-normal muscle function and manageable side effects. The committee concluded that mexiletine is currently the preferred, established treatment for NDM and other options are available when mexiletine is not suitable.\n\n## The company should compare mexiletine with other sodium channel blockers\n\nThe committee was aware that the remit for this appraisal was to appraise mexiletine (Namuscla) within its licensed indication for NDM. It understood that it would make recommendations within the terms of the marketing authorisation, as published in the manufacturer's summary of product characteristics. It noted that the comparator in the scope for this appraisal was established clinical management without mexiletine, including but not limited to lamotrigine and best supportive care. The company considered that mexiletine (Namuscla) is now the only licensed treatment for NDM and therefore compared mexiletine with placebo to represent best supportive care. The company also indicated that lamotrigine is not established in clinical practice because few people take it. The company explained that lamotrigine has a longer titration period than mexiletine, with intensive monitoring to reach higher doses if needed. It also believed that pain and fatigue are influenced by the placebo effect, and other sodium channel blockers would have no additional benefit to placebo as implemented in their comparison with best supportive care. The committee recalled comments from the evidence submissions that clinicians in England had used lamotrigine with success in people whose disease did not respond to mexiletine or who could not have mexiletine because of cardiac arrythmias. At consultation, the Association of British Neurologists (ABN) believed it was not reasonable to consider other sodium channel blockers as comparators. The ABN commented that lamotrigine is rarely used because they suggested it was not as effective as mexiletine and has a high discontinuation rate. But it noted that there is a direct comparator trial being set up. The committee considered that established clinical management without mexiletine cannot currently be observed in the NHS because mexiletine is already established in clinical practice with off-label use and, more recently, an interim access agreement for the licensed treatment (Namuscla). Therefore, the committee deemed the most appropriate comparison to be with what people currently taking mexiletine would have if mexiletine was not available. The clinical experts stated that if mexiletine was not available, patients would have another sodium channel blocker. The patient organisation representative and patient expert at the first committee meeting agreed with this. The committee concluded that comparing mexiletine with best supportive care was not appropriate because people would be offered other active treatments such as lamotrigine or other sodium channel blockers if mexiletine was not available, and that other active treatments would likely be more effective than best supportive care.\n\n# Clinical evidence\n\n## The main clinical-effectiveness evidence comes from the MYOMEX trial, with supporting evidence from other studies\n\nThe main clinical evidence for mexiletine comes from MYOMEX, a randomised crossover trial of 26\xa0patients with NDM comparing mexiletine with placebo. The primary outcome was muscle stiffness as measured by visual analogue scale, but the efficacy evidence used in the economic model was a secondary outcome measure, the Individualised Neuromuscular Quality of Life (INQoL) questionnaire (see section\xa03.10). Supporting evidence came from 3\xa0other studies:\n\nSuetterlin et al. (2015) – a retrospective review of 63\xa0UK patients with NDM taking mexiletine for 6\xa0months or more\n\nStatland et al. (2012) – a randomised crossover trial of 59\xa0patients comparing mexiletine with placebo\n\nStunnenberg et al. (2015) – an aggregated study of patients individually randomised to mexiletine or placebo in a crossover design for 30\xa0patients with NDM in the Dutch neuromuscular database.These trials were used as supporting clinical evidence and used to inform some economic model parameters and scenario analyses. The committee concluded that all the evidence, combined with the statements that mexiletine has been standard practice for over 15\xa0years, suggest mexiletine is effective for relieving myotonia symptoms. However, the committee also noted that there were no comparisons of mexiletine with an active comparator.\n\n## MYOMEX is broadly generalisable to NHS clinical practice\n\nMYOMEX included people aged between 18\xa0and\xa065 with genetically confirmed NDM and with myotonic symptoms severe enough to justify treatment. The severity of symptoms was evaluated by whether it affected more than 1\xa0segment of the body and if it impacted on 3\xa0or more daily activities. The clinical experts explained that there are no formal methods of assessing severity of NDM because of the large amount of heterogeneity between patient symptoms and needs (see section\xa03.1). However, they considered that the severity inclusion criteria would be broadly generalisable to NHS clinical practice. The company noted that the small number of people aged over\xa065 who have treatment for NDM would not have different treatment to those under\xa065, therefore it does not consider the age criteria to be a limitation. The committee concluded that MYOMEX was broadly generalisable but noted the limitations of the inclusion criteria.\n\n## There are significant limitations with the design of the MYOMEX trial\n\nA large proportion of patients in MYOMEX had previously had mexiletine. The clinical expert stated that this would be expected because there are few people with NDM who have not had mexiletine because it is a rare condition and mexiletine is routinely offered as a first treatment option. The ERG noted, and the clinical expert agreed, that the recognisable side effects of mexiletine could have effectively unblinded patients to which treatment they had. This is supported by the Statland et al. study in which around 80% of patients correctly guessed which treatment they had. The ERG considered that unblinding could potentially bias results because most of the outcomes are patient reported. Additionally, the ERG noted that there was potential for a carry-over effect between the 2\xa0phases of the crossover trial if there was not enough time between the phases (the washout period). People in the MYOMEX trial had a 4‑ to 8‑day washout period and the company presented analysis that there was no statistical evidence of a carry-over effect and the ERG noted that data from the first phase only also showed similar changes in muscle stiffness to both phases combined. However, the ERG noted the Statland et al. trial had at least a 7‑day washout period and there was a statistically significant carry-over effect. The committee noted that MYOMEX included few patients and it was uncertain if the trial was powered to detect a carry-over effect. It also noted that MYOMEX had a short duration of only 18\xa0days in each phase, so there is uncertainty in how effectiveness is maintained over a lifetime of treatment. At consultation, the company said that no risk of bias was found in the MYOMEX trial but did not provide evidence on this. The committee concluded that potential for unblinding and carry-over effects, short trial duration and few patients contribute substantial uncertainty to the MYOMEX results.\n\n## The dose and dosing schedule of mexiletine in MYOMEX does not match how it is used in clinical practice\n\nNamuscla is a new formulation of mexiletine that uses different dose measurements to previous off‑label use (a 167\xa0mg capsule of Namuscla formulation is equivalent to 200\xa0mg of imported mexiletine). However, all the clinical evidence uses the imported formulation of mexiletine. The daily dose in the MYOMEX trial started at 200\xa0mg for 3\xa0days, at which point all patients had a dose titration up to 400\xa0mg for a further 3\xa0days and then a final titration to 600\xa0mg for 12\xa0days, at which point efficacy was assessed. The summary of product characteristics for Namuscla states that the dosing schedule is based on clinical response and can be increased after at least 1\xa0week of treatment in 167\xa0mg (200\xa0mg imported mexiletine dose equivalent) increments to a maximum dose of 500\xa0mg (600\xa0mg equivalent). The clinical experts stated that the rapid forced dose titration to 600\xa0mg in MYOMEX does not represent current clinical management and is not in line with the summary of product characteristics. Currently, some people have dose titration in smaller off‑label 100\xa0mg dose increments at a more cautious rate of titration to avoid gastric side effects of mexiletine. Some people who are experienced with mexiletine use could have a faster rate of titration, but the clinical experts considered that this would not be as fast as in MYOMEX. The committee considered that because of the short duration of the MYOMEX trial, some adverse events might not have been reported. In clinical practice, such adverse events could take much longer than the MYOMEX trial duration to emerge. The clinical experts stated that most patients currently have between 300\xa0mg and 400\xa0mg of imported mexiletine but patients with more severe symptoms, or patients with specific subgroups of myotonia that need greater doses, can have 600\xa0mg doses or greater. The company considered the average daily dose of 417\xa0mg in the Suetterlin et al. retrospective review to be the most accurate dose for modelling, and therefore included 15\xa0capsules a week (equivalent to a daily dose of 429\xa0mg) in its base case. The committee noted the difference between this dose and the 600\xa0mg dose that was used at the point of assessment of efficacy in MYOMEX. It considered that it is not usually appropriate to separate the costs and benefits of treatments. The company stated that people in MYOMEX had the opportunity to immediately continue treatment with mexiletine at a dosage adapted to their clinical response and tolerance to the drug, after the initial titration to 600\xa0mg. The company explained that the average dose used in clinical practice at the largest treating centre in the UK was 300\xa0mg to 400\xa0mg, with 600\xa0mg not usually needed to reach maximum quality-of-life improvements. The company stated that the experts it consulted with had estimated that 400\xa0mg was the average dose in clinical practice. The committee decided it was appropriate to consider the costs of the 429\xa0mg dose (informed by Suetterlin et al. and clinical expert opinion on current practice). However, it also considered a scenario with the costs of the 600\xa0mg dose (as was seen in MYOMEX), because it was mindful that efficacy estimates in the trial were taken once treatment had been titrated up to the 600\xa0mg daily dose, so there would be uncertainty around the clinical-effectiveness results. The committee concluded that the dose and dosing schedule in MYOMEX does not reflect how mexiletine is currently used or would be used in clinical practice, so the cost of mexiletine is uncertain.\n\n# The company's economic model\n\n## The company's economic model does not represent clinical practice\n\nThe company's economic model has a simple structure with 3\xa0states: 'alive on treatment', 'alive with no treatment' and 'death'. The transition between alive on treatment and alive with no treatment is based on the discontinuation rate of the Suetterlin et al. study, and the transitions to death are based on general population mortality. The ERG considered that the model was simplistic and did not represent conventional health states such as disease severity or disease progression. However, in the absence of more data on the natural history of the disease, it was adequate for a comparison with best supportive care. The ERG also provided an indicative comparison with lamotrigine. It considered an indirect treatment comparison was not possible so provided analysis that varied the expected utility value of lamotrigine between best supportive care and mexiletine. The committee considered that 'alive with no treatment' would not happen in clinical practice because other treatments are available and would be used (see section\xa03.3). This would affect both how the comparator arm is created in the model and the subsequent treatments after stopping mexiletine. The committee also noted that not everyone's disease in clinical practice would be expected to respond to treatment with mexiletine; MYOMEX and the Suetterlin et al. study selected patients whose disease would be more likely to respond (see section\xa03.6). The committee concluded that the economic model does not reflect what would happen in clinical practice.\n\n## The natural history of the disease is not well characterised\n\nThe company considered that the disease progresses over time based on testimony that symptoms worsen after diagnosis. Therefore, it included a 15% reduction in quality of life after a modelled 'progression' event in the model. This event was modelled to happen at a faster rate for people who had not had treatment; the rate was estimated based on clinical opinion elicited through a Delphi panel. The clinical experts stated that there is no long-term evidence on the natural history of the disease and that treatment is only aimed at relieving symptoms. It is not disease modifying. However, some patients may experience muscle weakening later in life, which may be affected by treatment status. The ERG considered that the implementation of any disease progression in the model and its impact on quality of life was very uncertain. A single decrease in quality of life is not likely to reflect the natural history of the condition and the appropriateness of a 15% reduction in addition to differences seen in the trial was not justified by the evidence. The ERG removed this assumption in its base case with minimal effect on the incremental cost-effectiveness ratio (ICER). The committee considered that the natural history of the disease is uncertain and likely to be dependent on each patient's needs and preferences. It also considered that if an effect existed, the evidence for a differential rate of progression was not robust and the size of the effect on quality of life was not supported by any evidence. The committee concluded that there was no evidence of a worsening of disease for people having best supportive care and because mexiletine only treats the symptoms of the disease, it agreed with the ERG's removal of this assumption. At consultation, the company removed any disease progression assumptions from its analyses.\n\n# Health-related quality of life\n\n## Generic quality-of-life instruments can measure health-related quality of life in people with NDM\n\nMYOMEX measured only the condition-specific INQoL tool as a quality-of-life measurement. The company considered that the suitability of generic quality-of-life measurement tools such as EuroQoL 5\xa0dimensions (EQ‑5D‑3L) to effectively capture the quality-of-life implications of muscle locking in NDM is unknown. Therefore, the company used INQoL data conceptually mapped to EQ‑5D‑3L utility values using company valuation studies in its base case. The ERG considered that the company did not show that generic measures of quality of life are unable to measure health-related quality of life of people with NDM. It considers generic instruments can be advantageous for capturing broader aspects of health, including comorbidities and adverse events. At the request of the NICE technical team, the ERG provided SF‑36 data from the Statland et al. trial mapped to EQ‑5D‑3L utilities as a scenario analysis. The committee noted that generic quality-of-life instruments are included in the NICE reference case to achieve consistency in decision making across different diseases. The committee considered that domains such as physical function and activity in the SF‑36 matched issues described by the patient expert. It considered that generic quality-of-life instruments can measure health-related quality of life of people with NDM, particularly through domains such as mobility, usual activities and pain. However, it recognised that some elements of muscle locking may be more difficult to capture. It concluded that the generic SF‑36 data from the Statland et al. trial could be included in its considerations.\n\n## The utility values derived from the company's discrete choice valuation experiment are implausible\n\nThe company required a valuation study to map INQoL measurements from MYOMEX to EQ‑5D‑3L utility values (see section\xa03.10). The company commissioned a discrete choice experiment (DCE), which compared 2\xa0hypothetical health states drawn from the INQoL questionnaire. The ERG noted several problems with the DCE valuation studies:\n\nA lack of clear ordering preference in the language used to describe health states (monotonicity), for example the difference between 'some' and 'moderate' problems may not be clear to people taking part.\n\nMany logical inconsistencies, some of which could not be explained by lack of clear ordering. This suggests lack of understanding or attention to the task.\n\nLack of adequate quality-control checks (other than whether the task was completed).\n\nEight attributes of the INQoL were varied at the same time, which may have been too complex for people taking part.Conceptual mapping to EQ‑5D‑3L introduces several problems including issues with anchoring the valuation model to the appropriate top and bottom EQ‑5D‑3L health state. The company chose a scenario that assumed the worst health state in the INQoL was equivalent or 'anchored' to the worst state in the EQ‑5D‑3L but also provided a scenario with different anchoring assumptions. The ERG considered that the utility values derived from each of the scenarios were substantially different, which showed considerable uncertainty with the conceptual mapping method. The committee saw the individual patient utility values for MYOMEX patients derived from the DCE study and considered the range of utility values to be implausible and some patients to have implausibly low utility. The clinical experts agreed that some of the utility values were implausibly low and did not represent the patient population seen in clinical practice. The committee concluded that the utility values and modelled treatment effect derived from the DCE were implausible and considered other valuation methods.\n\n## The utility values derived from the company's vignette valuation study and from the Statland et al. study are uncertain\n\nThe company also provided a vignette time trade‑off study that asked people taking part to compare living in a hypothetical health state drawn from the INQoL for 10\xa0years compared with 10 minus a given number of years in perfect health. The ERG considered that the vignette study had many of the same problems as the DCE study (see section\xa03.11) but also had potential issues with the study design, such as lack of warm up exercises for the complex task and lack of explanation for some of the health states. The ERG preferred the vignette study because it avoided issues with conceptual mapping and produced a more plausible treatment effect. The committee agreed that the utility values derived from the vignette study were more plausible. The ERG also presented utility values derived from SF‑36 data in the Statland et al. trial (see section\xa03.10), which produced a treatment effect much lower than any of the company valuation studies. The ERG considered this to be validation that the vignette study should be considered but cautioned that the algorithm to map SF‑36 to EQ‑5D‑3L utilities can underestimate severe health states. The ERG also considered the data from Statland et al. publication to be limited because only the reported mean values could be used and some data was missing for the crossover periods. The committee noted that section\xa05.3.9 of NICE's guide to the methods of technology appraisal 2013 states that when mapping to EQ‑5D, the mapping function chosen should be based on data sets containing both health-related quality-of-life measures. The committee considered this was only available for the SF‑36 data and it had not been justified that SF‑36 instrument could not measure quality of life of people with NDM (see section\xa03.10). The committee noted that all utility values presented were not compared with other sodium channel blockers and were therefore not the comparison of interest (see section\xa03.3). However, for the comparison with best supportive care, it considered that both sets of utility data presented were highly uncertain. The committee concluded that both sets of utility values could be considered with caution.\n\n## The company's hybrid model cannot overcome the problems with the discrete choice experiment\n\nAt consultation, the company provided analyses using a new hybrid model approach, combining data from the DCE and the vignette study. The ERG considered that the hybrid modelling had been well conducted, and that linking data from the 2\xa0studies resolved the anchoring issues for the DCE. But it explained that reanalysis of data taken from the DCE would not be able to resolve the DCE's design issues. The ERG still preferred the vignette approach for utility valuation. Many of the treatment effect utility values are considered confidential so cannot be shown here. The Statland et al. mapping gave a treatment effect of\xa00.1, whereas the vignette approach gave a value greater than this. The company's preferred hybrid model resulted in an even larger treatment effect than both the Statland et al. mapping and the vignette approach. The committee considered that the treatment effect from the Statland et al. mapping would be an underestimate (because the algorithm used reduces extreme values), giving an unrealistic difference in the utilities on and off treatment. In the absence of a burden of disease study, the committee considered both the vignette approach and the Statland et al. mapping in their decision making, and agreed that the utility increase from mexiletine would be somewhere between the values generated by these 2\xa0approaches. The committee considered there was a high level of uncertainty associated with these 2\xa0utility valuation approaches.\n\n## The reduction in quality of life for carers of people with NDM should be removed as an assumption\n\nAt technical engagement, the company considered there to be a case for including carer disutility in the appraisal because carers would also expect to have a reduction in quality of life without treatment. The company included a carer disutility as published in NICE's highly specialised technologies guidance on ataluren for treating Duchenne muscular dystrophy with a nonsense mutation in the dystrophin gene of\xa00.11 for an estimated 20% of patients with severe NDM. The ERG considered it could be appropriate to apply a carer disutility for patients who had no treatment, but it was uncertain how many people have severe enough symptoms to need care. It also noted that the disutility from NICE's guidance on ataluren for treating Duchenne muscular dystrophy is for non-ambulatory patients with progressive loss of motor function in the upper body, but no patients in MYOMEX needed to use wheelchairs or walking aids to complete a walking test of 3\xa0to\xa05\xa0metres. The clinical expert stated that non-ambulatory patients with NDM are very rare, having only ever seen 1\xa0patient who needed to use a wheelchair. The committee considered that patients not having mexiletine would have another treatment (see section\xa03.3), and therefore the carer disutility would have been overestimated. The committee noted comments from the consultation that people with the condition and their carers had a better quality of life because of mexiletine, and carers would face a lifetime of caring without it. The company had planned to present results from a carer study, but this had ethical approval delays. Instead, it provided a scenario using carer disutility for carers of people with multiple sclerosis as a proxy. The ERG thought the resulting disutility could be an overestimate and noted that this scenario also includes carers of non-ambulatory people, with substantial uncertainties unresolved. The committee acknowledged the impact of caring for someone with NDM has, but that there was no appropriate data available to do a relevant scenario analysis. It concluded that it had not seen enough evidence to justify including consideration of carer quality of life, and that inclusion of this assumption is highly uncertain and should be removed.\n\n# Resource use\n\n## The costs of resource use for people with NDM who are not having treatment is likely to be overestimated\n\nThe company considered that people who do not have treatment would use 3\xa0times the number of resources as somebody having mexiletine. This includes increased costs for admissions for falls, physiotherapy and other therapies. The company validated this multiplier using estimation from an advisory board. The ERG considered the justification behind the advisory board findings to be incorrect because it used both the estimated frequency of resource use and the estimated number of people using the resource when only the frequency of resource use is needed for use in the model. The ERG therefore used only the frequency of resource use multiplier in its base case. The committee considered that this change had minimal effect on the ICER. It also noted that any comparison with best supportive care would overestimate the difference in resource use because many people would have other active treatments such as lamotrigine or other sodium channel blockers (see section\xa03.3). The committee concluded that the ERG amendments were likely to be appropriate for any comparison with best supportive care but would not reflect what would happen in clinical practice.\n\n# Cost-effectiveness estimate\n\n## Because of the uncertainty an acceptable ICER is £20,000 per QALY gained\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty, specifically:\n\nImpact from differing cost and potential difference in effectiveness of mexiletine because of the different options for the average dose (429\xa0mg, 600\xa0mg) preferred by the company and the ERG.\n\nProblems with the MYOMEX clinical trial, including potential carry-over effects and unintentional blinding, short trial duration and a small number of patients.\n\nUnknown true treatment effect in terms of utility from mexiletine treatment.Therefore, it agreed that an acceptable ICER would be around £20,000 per QALY gained.\n\n## Mexiletine is cost effective for people with NDM\n\nBoth the company's and ERG's base case after consultation included removing the disease progression assumptions (see section\xa03.9). But the ERG base case used the vignette valuation study (see section\xa03.12), 600\xa0mg mexiletine dose for the costs and benefits of treatment (see section\xa03.7), reduction of the resource use multiplier (see section\xa03.15) and removed carer disutility because of the uncertainty around symptom severity and need for care (see section\xa03.14). The committee-preferred assumptions differed from the revised ERG base-case assumptions for the comparison with best supportive care. It considered that:\n\nIt is appropriate to consider the costs of the 429\xa0mg dose in line with clinical practice. However, this is associated with uncertainty because the mexiletine efficacy data has been derived from the 600\xa0mg equivalent dose (see section\xa03.7).\n\nIt is appropriate to explore scenarios using utilities derived from SF‑36 data in the Statland et al. trial because it has the advantage of being a generic health-related quality-of-life measurement, as well as to consider those produced by the ERG-preferred vignette approach. However, the committee noted that there is substantial uncertainty in the utility values. (see section\xa03.12 and section\xa03.13).Using the vignette approach and the scenario with the 429\xa0mg dose, the ICER was £19,039 per QALY gained for mexiletine (Namuscla) compared with best supportive care. When the 600\xa0mg dose was used, the ICER exceeded £30,000 per QALY. The committee considered that comparison with best supportive care was not appropriate (see section\xa03.3) and the indicative ERG analysis comparison with lamotrigine (see section\xa03.8) suggests this would increase the ICER if lamotrigine's treatment effect was greater than placebo. It accepted that if the utility gain associated with an active comparator was very modest, the ICER would remain below £20,000 per QALY gained. The committee recognised the serious limitations in the cost-effectiveness modelling. However, it also acknowledged that the evidence base is necessarily weaker for some technologies, such as those used to treat rare diseases. On balance, and taking into consideration the likelihood of decision error and its consequences, the committee concluded that mexiletine (Namuscla) was a cost-effective use of NHS resources and recommended it for routine commissioning.\n\n# Equalities considerations\n\n## There are no equality issues that can be addressed by the committee\n\nThe committee noted that disability is a protected characteristic and that people with NDM have a disability that could make travel to regional neurology centres for treatment more difficult. The committee noted that any equalities issue relating to geographical access to treatment with NDM would already be realised because mexiletine is current standard practice. However, the committee concluded that this potential equality issue could not be addressed in the guidance recommendations.\n\nAt consultation, it was noted that there are possible sex-based differences in alternative treatment suitability. For example, an increased risk of major birth defects in pregnancy have been seen with phenytoin, and changes in the body during pregnancy may affect lamotrigine levels or therapeutic effect. However, the committee noted that mexiletine should be avoided during pregnancy. It concluded that this potential equality issue could not be addressed in the guidance recommendations."}
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https://www.nice.org.uk/guidance/ta748
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Evidence-based recommendations on mexiletine (Namuscla) for treating the symptoms of myotonia in adults with non-dystrophic myotonic disorders.
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3da66e25e1647f85bfeceb093efa3598e7de33d8
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nice
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Synergo for non-muscle-invasive bladder cancer
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Synergo for non-muscle-invasive bladder cancer
Evidence-based recommendations on Synergo for non-muscle-invasive bladder cancer.
# Recommendations
Synergo shows promise for high-risk non-muscle-invasive bladder cancer that has not responded to or has recurred after Bacillus Calmette-Guerin (BCG) treatment, or when people cannot or do not want to have BCG treatment. However there is not enough good-quality evidence to support the case for routine adoption. Synergo should only be used with special arrangements as outlined by NICE interventional procedures guidance on intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer.
Research is recommended on the benefits and costs of Synergo for high-risk non-muscle-invasive bladder cancer. This is to address the uncertainty in the evidence base and to inform a revised cost analysis to assess the impact of Synergo on cystectomy rates or repeat cystoscopies in people who cannot have a cystectomy. Because randomised controlled trials are challenging in this patient population, further collection and analysis of observational and NHS audit data is recommended. Find out details of required research outcomes in the section on further research in this guidance.
Why the committee made these recommendations
Synergo delivers chemotherapy and microwave energy to the bladder. Clinical experts advise that chemotherapy using Synergo would be used in the NHS for high-risk non-muscle-invasive bladder cancer after BCG has not worked, or if someone cannot or does not want to have BCG.
Synergo offers an alternative treatment to the limited options available for these people, which include radical cystectomy (removal of the bladder) or regular cystoscopies (a procedure to look inside the bladder to check for tumours and remove them if necessary). The experts advise that using Synergo for intermediate-risk cancer is unlikely to be practical. Also, there are other effective treatments available for these people.
There is some evidence that chemotherapy using Synergo could reduce the chance of the cancer returning. But this observation comes from a trial that does not reflect how Synergo is likely to be used in the NHS.
Cost modelling for Synergo is uncertain and does not reflect how it is likely to be used in the NHS. Because of this and the limitations in the clinical evidence, further research is recommended into using Synergo in high-risk non-muscle-invasive bladder cancer.# The technology
# Technology
Synergo treats non-muscle-invasive bladder cancer (NMIBC) using a radiofrequency-induced thermo-chemotherapeutic effect (RITE). It heats the superficial layers of the bladder wall using controlled radiofrequency radiation (non-ionising microwave radiation), and flushes the bladder with a chemotherapy drug at the same time. The drug solution is continuously pumped out of the bladder, cooled, and recirculated to prevent overheating. A miniature antenna in the catheter directs radiofrequency radiation at the bladder wall tissue. Synergo aims to improve the delivery and efficacy of chemotherapy with the objective of reducing tumour recurrence and disease progression. It is another treatment option for NMIBC, in addition to Bacillus Calmette-Guerin (BCG) therapy and radical cystectomy.
The technology is an intravesical irrigation system combined with an energy delivering unit. The system has a radiofrequency generator that delivers radiofrequency energy at 915 MHz (the lower limit of microwave electromagnetism). It also includes a drug circulating unit and a microprocessor with application-specific software. The user interface consists of a computer, monitor with touch screen, and barcode reader. The software monitors and records treatment parameters in real time during the treatment session. Synergo is CE marked as a class IIb medical device.
# Care pathway
NICE has not made recommendations on the position of device-assisted chemotherapy treatments like Synergo in the NHS clinical pathway for bladder cancer.
Expert advice suggests the technology is being used in the NHS as an alternative to further intravesical treatment or cystectomy in high-risk NMIBC if:
it has not responded to BCG treatment or has recurred after treatment, or
when people cannot or do not want to have BCG treatment, or when it's not available.
# Innovative aspects
The innovative aspects are the use of radiofrequency radiation (non-ionising microwave radiation) to deliver controlled electromagnetic energy directly to the walls of the bladder, along with instillations of the bladder with chemotherapy. This microwave-induced hyperthermia is designed to make the chemotherapy more effective.
# Intended use
Synergo is intended for intermediate-risk or high-risk NMIBC. People have Synergo as outpatients in specialist centres. There is no need for general anaesthesia during treatment, but local anaesthetic lubricating gel may be used to insert the treatment catheter. Synergo is administered by healthcare professionals such as bladder cancer nurse specialists or consultant urologists trained in using Synergo, in secondary and tertiary care settings.
# Costs
The total annual cost of Synergo therapy is £11,650 per patient (based on 12 treatment sessions). This includes the following costs:
administering mitomycin C (MMC): £4,585 per patient
the annual lease for the Synergo device: £327 per patient
consumables: £490 per use
minutes of Band 7 Nurse time to administer the treatment with Synergo: £72.For more information about the technology, see the website for Synergo.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The main clinical evidence comprises 19 studies
The evidence assessed by the EAC included 19 studies reported across 20 full text publications. Of the included studies, 5 were comparative (3 randomised controlled trials and 2 observational studies) and 14 were single-arm observational studies. The comparative evidence included a total of 595 people with intermediate-risk or high-risk non-muscle-invasive bladder cancer (NMIBC), of whom 247 had treatment with mitomycin C (MMC) using Synergo. Nineteen abstracts identified were not included in the evidence review. For full details of the clinical evidence, see section 3 of the assessment report in the supporting documentation on the NICE website.
## The 3 pivotal RCTs position Synergo differently in the clinical pathway
Two RCTs compared treatment with MMC using Synergo with Bacillus Calmette-Guerin (BCG) therapy in intermediate-risk and high-risk NMIBC patients (Arends et al. 2016 and the HYMN trial ). Arends et al. assessed treatment with Synergo first line, including in people with intermediate-risk cancer who would not normally be offered BCG first line in the NHS. The HYMN trial was a UK-based RCT that included people with NMIBC for which BCG treatment had failed. Colombo et al. (2003 and 2011) compared MMC using Synergo with MMC alone in people with primary or recurrent intermediate-risk and high-risk NMIBC, with 10‑year follow-up data.
## One RCT showed significantly better disease-free survival with MMC using Synergo compared with MMC alone
In the trial with a 10‑year follow up (Colombo et al. 2011) disease-free survival was significantly better with MMC using Synergo than with MMC alone (p<0.004). But there was no significant difference in overall survival (p=0.558). The 2 RCTs comparing MMC using Synergo with BCG showed no difference in recurrence-free survival (Arends et al. 2016) or disease-free survival (the HYMN trial). In people with non carcinoma in-situ (CIS) recurrence (papillary tumours only), the HYMN trial showed a non-significant difference in disease-free survival with Synergo compared with BCG (53% compared with 24%; p=0.11).
## All 3 trials stopped early, which is likely to affect results
All 3 trials stopped early for various reasons: Colombo et al. because of significantly better efficacy with MMC using Synergo, the HYMN trial because of higher than expected CIS recurrence rate in the Synergo arm, and Arends et al. because of slow recruitment.
## All trials used a low-dose adjuvant regimen so some people with CIS may have had treatment that was not effective enough
All trials only offered an adjuvant regimen (two 30‑minute cycles of 20 mg MMC) so 68% of people in the HYMN trial and 22% in Arends et al. with CIS may have not had effective enough treatment. In practice they would have had a higher ablative dose (two 30‑minute cycles of 40 mg MMC). Colombo et al. (2003, 2011) included only 1 patient with CIS so most people in this trial are likely to have had treatment with an appropriate regimen. Whether the ablative regimen using Synergo is more effective than other treatment options in people with CIS cannot be determined from the evidence currently available.
## The UK-based RCT that best reflected Synergo use in the NHS had substantial limitations
The HYMN trial was considered to most accurately reflect Synergo use in the NHS. This is because it was a UK-based RCT which included people with NMIBC for whom BCG treatment had failed. The study also included mostly people with high-risk cancer (87%). The EAC noted that the HYMN trial had several issues, which limits the quality and certainty of the results. Not all people in the comparator arm had treatment with BCG. The comparator was BCG or standard care, so some people had treatment with MMC alone or MMC-EMDA (electromotive drug administration of MMC). More people in the Synergo arm had concurrent papillary and CIS tumours, which have a higher risk of recurrence and progression. And the trial did not report on the type of BCG failure before enrolment, although the numbers who had fewer than or more than 6 instillations were reported.
## One retrospective comparative study reports post-cystectomy outcomes in people who have had previous treatment with Synergo
Sri et al. (2020) was a retrospective cohort study that included people who had radical cystectomy for high-risk NMIBC. It compared outcomes between people who had a:
primary cystectomy, or cystectomy immediately after BCG failure (102 people) and
cystectomy after treatment with MMC using Synergo, after BCG failure (36 people). The study reported no significant difference in the time to recurrence or mortality (all-cause and cancer-specific) between the 2 groups. Results suggested that delaying a cystectomy to have second-line treatment with Synergo did not worsen oncological outcomes compared with having the cystectomy straight away and no treatment with Synergo. But relatively few people in the study had treatment with Synergo, and the EAC considered it to have a high risk of selection bias.
## No comparative study looked at high-risk NMIBC alone and no distinction can be made between the results of the different risk groups
All studies included people with intermediate-risk and high-risk NMIBC and in most cases the results were not reported separately. The extent to which results can be generalised to a high-risk group only is therefore uncertain.
## The non-comparative studies were considered to be of low to medium methodological quality
Fourteen non-comparative studies reported on treatment with Synergo in people with intermediate-risk and high-risk NMIBC. Overall, the non-comparative studies were considered to be of low to medium methodological quality. This was because of, for example, retrospective analyses, small patient numbers, lack of comparators, limited outcomes reported, unclear reporting of risk classifications and, in some cases, uncertainty about whether there was patient overlap between studies. Only 2 were considered prospective studies (Erturhan 2015 and Kiss 2015) and 2 included UK centres (Sooriakumaran 2016; Van Valenburg 2018). There was a high level of heterogeneity in patient characteristics, treatment schedule and follow-up time. Recurrence rates (reported in 13 studies) varied depending on whether an ablative or adjuvant regimen was used, whether patients had had previous BCG treatments, and whether patients had concomitant CIS.
## Adverse events appear to be mild to moderate and transient, with few patients stopping treatment because of side effects
Outcomes related to safety, tolerability and adverse events of Synergo therapy were reported in 18 studies and overall were reported to be mild to moderate and transient with few patients stopping treatment because of side effects. The most common adverse events during treatment included pain and spasms. After treatment, the most common adverse events were painful or difficult urination (or both), urination at night, and increased urinary frequency. For full details of the adverse events, see section 6 of the assessment report in the supporting documentation on the NICE website.
# Cost evidence
## The company model only compares treatment with MMC using Synergo and MMC alone
The company submitted a de novo cost analysis, which compared MMC using Synergo with MMC alone in people with intermediate-risk and high-risk NMIBC, for whom BCG is either unavailable or unsuitable. It used a Markov model comprising 4 health states: remission, recurrence (treated with radical cystectomy in all cases), post-cystectomy, and death. The model had a 1-year cycle length and a lifetime time horizon. The population age was 64 years. BCG was not included in the model as a comparator or as part of the clinical pathway. This was because the company considered it inappropriate to use the available comparative evidence between MMC using Synergo and BCG. Overall, the company's model showed that, compared with MMC alone, treatment with MMC using Synergo was associated with a cost saving of £4,466 per patient over a lifetime time horizon. For full details of the cost evidence, see section 4 of the EAC's assessment report in the supporting documentation on the NICE website.
## The company model results are robust but limited by their relevance to the positioning in the clinical pathway
The company's one-way sensitivity analysis showed that cost saving estimates were most sensitive to changes in the cost of Synergo, the risk of recurrence and the cost of stoma management. None of the variations in parameters made treatment with Synergo cost incurring over a lifetime time horizon.
The EAC updated the company model and treatment with Synergo was found to be cost saving by £3,549 per patient over a lifetime horizon. The key drivers of the model were the cost of Synergo, the risk of recurrence, stoma management and the cost of cystectomy. The EAC noted that in the NHS it is unlikely that the decision would be between using MMC with Synergo and MMC alone.
## Additional modelling by the EAC shows that MMC using Synergo is likely to be cost incurring compared with second-line BCG
The EAC did another additional analysis that better reflected current NHS use of the technology by only including people with recurrence of NMIBC after BCG therapy. Treatment with MMC using Synergo was modelled as an alternative to further BCG therapy in people with intermediate-risk or high-risk NMIBC whose disease recurred after intravesical therapy with BCG. The EAC amended the base case model using data from the subgroup analysis of patients without CIS in the HYMN trial (n=33), who were considered to have had treatment with the appropriate dose (adjuvant regimen). Except for costing for BCG therapy instead of MMC alone, all other costs were unchanged. The EAC removed the adverse events costs for MMC using Synergo, because the cost of adverse events was assumed to be similar for MMC using Synergo and BCG therapy. Mortality parameters remained unchanged.
Compared with BCG as a second-line treatment for patients with no CIS, treatment with MMC using Synergo was associated with an increased cost per patient of £9,858 over a lifetime horizon. Key drivers of the model were treatment costs, annual recurrence rates and starting age. None of the 20% variations in parameters made treatment with MMC using Synergo cost saving over a lifetime horizon.
## Treatment with MMC using Synergo is associated with fewer cystectomies and an increase in life years gained and QALYs
All models resulted in fewer radical cystectomies and an increase in total life years and quality-adjusted life years (QALYs). In the model comparing treatment with MMC using Synergo with MMC alone, the incremental reduction in cystectomies was 0.22 per person and the increases in total life years and QALYs per person were 2.15 and 2.35, respectively. In the model that compared MMC using Synergo with second-line BCG, these changes were smaller: a 0.02 per person reduction in cystectomies, and a 0.8 and 0.79 increase in the total life years and QALYs per person, respectively.
## Exploratory analysis suggests that MMC using Synergo is likely to be cost incurring compared with cystectomy in NMIBC that does not respond to BCG
The EAC did an exploratory analysis on the cost impact of treating NMIBC that did not respond to BCG with MMC using Synergo compared with radical cystectomy. It was based on the additional modelling for Synergo compared with second-line BCG therapy. It showed that treatment using Synergo was cost incurring by £12,180 per patient compared with cystectomy but was associated with a gain in life years and avoided cystectomy in 4% of people, modelled over a lifetime horizon. For full details, see the addendum to the EAC's assessment report in the supporting documentation on the NICE website.# Committee discussion
# Position in pathway and unmet need
## Treatment options for high-risk NMIBC after BCG failure or when people cannot have or do not want BCG are limited
The patient and clinical experts said that there are few alternatives to radical cystectomy for people with high-risk non-muscle-invasive bladder cancer (NMIBC) that has not responded to or has recurred after Bacillus Calmette-Guerin (BCG) treatment, or when people cannot have BCG treatment. The clinical experts explained that if people do not want or cannot have a cystectomy, the only options are to have experimental treatment through clinical trials, or cystoscopy every 3 months to monitor disease progression and resection to remove visible tumours. The committee agreed that there is an unmet clinical need for additional treatment options in high-risk NMIBC after BCG failure or when people cannot have or do not want BCG treatment. Mitomycin C (MMC) using Synergo may offer an additional option for these people.
## The appropriate place for Synergo in the clinical pathway is for high-risk NMIBC after BCG failure or when people cannot have or do not want BCG
The clinical experts noted that, compared with MMC alone or BCG therapy, treatment with Synergo requires additional nurse time. This is because a specialist nurse has to accompany the patient throughout the treatment session. Because there are a lot of people with intermediate-risk cancer, or high-risk cancer needing first-line treatment (indicated for BCG), routine use of Synergo in these groups would be resource intensive and it would be difficult to cope with the demand in clinical practice. They agreed that the area with the greatest clinical need, and therefore the most appropriate place for Synergo in the pathway, was as an alternative to further intravesical therapy with BCG or radical cystectomy for high-risk NMIBC that has not responded to, or recurred after, BCG treatment. The clinical experts said it could also be considered for people who cannot tolerate BCG or who have a contraindication, or if access to BCG is limited. Clinical experts noted that there had been a national BCG shortage in the past and MMC using Synergo was used during this time as an alternative first-line treatment in high-risk NMIBC. The committee concluded that it would base its decision making on using Synergo for high-risk NMIBC that has not responded to or has recurred after BCG treatment, or when people cannot or do not want to have BCG treatment.
# Clinical-effectiveness overview
## Synergo shows promise but the clinical benefit is uncertain because of limitations in the evidence
The 3 randomised controlled trials (RCTs) positioned Synergo differently in the clinical pathway and all stopped early. The clinical experts agreed that, of the 3 RCTs, the HYMN trial (a phase 3, multicentre, open-label RCT) best reflected the most appropriate position in the NHS clinical pathway. This is because it included people with recurrence of NMIBC after BCG therapy. However, they explained that a second course of BCG therapy (which was the comparator in the HYMN trial) is not usually offered for high-risk NMIBC that does not respond to BCG. Overall, the committee considered the RCT evidence was not particularly generalisable to these groups because of the comparators in the trials (MMC alone , further BCG therapy or MMC-EMDA ). The trials also had a heterogenous patient population that included people with intermediate-risk and high-risk cancer, different categories of BCG failure, and people with both papillary and carcinoma in-situ (CIS) tumours. And none of the trials involved an appropriate ablative dose for people with CIS tumours, which introduced further uncertainty in this subgroup. Experts advised the committee that CIS tumours differ from papillary tumours and appear to be more difficult to treat. The committee concluded that the clinical benefit at the appropriate position in the NHS treatment pathway was unclear from the available RCT evidence. But, based on expert advice, it agreed that Synergo showed promise.
## Synergo after BCG failure does not seem to affect long-term outcomes after radical cystectomy
A clinical expert said that data published from their NHS centre shows that outcomes (time to recurrence and mortality) are the same after radical cystectomy for people who had treatment with Synergo and people who did not (Sri et al. 2020; see section 3.7). The committee was reassured that offering treatment with Synergo after BCG failure does not seem to affect patients' long-term outcomes.
# NHS considerations overview
## Appropriate patient selection is important for successful treatment
The clinical experts said patient selection was important when considering treatment with Synergo. They said that before starting treatment with Synergo, the person should have an up-to-date cystoscopy and repeat transurethral resection of bladder tumour (TURBT) to confirm the absence of residual papillary tumours and ensure the prostatic urethra is free of disease. The clinical experts said that Synergo would not be recommended for cancer that is suspected to have spread outside the bladder or in people with bladder wall diverticulum (a pouch, pocket or sac that protrudes out of the bladder wall). One of the clinical experts said that Synergo may be more effective than suggested by the HYMN trial because of suboptimal case selection in the trial.
## Synergo should be delivered in specialist centres by healthcare professionals trained in using it
The clinical experts said that Synergo should not be delivered in every hospital but in specialised centres only, and offered on a regional cancer network basis. This is because patient selection and treatment require consultants specialised in treating bladder cancer and a dedicated team of bladder cancer nurse specialists trained in using the technology. The clinical experts and company confirmed that currently treatment with MMC using Synergo is delivered at 5 NHS centres. The patient expert noted that, because access to Synergo is limited to a small number of NHS centres, some people may have to travel long distances for treatment. However, they said that people were willing to travel because there were few other acceptable treatment options available. The patient expert also said that many clinicians do not seem to be aware of Synergo as a treatment option, or are reluctant to offer it if travel is needed. They noted this may disadvantage some people who may be willing to have treatment with Synergo. The clinical experts also explained that the company provides theory-based and practical training with the system. One clinical expert said that their centre has also developed specific in-house training for nurse competency.
# Side effects and adverse events
## Side effects with Synergo are normally short term and can be managed by a nurse team
The patient expert said that pain during treatment with Synergo built up over the course of treatment sessions, but that it was possible to learn how to manage the side effects. They said it did not stop them from continuing with treatment. The clinical experts explained that treatment with Synergo is intensive and that side effects vary between people. But they noted they are mostly tolerated and can normally be managed by a dedicated nurse team. The patient and clinical experts also said that the posterior wall of the bladder can be burnt during treatment with Synergo. The clinical experts explained that this is an anticipated side effect of Synergo, is often symptomless and is normally seen during routine follow-up cystoscopies. They said that this reaction appears to resolve without medical treatment. The committee also acknowledged that adverse events and treatment side effects may differ for men and women and that treatment with Synergo is contraindicated in pregnancy.
## Caution is needed if a person has implantable cardiac devices or metallic implants
The clinical experts explained that caution is needed when Synergo is used for people with pacemakers or implantable cardiac devices. They said these people should have a cardiologist involved in their treatment. The company confirmed that there is information on cardiac monitoring for these people in the user manual for the technology. A clinical expert also explained that 1 person with metal in their pelvis had increased pain with Synergo treatment. Metallic implants are also listed as a precaution in the user manual.
# Cost modelling overview
## Economic modelling is limited by the available clinical evidence and its relevance to the NHS clinical pathway
The committee accepted the external assessment centre's (EAC) changes to the company model, which showed treatment with MMC using Synergo was cost saving when compared with MMC alone. However, the committee agreed that the modelled clinical scenario comparing MMC using Synergo with MMC alone does not reflect use of the technology in the NHS so has limited relevance. The committee agreed that the additional analysis by the EAC using data from the HYMN trial better reflected current NHS use and that, in this clinical scenario, use of Synergo is likely to be cost incurring. But the committee also noted that the clinical evidence used to populate the model had substantial limitations, which affected the robustness of the model and the certainty of the results. The committee accepted the EAC's additional economic modelling but considered that, because of the uncertainties and the lack of robust clinical data to inform the model, it was difficult to draw firm conclusions about any cost benefits in high-risk NMIBC after BCG failure or when people cannot have BCG.
## Model assumptions do not fully capture how all people eligible for Synergo are clinically managed
The EAC's additional economic model compared MMC using Synergo with second-line BCG. It assumed that everyone who subsequently has a recurrence is offered and accepts cystectomy. The clinical experts said that not all people are fit enough or willing to have surgery, and that these people would normally have repeat cystoscopy and TURBT every 3 months to monitor disease progression and remove recurrent tumours. The clinical experts also noted that some people with a high risk of progression would not be offered further BCG and would be considered for cystectomy instead. The committee understood the difficulties in modelling because of the lack of relevant data, but did not believe an appropriate comparison was made. The EAC explored the cost impact of reducing how many people had a cystectomy for recurrence after intravesical treatment in all models through additional sensitivity analysis. It also did exploratory modelling evaluating the cost of MMC using Synergo compared with cystectomy. It emphasised that these analyses were exploratory only and had several limitations, including uncertainty about the mortality rate for people unable or unwilling to have a cystectomy. The committee concluded that the modelling and assumptions do not fully capture the clinical management of all people eligible for Synergo. Based on the analyses presented at its preferred position in the treatment pathway Synergo was not likely to be cost saving.
## In the models Synergo increases QALYs and life years, and reduces radical cystectomies, but the results are uncertain
The committee noted that in all the models using Synergo resulted in a reduction in radical cystectomies, an increase in total life years and an increase in quality-adjusted life years (QALYs). But the committee concluded that these results were highly uncertain because the models, and the data used to populate them, had limited relevance to the NHS.
# Further research
## RCTs may not be feasible
Two of the RCTs for Synergo did not recruit enough people. The clinical experts highlighted the challenges of doing RCTs in a patient population with high-risk cancer after BCG failure or in people who cannot have BCG. The relatively small number of patients per NHS centre for whom BCG had not worked, and who would be eligible for Synergo treatment, makes trial recruitment difficult. Because there are few NHS centres currently offering treatment with Synergo, some people will need to travel for treatment, which would further affect participation in trials. One clinical expert noted that single-arm trials are now being accepted because of the ethical implications of doing RCTs in patients with high-risk NMIBC that has not responded to BCG. The committee accepted the challenges in doing RCTs in this patient population and agreed that further evidence from RCTs may not be feasible.
## A retrospective analysis of audit data may provide additional evidence on Synergo use in the UK
The clinical experts confirmed that all NHS centres using Synergo are required to prospectively collect outcome data in accordance with recommendations set out by NICE interventional procedures guidance on intravesical microwave hyperthermia and chemotherapy for NMIBC. The committee concluded that analysing the data collected from UK centres using Synergo may help address the uncertainty in the evidence base. In addition, collecting resource use data will inform a revised cost analysis comparing Synergo to cystectomy or repeat cystoscopies in people who cannot have cystectomy. Outcomes should include bladder preservation rates and bladder cancer-specific mortality, as well as the outcomes suggested by NICE's interventional procedures audit tool.
## More information is needed on the additional clinical benefits of inducing hyperthermia using radiofrequency energy
The committee felt that without more robust evidence of clinical effectiveness, further information is needed to better understand how Synergo works and if the microwave energy has an additional biological effect beyond heating. The committee understood that the frequency of radiofrequency used by the Synergo system (915 MHz) is an unlicensed and safe frequency used in radiocommunication. The company explained that preclinical data showed a direct and selective effect of radiofrequency on cancer cells. It also said that studies showed increased concentrations of MMC in the bladder wall of people having treatment with Synergo. The committee noted there are other device-assisted chemotherapy options currently used in the NHS. In particular, conductive hyperthermic intravesical chemotherapy, which heats the circulating chemotherapy drug outside the bladder. The committee was aware that published evidence on the efficacy of other device-assisted chemotherapy options is limited at present. However, it agreed that information on the benefits and costs of Synergo, compared with other device-assisted chemotherapy technologies available in the NHS, could improve clinical decision making.
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{'Recommendations': 'Synergo shows promise for high-risk non-muscle-invasive bladder cancer that has not responded to or has recurred after Bacillus Calmette-Guerin (BCG) treatment, or when people cannot or do not want to have BCG treatment. However there is not enough good-quality evidence to support the case for routine adoption. Synergo should only be used with special arrangements as outlined by NICE interventional procedures guidance on intravesical microwave hyperthermia and chemotherapy for non-muscle-invasive bladder cancer.\n\nResearch is recommended on the benefits and costs of Synergo for high-risk non-muscle-invasive bladder cancer. This is to address the uncertainty in the evidence base and to inform a revised cost analysis to assess the impact of Synergo on cystectomy rates or repeat cystoscopies in people who cannot have a cystectomy. Because randomised controlled trials are challenging in this patient population, further collection and analysis of observational and NHS audit data is recommended. Find out details of required research outcomes in the section on further research in this guidance.\n\nWhy the committee made these recommendations\n\nSynergo delivers chemotherapy and microwave energy to the bladder. Clinical experts advise that chemotherapy using Synergo would be used in the NHS for high-risk non-muscle-invasive bladder cancer after BCG has not worked, or if someone cannot or does not want to have BCG.\n\nSynergo offers an alternative treatment to the limited options available for these people, which include radical cystectomy (removal of the bladder) or regular cystoscopies (a procedure to look inside the bladder to check for tumours and remove them if necessary). The experts advise that using Synergo for intermediate-risk cancer is unlikely to be practical. Also, there are other effective treatments available for these people.\n\nThere is some evidence that chemotherapy using Synergo could reduce the chance of the cancer returning. But this observation comes from a trial that does not reflect how Synergo is likely to be used in the NHS.\n\nCost modelling for Synergo is uncertain and does not reflect how it is likely to be used in the NHS. Because of this and the limitations in the clinical evidence, further research is recommended into using Synergo in high-risk non-muscle-invasive bladder cancer.', 'The technology': "# Technology\n\nSynergo treats non-muscle-invasive bladder cancer (NMIBC) using a radiofrequency-induced thermo-chemotherapeutic effect (RITE). It heats the superficial layers of the bladder wall using controlled radiofrequency radiation (non-ionising microwave radiation), and flushes the bladder with a chemotherapy drug at the same time. The drug solution is continuously pumped out of the bladder, cooled, and recirculated to prevent overheating. A miniature antenna in the catheter directs radiofrequency radiation at the bladder wall tissue. Synergo aims to improve the delivery and efficacy of chemotherapy with the objective of reducing tumour recurrence and disease progression. It is another treatment option for NMIBC, in addition to Bacillus Calmette-Guerin (BCG) therapy and radical cystectomy.\n\nThe technology is an intravesical irrigation system combined with an energy delivering unit. The system has a radiofrequency generator that delivers radiofrequency energy at 915\xa0MHz (the lower limit of microwave electromagnetism). It also includes a drug circulating unit and a microprocessor with application-specific software. The user interface consists of a computer, monitor with touch screen, and barcode reader. The software monitors and records treatment parameters in real time during the treatment session. Synergo is CE marked as a class IIb medical device.\n\n# Care pathway\n\nNICE has not made recommendations on the position of device-assisted chemotherapy treatments like Synergo in the NHS clinical pathway for bladder cancer.\n\nExpert advice suggests the technology is being used in the NHS as an alternative to further intravesical treatment or cystectomy in high-risk NMIBC if:\n\nit has not responded to BCG treatment or has recurred after treatment, or\n\nwhen people cannot or do not want to have BCG treatment, or when it's not available.\n\n# Innovative aspects\n\nThe innovative aspects are the use of radiofrequency radiation (non-ionising microwave radiation) to deliver controlled electromagnetic energy directly to the walls of the bladder, along with instillations of the bladder with chemotherapy. This microwave-induced hyperthermia is designed to make the chemotherapy more effective.\n\n# Intended use\n\nSynergo is intended for intermediate-risk or high-risk NMIBC. People have Synergo as outpatients in specialist centres. There is no need for general anaesthesia during treatment, but local anaesthetic lubricating gel may be used to insert the treatment catheter. Synergo is administered by healthcare professionals such as bladder cancer nurse specialists or consultant urologists trained in using Synergo, in secondary and tertiary care settings.\n\n# Costs\n\nThe total annual cost of Synergo therapy is £11,650 per patient (based on 12\xa0treatment sessions). This includes the following costs:\n\nadministering mitomycin\xa0C (MMC): £4,585 per patient\n\nthe annual lease for the Synergo device: £327 per patient\n\nconsumables: £490 per use\n\nminutes of Band 7 Nurse time to administer the treatment with Synergo: £72.For more information about the technology, see the website for Synergo.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 19 studies\n\nThe evidence assessed by the EAC included 19\xa0studies reported across 20 full text publications. Of the included studies, 5 were comparative (3 randomised controlled trials [RCTs] and 2 observational studies) and 14 were single-arm observational studies. The comparative evidence included a total of 595 people with intermediate-risk or high-risk non-muscle-invasive bladder cancer (NMIBC), of whom 247 had treatment with mitomycin\xa0C (MMC) using Synergo. Nineteen abstracts identified were not included in the evidence review. For full details of the clinical evidence, see section 3 of the assessment report in the supporting documentation on the NICE website.\n\n## The 3 pivotal RCTs position Synergo differently in the clinical pathway\n\nTwo RCTs compared treatment with MMC using Synergo with Bacillus Calmette-Guerin (BCG) therapy in intermediate-risk and high-risk NMIBC patients (Arends et al. 2016 and the HYMN trial [Tan et al. 2019]). Arends et al. assessed treatment with Synergo first line, including in people with intermediate-risk cancer who would not normally be offered BCG first line in the NHS. The HYMN trial was a UK-based RCT that included people with NMIBC for which BCG treatment had failed. Colombo et al. (2003 and 2011) compared MMC using Synergo with MMC alone in people with primary or recurrent intermediate-risk and high-risk NMIBC, with 10‑year follow-up data.\n\n## One RCT showed significantly better disease-free survival with MMC using Synergo compared with MMC alone\n\nIn the trial with a 10‑year follow up (Colombo et al. 2011) disease-free survival was significantly better with MMC using Synergo than with MMC alone (p<0.004). But there was no significant difference in overall survival (p=0.558). The 2 RCTs comparing MMC using Synergo with BCG showed no difference in recurrence-free survival (Arends et al. 2016) or disease-free survival (the HYMN trial). In people with non carcinoma in-situ (CIS) recurrence (papillary tumours only), the HYMN trial showed a non-significant difference in disease-free survival with Synergo compared with BCG (53% compared with 24%; p=0.11).\n\n## All 3 trials stopped early, which is likely to affect results\n\nAll 3 trials stopped early for various reasons: Colombo et al. because of significantly better efficacy with MMC using Synergo, the HYMN trial because of higher than expected CIS recurrence rate in the Synergo arm, and Arends et al. because of slow recruitment.\n\n## All trials used a low-dose adjuvant regimen so some people with CIS may have had treatment that was not effective enough\n\nAll trials only offered an adjuvant regimen (two 30‑minute cycles of 20\xa0mg MMC) so 68% of people in the HYMN trial and 22% in Arends et al. with CIS may have not had effective enough treatment. In practice they would have had a higher ablative dose (two 30‑minute cycles of 40\xa0mg MMC). Colombo et al. (2003, 2011) included only 1 patient with CIS so most people in this trial are likely to have had treatment with an appropriate regimen. Whether the ablative regimen using Synergo is more effective than other treatment options in people with CIS cannot be determined from the evidence currently available.\n\n## The UK-based RCT that best reflected Synergo use in the NHS had substantial limitations\n\nThe HYMN trial was considered to most accurately reflect Synergo use in the NHS. This is because it was a UK-based RCT which included people with NMIBC for whom BCG treatment had failed. The study also included mostly people with high-risk cancer (87%). The EAC noted that the HYMN trial had several issues, which limits the quality and certainty of the results. Not all people in the comparator arm had treatment with BCG. The comparator was BCG or standard care, so some people had treatment with MMC alone or MMC-EMDA (electromotive drug administration of MMC). More people in the Synergo arm had concurrent papillary and CIS tumours, which have a higher risk of recurrence and progression. And the trial did not report on the type of BCG failure before enrolment, although the numbers who had fewer than or more than 6 instillations were reported.\n\n## One retrospective comparative study reports post-cystectomy outcomes in people who have had previous treatment with Synergo\n\nSri et al. (2020) was a retrospective cohort study that included people who had radical cystectomy for high-risk NMIBC. It compared outcomes between people who had a:\n\nprimary cystectomy, or cystectomy immediately after BCG failure (102 people) and\n\ncystectomy after treatment with MMC using Synergo, after BCG failure (36 people). The study reported no significant difference in the time to recurrence or mortality (all-cause and cancer-specific) between the 2 groups. Results suggested that delaying a cystectomy to have second-line treatment with Synergo did not worsen oncological outcomes compared with having the cystectomy straight away and no treatment with Synergo. But relatively few people in the study had treatment with Synergo, and the EAC considered it to have a high risk of selection bias.\n\n## No comparative study looked at high-risk NMIBC alone and no distinction can be made between the results of the different risk groups\n\nAll studies included people with intermediate-risk and high-risk NMIBC and in most cases the results were not reported separately. The extent to which results can be generalised to a high-risk group only is therefore uncertain.\n\n## The non-comparative studies were considered to be of low to medium methodological quality\n\nFourteen non-comparative studies reported on treatment with Synergo in people with intermediate-risk and high-risk NMIBC. Overall, the non-comparative studies were considered to be of low to medium methodological quality. This was because of, for example, retrospective analyses, small patient numbers, lack of comparators, limited outcomes reported, unclear reporting of risk classifications and, in some cases, uncertainty about whether there was patient overlap between studies. Only 2 were considered prospective studies (Erturhan 2015 and Kiss 2015) and 2 included UK centres (Sooriakumaran 2016; Van Valenburg 2018). There was a high level of heterogeneity in patient characteristics, treatment schedule and follow-up time. Recurrence rates (reported in 13 studies) varied depending on whether an ablative or adjuvant regimen was used, whether patients had had previous BCG treatments, and whether patients had concomitant CIS.\n\n## Adverse events appear to be mild to moderate and transient, with few patients stopping treatment because of side effects\n\nOutcomes related to safety, tolerability and adverse events of Synergo therapy were reported in 18 studies and overall were reported to be mild to moderate and transient with few patients stopping treatment because of side effects. The most common adverse events during treatment included pain and spasms. After treatment, the most common adverse events were painful or difficult urination (or both), urination at night, and increased urinary frequency. For full details of the adverse events, see\xa0section 6 of the assessment report in the supporting documentation on the NICE website.\n\n# Cost evidence\n\n## The company model only compares treatment with MMC using Synergo and MMC alone\n\nThe company submitted a de novo cost analysis, which compared MMC using Synergo with MMC alone in people with intermediate-risk and high-risk NMIBC, for whom BCG is either unavailable or unsuitable. It used a Markov model comprising 4 health states: remission, recurrence (treated with radical cystectomy in all cases), post-cystectomy, and death. The model had a 1-year cycle length and a lifetime time horizon. The population age was 64 years. BCG was not included in the model as a comparator or as part of the clinical pathway. This was because the company considered it inappropriate to use the available comparative evidence between MMC using Synergo and BCG. Overall, the company's model showed that, compared with MMC alone, treatment with MMC using Synergo was associated with a cost saving of £4,466 per patient over a lifetime time horizon. For full details of the cost evidence, see section 4 of the EAC's assessment report in the supporting documentation on the NICE website.\n\n## The company model results are robust but limited by their relevance to the positioning in the clinical pathway\n\nThe company's one-way sensitivity analysis showed that cost saving estimates were most sensitive to changes in the cost of Synergo, the risk of recurrence and the cost of stoma management. None of the variations in parameters made treatment with Synergo cost incurring over a lifetime time horizon.\n\nThe EAC updated the company model and treatment with Synergo was found to be cost saving by £3,549 per patient over a lifetime horizon. The key drivers of the model were the cost of Synergo, the risk of recurrence, stoma management and the cost of cystectomy. The EAC noted that in the NHS it is unlikely that the decision would be between using MMC with Synergo and MMC alone.\n\n## Additional modelling by the EAC shows that MMC using Synergo is likely to be cost incurring compared with second-line BCG\n\nThe EAC did another additional analysis that better reflected current NHS use of the technology by only including people with recurrence of NMIBC after BCG therapy. Treatment with MMC using Synergo was modelled as an alternative to further BCG therapy in people with intermediate-risk or high-risk NMIBC whose disease recurred after intravesical therapy with BCG. The EAC amended the base case model using data from the subgroup analysis of patients without CIS in the HYMN trial (n=33), who were considered to have had treatment with the appropriate dose (adjuvant regimen). Except for costing for BCG therapy instead of MMC alone, all other costs were unchanged. The EAC removed the adverse events costs for MMC using Synergo, because the cost of adverse events was assumed to be similar for MMC using Synergo and BCG therapy. Mortality parameters remained unchanged.\n\nCompared with BCG as a second-line treatment for patients with no CIS, treatment with MMC using Synergo was associated with an increased cost per patient of £9,858 over a lifetime horizon. Key drivers of the model were treatment costs, annual recurrence rates and starting age. None of the 20% variations in parameters made treatment with MMC using Synergo cost saving over a lifetime horizon.\n\n## Treatment with MMC using Synergo is associated with fewer cystectomies and an increase in life years gained and QALYs\n\nAll models resulted in fewer radical cystectomies and an increase in total life years and quality-adjusted life years (QALYs). In the model comparing treatment with MMC using Synergo with MMC alone, the incremental reduction in cystectomies was 0.22 per person and the increases in total life years and QALYs per person were 2.15 and 2.35, respectively. In the model that compared MMC using Synergo with second-line BCG, these changes were smaller: a 0.02 per person reduction in cystectomies, and a 0.8 and 0.79 increase in the total life years and QALYs per person, respectively.\n\n## Exploratory analysis suggests that MMC using Synergo is likely to be cost incurring compared with cystectomy in NMIBC that does not respond to BCG\n\nThe EAC did an exploratory analysis on the cost impact of treating NMIBC that did not respond to BCG with MMC using Synergo compared with radical cystectomy. It was based on the additional modelling for Synergo compared with second-line BCG therapy. It showed that treatment using Synergo was cost incurring by £12,180 per patient compared with cystectomy but was associated with a gain in life years and avoided cystectomy in 4% of people, modelled over a lifetime horizon. For full details, see the addendum to the EAC's assessment report in the supporting documentation on the NICE website.", 'Committee discussion': "# Position in pathway and unmet need\n\n## Treatment options for high-risk NMIBC after BCG failure or when people cannot have or do not want BCG are limited\n\nThe patient and clinical experts said that there are few alternatives to radical cystectomy for people with high-risk non-muscle-invasive bladder cancer (NMIBC) that has not responded to or has recurred after Bacillus Calmette-Guerin (BCG) treatment, or when people cannot have BCG treatment. The clinical experts explained that if people do not want or cannot have a cystectomy, the only options are to have experimental treatment through clinical trials, or cystoscopy every 3\xa0months to monitor disease progression and resection to remove visible tumours. The committee agreed that there is an unmet clinical need for additional treatment options in high-risk NMIBC after BCG failure or when people cannot have or do not want BCG treatment. Mitomycin\xa0C (MMC) using Synergo may offer an additional option for these people.\n\n## The appropriate place for Synergo in the clinical pathway is for high-risk NMIBC after BCG failure or when people cannot have or do not want BCG\n\nThe clinical experts noted that, compared with MMC alone or BCG therapy, treatment with Synergo requires additional nurse time. This is because a specialist nurse has to accompany the patient throughout the treatment session. Because there are a lot of people with intermediate-risk cancer, or high-risk cancer needing first-line treatment (indicated for BCG), routine use of Synergo in these groups would be resource intensive and it would be difficult to cope with the demand in clinical practice. They agreed that the area with the greatest clinical need, and therefore the most appropriate place for Synergo in the pathway, was as an alternative to further intravesical therapy with BCG or radical cystectomy for high-risk NMIBC that has not responded to, or recurred after, BCG treatment. The clinical experts said it could also be considered for people who cannot tolerate BCG or who have a contraindication, or if access to BCG is limited. Clinical experts noted that there had been a national BCG shortage in the past and MMC using Synergo was used during this time as an alternative first-line treatment in high-risk NMIBC. The committee concluded that it would base its decision making on using Synergo for high-risk NMIBC that has not responded to or has recurred after BCG treatment, or when people cannot or do not want to have BCG treatment.\n\n# Clinical-effectiveness overview\n\n## Synergo shows promise but the clinical benefit is uncertain because of limitations in the evidence\n\nThe 3 randomised controlled trials (RCTs) positioned Synergo differently in the clinical pathway and all stopped early. The clinical experts agreed that, of the 3 RCTs, the HYMN trial (a phase 3, multicentre, open-label RCT) best reflected the most appropriate position in the NHS clinical pathway. This is because it included people with recurrence of NMIBC after BCG therapy. However, they explained that a second course of BCG therapy (which was the comparator in the HYMN trial) is not usually offered for high-risk NMIBC that does not respond to BCG. Overall, the committee considered the RCT evidence was not particularly generalisable to these groups because of the comparators in the trials (MMC alone [Colombo et al. 2003, 2011], further BCG therapy [HYMN trial] or MMC-EMDA [Arends et al. 2016]). The trials also had a heterogenous patient population that included people with intermediate-risk and high-risk cancer, different categories of BCG failure, and people with both papillary and carcinoma in-situ (CIS) tumours. And none of the trials involved an appropriate ablative dose for people with CIS tumours, which introduced further uncertainty in this subgroup. Experts advised the committee that CIS tumours differ from papillary tumours and appear to be more difficult to treat. The committee concluded that the clinical benefit at the appropriate position in the NHS treatment pathway was unclear from the available RCT evidence. But, based on expert advice, it agreed that Synergo showed promise.\n\n## Synergo after BCG failure does not seem to affect long-term outcomes after radical cystectomy\n\nA clinical expert said that data published from their NHS centre shows that outcomes (time to recurrence and mortality) are the same after radical cystectomy for people who had treatment with Synergo and people who did not (Sri et al. 2020; see section 3.7). The committee was reassured that offering treatment with Synergo after BCG failure does not seem to affect patients' long-term outcomes.\n\n# NHS considerations overview\n\n## Appropriate patient selection is important for successful treatment\n\nThe clinical experts said patient selection was important when considering treatment with Synergo. They said that before starting treatment with Synergo, the person should have an up-to-date cystoscopy and repeat transurethral resection of bladder tumour (TURBT) to confirm the absence of residual papillary tumours and ensure the prostatic urethra is free of disease. The clinical experts said that Synergo would not be recommended for cancer that is suspected to have spread outside the bladder or in people with bladder wall diverticulum (a pouch, pocket or sac that protrudes out of the bladder wall). One of the clinical experts said that Synergo may be more effective than suggested by the HYMN trial because of suboptimal case selection in the trial.\n\n## Synergo should be delivered in specialist centres by healthcare professionals trained in using it\n\nThe clinical experts said that Synergo should not be delivered in every hospital but in specialised centres only, and offered on a regional cancer network basis. This is because patient selection and treatment require consultants specialised in treating bladder cancer and a dedicated team of bladder cancer nurse specialists trained in using the technology. The clinical experts and company confirmed that currently treatment with MMC using Synergo is delivered at 5 NHS centres. The patient expert noted that, because access to Synergo is limited to a small number of NHS centres, some people may have to travel long distances for treatment. However, they said that people were willing to travel because there were few other acceptable treatment options available. The patient expert also said that many clinicians do not seem to be aware of Synergo as a treatment option, or are reluctant to offer it if travel is needed. They noted this may disadvantage some people who may be willing to have treatment with Synergo. The clinical experts also explained that the company provides theory-based and practical training with the system. One clinical expert said that their centre has also developed specific in-house training for nurse competency.\n\n# Side effects and adverse events\n\n## Side effects with Synergo are normally short term and can be managed by a nurse team\n\nThe patient expert said that pain during treatment with Synergo built up over the course of treatment sessions, but that it was possible to learn how to manage the side effects. They said it did not stop them from continuing with treatment. The clinical experts explained that treatment with Synergo is intensive and that side effects vary between people. But they noted they are mostly tolerated and can normally be managed by a dedicated nurse team. The patient and clinical experts also said that the posterior wall of the bladder can be burnt during treatment with Synergo. The clinical experts explained that this is an anticipated side effect of Synergo, is often symptomless and is normally seen during routine follow-up cystoscopies. They said that this reaction appears to resolve without medical treatment. The committee also acknowledged that adverse events and treatment side effects may differ for men and women and that treatment with Synergo is contraindicated in pregnancy.\n\n## Caution is needed if a person has implantable cardiac devices or metallic implants\n\nThe clinical experts explained that caution is needed when Synergo is used for people with pacemakers or implantable cardiac devices. They said these people should have a cardiologist involved in their treatment. The company confirmed that there is information on cardiac monitoring for these people in the user manual for the technology. A clinical expert also explained that 1 person with metal in their pelvis had increased pain with Synergo treatment. Metallic implants are also listed as a precaution in the user manual.\n\n# Cost modelling overview\n\n## Economic modelling is limited by the available clinical evidence and its relevance to the NHS clinical pathway\n\nThe committee accepted the external assessment centre's (EAC) changes to the company model, which showed treatment with MMC using Synergo was cost saving when compared with MMC alone. However, the committee agreed that the modelled clinical scenario comparing MMC using Synergo with MMC alone does not reflect use of the technology in the NHS so has limited relevance. The committee agreed that the additional analysis by the EAC using data from the HYMN trial better reflected current NHS use and that, in this clinical scenario, use of Synergo is likely to be cost incurring. But the committee also noted that the clinical evidence used to populate the model had substantial limitations, which affected the robustness of the model and the certainty of the results. The committee accepted the EAC's additional economic modelling but considered that, because of the uncertainties and the lack of robust clinical data to inform the model, it was difficult to draw firm conclusions about any cost benefits in high-risk NMIBC after BCG failure or when people cannot have BCG.\n\n## Model assumptions do not fully capture how all people eligible for Synergo are clinically managed\n\nThe EAC's additional economic model compared MMC using Synergo with second-line BCG. It assumed that everyone who subsequently has a recurrence is offered and accepts cystectomy. The clinical experts said that not all people are fit enough or willing to have surgery, and that these people would normally have repeat cystoscopy and TURBT every 3\xa0months to monitor disease progression and remove recurrent tumours. The clinical experts also noted that some people with a high risk of progression would not be offered further BCG and would be considered for cystectomy instead. The committee understood the difficulties in modelling because of the lack of relevant data, but did not believe an appropriate comparison was made. The EAC explored the cost impact of reducing how many people had a cystectomy for recurrence after intravesical treatment in all models through additional sensitivity analysis. It also did exploratory modelling evaluating the cost of MMC using Synergo compared with cystectomy. It emphasised that these analyses were exploratory only and had several limitations, including uncertainty about the mortality rate for people unable or unwilling to have a cystectomy. The committee concluded that the modelling and assumptions do not fully capture the clinical management of all people eligible for Synergo. Based on the analyses presented at its preferred position in the treatment pathway Synergo was not likely to be cost saving.\n\n## In the models Synergo increases QALYs and life years, and reduces radical cystectomies, but the results are uncertain\n\nThe committee noted that in all the models using Synergo resulted in a reduction in radical cystectomies, an increase in total life years and an increase in quality-adjusted life years (QALYs). But the committee concluded that these results were highly uncertain because the models, and the data used to populate them, had limited relevance to the NHS.\n\n# Further research\n\n## RCTs may not be feasible\n\nTwo of the RCTs for Synergo did not recruit enough people. The clinical experts highlighted the challenges of doing RCTs in a patient population with high-risk cancer after BCG failure or in people who cannot have BCG. The relatively small number of patients per NHS centre for whom BCG had not worked, and who would be eligible for Synergo treatment, makes trial recruitment difficult. Because there are few NHS centres currently offering treatment with Synergo, some people will need to travel for treatment, which would further affect participation in trials. One clinical expert noted that single-arm trials are now being accepted because of the ethical implications of doing RCTs in patients with high-risk NMIBC that has not responded to BCG. The committee accepted the challenges in doing RCTs in this patient population and agreed that further evidence from RCTs may not be feasible.\n\n## A retrospective analysis of audit data may provide additional evidence on Synergo use in the UK\n\nThe clinical experts confirmed that all NHS centres using Synergo are required to prospectively collect outcome data in accordance with recommendations set out by NICE interventional procedures guidance on intravesical microwave hyperthermia and chemotherapy for NMIBC. The committee concluded that analysing the data collected from UK centres using Synergo may help address the uncertainty in the evidence base. In addition, collecting resource use data will inform a revised cost analysis comparing Synergo to cystectomy or repeat cystoscopies in people who cannot have cystectomy. Outcomes should include bladder preservation rates and bladder cancer-specific mortality, as well as the outcomes suggested by NICE's interventional procedures audit tool.\n\n## More information is needed on the additional clinical benefits of inducing hyperthermia using radiofrequency energy\n\nThe committee felt that without more robust evidence of clinical effectiveness, further information is needed to better understand how Synergo works and if the microwave energy has an additional biological effect beyond heating. The committee understood that the frequency of radiofrequency used by the Synergo system (915\xa0MHz) is an unlicensed and safe frequency used in radiocommunication. The company explained that preclinical data showed a direct and selective effect of radiofrequency on cancer cells. It also said that studies showed increased concentrations of MMC in the bladder wall of people having treatment with Synergo. The committee noted there are other device-assisted chemotherapy options currently used in the NHS. In particular, conductive hyperthermic intravesical chemotherapy, which heats the circulating chemotherapy drug outside the bladder. The committee was aware that published evidence on the efficacy of other device-assisted chemotherapy options is limited at present. However, it agreed that information on the benefits and costs of Synergo, compared with other device-assisted chemotherapy technologies available in the NHS, could improve clinical decision making."}
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https://www.nice.org.uk/guidance/mtg61
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Evidence-based recommendations on Synergo for non-muscle-invasive bladder cancer.
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250c634d6dc26aedc0a51a6c61cd8965c76b4d22
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nice
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Fever in under 5s: assessment and initial management
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Fever in under 5s: assessment and initial management
This guideline covers the assessment and early management of fever with no obvious cause in children aged under 5. It aims to improve clinical assessment and help healthcare professionals diagnose serious illness among young children who present with fever in primary and secondary care.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Thermometers and the detection of fever
## Oral and rectal temperature measurements
Do not routinely use the oral and rectal routes to measure the body temperature of children aged 0 to 5 years.
## Measurement of body temperature at other sites
In infants under the age of 4 weeks, measure body temperature with an electronic thermometer in the axilla.
In children aged 4 weeks to 5 years, measure body temperature by one of the following methods:
electronic thermometer in the axilla
chemical dot thermometer in the axilla
infra-red tympanic thermometer.
Healthcare professionals who routinely use disposable chemical dot thermometers should consider using an alternative type of thermometer when multiple temperature measurements are required.
Forehead chemical thermometers are unreliable and should not be used by healthcare professionals.
## Subjective detection of fever by parents and carers
Reported parental perception of a fever should be considered valid and taken seriously by healthcare professionals.
# Clinical assessment of children with fever
First, healthcare professionals should identify any immediately life‑threatening features, including compromise of the airway, breathing or circulation, and decreased level of consciousness.
Think "Could this be sepsis?" and refer to the NICE guideline on sepsis: recognition, diagnosis and early management if a child presents with fever and symptoms or signs that indicate possible sepsis. Sepsis is a condition of life-threatening organ dysfunction due to a dysregulated host response to infection.
## Assessment of risk of serious illness
Assess children with feverish illness for the presence or absence of symptoms and signs that can be used to predict the risk of serious illness using the traffic light system (see table 2).
When assessing children with learning disabilities, take the individual child's learning disability into account when interpreting the traffic light table.
Recognise that children with any of the following symptoms or signs are in a high-risk group for serious illness:
pale/mottled/ashen/blue skin, lips or tongue
no response to social cues
appearing ill to a healthcare professional
does not wake or if roused does not stay awake
weak, high-pitched or continuous cry
grunting
respiratory rate greater than 60 breaths per minute
moderate or severe chest indrawing
reduced skin turgor
bulging fontanelle.
Recognise that children with any of the following symptoms or signs are in at least an intermediate-risk group for serious illness:
pallor of skin, lips or tongue reported by parent or carer
not responding normally to social cues
no smile
wakes only with prolonged stimulation
decreased activity
nasal flaring
dry mucous membranes
poor feeding in infants
reduced urine output
rigors.
Recognise that children who have all of the following features, and none of the high- or intermediate-risk features, are in a low-risk group for serious illness:
normal colour of skin, lips and tongue
responds normally to social cues
content or smiles
stays awake or awakens quickly
strong normal cry or not crying
normal skin and eyes
moist mucous membranes.
Measure and record temperature, heart rate, respiratory rate and capillary refill time as part of the routine assessment of a child with fever.
Recognise that a capillary refill time of 3 seconds or longer is an intermediate-risk group marker for serious illness ('amber' sign).
Measure the blood pressure of children with fever if the heart rate or capillary refill time is abnormal and the facilities to measure blood pressure are available.
In children older than 6 months do not use height of body temperature alone to identify those with serious illness.
Recognise that children younger than 3 months with a temperature of 38°C or higher are in a high-risk group for serious illness. (Note that some vaccinations have been found to induce fever in children aged under 3 months.)
Recognise that children aged 3 to 6 months with a temperature of 39°C or higher are in at least an intermediate-risk group for serious illness.
Do not use duration of fever to predict the likelihood of serious illness. However, children with a fever lasting 5 days or longer should be assessed for Kawasaki disease (see the recommendation on additional features of Kawasaki disease in the section on symptoms and signs of specific illnesses).
Recognise that children with tachycardia are in at least an intermediate‑risk group for serious illness. Use the Advanced Paediatric Life Support criteria in table 1 to define tachycardia.
Age
Heart rate (beats per minute)
Less than 12 months
More than 160
to 24 months
More than 150
to 5 years
More than 140
Assess children with fever for signs of dehydration. Look for:
prolonged capillary refill time
abnormal skin turgor
abnormal respiratory pattern
weak pulse
cool extremities.
## Symptoms and signs of specific illnesses
Look for a source of fever and check for the presence of symptoms and signs that are associated with specific diseases (see table 3).
Also see the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.
Consider meningococcal disease in any child with fever and a non‑blanching rash, particularly if any of the following features are present:
an ill-looking child
lesions larger than 2 mm in diameter (purpura)
a capillary refill time of 3 seconds or longer
neck stiffness.
Consider bacterial meningitis in a child with fever and any of the following features:
neck stiffness
bulging fontanelle
decreased level of consciousness
convulsive status epilepticus.
Be aware that classic signs of meningitis (neck stiffness, bulging fontanelle, high-pitched cry) are often absent in infants with bacterial meningitis.
Consider herpes simplex encephalitis in children with fever and any of the following features:
focal neurological signs
focal seizures
decreased level of consciousness.
Consider pneumonia in children with fever and any of the following signs:
tachypnoea (respiratory rate greater than 60 breaths per minute, age 0 to 5 months; greater than 50 breaths per minute, age 6 to 12 months; greater than 40 breaths per minute, age older than 12 months)
crackles in the chest
nasal flaring
chest indrawing
cyanosis
-xygen saturation of 95% or less when breathing air. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Consider urinary tract infection in a baby or child under 5 with fever. See the symptoms and signs that increase the likelihood that a UTI is present in the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s.
Consider septic arthritis or osteomyelitis in children with fever and any of the following signs:
swelling of a limb or joint
not using an extremity
non-weight bearing.
Be aware of the possibility of Kawasaki disease in children with fever that has lasted 5 days or longer. Additional features of Kawasaki disease may include:
bilateral conjunctival injection without exudate
erythema and cracking of lips, strawberry tongue, or erythema of oral and pharyngeal mucosa
-edema and erythema in the hands and feet
polymorphous rash
cervical lymphadenopathy.
Ask parents or carers about the presence of these features since the onset of fever, because they may have resolved by the time of assessment.
Be aware that children under 1 year may present with fewer clinical features of Kawasaki disease in addition to fever, but may be at higher risk of coronary artery abnormalities than older children.
For a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on Kawasaki disease .
Full details of the evidence and the committee's discussion are in evidence review A: Signs and symptoms predicting Kawasaki disease.
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## Imported infections
When assessing a child with feverish illness, enquire about recent travel abroad and consider the possibility of imported infections according to the region visited. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
Refer to table 3 in the NICE guideline on sepsis if a child presents with fever and symptoms or signs that indicate possible sepsis.
Children with fever and any of the symptoms or signs in the red column should be recognised as being at high risk. Similarly, children with fever and any of the symptoms or signs in the amber column and none in the red column should be recognised as being at intermediate risk. Children with symptoms and signs in the green column and none in the amber or red columns are at low risk. The management of children with fever should be directed by the level of risk.
This traffic light table should be used in conjunction with the recommendations in this guideline on investigations and initial management in children with fever.
A colour version of this table is available on the NICE tools and resources page.
Green – low risk
Amber – intermediate risk
Red – high risk
Colour
(of skin, lips or tongue)
Normal colour
Pallor reported by parent/carer
Pale, mottled, ashen or blue
Activity
Responds normally to social cues
Content or smiles
Stays awake or awakens quickly
Strong normal cry or not crying
Not responding normally to social cues
No smile
Wakes only with prolonged stimulation
Decreased activity
No response to social cues
Appears ill to a healthcare professional
Does not wake or if roused does not stay awake
Weak, high-pitched or continuous cry
Respiratory
Nasal flaring
Tachypnoea: respiratory rate
50 breaths per minute, age 6 to 12 months;
40 breaths per minute, age more than 12 months
Oxygen saturation less than or equal to 95% in air
Crackles in the chest
Grunting
Tachypnoea: respiratory rate more than 60 breaths per minute
Moderate or severe chest indrawing
Circulation and hydration
Normal skin and eyes
Moist mucous membranes
Tachycardia:
More than 160 beats per minute, age less than 12 months
More than 150 beats per minute, age 12 to 24 months
More than 140 beats per minute, age 2 to 5 years
Capillary refill time more than or equal to 3 seconds
Dry mucous membranes
Poor feeding in infants
Reduced urine output
Reduced skin turgor
Other
None of the amber or red symptoms or signs
Age 3 to 6 months, temperature more than or equal to 39°C
Fever for more than or equal to 5 days
Rigors
Swelling of a limb or joint
Non-weight bearing limb or not using an extremity
Age less than 3 months, temperature more than or equal to 38°C
Non-blanching rash
Bulging fontanelle
Neck stiffness
Status epilepticus
Focal neurological signs
Focal seizures
Note that some vaccinations have been found to induce fever in children aged under 3 months.
Diagnosis to be considered
Symptoms and signs in conjunction with fever
Meningococcal disease
Non-blanching rash, particularly with 1 or more of the following:
an ill-looking child
lesions larger than 2 mm in diameter (purpura)
capillary refill time of more than or equal to 3 seconds
neck stiffness
Bacterial meningitis
Neck stiffness
Bulging fontanelle
Decreased level of consciousness
Convulsive status epilepticus
Herpes simplex encephalitis
Focal neurological signs
Focal seizures
Decreased level of consciousness
Pneumonia
Tachypnoea (respiratory rate more than 60 breaths per minute, age 0 to 5 months; more than 50 breaths per minute, age 6 to 12 months; more than 40 breaths per minute, age more than 12 months)
Crackles in the chest
Nasal flaring
Chest indrawing
Cyanosis
Oxygen saturation less than or equal to 95%
Urinary tract infection (UTI)
These symptoms and signs increase the likelihood that a UTI is present and should be used to inform a decision about whether urine collection and testing is necessary. They are taken from the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s
Painful urination (dysuria)
More frequent urination
New bedwetting
Foul smelling (malodorous) urine
Darker urine
Cloudy urine
Frank haematuria (visible blood in urine)
Reduced fluid intake
Shivering
Abdominal pain
Loin tenderness or suprapubic tenderness
Capillary refill longer than 3 seconds
Previous history of confirmed urinary tract infection
Septic arthritis
Swelling of a limb or joint
Not using an extremity
Non-weight bearing
Kawasaki disease
Fever for 5 days or longer and may have some of the following:
bilateral conjunctival injection without exudate
erythema and cracking of lips; strawberry tongue; or erythema of oral and pharyngeal mucosa
-edema and erythema in the hands and feet
polymorphous rash
cervical lymphadenopathy
# Management by remote assessment
Remote assessment refers to situations in which a child is assessed by a healthcare professional who is unable to examine the child because the child is geographically remote from the assessor (for example, telephone calls to NHS 111). Therefore, assessment is largely an interpretation of symptoms rather than physical signs. The guidance in this section may also apply to healthcare professionals whose scope of practice does not include the physical examination of a young child (for example, community pharmacists).
## Management according to risk of serious illness
Healthcare professionals performing a remote assessment of a child with fever should seek to identify symptoms and signs of serious illness and specific diseases as described in the section on clinical assessment of children with fever and summarised in tables 2 and 3.
Children whose symptoms or combination of symptoms suggest an immediately life-threatening illness (see the recommendations on life-threatening features of illness in children) should be referred immediately for emergency medical care by the most appropriate means of transport (usually 999 ambulance).
Children with any 'red' features but who are not considered to have an immediately life-threatening illness should be urgently assessed by a healthcare professional in a face-to-face setting within 2 hours.
Children with 'amber' but no 'red' features should be assessed by a healthcare professional in a face-to-face setting. The urgency of this assessment should be determined by the clinical judgement of the healthcare professional carrying out the remote assessment.
Children with 'green' features and none of the 'amber' or 'red' features can be cared for at home with appropriate advice for parents and carers, including advice on when to seek further attention from the healthcare services (see the section on care at home).
# Management by the non-paediatric practitioner
In this guideline, a non-paediatric practitioner is defined as a healthcare professional who has not had specific training or who does not have expertise in the assessment and treatment of children and their illnesses. This term includes healthcare professionals working in primary care, but it may also apply to many healthcare professionals in general emergency departments.
## Clinical assessment
Management by a non-paediatric practitioner should start with a clinical assessment as described in the section on clinical assessment of children with fever. Healthcare practitioners should attempt to identify symptoms and signs of serious illness and specific diseases as summarised in tables 2 and 3.
## Management according to risk of serious illness
Children whose symptoms or combination of symptoms and signs suggest an immediately life-threatening illness (see the recommendation on identifying life-threatening features) should be referred immediately for emergency medical care by the most appropriate means of transport (usually 999 ambulance).
Children with any 'red' features but who are not considered to have an immediately life-threatening illness should be referred urgently to the care of a paediatric specialist.
If any 'amber' features are present and no diagnosis has been reached, provide parents or carers with a 'safety net' or refer to specialist paediatric care for further assessment. The safety net should be 1 or more of the following:
providing the parent or carer with verbal and/or written information on warning symptoms and how further healthcare can be accessed (see the recommendation on advising parents or carers in the section on advice for care at home)
arranging further follow-up at a specified time and place
liaising with other healthcare professionals, including out-of-hours providers, to ensure direct access for the child if further assessment is required.
Children with 'green' features and none of the 'amber' or 'red' features can be cared for at home with appropriate advice for parents and carers, including advice on when to seek further attention from the healthcare services (see the section on advice for care at home).
## Tests by the non-paediatric practitioner
Children with symptoms and signs suggesting pneumonia who are not admitted to hospital should not routinely have a chest X-ray.
See the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s for when to test the urine of babies and children with fever for a UTI.
When a child has been given antipyretics, do not rely on a decrease or lack of decrease in temperature to differentiate between serious and non‑serious illness.
## Use of antibiotics by the non-paediatric practitioner
Do not prescribe oral antibiotics to children with fever without apparent source.
Give parenteral antibiotics to children with suspected meningococcal disease at the earliest opportunity (either benzylpenicillin or a third‑generation cephalosporin). See the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.
# Management by the paediatric specialist
In this guideline, the term paediatric specialist refers to a healthcare professional who has had specific training or has recognised expertise in the assessment and treatment of children and their illnesses. Examples include paediatricians, or healthcare professionals working in children's emergency departments.
## Children younger than 5 years
Management by the paediatric specialist should start with a clinical assessment as described in the section on clinical assessment of children with fever. The healthcare professional should attempt to identify symptoms and signs of serious illness and specific diseases as summarised in tables 2 and 3.
## Children younger than 3 months
Infants younger than 3 months with fever should be observed and have the following vital signs measured and recorded:
temperature
heart rate
respiratory rate.
Perform the following investigations in infants younger than 3 months with fever:
full blood count
blood culture
C-reactive protein
urine testing for urinary tract infection (see the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s)
chest X-ray only if respiratory signs are present
stool culture, if diarrhoea is present.
Perform lumbar puncture in the following children with fever (unless contraindicated):
infants younger than 1 month
all infants aged 1 to 3 months who appear unwell
infants aged 1 to 3 months with a white blood cell count (WBC) less than 5 times 109 per litre or greater than 15 times 109 per litre.
When indicated, perform a lumbar puncture without delay and, whenever possible, before the administration of antibiotics.
Give parenteral antibiotics to:
infants younger than 1 month with fever
all infants aged 1 to 3 months with fever who appear unwell
infants aged 1 to 3 months with WBC less than 5 times 109 per litre or greater than 15 times 109 per litre.
When parenteral antibiotics are indicated for infants younger than 3 months of age, a third-generation cephalosporin (for example cefotaxime or ceftriaxone) should be given plus an antibiotic active against listeria (for example, ampicillin or amoxicillin).
## Children aged 3 months or older
Perform the following investigations in children with fever without apparent source who present to paediatric specialists with 1 or more 'red' features:
full blood count
blood culture
C-reactive protein
urine testing for urinary tract infection (see the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s).
The following investigations should also be considered in children with 'red' features, as guided by the clinical assessment:
lumbar puncture in children of all ages (if not contraindicated)
chest X-ray irrespective of body temperature and WBC
serum electrolytes and blood gas.
Children with fever without apparent source presenting to paediatric specialists who have 1 or more 'amber' features, should have the following investigations performed unless deemed unnecessary by an experienced paediatrician:
urine should be collected and tested for urinary tract infection (see the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s)
blood tests: full blood count, C-reactive protein and blood cultures
lumbar puncture should be considered for children younger than 1 year
chest X-ray in a child with a fever greater than 39°C and WBC greater than 20 times 109 per litre.
Children who have been referred to a paediatric specialist with fever without apparent source and who have no features of serious illness (that is, the 'green' group), should have urine tested for urinary tract infection and be assessed for symptoms and signs of pneumonia (see table 3 and the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s).
Do not routinely perform blood tests and chest X-rays in children with fever who have no features of serious illness (that is, the 'green' group).
## Viral co-infection
Febrile children with proven respiratory syncytial virus or influenza infection should be assessed for features of serious illness. Consideration should be given to urine testing for urinary tract infection (see the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s).
## Observation in hospital
In children aged 3 months or older with fever without apparent source, a period of observation in hospital (with or without investigations) should be considered as part of the assessment to help differentiate non-serious from serious illness.
When a child has been given antipyretics, do not rely on a decrease or lack of decrease in temperature at 1 to 2 hours to differentiate between serious and non-serious illness. Nevertheless, in order to detect possible clinical deterioration, all children in hospital with 'amber' or 'red' features should still be reassessed after 1 to 2 hours.
## Immediate treatment by the paediatric specialist (for children of all ages)
Children with fever and shock presenting to specialist paediatric care or an emergency department should be:
given an immediate intravenous fluid bolus of 10 ml/kg; the initial fluid should normally be 0.9% sodium chloride
actively monitored and given further fluid boluses as necessary.
Give immediate parenteral antibiotics to children with fever presenting to specialist paediatric care or an emergency department if they are:
shocked
unrousable
showing signs of meningococcal disease.
Immediate parenteral antibiotics should be considered for children with fever and reduced levels of consciousness. In these cases symptoms and signs of meningitis and herpes simplex encephalitis should be sought (see table 3 and the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s).
When parenteral antibiotics are indicated, a third-generation cephalosporin (for example, cefotaxime or ceftriaxone) should be given, until culture results are available. For children younger than 3 months, an antibiotic active against listeria (for example, ampicillin or amoxicillin) should also be given.
Give intravenous aciclovir to children with fever and symptoms and signs suggestive of herpes simplex encephalitis (see the section on herpes simplex encephalitis).
Oxygen should be given to children with fever who have signs of shock or oxygen saturation (SpO2) of less than 92% when breathing air. Treatment with oxygen should also be considered for children with an SpO2 of greater than 92%, as clinically indicated. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.
## Causes and incidence of serious bacterial infection
In a child presenting to hospital with a fever and suspected serious bacterial infection, requiring immediate treatment, antibiotics should be directed against Neisseria meningitidis, Streptococcus pneumoniae, Escherichia coli, Staphylococcus aureus and Haemophilus influenzae type b. A third-generation cephalosporin (for example, cefotaxime or ceftriaxone) is appropriate, until culture results are available. For infants younger than 3 months, an antibiotic active against listeria (for example, ampicillin or amoxicillin) should be added.
Refer to local treatment guidelines when rates of bacterial antibiotic resistance are significant.
## Admission to and discharge from hospital
In addition to the child's clinical condition, consider the following factors when deciding whether to admit a child with fever to hospital:
social and family circumstances
-ther illnesses that affect the child or other family members
parental anxiety and instinct (based on their knowledge of their child)
contacts with other people who have serious infectious diseases
recent travel abroad to tropical or subtropical areas, or areas with a high risk of endemic infectious disease
when the parent or carer's concern for their child's current illness has caused them to seek healthcare advice repeatedly
where the family has experienced a previous serious illness or death due to feverish illness which has increased their anxiety levels
when a feverish illness has no obvious cause, but the child remains ill longer than expected for a self-limiting illness.
If it is decided that a child does not need to be admitted to hospital, but no diagnosis has been reached, provide a safety net for parents and carers if any 'red' or 'amber' features are present. The safety net should be 1 or more of the following:
providing the parent or carer with verbal and/or written information on warning symptoms and how further healthcare can be accessed (see the recommendation on advising parents or carers in the section on advice for home care)
arranging further follow-up at a specified time and place
liaising with other healthcare professionals, including out-of-hours providers, to ensure direct access for the child if further assessment is required.
Children with 'green' features and none of the 'amber' or 'red' features can be cared for at home with appropriate advice for parents and carers, including advice on when to seek further attention from the healthcare services (see the section on advice for home care).
## Referral to paediatric intensive care
Children with fever who are shocked, unrousable or showing signs of meningococcal disease should be urgently reviewed by an experienced paediatrician and consideration given to referral to paediatric intensive care.
Give parenteral antibiotics to children with suspected meningococcal disease at the earliest opportunity (either benzylpenicillin or a third‑generation cephalosporin).
Children admitted to hospital with meningococcal disease should be under paediatric care, supervised by a consultant and have their need for inotropes assessed.
# Antipyretic interventions
## Effects of body temperature reduction
Antipyretic agents do not prevent febrile convulsions and should not be used specifically for this purpose.
## Physical interventions to reduce body temperature
Tepid sponging is not recommended for the treatment of fever.
Children with fever should not be underdressed or over-wrapped.
## Drug interventions to reduce body temperature
Consider using either paracetamol or ibuprofen in children with fever who appear distressed.
Do not use antipyretic agents with the sole aim of reducing body temperature in children with fever.
When using paracetamol or ibuprofen in children with fever:
continue only as long as the child appears distressed
consider changing to the other agent if the child's distress is not alleviated
do not give both agents simultaneously
-nly consider alternating these agents if the distress persists or recurs before the next dose is due.
# Advice for home care
## Care at home
Advise parents or carers to manage their child's temperature as described in the section on antipyretic interventions.
Advise parents or carers looking after a feverish child at home:
to offer the child regular fluids (where a baby or child is breastfed the most appropriate fluid is breast milk)
how to detect signs of dehydration by looking for the following features:
sunken fontanelle
dry mouth
sunken eyes
absence of tears
poor overall appearance
to encourage their child to drink more fluids and consider seeking further advice if they detect signs of dehydration
how to identify a non-blanching rash
to check their child during the night
to keep their child away from nursery or school while the child's fever persists but to notify the school or nursery of the illness.
## When to seek further help
Following contact with a healthcare professional, parents and carers who are looking after their feverish child at home should seek further advice if:
the child has a fit
the child develops a non-blanching rash
the parent or carer feels that the child is less well than when they previously sought advice
the parent or carer is more worried than when they previously sought advice
the fever lasts 5 days or longer
the parent or carer is distressed, or concerned that they are unable to look after their child.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.
## Fever
For the purposes of this guideline, fever was defined as an elevation of body temperature above the normal daily variation.
## Social cues
A child's response to social interaction with a parent or healthcare professional, such as response to their name, smiling and/or giggling.# Recommendations for research
The guideline committee has made the following recommendations for research. As part of the update, the guideline committee made an additional research recommendation on Kawasaki disease.
# Key recommendations for research
## Symptoms and signs of serious illness
The Guideline Development Group (GDG) recommends a UK-based epidemiological study on the symptoms and signs of serious illness.
## Management by remote assessment
The GDG recommends that a UK study is undertaken to determine the validity of symptoms reported on remote assessment for children with fever.
## Diagnosis
The GDG recommends that a UK study of the performance characteristics and cost-effectiveness of procalcitonin versus C-reactive protein in identifying serious bacterial infection in children with fever without apparent source be carried out.
## Antipyretics
The GDG recommends that studies are conducted in primary care and secondary care to determine whether examination or re-examination after a dose of antipyretic medication is of benefit in differentiating children with serious illness from those with other conditions.
## Home-based antipyretic use
The GDG recommends studies on home-based antipyretic use and parental perception of distress caused by fever.
# Other recommendations for research
## Thermometers and the detection of fever
Measuring temperature in young babies: tympanic versus axilla electronic versus axilla chemical dot versus temporal artery.
## Management according to risk of serious illness
The GDG recommends that research is carried out on referral patterns between primary and secondary care for children with fever, so the health economic impact of this and future guidelines can be estimated.
## Signs and symptoms of Kawasaki disease
Which signs and symptoms (or combinations of signs and symptoms) predict a diagnosis of Kawasaki disease in children under 5 presenting with fever lasting 5 days or more?
For a short explanation of why the committee made the recommendation for research, see the rationale on Kawasaki disease .
Full details of the evidence and the committee's discussion are in evidence review A: signs and symptoms predicting Kawasaki disease.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.
# Kawasaki disease
Recommendations 1.2.25 to 1.2.27
## Why the committee made the recommendations
Prompt diagnosis and treatment of Kawasaki disease can prevent long-term cardiac complications. The 2013 version of the NICE guideline recommended that Kawasaki disease should be considered when children had a fever lasting 5 days and 4 of the 5 principal features specified by the American Heart Association diagnostic criteria. However, the evidence from case-series suggested that often fewer than 4 features are present early in the course of the illness, and some children may have 'incomplete' Kawasaki disease, in which fewer than 4 features are present throughout the course of the illness. Because of this, clinicians should think about Kawasaki disease in all children who have a fever lasting 5 days or longer, even when no additional features are present, and should be aware of the principal features of Kawasaki disease that would increase the probability of a Kawasaki disease diagnosis.
Based on the experience of the committee, features of Kawasaki disease may appear and disappear through the course of the illness, so it is important to ask parents and carers about and document these features to reach the correct diagnosis.
The evidence also showed that some of the principal features of Kawasaki disease are less common in children under 1 year. This was consistent with the committee's experience that incomplete Kawasaki disease is more common in this age group, so they wanted clinicians to be aware of this when thinking about Kawasaki disease as a possible diagnosis.
There is no existing evidence on how accurate most signs or symptoms are at ruling in or out Kawasaki disease in a group of children with fever. The committee made a research recommendation for a diagnostic accuracy study in this area to allow more specific recommendations to be made when the guideline is updated.
## How the recommendations might affect practice
The recommendations should prompt clinicians to think about Kawasaki disease with fewer clinical features, which may result in more children being referred for assessment in secondary care. However, prompt identification and treatment of children with Kawasaki disease will reduce the number of children with long-term cardiac complications, which will reduce long-term costs for the NHS.
Full details of the evidence and the committee's discussion are in evidence review A: signs and symptoms predicting Kawasaki disease.
Return to recommendations# Context
Feverish illness in young children usually indicates an underlying infection and is a cause of concern for parents and carers. Feverish illness is very common in young children, with between 20 and 40% of parents reporting such an illness each year. As a result, fever is probably the most common reason for a child to be taken to the doctor. Feverish illness is also the second most common reason for a child being admitted to hospital. Despite advances in healthcare, infections remain the leading cause of death in children under the age of 5 years.
Fever in young children can be a diagnostic challenge for healthcare professionals because it is often difficult to identify the cause. In most cases, the illness is due to a self-limiting viral infection. However, fever may also be the presenting feature of serious bacterial infections such as meningitis or pneumonia. A significant number of children have no obvious cause of fever despite careful assessment. These children with fever without apparent source are of particular concern to healthcare professionals because it is especially difficult to distinguish between simple viral illnesses and life-threatening bacterial infections in this group. As a result, there is a perceived need to improve the recognition, assessment and immediate treatment of feverish illnesses in children.
The introduction of new vaccination programmes in the UK may have significantly reduced the level of admissions to hospital resulting from diseases covered by this guideline. For example, early analysis of the pneumococcal vaccination programme in England showed that the incidence of pneumococcal-related disease had fallen 98% in children younger than 2 years since vaccination was introduced. However, evidence suggests a 68% increase in the prevalence of disease caused by subtypes of bacteria not covered by vaccination programmes. Also, potentially serious cases of feverish illness are likely to be rare, so it is important that information is in place to help healthcare professionals distinguish these from mild cases.
This guideline is designed to assist healthcare professionals in the initial assessment and immediate treatment of young children with fever presenting to primary or secondary care. The guideline should be followed until a clinical diagnosis of the underlying condition has been made. Once a diagnosis has been made, the child should be treated according to national or local guidance for that condition.
Parents or carers of a child with fever may approach a range of different healthcare professionals as their first point of contact, for example, a GP, a pharmacist or an emergency care practitioner. The training and experience of the healthcare professionals involved in the child's care will vary and each should interpret the guidance according to the scope of their own practice.
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.
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{'Recommendations': 'People have the right to be involved in discussions and make informed decisions about their care, as described in NICE\'s information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Thermometers and the detection of fever\n\n## Oral and rectal temperature measurements\n\nDo not routinely use the oral and rectal routes to measure the body temperature of children aged 0\xa0to 5\xa0years. \n\n## Measurement of body temperature at other sites\n\nIn infants under the age of 4\xa0weeks, measure body temperature with an electronic thermometer in the axilla. \n\nIn children aged 4\xa0weeks to 5\xa0years, measure body temperature by one of the following methods:\n\nelectronic thermometer in the axilla\n\nchemical dot thermometer in the axilla\n\ninfra-red tympanic thermometer. \n\nHealthcare professionals who routinely use disposable chemical dot thermometers should consider using an alternative type of thermometer when multiple temperature measurements are required. \n\nForehead chemical thermometers are unreliable and should not be used by healthcare professionals. \n\n## Subjective detection of fever by parents and carers\n\nReported parental perception of a fever should be considered valid and taken seriously by healthcare professionals. \n\n# Clinical assessment of children with fever\n\nFirst, healthcare professionals should identify any immediately life‑threatening features, including compromise of the airway, breathing or circulation, and decreased level of consciousness. \n\nThink "Could this be sepsis?" and refer to the NICE guideline on sepsis: recognition, diagnosis and early management if a child presents with fever and symptoms or signs that indicate possible sepsis. Sepsis is a condition of life-threatening organ dysfunction due to a dysregulated host response to infection.\n\n## Assessment of risk of serious illness\n\nAssess children with feverish illness for the presence or absence of symptoms and signs that can be used to predict the risk of serious illness using the traffic light system (see table\xa02). \n\nWhen assessing children with learning disabilities, take the individual child\'s learning disability into account when interpreting the traffic light table. \n\nRecognise that children with any of the following symptoms or signs are in a high-risk group for serious illness:\n\npale/mottled/ashen/blue skin, lips or tongue\n\nno response to social cues\n\nappearing ill to a healthcare professional\n\ndoes not wake or if roused does not stay awake\n\nweak, high-pitched or continuous cry\n\ngrunting\n\nrespiratory rate greater than 60\xa0breaths per minute\n\nmoderate or severe chest indrawing\n\nreduced skin turgor\n\nbulging fontanelle. \n\nRecognise that children with any of the following symptoms or signs are in at least an intermediate-risk group for serious illness:\n\npallor of skin, lips or tongue reported by parent or carer\n\nnot responding normally to social cues\n\nno smile\n\nwakes only with prolonged stimulation\n\ndecreased activity\n\nnasal flaring\n\ndry mucous membranes\n\npoor feeding in infants\n\nreduced urine output\n\nrigors. \n\nRecognise that children who have all of the following features, and none of the high- or intermediate-risk features, are in a low-risk group for serious illness:\n\nnormal colour of skin, lips and tongue\n\nresponds normally to social cues\n\ncontent or smiles\n\nstays awake or awakens quickly\n\nstrong normal cry or not crying\n\nnormal skin and eyes\n\nmoist mucous membranes. \n\nMeasure and record temperature, heart rate, respiratory rate and capillary refill time as part of the routine assessment of a child with fever. \n\nRecognise that a capillary refill time of 3\xa0seconds or longer is an intermediate-risk group marker for serious illness (\'amber\' sign). \n\nMeasure the blood pressure of children with fever if the heart rate or capillary refill time is abnormal and the facilities to measure blood pressure are available. \n\nIn children older than 6\xa0months do not use height of body temperature alone to identify those with serious illness. \n\nRecognise that children younger than 3\xa0months with a temperature of 38°C or higher are in a high-risk group for serious illness. (Note that some vaccinations have been found to induce fever in children aged under 3\xa0months.) \n\nRecognise that children aged 3\xa0to 6\xa0months with a temperature of 39°C or higher are in at least an intermediate-risk group for serious illness. \n\nDo not use duration of fever to predict the likelihood of serious illness. However, children with a fever lasting 5\xa0days or longer should be assessed for Kawasaki disease (see the recommendation on additional features of Kawasaki disease in the section on symptoms and signs of specific illnesses). [2013, amended 2019]\n\nRecognise that children with tachycardia are in at least an intermediate‑risk group for serious illness. Use the Advanced Paediatric Life Support criteria in table\xa01 to define tachycardia. \n\nAge\n\nHeart rate (beats per minute)\n\nLess than 12\xa0months\n\nMore than 160\n\nto 24\xa0months\n\nMore than 150\n\nto 5\xa0years\n\nMore than 140\n\nAssess children with fever for signs of dehydration. Look for:\n\nprolonged capillary refill time\n\nabnormal skin turgor\n\nabnormal respiratory pattern\n\nweak pulse\n\ncool extremities. \n\n## Symptoms and signs of specific illnesses\n\nLook for a source of fever and check for the presence of symptoms and signs that are associated with specific diseases (see table\xa03). \n\nAlso see the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s.\n\nConsider meningococcal disease in any child with fever and a non‑blanching rash, particularly if any of the following features are present:\n\nan ill-looking child\n\nlesions larger than 2\xa0mm in diameter (purpura)\n\na capillary refill time of 3\xa0seconds or longer\n\nneck stiffness. \n\nConsider bacterial meningitis in a child with fever and any of the following features:\n\nneck stiffness\n\nbulging fontanelle\n\ndecreased level of consciousness\n\nconvulsive status epilepticus. [2007, amended 2013]\n\nBe aware that classic signs of meningitis (neck stiffness, bulging fontanelle, high-pitched cry) are often absent in infants with bacterial meningitis. \n\nConsider herpes simplex encephalitis in children with fever and any of the following features:\n\nfocal neurological signs\n\nfocal seizures\n\ndecreased level of consciousness. \n\nConsider pneumonia in children with fever and any of the following signs:\n\ntachypnoea (respiratory rate greater than 60\xa0breaths per minute, age\xa00\xa0to 5\xa0months; greater than 50\xa0breaths per minute, age\xa06\xa0to\xa012\xa0months; greater than 40\xa0breaths per minute, age older than 12\xa0months)\n\ncrackles in the chest\n\nnasal flaring\n\nchest indrawing\n\ncyanosis\n\noxygen saturation of 95% or less when breathing air. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nConsider urinary tract infection in a baby or child under\xa05 with fever. See the symptoms and signs that increase the likelihood that a UTI is present in the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s. [2007, amended 2022]\n\nConsider septic arthritis or osteomyelitis in children with fever and any of the following signs:\n\nswelling of a limb or joint\n\nnot using an extremity\n\nnon-weight bearing. \n\nBe aware of the possibility of Kawasaki disease in children with fever that has lasted 5\xa0days or longer. Additional features of Kawasaki disease may include:\n\nbilateral conjunctival injection without exudate\n\nerythema and cracking of lips, strawberry tongue, or erythema of oral and pharyngeal mucosa\n\noedema and erythema in the hands and feet\n\npolymorphous rash\n\ncervical lymphadenopathy. \n\nAsk parents or carers about the presence of these features since the onset of fever, because they may have resolved by the time of assessment. \n\nBe aware that children under 1\xa0year may present with fewer clinical features of Kawasaki disease in addition to fever, but may be at higher risk of coronary artery abnormalities than older children. \n\nFor a short explanation of why the committee made the 2019 recommendations and how they might affect practice, see the rationale and impact section on Kawasaki disease\xa0.\n\nFull details of the evidence and the committee\'s discussion are in evidence review\xa0A: Signs and symptoms predicting Kawasaki disease.\n\nLoading. Please wait.\n\n## Imported infections\n\nWhen assessing a child with feverish illness, enquire about recent travel abroad and consider the possibility of imported infections according to the region visited. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\nRefer to table 3 in the NICE guideline on sepsis if a child presents with fever and symptoms or signs that indicate possible sepsis.\n\nChildren with fever and any of the symptoms or signs in the red column should be recognised as being at high risk. Similarly, children with fever and any of the symptoms or signs in the amber column and none in the red column should be recognised as being at intermediate risk. Children with symptoms and signs in the green column and none in the amber or red columns are at low risk. The management of children with fever should be directed by the level of risk.\n\nThis traffic light table should be used in conjunction with the recommendations in this guideline on investigations and initial management in children with fever.\n\nA colour version of this table is available on the NICE tools and resources page.\n\n\n\nGreen – low risk\n\nAmber – intermediate risk\n\nRed – high risk\n\nColour\n\n(of skin, lips or tongue)\n\nNormal colour\n\nPallor reported by parent/carer\n\nPale, mottled, ashen or blue\n\nActivity\n\nResponds normally to social cues\n\nContent or smiles\n\nStays awake or awakens quickly\n\nStrong normal cry or not crying\n\nNot responding normally to social cues\n\nNo smile\n\nWakes only with prolonged stimulation\n\nDecreased activity\n\nNo response to social cues\n\nAppears ill to a healthcare professional\n\nDoes not wake or if roused does not stay awake\n\nWeak, high-pitched or continuous cry\n\nRespiratory\n\n–\n\nNasal flaring\n\nTachypnoea: respiratory rate\n\n>50\xa0breaths per minute, age 6 to 12\xa0months;\n\n>40\xa0breaths per minute, age more than 12\xa0months\n\nOxygen saturation less than or equal to 95% in air\n\nCrackles in the chest\n\nGrunting\n\nTachypnoea: respiratory rate more than 60\xa0breaths per minute\n\nModerate or severe chest indrawing\n\nCirculation and hydration\n\nNormal skin and eyes\n\nMoist mucous membranes\n\nTachycardia:\n\nMore than 160\xa0beats per minute, age less than 12\xa0months\n\nMore than 150\xa0beats per minute, age\xa012 to 24\xa0months\n\nMore than 140\xa0beats per minute, age\xa02 to 5\xa0years\n\nCapillary refill time more than or equal to 3\xa0seconds\n\nDry mucous membranes\n\nPoor feeding in infants\n\nReduced urine output\n\nReduced skin turgor\n\nOther\n\nNone of the amber or red symptoms or signs\n\nAge 3 to 6\xa0months, temperature more than or equal to 39°C\n\nFever for more than or equal to 5\xa0days\n\nRigors\n\nSwelling of a limb or joint\n\nNon-weight bearing limb or not using an extremity\n\nAge less than 3\xa0months, temperature more than or equal to 38°C\n\nNon-blanching rash\n\nBulging fontanelle\n\nNeck stiffness\n\nStatus epilepticus\n\nFocal neurological signs\n\nFocal seizures\n\nNote that some vaccinations have been found to induce fever in children aged under 3\xa0months.\n\nDiagnosis to be considered\n\nSymptoms and signs in conjunction with fever\n\nMeningococcal disease\n\nNon-blanching rash, particularly with 1 or more of the following:\n\nan ill-looking child\n\nlesions larger than 2\xa0mm in diameter (purpura)\n\ncapillary refill time of more than or equal to 3\xa0seconds\n\nneck stiffness\n\nBacterial meningitis\n\nNeck stiffness\n\nBulging fontanelle\n\nDecreased level of consciousness\n\nConvulsive status epilepticus\n\nHerpes simplex encephalitis\n\nFocal neurological signs\n\nFocal seizures\n\nDecreased level of consciousness\n\nPneumonia\n\nTachypnoea (respiratory rate more than 60 breaths per minute, age 0 to 5\xa0months; more than 50 breaths per minute, age\xa06\xa0to\xa012\xa0months; more than 40 breaths per minute, age more than 12\xa0months)\n\nCrackles in the chest\n\nNasal flaring\n\nChest indrawing\n\nCyanosis\n\nOxygen saturation less than or equal to 95%\n\nUrinary tract infection (UTI)\n\nThese symptoms and signs increase the likelihood that a UTI is present and should be used to inform a decision about whether urine collection and testing is necessary. They are taken from the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s\n\n\n\nPainful urination (dysuria)\n\nMore frequent urination\n\nNew bedwetting\n\nFoul smelling (malodorous) urine\n\nDarker urine\n\nCloudy urine\n\nFrank haematuria (visible blood in urine)\n\nReduced fluid intake\n\nShivering\n\nAbdominal pain\n\nLoin tenderness or suprapubic tenderness\n\nCapillary refill longer than 3\xa0seconds\n\nPrevious history of confirmed urinary tract infection\n\nSeptic arthritis\n\nSwelling of a limb or joint\n\nNot using an extremity\n\nNon-weight bearing\n\nKawasaki disease \n\nFever for 5\xa0days or longer and may have some of the following:\n\nbilateral conjunctival injection without exudate\n\nerythema and cracking of lips; strawberry tongue; or erythema of oral and pharyngeal mucosa\n\noedema and erythema in the hands and feet\n\npolymorphous rash\n\ncervical lymphadenopathy\n\n# Management by remote assessment\n\nRemote assessment refers to situations in which a child is assessed by a healthcare professional who is unable to examine the child because the child is geographically remote from the assessor (for example, telephone calls to NHS 111). Therefore, assessment is largely an interpretation of symptoms rather than physical signs. The guidance in this section may also apply to healthcare professionals whose scope of practice does not include the physical examination of a young child (for example, community pharmacists).\n\n## Management according to risk of serious illness\n\nHealthcare professionals performing a remote assessment of a child with fever should seek to identify symptoms and signs of serious illness and specific diseases as described in the section on clinical assessment of children with fever and summarised in tables\xa02 and\xa03. \n\nChildren whose symptoms or combination of symptoms suggest an immediately life-threatening illness (see the recommendations on life-threatening features of illness in children) should be referred immediately for emergency medical care by the most appropriate means of transport (usually 999 ambulance). \n\nChildren with any \'red\' features but who are not considered to have an immediately life-threatening illness should be urgently assessed by a healthcare professional in a face-to-face setting within 2\xa0hours. \n\nChildren with \'amber\' but no \'red\' features should be assessed by a healthcare professional in a face-to-face setting. The urgency of this assessment should be determined by the clinical judgement of the healthcare professional carrying out the remote assessment. \n\nChildren with \'green\' features and none of the \'amber\' or \'red\' features can be cared for at home with appropriate advice for parents and carers, including advice on when to seek further attention from the healthcare services (see the section on care at home). [2007, amended 2013]\n\n# Management by the non-paediatric practitioner\n\nIn this guideline, a non-paediatric practitioner is defined as a healthcare professional who has not had specific training or who does not have expertise in the assessment and treatment of children and their illnesses. This term includes healthcare professionals working in primary care, but it may also apply to many healthcare professionals in general emergency departments.\n\n## Clinical assessment\n\nManagement by a non-paediatric practitioner should start with a clinical assessment as described in the section on clinical assessment of children with fever. Healthcare practitioners should attempt to identify symptoms and signs of serious illness and specific diseases as summarised in tables\xa02 and 3. \n\n## Management according to risk of serious illness\n\nChildren whose symptoms or combination of symptoms and signs suggest an immediately life-threatening illness (see the recommendation on identifying life-threatening features) should be referred immediately for emergency medical care by the most appropriate means of transport (usually 999 ambulance). \n\nChildren with any \'red\' features but who are not considered to have an immediately life-threatening illness should be referred urgently to the care of a paediatric specialist. \n\nIf any \'amber\' features are present and no diagnosis has been reached, provide parents or carers with a \'safety net\' or refer to specialist paediatric care for further assessment. The safety net should be 1 or more of the following:\n\nproviding the parent or carer with verbal and/or written information on warning symptoms and how further healthcare can be accessed (see the recommendation on advising parents or carers in the section on advice for care at home)\n\narranging further follow-up at a specified time and place\n\nliaising with other healthcare professionals, including out-of-hours providers, to ensure direct access for the child if further assessment is required. \n\nChildren with \'green\' features and none of the \'amber\' or \'red\' features can be cared for at home with appropriate advice for parents and carers, including advice on when to seek further attention from the healthcare services (see the section on advice for care at home). [2007, amended 2013]\n\n## Tests by the non-paediatric practitioner\n\nChildren with symptoms and signs suggesting pneumonia who are not admitted to hospital should not routinely have a chest X-ray. \n\nSee the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s for when to test the urine of babies and children with fever for a UTI. \n\nWhen a child has been given antipyretics, do not rely on a decrease or lack of decrease in temperature to differentiate between serious and non‑serious illness. \n\n## Use of antibiotics by the non-paediatric practitioner\n\nDo not prescribe oral antibiotics to children with fever without apparent source. \n\nGive parenteral antibiotics to children with suspected meningococcal disease at the earliest opportunity (either benzylpenicillin or a third‑generation cephalosporin). See the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s. \n\n# Management by the paediatric specialist\n\nIn this guideline, the term paediatric specialist refers to a healthcare professional who has had specific training or has recognised expertise in the assessment and treatment of children and their illnesses. Examples include paediatricians, or healthcare professionals working in children\'s emergency departments.\n\n## Children younger than 5 years\n\nManagement by the paediatric specialist should start with a clinical assessment as described in the section on clinical assessment of children with fever. The healthcare professional should attempt to identify symptoms and signs of serious illness and specific diseases as summarised in tables\xa02 and\xa03. \n\n## Children younger than 3 months\n\nInfants younger than 3\xa0months with fever should be observed and have the following vital signs measured and recorded:\n\ntemperature\n\nheart rate\n\nrespiratory rate. \n\nPerform the following investigations in infants younger than 3\xa0months with fever:\n\nfull blood count\n\nblood culture\n\nC-reactive protein\n\nurine testing for urinary tract infection (see the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s)\n\nchest X-ray only if respiratory signs are present\n\nstool culture, if diarrhoea is present. \n\nPerform lumbar puncture in the following children with fever (unless contraindicated):\n\ninfants younger than 1\xa0month\n\nall infants aged 1 to 3\xa0months who appear unwell\n\ninfants aged 1 to 3\xa0months with a white blood cell count (WBC) less than 5 times 109 per litre or greater than 15 times 109 per litre. [2007, amended 2013]\n\nWhen indicated, perform a lumbar puncture without delay and, whenever possible, before the administration of antibiotics. \n\nGive parenteral antibiotics to:\n\ninfants younger than 1\xa0month with fever\n\nall infants aged 1 to 3\xa0months with fever who appear unwell\n\ninfants aged 1 to 3\xa0months with WBC less than 5 times 109 per litre or greater than 15 times 109 per litre. [2007, amended 2013]\n\nWhen parenteral antibiotics are indicated for infants younger than 3\xa0months of age, a third-generation cephalosporin (for example cefotaxime or ceftriaxone) should be given plus an antibiotic active against listeria (for example, ampicillin or amoxicillin). \n\n## Children aged 3 months or older\n\nPerform the following investigations in children with fever without apparent source who present to paediatric specialists with 1 or more \'red\' features:\n\nfull blood count\n\nblood culture\n\nC-reactive protein\n\nurine testing for urinary tract infection (see the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s). \n\nThe following investigations should also be considered in children with \'red\' features, as guided by the clinical assessment:\n\nlumbar puncture in children of all ages (if not contraindicated)\n\nchest X-ray irrespective of body temperature and WBC\n\nserum electrolytes and blood gas. \n\nChildren with fever without apparent source presenting to paediatric specialists who have 1 or more \'amber\' features, should have the following investigations performed unless deemed unnecessary by an experienced paediatrician:\n\nurine should be collected and tested for urinary tract infection (see the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s)\n\nblood tests: full blood count, C-reactive protein and blood cultures\n\nlumbar puncture should be considered for children younger than 1\xa0year\n\nchest X-ray in a child with a fever greater than 39°C and WBC greater than 20 times 109 per litre. \n\nChildren who have been referred to a paediatric specialist with fever without apparent source and who have no features of serious illness (that is, the \'green\' group), should have urine tested for urinary tract infection and be assessed for symptoms and signs of pneumonia (see table 3 and the sections on urine collection, preservation and testing in the NICE guideline on urinary tract infection in under 16s). \n\nDo not routinely perform blood tests and chest X-rays in children with fever who have no features of serious illness (that is, the \'green\' group). \n\n## Viral co-infection\n\nFebrile children with proven respiratory syncytial virus or influenza infection should be assessed for features of serious illness. Consideration should be given to urine testing for urinary tract infection (see the section on symptoms and signs in the NICE guideline on urinary tract infection in under 16s). \n\n## Observation in hospital\n\nIn children aged 3\xa0months or older with fever without apparent source, a period of observation in hospital (with or without investigations) should be considered as part of the assessment to help differentiate non-serious from serious illness. \n\nWhen a child has been given antipyretics, do not rely on a decrease or lack of decrease in temperature at 1 to 2\xa0hours to differentiate between serious and non-serious illness. Nevertheless, in order to detect possible clinical deterioration, all children in hospital with \'amber\' or \'red\' features should still be reassessed after 1 to 2\xa0hours. \n\n## Immediate treatment by the paediatric specialist (for children of all ages)\n\nChildren with fever and shock presenting to specialist paediatric care or an emergency department should be:\n\ngiven an immediate intravenous fluid bolus of 10\xa0ml/kg; the initial fluid should normally be 0.9% sodium chloride\n\nactively monitored and given further fluid boluses as necessary. \n\nGive immediate parenteral antibiotics to children with fever presenting to specialist paediatric care or an emergency department if they are:\n\nshocked\n\nunrousable\n\nshowing signs of meningococcal disease. \n\nImmediate parenteral antibiotics should be considered for children with fever and reduced levels of consciousness. In these cases symptoms and signs of meningitis and herpes simplex encephalitis should be sought (see table 3 and the NICE guideline on meningitis (bacterial) and meningococcal septicaemia in under 16s). \n\nWhen parenteral antibiotics are indicated, a third-generation cephalosporin (for example, cefotaxime or ceftriaxone) should be given, until culture results are available. For children younger than 3\xa0months, an antibiotic active against listeria (for example, ampicillin or amoxicillin) should also be given. \n\nGive intravenous aciclovir to children with fever and symptoms and signs suggestive of herpes simplex encephalitis (see the section on herpes simplex encephalitis). \n\nOxygen should be given to children with fever who have signs of shock or oxygen saturation (SpO2) of less than 92% when breathing air. Treatment with oxygen should also be considered for children with an SpO2 of greater than 92%, as clinically indicated. Be aware that some pulse oximeters can underestimate or overestimate oxygen saturation levels, especially if the saturation level is borderline. Overestimation has been reported in people with dark skin. See also the NHS England Patient Safety Alert on the risk of harm from inappropriate placement of pulse oximeter probes.\n\n## Causes and incidence of serious bacterial infection\n\nIn a child presenting to hospital with a fever and suspected serious bacterial infection, requiring immediate treatment, antibiotics should be directed against Neisseria meningitidis, Streptococcus pneumoniae, Escherichia coli, Staphylococcus aureus and Haemophilus influenzae type b. A third-generation cephalosporin (for example, cefotaxime or ceftriaxone) is appropriate, until culture results are available. For infants younger than 3\xa0months, an antibiotic active against listeria (for example, ampicillin or amoxicillin) should be added. \n\nRefer to local treatment guidelines when rates of bacterial antibiotic resistance are significant. \n\n## Admission to and discharge from hospital\n\nIn addition to the child\'s clinical condition, consider the following factors when deciding whether to admit a child with fever to hospital:\n\nsocial and family circumstances\n\nother illnesses that affect the child or other family members\n\nparental anxiety and instinct (based on their knowledge of their child)\n\ncontacts with other people who have serious infectious diseases\n\nrecent travel abroad to tropical or subtropical areas, or areas with a high risk of endemic infectious disease\n\nwhen the parent or carer\'s concern for their child\'s current illness has caused them to seek healthcare advice repeatedly\n\nwhere the family has experienced a previous serious illness or death due to feverish illness which has increased their anxiety levels\n\nwhen a feverish illness has no obvious cause, but the child remains ill longer than expected for a self-limiting illness. \n\nIf it is decided that a child does not need to be admitted to hospital, but no diagnosis has been reached, provide a safety net for parents and carers if any \'red\' or \'amber\' features are present. The safety net should be 1 or more of the following:\n\nproviding the parent or carer with verbal and/or written information on warning symptoms and how further healthcare can be accessed (see the recommendation on advising parents or carers in the section on advice for home care)\n\narranging further follow-up at a specified time and place\n\nliaising with other healthcare professionals, including out-of-hours providers, to ensure direct access for the child if further assessment is required. \n\nChildren with \'green\' features and none of the \'amber\' or \'red\' features can be cared for at home with appropriate advice for parents and carers, including advice on when to seek further attention from the healthcare services (see the section on advice for home care). [2007, amended 2013]\n\n## Referral to paediatric intensive care\n\nChildren with fever who are shocked, unrousable or showing signs of meningococcal disease should be urgently reviewed by an experienced paediatrician and consideration given to referral to paediatric intensive care. \n\nGive parenteral antibiotics to children with suspected meningococcal disease at the earliest opportunity (either benzylpenicillin or a third‑generation cephalosporin). \n\nChildren admitted to hospital with meningococcal disease should be under paediatric care, supervised by a consultant and have their need for inotropes assessed. \n\n# Antipyretic interventions\n\n## Effects of body temperature reduction\n\nAntipyretic agents do not prevent febrile convulsions and should not be used specifically for this purpose. \n\n## Physical interventions to reduce body temperature\n\nTepid sponging is not recommended for the treatment of fever. \n\nChildren with fever should not be underdressed or over-wrapped. \n\n## Drug interventions to reduce body temperature\n\nConsider using either paracetamol or ibuprofen in children with fever who appear distressed. \n\nDo not use antipyretic agents with the sole aim of reducing body temperature in children with fever. \n\nWhen using paracetamol or ibuprofen in children with fever:\n\ncontinue only as long as the child appears distressed\n\nconsider changing to the other agent if the child\'s distress is not alleviated\n\ndo not give both agents simultaneously\n\nonly consider alternating these agents if the distress persists or recurs before the next dose is due. \n\n# Advice for home care\n\n## Care at home\n\nAdvise parents or carers to manage their child\'s temperature as described in the section on antipyretic interventions. \n\nAdvise parents or carers looking after a feverish child at home:\n\nto offer the child regular fluids (where a baby or child is breastfed the most appropriate fluid is breast milk)\n\nhow to detect signs of dehydration by looking for the following features:\n\n\n\nsunken fontanelle\n\ndry mouth\n\nsunken eyes\n\nabsence of tears\n\npoor overall appearance\n\n\n\nto encourage their child to drink more fluids and consider seeking further advice if they detect signs of dehydration\n\nhow to identify a non-blanching rash\n\nto check their child during the night\n\nto keep their child away from nursery or school while the child\'s fever persists but to notify the school or nursery of the illness. \n\n## When to seek further help\n\nFollowing contact with a healthcare professional, parents and carers who are looking after their feverish child at home should seek further advice if:\n\nthe child has a fit\n\nthe child develops a non-blanching rash\n\nthe parent or carer feels that the child is less well than when they previously sought advice\n\nthe parent or carer is more worried than when they previously sought advice\n\nthe fever lasts 5\xa0days or longer\n\nthe parent or carer is distressed, or concerned that they are unable to look after their child. [2007, amended 2019]\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.\n\n## Fever\n\nFor the purposes of this guideline, fever was defined as an elevation of body temperature above the normal daily variation.\n\n## Social cues\n\nA child\'s response to social interaction with a parent or healthcare professional, such as response to their name, smiling and/or giggling.', 'Recommendations for research': "The guideline committee has made the following recommendations for research. As part of the update, the guideline committee made an additional research recommendation on Kawasaki disease.\n\n# Key recommendations for research\n\n## Symptoms and signs of serious illness\n\nThe Guideline Development Group (GDG) recommends a UK-based epidemiological study on the symptoms and signs of serious illness. \n\n## Management by remote assessment\n\nThe GDG recommends that a UK study is undertaken to determine the validity of symptoms reported on remote assessment for children with fever. \n\n## Diagnosis\n\nThe GDG recommends that a UK study of the performance characteristics and cost-effectiveness of procalcitonin versus C-reactive protein in identifying serious bacterial infection in children with fever without apparent source be carried out. \n\n## Antipyretics\n\nThe GDG recommends that studies are conducted in primary care and secondary care to determine whether examination or re-examination after a dose of antipyretic medication is of benefit in differentiating children with serious illness from those with other conditions. \n\n## Home-based antipyretic use\n\nThe GDG recommends studies on home-based antipyretic use and parental perception of distress caused by fever. \n\n# Other recommendations for research\n\n## Thermometers and the detection of fever\n\nMeasuring temperature in young babies: tympanic versus axilla electronic versus axilla chemical dot versus temporal artery. \n\n## Management according to risk of serious illness\n\nThe GDG recommends that research is carried out on referral patterns between primary and secondary care for children with fever, so the health economic impact of this and future guidelines can be estimated. \n\n## Signs and symptoms of Kawasaki disease\n\nWhich signs and symptoms (or combinations of signs and symptoms) predict a diagnosis of Kawasaki disease in children under 5 presenting with fever lasting 5 days or more? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on Kawasaki disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: signs and symptoms predicting Kawasaki disease.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice. They link to details of the evidence and a full description of the committee's discussion.\n\n# Kawasaki disease\n\nRecommendations 1.2.25 to 1.2.27\n\n## Why the committee made the recommendations\n\nPrompt diagnosis and treatment of Kawasaki disease can prevent long-term cardiac complications. The 2013 version of the NICE guideline recommended that Kawasaki disease should be considered when children had a fever lasting 5\xa0days and 4 of the 5\xa0principal features specified by the American Heart Association diagnostic criteria. However, the evidence from case-series suggested that often fewer than 4\xa0features are present early in the course of the illness, and some children may have 'incomplete' Kawasaki disease, in which fewer than 4\xa0features are present throughout the course of the illness. Because of this, clinicians should think about Kawasaki disease in all children who have a fever lasting 5\xa0days or longer, even when no additional features are present, and should be aware of the principal features of Kawasaki disease that would increase the probability of a Kawasaki disease diagnosis.\n\nBased on the experience of the committee, features of Kawasaki disease may appear and disappear through the course of the illness, so it is important to ask parents and carers about and document these features to reach the correct diagnosis.\n\nThe evidence also showed that some of the principal features of Kawasaki disease are less common in children under 1\xa0year. This was consistent with the committee's experience that incomplete Kawasaki disease is more common in this age group, so they wanted clinicians to be aware of this when thinking about Kawasaki disease as a possible diagnosis.\n\nThere is no existing evidence on how accurate most signs or symptoms are at ruling in or out Kawasaki disease in a group of children with fever. The committee made a research recommendation for a diagnostic accuracy study in this area to allow more specific recommendations to be made when the guideline is updated.\n\n## How the recommendations might affect practice\n\nThe recommendations should prompt clinicians to think about Kawasaki disease with fewer clinical features, which may result in more children being referred for assessment in secondary care. However, prompt identification and treatment of children with Kawasaki disease will reduce the number of children with long-term cardiac complications, which will reduce long-term costs for the NHS.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: signs and symptoms predicting Kawasaki disease.\n\nReturn to recommendations", 'Context': "Feverish illness in young children usually indicates an underlying infection and is a cause of concern for parents and carers. Feverish illness is very common in young children, with between 20 and 40% of parents reporting such an illness each year. As a result, fever is probably the most common reason for a child to be taken to the doctor. Feverish illness is also the second most common reason for a child being admitted to hospital. Despite advances in healthcare, infections remain the leading cause of death in children under the age of 5\xa0years.\n\nFever in young children can be a diagnostic challenge for healthcare professionals because it is often difficult to identify the cause. In most cases, the illness is due to a self-limiting viral infection. However, fever may also be the presenting feature of serious bacterial infections such as meningitis or pneumonia. A significant number of children have no obvious cause of fever despite careful assessment. These children with fever without apparent source are of particular concern to healthcare professionals because it is especially difficult to distinguish between simple viral illnesses and life-threatening bacterial infections in this group. As a result, there is a perceived need to improve the recognition, assessment and immediate treatment of feverish illnesses in children.\n\nThe introduction of new vaccination programmes in the UK may have significantly reduced the level of admissions to hospital resulting from diseases covered by this guideline. For example, early analysis of the pneumococcal vaccination programme in England showed that the incidence of pneumococcal-related disease had fallen 98% in children younger than 2\xa0years since vaccination was introduced. However, evidence suggests a 68% increase in the prevalence of disease caused by subtypes of bacteria not covered by vaccination programmes. Also, potentially serious cases of feverish illness are likely to be rare, so it is important that information is in place to help healthcare professionals distinguish these from mild cases.\n\nThis guideline is designed to assist healthcare professionals in the initial assessment and immediate treatment of young children with fever presenting to primary or secondary care. The guideline should be followed until a clinical diagnosis of the underlying condition has been made. Once a diagnosis has been made, the child should be treated according to national or local guidance for that condition.\n\nParents or carers of a child with fever may approach a range of different healthcare professionals as their first point of contact, for example, a GP, a pharmacist or an emergency care practitioner. The training and experience of the healthcare professionals involved in the child's care will vary and each should interpret the guidance according to the scope of their own practice.\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients."}
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https://www.nice.org.uk/guidance/ng143
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This guideline covers the assessment and early management of fever with no obvious cause in children aged under 5. It aims to improve clinical assessment and help healthcare professionals diagnose serious illness among young children who present with fever in primary and secondary care.
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f793e6939a6eebb772ce3728fbc259876948d44d
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nice
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Percutaneous implantation of pulmonary artery pressure sensors for monitoring treatment of chronic heart failure
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Percutaneous implantation of pulmonary artery pressure sensors for monitoring treatment of chronic heart failure
Evidence-based recommendations on percutaneous implantation of pulmonary artery pressure sensors for monitoring treatment of chronic heart failure in adults. This involves putting a small electronic pressure sensor into the pulmonary artery to measure blood pressure.
# Recommendations
Evidence on the safety and efficacy of percutaneous implantation of pulmonary artery pressure sensors for monitoring treatment of chronic heart failure is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.
Patient selection, continuing monitoring and management should be done by a multidisciplinary team. This should include healthcare professionals (both a doctor and a nurse) experienced in managing chronic heart failure, and interventional specialists experienced in right-heart catheterisation and inserting this device.# The condition, current treatments and procedure
# The condition
Heart failure happens when the pumping action of the heart is impaired by structural or functional abnormalities. It can lead to reduced blood flow to the body tissues and increased filling pressure in the heart. This causes congestion and oedema in the lungs (causing breathlessness) and the body (causing swelling in the legs). Symptoms include breathlessness, reduced exercise tolerance, oedema, fatigue and malaise.
# Current treatments
Diagnosis and management of chronic heart failure is described in NICE's guideline on chronic heart failure in adults. Treatments include lifestyle changes, medicines, device implantation (to help control heart rhythm) and heart surgery (such as a bypass operation or a heart transplant).
Chronic heart failure needs regular monitoring to identify signs of deterioration and modify treatment, with the aim of improving the patient's quality of life and avoiding hospital admissions. Monitoring includes assessment of functional capacity, fluid status, blood pressure, cardiac rhythm, renal function, and cognitive and nutritional status. Medication is reviewed and adjusted if necessary. Implantable devices to monitor haemodynamic changes may assist heart failure monitoring.
# The procedure
A delivery catheter is introduced into a large vein (usually the femoral vein) under local anaesthesia. Under radiological guidance, the catheter is used to pass a small pressure sensor through the heart and into a suitable branch of the pulmonary artery. The pressure sensor is deployed and the delivery catheter removed. Data on pulmonary artery pressure (PAP), such as pressure trend information and PAP waveforms, is transmitted from the sensor to an external monitor in the patient's home. The monitor securely transmits the data to a remote database that can be accessed by the heart failure team. The patient usually collects and transmits data daily, or more often if needed by the heart failure team.
This procedure makes data available that can be used to guide the ongoing monitoring and management of chronic heart failure. The aim is to reduce hospitalisations caused by heart failure.
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{'Recommendations': 'Evidence on the safety and efficacy of percutaneous implantation of pulmonary artery pressure sensors for monitoring treatment of chronic heart failure is adequate to support using this procedure provided that standard arrangements are in place for clinical governance, consent and audit. Find out what standard arrangements mean on the NICE interventional procedures guidance page.\n\nPatient selection, continuing monitoring and management should be done by a multidisciplinary team. This should include healthcare professionals (both a doctor and a nurse) experienced in managing chronic heart failure, and interventional specialists experienced in right-heart catheterisation and inserting this device.', 'The condition, current treatments and procedure': "# The condition\n\nHeart failure happens when the pumping action of the heart is impaired by structural or functional abnormalities. It can lead to reduced blood flow to the body tissues and increased filling pressure in the heart. This causes congestion and oedema in the lungs (causing breathlessness) and the body (causing swelling in the legs). Symptoms include breathlessness, reduced exercise tolerance, oedema, fatigue and malaise.\n\n# Current treatments\n\nDiagnosis and management of chronic heart failure is described in NICE's guideline on chronic heart failure in adults. Treatments include lifestyle changes, medicines, device implantation (to help control heart rhythm) and heart surgery (such as a bypass operation or a heart transplant).\n\nChronic heart failure needs regular monitoring to identify signs of deterioration and modify treatment, with the aim of improving the patient's quality of life and avoiding hospital admissions. Monitoring includes assessment of functional capacity, fluid status, blood pressure, cardiac rhythm, renal function, and cognitive and nutritional status. Medication is reviewed and adjusted if necessary. Implantable devices to monitor haemodynamic changes may assist heart failure monitoring.\n\n# The procedure\n\nA delivery catheter is introduced into a large vein (usually the femoral vein) under local anaesthesia. Under radiological guidance, the catheter is used to pass a small pressure sensor through the heart and into a suitable branch of the pulmonary artery. The pressure sensor is deployed and the delivery catheter removed. Data on pulmonary artery pressure (PAP), such as pressure trend information and PAP waveforms, is transmitted from the sensor to an external monitor in the patient's home. The monitor securely transmits the data to a remote database that can be accessed by the heart failure team. The patient usually collects and transmits data daily, or more often if needed by the heart failure team.\n\nThis procedure makes data available that can be used to guide the ongoing monitoring and management of chronic heart failure. The aim is to reduce hospitalisations caused by heart failure."}
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https://www.nice.org.uk/guidance/ipg711
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Evidence-based recommendations on percutaneous implantation of pulmonary artery pressure sensors for monitoring treatment of chronic heart failure in adults. This involves putting a small electronic pressure sensor into the pulmonary artery to measure blood pressure.
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53c4b1c08cf939370d0e932c0538746be0ef3756
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nice
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Ectopic pregnancy and miscarriage: diagnosis and initial management
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Ectopic pregnancy and miscarriage: diagnosis and initial management
This guideline covers diagnosing and managing ectopic pregnancy and miscarriage in women with complications, such as pain and bleeding, in early pregnancy (that is, up to 13 completed weeks of pregnancy). It aims to improve how early pregnancy loss is diagnosed, and the support women are given, to limit the psychological impact of their loss.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Support and information giving
Treat all women with early pregnancy complications with dignity and respect. Be aware that women will react to complications or the loss of a pregnancy in different ways. Provide all women with information and support in a sensitive manner, taking into account their individual circumstances and emotional response. For more guidance about providing information, see the NICE guideline on patient experience in adult NHS services.
Healthcare professionals providing care for women with early pregnancy complications in any setting should be aware that early pregnancy complications can cause significant distress for some women and their partners. Healthcare professionals providing care for these women should be given training in how to communicate sensitively and breaking bad news. Non-clinical staff such as receptionists working in settings where early pregnancy care is provided should also be given training on how to communicate sensitively with women who experience early pregnancy complications. For more guidance about support, see recommendation 1.9.4 on traumatic birth, stillbirth and miscarriage in the NICE guideline on antenatal and postnatal mental health.
Throughout a woman's care, provide the woman and (with her consent) her partner specific evidence-based information in a variety of formats. This should include (as appropriate):
when and how to seek help if existing symptoms worsen or new symptoms develop, including a 24‑hour contact telephone number
what to expect during the time she is waiting for an ultrasound scan
what to expect during the course of her care (including expectant management), such as the potential length and extent of pain and/or bleeding, and possible side effects; this information should be tailored to the care she receives
information about postoperative care (for women undergoing surgery)
what to expect during the recovery period – for example, when it is possible to resume sexual activity and/or try to conceive again, and what to do if she becomes pregnant again; this information should be tailored to the care she receives
information about the likely impact of her treatment on future fertility
where to access support and counselling services, including leaflets, web addresses and helpline numbers for support organisations.Ensure that sufficient time is available to discuss these issues with women during the course of her care and arrange an additional appointment if more time is needed.
After an early pregnancy loss, offer the woman the option of a follow‑up appointment with a healthcare professional of her choice.
# Early pregnancy assessment services
Regional services should be organised so that an early pregnancy assessment service is available 7 days a week for women with early pregnancy complications, where scanning can be carried out and decisions about management made.
An early pregnancy assessment service should:
be a dedicated service provided by healthcare professionals competent to diagnose and care for women with pain and/or bleeding in early pregnancy and
-ffer ultrasound and assessment of serum human chorionic gonadotrophin (hCG) levels and
be staffed by healthcare professionals with training in sensitive communication and breaking bad news.
Early pregnancy assessment services should accept self-referrals from women who have had recurrent miscarriage or a previous ectopic or molar pregnancy. Although additional care for women with recurrent miscarriage is not included in the scope of the guideline, the Guideline Development Group recognised that it is common clinical practice to allow these women to self-refer to an early pregnancy assessment service and wished this to remain the case. All other women with pain and/or bleeding should be assessed by a healthcare professional (such as a GP, accident and emergency doctor, midwife or nurse) before referral to an early pregnancy assessment service.
Ensure that a system is in place to enable women referred to their local early pregnancy assessment service to attend within 24 hours if the clinical situation warrants this. If the service is not available, and the clinical symptoms warrant further assessment, refer women to the nearest accessible facility that offers specialist clinical assessment and ultrasound scanning (such as a gynaecology ward or A&E service with access to specialist gynaecology support).
# Symptoms and signs of ectopic pregnancy and initial assessment
Refer women who are haemodynamically unstable, or in whom there is significant concern about the degree of pain or bleeding, directly to A&E.
Be aware that atypical presentation for ectopic pregnancy is common.
Be aware that ectopic pregnancy can present with a variety of symptoms. Even if a symptom is less common, it may still be significant. Symptoms of ectopic pregnancy include:
common symptoms:
abdominal or pelvic pain
amenorrhoea or missed period
vaginal bleeding with or without clots
-ther reported symptoms:
breast tenderness
gastrointestinal symptoms
dizziness, fainting or syncope
shoulder tip pain
urinary symptoms
passage of tissue
rectal pressure or pain on defecation.
Be aware that ectopic pregnancy can present with a variety of signs on examination by a healthcare professional. Signs of ectopic pregnancy include:
more common signs:
pelvic tenderness
adnexal tenderness
abdominal tenderness
-ther reported signs:
cervical motion tenderness
rebound tenderness or peritoneal signs
pallor
abdominal distension
enlarged uterus
tachycardia (more than 100 beats per minute) or hypotension (less than 100/60 mmHg)
shock or collapse
-rthostatic hypotension.
During clinical assessment of women of reproductive age, be aware that:
they may be pregnant, and think about offering a pregnancy test even when symptoms are non-specific and
the symptoms and signs of ectopic pregnancy can resemble the common symptoms and signs of other conditions – for example, gastrointestinal conditions or urinary tract infection.
All healthcare professionals involved in the care of women of reproductive age should have access to pregnancy tests.
Refer immediately to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) for further assessment of women with a positive pregnancy test and the following on examination:
pain and abdominal tenderness or
pelvic tenderness or
cervical motion tenderness.
Exclude the possibility of ectopic pregnancy, even in the absence of risk factors (such as previous ectopic pregnancy), because about a third of women with an ectopic pregnancy will have no known risk factors.
Refer to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) women with bleeding or other symptoms and signs of early pregnancy complications who have:
pain or
a pregnancy of 6 weeks' gestation or more or
a pregnancy of uncertain gestation.The urgency of this referral depends on the clinical situation.
Use expectant management for women with a pregnancy of less than 6 weeks' gestation who are bleeding but not in pain, and who have no risk factors, such as a previous ectopic pregnancy. Advise these women:
to return if bleeding continues or pain develops
to repeat a urine pregnancy test after 7 to 10 days and to return if it is positive
a negative pregnancy test means that the pregnancy has miscarried.
Refer women who return with worsening symptoms and signs that could suggest an ectopic pregnancy to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) for further assessment. The decision about whether she should be seen immediately or within 24 hours will depend on the clinical situation.
If a woman is referred to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available), explain the reasons for the referral and what she can expect when she arrives there.
# Diagnosis of viable intrauterine pregnancy and of tubal ectopic pregnancy
Offer women who attend an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) a transvaginal ultrasound scan to identify the location of the pregnancy and whether there is a fetal pole and heartbeat.
Consider a transabdominal ultrasound scan for women with an enlarged uterus or other pelvic pathology, such as fibroids or an ovarian cyst.
If a transvaginal ultrasound scan is unacceptable to the woman, offer a transabdominal ultrasound scan and explain the limitations of this method of scanning.
## Using ultrasound scans for diagnosis of viable intrauterine pregnancy
Inform women that the diagnosis of miscarriage using 1 ultrasound scan cannot be guaranteed to be 100% accurate and there is a small chance that the diagnosis may be incorrect, particularly at very early gestational ages.
When performing an ultrasound scan to determine the viability of an intrauterine pregnancy, first look to identify a fetal heartbeat. If there is no visible heartbeat but there is a visible fetal pole, measure the crown–rump length. Only measure the mean gestational sac diameter if the fetal pole is not visible.
If the crown–rump length is less than 7.0 mm with a transvaginal ultrasound scan and there is no visible heartbeat, perform a second scan a minimum of 7 days after the first before making a diagnosis. Further scans may be needed before a diagnosis can be made.
If the crown–rump length is 7.0 mm or more with a transvaginal ultrasound scan and there is no visible heartbeat:
seek a second opinion on the viability of the pregnancy and/or
perform a second scan a minimum of 7 days after the first before making a diagnosis.
If there is no visible heartbeat when the crown–rump length is measured using a transabdominal ultrasound scan:
record the size of the crown–rump length and
perform a second scan a minimum of 14 days after the first before making a diagnosis.
If the mean gestational sac diameter is less than 25.0 mm with a transvaginal ultrasound scan and there is no visible fetal pole, perform a second scan a minimum of 7 days after the first before making a diagnosis. Further scans may be needed before a diagnosis can be made.
If the mean gestational sac diameter is 25.0 mm or more using a transvaginal ultrasound scan and there is no visible fetal pole:
seek a second opinion on the viability of the pregnancy and/or
perform a second scan a minimum of 7 days after the first before making a diagnosis.
If there is no visible fetal pole and the mean gestational sac diameter is measured using a transabdominal ultrasound scan:
record the size of the mean gestational sac diameter and
perform a second scan a minimum of 14 days after the first before making a diagnosis.
Do not use gestational age from the last menstrual period alone to determine whether a fetal heartbeat should be visible.
Inform women that the date of their last menstrual period may not give an accurate representation of gestational age because of variability in the menstrual cycle.
Inform women what to expect while waiting for a repeat scan and that waiting for a repeat scan has no detrimental effects on the outcome of the pregnancy.
Give women a 24‑hour contact telephone number so that they can speak to someone with experience of caring for women with early pregnancy complications who understands their needs and can advise on appropriate care. See also recommendation 1.1.3 for details of further information that should be provided.
When diagnosing complete miscarriage on an ultrasound scan, in the absence of a previous scan confirming an intrauterine pregnancy, always be aware of the possibility of a pregnancy of unknown location. Advise these women to return for follow‑up (for example, hCG levels, ultrasound scans) until a definitive diagnosis is obtained. (See also recommendations on human chorionic gonadotrophin measurements in women with pregnancy of unknown location.)
## Using ultrasound scans for diagnosis of tubal ectopic pregnancy
When carrying out a transvaginal ultrasound scan in early pregnancy, look for these signs indicating there is a tubal ectopic pregnancy:
an adnexal mass, moving separate to the ovary (sometimes called the 'sliding sign'), comprising a gestational sac containing a yolk sac or
an adnexal mass, moving separately to the ovary, comprising a gestational sac and fetal pole (with or without fetal heartbeat).
When carrying out a transvaginal ultrasound scan in early pregnancy, look for these signs indicating a high probability of a tubal ectopic pregnancy:
an adnexal mass, moving separately to the ovary (sometimes called the 'sliding sign'), with an empty gestational sac (sometimes described as a 'tubal ring' or 'bagel sign') or
a complex, inhomogeneous adnexal mass, moving separate to the ovary.If these features are present, take into account other intrauterine and adnexal features on the scan, the woman's clinical presentation and serum hCG levels before making a diagnosis.
When carrying out a transvaginal ultrasound scan in early pregnancy, look for these signs indicating a possible ectopic pregnancy:
an empty uterus or
a collection of fluid within the uterine cavity (sometimes described as a pseudo-sac; this collection of fluid must be differentiated from an early intrauterine sac, which is identified by the presence of an eccentrically located hypoechoic structure with a double decidual sign in the endometrium).If these features are present, take into account other intrauterine and adnexal features on the scan, the woman's clinical presentation and serum hCG levels before making a diagnosis. (See also recommendations on human chorionic gonadotrophin measurements in women with pregnancy of unknown location.)
When carrying out a transabdominal or transvaginal ultrasound scan in early pregnancy, look for a moderate to large amount of free fluid in the peritoneal cavity or Pouch of Douglas, which might represent haemoperitoneum. If this is present, take into account other intrauterine and adnexal features on the scan, the woman's clinical presentation and hCG levels before making a diagnosis.
When carrying out a transabdominal or transvaginal ultrasound scan during early pregnancy, scan the uterus and adnexae to see if there is a heterotopic pregnancy.
All ultrasound scans should be performed or directly supervised and reviewed by appropriately qualified healthcare professionals with training in, and experience of, diagnosing ectopic pregnancies.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on using ultrasound for diagnosis of a tubal ectopic pregnancy .
Full details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of ultrasound features for tubal ectopic pregnancy.
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## Human chorionic gonadotrophin measurements in women with pregnancy of unknown location
Be aware that women with a pregnancy of unknown location could have an ectopic pregnancy until the location is determined.
Do not use serum hCG measurements to determine the location of the pregnancy.
In a woman with a pregnancy of unknown location, place more importance on clinical symptoms than on serum hCG results, and review the woman's condition if any of her symptoms change, regardless of previous results and assessments.
Use serum hCG measurements only for assessing trophoblastic proliferation to help to determine subsequent management.
Take 2 serum hCG measurements as near as possible to 48 hours apart (but no earlier) to determine subsequent management of a pregnancy of unknown location. Take further measurements only after review by a senior healthcare professional.
Regardless of serum hCG levels, give women with a pregnancy of unknown location written information about what to do if they experience any new or worsening symptoms, including details about how to access emergency care 24 hours a day. Advise women to return if there are new symptoms or if existing symptoms worsen.
For a woman with an increase in serum hCG levels greater than 63% after 48 hours:
Inform her that she is likely to have a developing intrauterine pregnancy (although the possibility of an ectopic pregnancy cannot be excluded).
Offer her a transvaginal ultrasound scan to determine the location of the pregnancy between 7 and 14 days later. Consider an earlier scan for women with a serum hCG level greater than or equal to 1,500 IU/litre.
If a viable intrauterine pregnancy is confirmed, offer her routine antenatal care. See the NICE guideline on antenatal care.
If a viable intrauterine pregnancy is not confirmed, refer her for immediate clinical review by a senior gynaecologist.
For a woman with a decrease in serum hCG levels greater than 50% after 48 hours:
inform her that the pregnancy is unlikely to continue but that this is not confirmed and
provide her with oral and written information about where she can access support and counselling services; see also recommendation 1.1.3 for details of further information that should be provided
ask her to take a urine pregnancy test 14 days after the second serum hCG test, and explain that:
if the test is negative, no further action is necessary
if the test is positive, she should return to the early pregnancy assessment service for clinical review within 24 hours.
For a woman with a decrease in serum hCG levels less than 50%, or an increase less than 63%, refer her for clinical review in the early pregnancy assessment service within 24 hours.
For women with a pregnancy of unknown location, when using serial serum hCG measurements, do not use serum progesterone measurements as an adjunct to diagnose either viable intrauterine pregnancy or ectopic pregnancy.
# Management of miscarriage
## Threatened miscarriage
Advise a woman with a confirmed intrauterine pregnancy with a fetal heartbeat who presents with vaginal bleeding, but has no history of previous miscarriage, that:
if her bleeding gets worse, or persists beyond 14 days, she should return for further assessment
if the bleeding stops, she should start or continue routine antenatal care.
Offer vaginal micronised progesterone 400 mg twice daily to women with an intrauterine pregnancy confirmed by a scan, if they have vaginal bleeding and have previously had a miscarriage.
If a fetal heartbeat is confirmed, continue progesterone until 16 completed weeks of pregnancy. In November 2021, this was an off-label use of vaginal micronised progesterone. See NICE's information on prescribing medicines.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on progestogens for preventing miscarriage .
Full details of the evidence and the committee's discussion are in evidence review C: progestogens for preventing miscarriage.
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## Expectant management
Use expectant management for 7 to 14 days as the first-line management strategy for women with a confirmed diagnosis of miscarriage. Explore management options other than expectant management if:
the woman is at increased risk of haemorrhage (for example, she is in the late first trimester) or
she has previous adverse and/or traumatic experience associated with pregnancy (for example, stillbirth, miscarriage or antepartum haemorrhage) or
she is at increased risk from the effects of haemorrhage (for example, if she has coagulopathies or is unable to have a blood transfusion) or
there is evidence of infection.
Offer medical management to women with a confirmed diagnosis of miscarriage if expectant management is not acceptable to the woman.
Explain what expectant management involves and that most women will need no further treatment. Also provide women with oral and written information about further treatment options.
Give all women undergoing expectant management of miscarriage oral and written information about what to expect throughout the process, advice on pain relief and where and when to get help in an emergency. See also recommendation 1.1.3 for details of further information that should be provided.
If the resolution of bleeding and pain indicate that the miscarriage has completed during 7 to 14 days of expectant management, advise the woman to take a urine pregnancy test after 3 weeks, and to return for individualised care if it is positive.
Offer a repeat scan if after the period of expectant management, the bleeding and pain:
have not started (suggesting that the process of miscarriage has not begun) or
are persisting and/or increasing (suggesting incomplete miscarriage).Discuss all treatment options (continued expectant management, medical management and surgical management) with the woman to allow her to make an informed choice.
Review the condition of a woman who opts for continued expectant management of miscarriage at a minimum of 14 days after the first follow‑up appointment.
## Medical management
In April 2019, the use of misoprostol in recommendations 1.5.12, 1.5.3 and 1.5.15 was off label. See NICE's information on prescribing medicines.
Do not offer mifepristone as a treatment for missed or incomplete miscarriage.
Offer vaginal misoprostol for the medical treatment of missed or incomplete miscarriage. Oral administration is an acceptable alternative if this is the woman's preference.
For women with a missed miscarriage, use a single dose of 800 micrograms of misoprostol.
Advise the woman that if bleeding has not started 24 hours after treatment, she should contact her healthcare professional to determine ongoing individualised care.
For women with an incomplete miscarriage, use a single dose of 600 micrograms of misoprostol. (800 micrograms can be used as an alternative to allow alignment of treatment protocols for both missed and incomplete miscarriage.)
Offer all women receiving medical management of miscarriage pain relief and anti-emetics as needed.
Inform women undergoing medical management of miscarriage about what to expect throughout the process, including the length and extent of bleeding and the potential side effects of treatment including pain, diarrhoea and vomiting.
Provide women with a urine pregnancy test to carry out at home 3 weeks after medical management of miscarriage unless they experience worsening symptoms, in which case advise them to return to the healthcare professional responsible for providing their medical management.
Advise women with a positive urine pregnancy test after 3 weeks to return for a review by a healthcare professional to ensure that there is no molar or ectopic pregnancy.
## Surgical management
Where clinically appropriate, offer women undergoing a miscarriage a choice of:
manual vacuum aspiration under local anaesthetic in an outpatient or clinic setting or
surgical management in a theatre under general anaesthetic.
Provide oral and written information to all women undergoing surgical management of miscarriage about the treatment options available and what to expect during and after the procedure. See also recommendation 1.1.3 for details of further information that should be provided.
# Management of tubal ectopic pregnancy
Give all women with an ectopic pregnancy oral and written information about:
the treatment options and what to expect during and after treatment
how they can contact a healthcare professional for advice after treatment if needed, and who this will be
where and when to get help in an emergency. See also recommendation 1.1.3 for details of further information that should be provided.
Inform women who have had an ectopic pregnancy that they can self-refer to an early pregnancy assessment service in future pregnancies if they have any early concerns.
## Expectant management
Offer expectant management as an option to women who:
are clinically stable and pain free and
have a tubal ectopic pregnancy measuring less than 35 mm with no visible heartbeat on transvaginal ultrasound scan and
have serum hCG levels of 1,000 IU/L or less and
are able to return for follow-up.
Consider expectant management as an option for women who:
are clinically stable and pain free and
have a tubal ectopic pregnancy measuring less than 35 mm with no visible heartbeat on transvaginal ultrasound scan and
have serum hCG levels above 1,000 IU/L and below 1,500 IU/L and
are able to return for follow-up.
For women with a tubal ectopic pregnancy being managed expectantly, repeat hCG levels on days 2, 4 and 7 after the original test and:
if hCG levels drop by 15% or more from the previous value on days 2, 4 and 7, then repeat weekly until a negative result (less than 20 IU/L) is obtained or
if hCG levels do not fall by 15%, stay the same or rise from the previous value, review the woman's clinical condition and seek senior advice to help decide further management.
Advise women that, based on limited evidence, there seems to be no difference following expectant or medical management in:
the rate of ectopic pregnancies ending naturally
the risk of tubal rupture
the need for additional treatment, but that they might need to be admitted urgently if their condition deteriorates
health status, depression or anxiety scores.
Advise women that the time taken for ectopic pregnancies to resolve and future fertility outcomes are likely to be the same with either expectant or medical management.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on expectant management of tubal ectopic pregnancy .
Full details of the evidence and the committee's discussion are in evidence review B: expectant versus medical management of ectopic pregnancy.
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## Medical and surgical management
In April 2019, the use of methotrexate in recommendations 1.6.8 to 1.6.11 was off label. See NICE's information on prescribing medicines.
Offer systemic methotrexate to women who:
have no significant pain and
have an unruptured tubal ectopic pregnancy with an adnexal mass smaller than 35 mm with no visible heartbeat and
have a serum hCG level less than 1,500 IU/litre and
do not have an intrauterine pregnancy (as confirmed on an ultrasound scan) and
are able to return for follow-up.Methotrexate should only be offered on a first visit when there is a definitive diagnosis of an ectopic pregnancy, and a viable intrauterine pregnancy has been excluded. Offer surgery where treatment with methotrexate is not acceptable to the woman.
Offer surgery as a first-line treatment to women who are unable to return for follow-up after methotrexate treatment or who have any of the following:
an ectopic pregnancy and significant pain
an ectopic pregnancy with an adnexal mass of 35 mm or larger
an ectopic pregnancy with a fetal heartbeat visible on an ultrasound scan
an ectopic pregnancy and a serum hCG level of 5,000 IU/litre or more.
Offer the choice of either methotrexate or surgical management to women with an ectopic pregnancy who have a serum hCG level of at least 1,500 IU/litre and less than 5,000 IU/litre, who are able to return for follow‑up and who meet all of the following criteria:
no significant pain
an unruptured ectopic pregnancy with an adnexal mass smaller than 35 mm with no visible heartbeat
no intrauterine pregnancy (as confirmed on an ultrasound scan). Advise women who choose methotrexate that their chance of needing further intervention is increased and they may need to be urgently admitted if their condition deteriorates.
For women with ectopic pregnancy who have had methotrexate, take 2 serum hCG measurements in the first week (days 4 and 7) after treatment and then 1 serum hCG measurement per week until a negative result is obtained. If hCG levels plateau or rise, reassess the woman's condition for further treatment.
## Performing laparoscopy
When surgical treatment is indicated for women with an ectopic pregnancy, it should be performed laparoscopically whenever possible, taking into account the condition of the woman and the complexity of the surgical procedure.
Surgeons providing care to women with ectopic pregnancy should be competent to perform laparoscopic surgery.
Commissioners and managers should ensure that equipment for laparoscopic surgery is available.
## Salpingectomy and salpingotomy
Offer a salpingectomy to women undergoing surgery for an ectopic pregnancy unless they have other risk factors for infertility.
Consider salpingotomy as an alternative to salpingectomy for women with risk factors for infertility such as contralateral tube damage.
Inform women having a salpingotomy that up to 1 in 5 women may need further treatment. This treatment may include methotrexate and/or a salpingectomy.
For women who have had a salpingotomy, take 1 serum hCG measurement at 7 days after surgery, then 1 serum hCG measurement per week until a negative result is obtained.
Advise women who have had a salpingectomy that they should take a urine pregnancy test after 3 weeks. Advise women to return for further assessment if the test is positive.
# Anti-D immunoglobulin prophylaxis
Offer anti-D immunoglobulin prophylaxis at a dose of 250 IU (50 micrograms) to all rhesus-negative women who have a surgical procedure to manage an ectopic pregnancy or a miscarriage.
Do not offer anti‑D immunoglobulin prophylaxis to women who:
receive solely medical management for an ectopic pregnancy or miscarriage or
have a threatened miscarriage or
have a complete miscarriage or
have a pregnancy of unknown location.
Do not use a Kleihauer test for quantifying feto-maternal haemorrhage.
# Terms used in this guideline
## Early pregnancy
Pregnancy in the first trimester (that is, up to 13 completed weeks of pregnancy).
## Expectant management
A management approach, also called 'wait and watch', when no medical or surgical treatment is given. The aim is to see if the condition will resolve naturally.
## Pregnancy of unknown location
When a woman has a positive pregnancy test, but no intrauterine or extrauterine pregnancy can be seen with a transvaginal ultrasound scan.# Recommendations for research
The guideline committee has made the following recommendations for research based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline.
# Early pregnancy assessment units
A national evaluation of early pregnancy assessment unit service provision should be carried out to identify factors affecting outcomes. Factors should include whether care is provided in a dedicated unit, staffing configuration and opening hours of dedicated services. Outcomes should include both process (service) outcomes and pregnancy-related outcomes. Data collected should be used to analyse the cost effectiveness of early pregnancy assessment units compared with other models of care.
## Why this is important
The first report of an early pregnancy assessment unit in England was published over 20 years ago, and prompted the rapid development of centres for the management of problems in early pregnancy. Today there are an estimated 150 early pregnancy assessment units in England and Wales (Association of Early Pregnancy Units, 2012). However, there is considerable variation between centres in access to services and levels of care provided. In addition, there has been very little good quality research on the effectiveness of early pregnancy assessment units in improving physical and emotional health compared with services provided outside of a dedicated unit.
A national audit of early pregnancy assessment services would help to make up for this lack of information. Such an audit should be along the lines of the National Caesarean Section Sentinel Audit, a cross-sectional national survey of service configuration and outcomes. Data recorded would include service location, opening hours and the healthcare professionals involved. Outcomes would include time of attendance, length of stay, admission rates, time to treatment and women's experience. Obtaining some of this information would involve early pregnancy services carrying out more formal follow‑up of women than they might do currently, for the duration of the audit. The evaluation should be structured to allow for comparisons between different models of care.
Comparative outcome data collected would be used to conduct an analysis of the cost effectiveness of early pregnancy assessment units compared with other models of care.
# Ultrasound for determining a viable intrauterine pregnancy
How does the timing and frequency of ultrasound examination affect diagnosis and outcomes of early pregnancy complications, including women's experience and cost effectiveness?
## Why this is important
The rationale behind the frequency of ultrasound to improve diagnosis and outcomes of early pregnancy complications addresses the problems associated with pregnancy of unknown location and intrauterine pregnancy of uncertain viability. The evidence base for the timing and frequency of scanning in early pregnancy is limited, and the number of scans is organised by individual units according to capacity and demand. Some healthcare professionals choose to wait 5 days between scans whereas others will wait 10 to 14 days. These decisions are driven by resource availability as well as clinical considerations, but in particular, the effect of different strategies on cost and women's experience is not clear. The literature suggests that there is no clear consensus, but there is general agreement that by 14 days a diagnosis will be clear. To establish the most appropriate time for scans, the efficacy of scans taken after 14 days could be compared with scans taken after 7 days for diagnosis of ectopic pregnancy or viability.
# Effectiveness of progestogens in women with recurrent miscarriage
What is the clinical and cost effectiveness of progesterone for improving outcomes in women with unexplained recurrent miscarriage?
## Why this is important
Women with previous pregnancy losses have an increased risk of miscarriage in subsequent pregnancies. Progesterone is essential for maintaining a healthy pregnancy, and there is evidence that it is safe for both women and fetuses.
A recent randomised controlled trial assessed the effectiveness of micronised vaginal progesterone supplementation in women with 3 or more first-trimester losses and did not show a benefit with progesterone therapy use during the first trimester, concluding that there is not enough evidence to support its use in women with unexplained recurrent miscarriage. However, this trial was designed to look for a 10% difference in live birth outcomes in those who received progesterone versus those who did not receive it. A larger randomised controlled trial is needed to determine if there is a smaller difference (for example 2.5% to 5%) which would still lead to a meaningful increase in live births and reduce the trauma of a further miscarriage for a number of women.
# Effectiveness of different progestogens in women at risk of miscarriage
What is the clinical and cost effectiveness of vaginal micronised progesterone versus other progesterone preparations in improving outcomes in women at risk of miscarriage?
## Why this is important
Evidence from a recent randomised controlled trial showed a small but important benefit for the outcome of live birth when vaginal micronised progesterone was given to women with early pregnancy bleeding and a history of one or more previous miscarriages. However, there was not enough evidence available to assess whether other formulations of progesterone would lead to other beneficial outcomes in this group of women. Research is needed to identify whether there is a difference in the effectiveness of micronised versus non-micronised progesterone therapy in women with early pregnancy bleeding and a history of one or more previous miscarriages.
# Management of miscarriage
In women with confirmed miscarriage, does the type of management strategy (expectant, medical and surgical) impact on women's experience, including psychological and emotional outcomes?
## Why this is important
The management of miscarriage in the UK has changed in many ways over the past 2 decades, particularly in the shift from inpatient to outpatient or day case care and the introduction of medical and expectant management as alternatives to surgery.
Despite these changes there is a lack of research into the effects of these different approaches from the woman's perspective, in particular their psychological and emotional impact. Miscarriage is distressing for most women, and the type of management itself might affect women's need for counselling, with a resulting cost to the NHS. Because of this it is an important area for research.
The deficiency in the literature could be addressed by a comparative study of women having the different management strategies (expectant, medical or surgical) and in a variety of clinical settings (for example, early pregnancy assessment unit, gynaecological ward or gynaecological emergency unit). The data collected could be both quantitative (using validated psychological health questionnaires) and qualitative (focusing particularly on women's experience of the particular type and setting of care).
# Comparison between expectant, medical or surgical management of ectopic pregnancy
In women with ectopic pregnancy, does the type of intervention impact on women's experience, including psychological and emotional outcomes?
## Why this is important
Currently there is no evidence exploring the psychological impact of the different treatments for ectopic pregnancy. However, the emotional impact of the condition can be significant, in some circumstances leading to post-traumatic stress disorder. A qualitative comparative study should be carried out to assess how this impact can be reduced. This would help to maximise women's emotional recovery in the short and long term, enable women and clinicians to decide the optimum treatment method and identify what support is needed for women during and after the process. It could also reduce the cost to the NHS of providing long-term counselling for affected women.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Using ultrasound for diagnosis of a tubal ectopic pregnancy
Recommendations 1.4.17 to 1.4.21
## Why the committee made the recommendations
There was good evidence that, when seen on ultrasound, the presence of an adnexal mass with features of an early pregnancy (a gestational sac containing a yolk sac or fetal pole, with or without a heartbeat) was a reliable indicator for ectopic pregnancy.
Other features such as a complex inhomogeneous adnexal mass, adnexal mass with an empty gestational sac, empty uterus, a collection of fluid in the uterine cavity or free peritoneal fluid might indicate a suspicion of an ectopic pregnancy, but the evidence showed they are not reliable enough features on their own to diagnose an ectopic pregnancy. The committee used their knowledge and experience to recommend that other scan features, clinical presentation and serum human chorionic gonadotrophin (hCG) levels should therefore be used as well to confirm or rule out the diagnosis of ectopic pregnancy.
## How the recommendations might affect practice
The recommendations will not change the amount of ultrasound scanning that is carried out but will standardise practice across the NHS. By defining the features that should be used to indicate the presence of an ectopic pregnancy, or a suspicion of an ectopic pregnancy (which can then be investigated further), the diagnosis of ectopic pregnancy should be improved and so risks to women will be reduced.
Return to recommendations
# Progestogens for preventing miscarriage
Recommendations 1.5.2 and 1.5.3
## Why the committee made the recommendations
There was good evidence that 400 mg twice daily of micronised vaginal progesterone increases the number of live births in women with early pregnancy bleeding and a previous miscarriage. There was no evidence of benefit for any other preparations or doses of progesterone, so the committee made a recommendation for research.
There was evidence of no benefit in women with early pregnancy bleeding but no previous miscarriage, nor in women with previous miscarriage but no early pregnancy bleeding in the current pregnancy. The committee made a recommendation for research to further assess the use of progesterone in women with recurrent miscarriage. There was no evidence of harm to the mother or baby from the use of progesterone, although the evidence is insufficient to rule out the possibility of rare events.
To reduce the risk of women with a pregnancy of unknown location or an ectopic pregnancy being given progesterone, the committee agreed that, as in the clinical studies, progesterone should only be given to women with intrauterine pregnancy confirmed with a scan. To avoid delay in starting treatment the committee agreed that progesterone could be started before a fetal heartbeat is detected. The evidence on which the recommendations were based had continued the progesterone treatment until 16 weeks of pregnancy so the committee used this duration of treatment in their recommendations.
The committee discussed that as a scan was needed to confirm the intrauterine pregnancy it would be appropriate for the initial prescription for progesterone to be provided by the Early Pregnancy Unit, with prescribing continued to 16 weeks (if a fetal heartbeat was detected) by the woman's GP. However, the committee were aware that shared care prescribing arrangements are usually agreed locally and so did not include this detail in their recommendations.
The committee confirmed that the recommendations for the use of progesterone are only for women with early pregnancy bleeding and a history of miscarriage. The recommendations are not applicable in other circumstances, such as after the use of mifepristone.
## How the recommendations might affect practice
The recommendations will increase the use of progestogens to prevent miscarriage but this is cost effective. The recommendations will standardise the preparation of progesterone used to treat threatened miscarriage.
Return to recommendations
# Expectant management of tubal ectopic pregnancy
Recommendations 1.6.3 to 1.6.7
## Why the committee made the recommendations
The evidence showed no significant differences in the number of ectopic pregnancies ending naturally, the need for additional treatment, the incidence of tubal rupture or the effect on health-related quality of life between expectant management and medical management, so the committee recommended that expectant management could be offered to clinically stable women with small ectopic pregnancies and low hCG levels, and should be considered for clinically stable women with small ectopic pregnancies and slightly higher hCG levels, as an alternative to medical management.
There was no evidence for the time taken for ectopic pregnancies to end naturally or the effects on future fertility but the committee agreed, based on their expertise and experience, that these outcomes were likely to be the same with expectant management compared with medical management.
## How the recommendations might affect practice
These recommendations will standardise the management of ectopic pregnancy and make expectant management available for women when it is clinically appropriate. More women might have expectant management of ectopic pregnancy as a result. This could result in cost savings through a reduction in drug use and treatment of associated side effects. Local protocols will be needed for assessment, monitoring and follow-up of women choosing expectant management.
Return to recommendations# Context
Ectopic pregnancy and miscarriage have an adverse effect on the quality of life of many women. Approximately 20% of pregnancies miscarry, and miscarriages can cause considerable distress. Early pregnancy loss accounts for over 50,000 admissions in the UK annually. The rate of ectopic pregnancy is 11 per 1,000 pregnancies, with a maternal mortality of 0.2 per 1,000 estimated ectopic pregnancies. About two-thirds of these deaths are associated with substandard care.
Women who do not access medical help readily (such as women who are recent migrants, asylum seekers, refugees, or women who have difficulty reading or speaking English) are particularly vulnerable. Improvement in the diagnosis and management of early pregnancy loss is therefore of vital importance, in order to reduce the incidence of the associated psychological morbidity and avoid the unnecessary deaths of women with ectopic pregnancies.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Support and information giving\n\nTreat all women with early pregnancy complications with dignity and respect. Be aware that women will react to complications or the loss of a pregnancy in different ways. Provide all women with information and support in a sensitive manner, taking into account their individual circumstances and emotional response. For more guidance about providing information, see the NICE guideline on patient experience in adult NHS services. \n\nHealthcare professionals providing care for women with early pregnancy complications in any setting should be aware that early pregnancy complications can cause significant distress for some women and their partners. Healthcare professionals providing care for these women should be given training in how to communicate sensitively and breaking bad news. Non-clinical staff such as receptionists working in settings where early pregnancy care is provided should also be given training on how to communicate sensitively with women who experience early pregnancy complications. For more guidance about support, see recommendation 1.9.4 on traumatic birth, stillbirth and miscarriage in the NICE guideline on antenatal and postnatal mental health. [2012, amended 2019]\n\nThroughout a woman's care, provide the woman and (with her consent) her partner specific evidence-based information in a variety of formats. This should include (as appropriate):\n\nwhen and how to seek help if existing symptoms worsen or new symptoms develop, including a 24‑hour contact telephone number\n\nwhat to expect during the time she is waiting for an ultrasound scan\n\nwhat to expect during the course of her care (including expectant management), such as the potential length and extent of pain and/or bleeding, and possible side effects; this information should be tailored to the care she receives\n\ninformation about postoperative care (for women undergoing surgery)\n\nwhat to expect during the recovery period – for example, when it is possible to resume sexual activity and/or try to conceive again, and what to do if she becomes pregnant again; this information should be tailored to the care she receives\n\ninformation about the likely impact of her treatment on future fertility\n\nwhere to access support and counselling services, including leaflets, web addresses and helpline numbers for support organisations.Ensure that sufficient time is available to discuss these issues with women during the course of her care and arrange an additional appointment if more time is needed. \n\nAfter an early pregnancy loss, offer the woman the option of a follow‑up appointment with a healthcare professional of her choice. \n\n# Early pregnancy assessment services\n\nRegional services should be organised so that an early pregnancy assessment service is available 7\xa0days a week for women with early pregnancy complications, where scanning can be carried out and decisions about management made. \n\nAn early pregnancy assessment service should:\n\nbe a dedicated service provided by healthcare professionals competent to diagnose and care for women with pain and/or bleeding in early pregnancy and\n\noffer ultrasound and assessment of serum human chorionic gonadotrophin (hCG) levels and\n\nbe staffed by healthcare professionals with training in sensitive communication and breaking bad news. \n\nEarly pregnancy assessment services should accept self-referrals from women who have had recurrent miscarriage or a previous ectopic or molar pregnancy. Although additional care for women with recurrent miscarriage is not included in the scope of the guideline, the Guideline Development Group recognised that it is common clinical practice to allow these women to self-refer to an early pregnancy assessment service and wished this to remain the case. All other women with pain and/or bleeding should be assessed by a healthcare professional (such as a GP, accident and emergency [A&E] doctor, midwife or nurse) before referral to an early pregnancy assessment service. \n\nEnsure that a system is in place to enable women referred to their local early pregnancy assessment service to attend within 24\xa0hours if the clinical situation warrants this. If the service is not available, and the clinical symptoms warrant further assessment, refer women to the nearest accessible facility that offers specialist clinical assessment and ultrasound scanning (such as a gynaecology ward or A&E service with access to specialist gynaecology support). \n\n# Symptoms and signs of ectopic pregnancy and initial assessment\n\nRefer women who are haemodynamically unstable, or in whom there is significant concern about the degree of pain or bleeding, directly to A&E. \n\nBe aware that atypical presentation for ectopic pregnancy is common. \n\nBe aware that ectopic pregnancy can present with a variety of symptoms. Even if a symptom is less common, it may still be significant. Symptoms of ectopic pregnancy include:\n\ncommon symptoms:\n\n\n\nabdominal or pelvic pain\n\namenorrhoea or missed period\n\nvaginal bleeding with or without clots\n\n\n\nother reported symptoms:\n\n\n\nbreast tenderness\n\ngastrointestinal symptoms\n\ndizziness, fainting or syncope\n\nshoulder tip pain\n\nurinary symptoms\n\npassage of tissue\n\nrectal pressure or pain on defecation. \n\n\n\nBe aware that ectopic pregnancy can present with a variety of signs on examination by a healthcare professional. Signs of ectopic pregnancy include:\n\nmore common signs:\n\n\n\npelvic tenderness\n\nadnexal tenderness\n\nabdominal tenderness\n\n\n\nother reported signs:\n\n\n\ncervical motion tenderness\n\nrebound tenderness or peritoneal signs\n\npallor\n\nabdominal distension\n\nenlarged uterus\n\ntachycardia (more than 100\xa0beats per minute) or hypotension (less than 100/60\xa0mmHg)\n\nshock or collapse\n\northostatic hypotension. \n\n\n\nDuring clinical assessment of women of reproductive age, be aware that:\n\nthey may be pregnant, and think about offering a pregnancy test even when symptoms are non-specific and\n\nthe symptoms and signs of ectopic pregnancy can resemble the common symptoms and signs of other conditions – for example, gastrointestinal conditions or urinary tract infection. \n\nAll healthcare professionals involved in the care of women of reproductive age should have access to pregnancy tests. \n\nRefer immediately to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) for further assessment of women with a positive pregnancy test and the following on examination:\n\npain and abdominal tenderness or\n\npelvic tenderness or\n\ncervical motion tenderness. \n\nExclude the possibility of ectopic pregnancy, even in the absence of risk factors (such as previous ectopic pregnancy), because about a third of women with an ectopic pregnancy will have no known risk factors. \n\nRefer to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) women with bleeding or other symptoms and signs of early pregnancy complications who have:\n\npain or\n\na pregnancy of 6\xa0weeks' gestation or more or\n\na pregnancy of uncertain gestation.The urgency of this referral depends on the clinical situation. \n\nUse expectant management for women with a pregnancy of less than 6\xa0weeks' gestation who are bleeding but not in pain, and who have no risk factors, such as a previous ectopic pregnancy. Advise these women:\n\nto return if bleeding continues or pain develops\n\nto repeat a urine pregnancy test after 7 to 10\xa0days and to return if it is positive\n\na negative pregnancy test means that the pregnancy has miscarried. [2012, amended 2019]\n\nRefer women who return with worsening symptoms and signs that could suggest an ectopic pregnancy to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) for further assessment. The decision about whether she should be seen immediately or within 24\xa0hours will depend on the clinical situation. \n\nIf a woman is referred to an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available), explain the reasons for the referral and what she can expect when she arrives there. \n\n# Diagnosis of viable intrauterine pregnancy and of tubal ectopic pregnancy\n\nOffer women who attend an early pregnancy assessment service (or out-of-hours gynaecology service if the early pregnancy assessment service is not available) a transvaginal ultrasound scan to identify the location of the pregnancy and whether there is a fetal pole and heartbeat. \n\nConsider a transabdominal ultrasound scan for women with an enlarged uterus or other pelvic pathology, such as fibroids or an ovarian cyst. \n\nIf a transvaginal ultrasound scan is unacceptable to the woman, offer a transabdominal ultrasound scan and explain the limitations of this method of scanning. \n\n## Using ultrasound scans for diagnosis of viable intrauterine pregnancy\n\nInform women that the diagnosis of miscarriage using 1\xa0ultrasound scan cannot be guaranteed to be 100% accurate and there is a small chance that the diagnosis may be incorrect, particularly at very early gestational ages. \n\nWhen performing an ultrasound scan to determine the viability of an intrauterine pregnancy, first look to identify a fetal heartbeat. If there is no visible heartbeat but there is a visible fetal pole, measure the crown–rump length. Only measure the mean gestational sac diameter if the fetal pole is not visible. \n\nIf the crown–rump length is less than 7.0\xa0mm with a transvaginal ultrasound scan and there is no visible heartbeat, perform a second scan a minimum of 7\xa0days after the first before making a diagnosis. Further scans may be needed before a diagnosis can be made. \n\nIf the crown–rump length is 7.0\xa0mm or more with a transvaginal ultrasound scan and there is no visible heartbeat:\n\nseek a second opinion on the viability of the pregnancy and/or\n\nperform a second scan a minimum of 7\xa0days after the first before making a diagnosis. \n\nIf there is no visible heartbeat when the crown–rump length is measured using a transabdominal ultrasound scan:\n\nrecord the size of the crown–rump length and\n\nperform a second scan a minimum of 14\xa0days after the first before making a diagnosis. \n\nIf the mean gestational sac diameter is less than 25.0\xa0mm with a transvaginal ultrasound scan and there is no visible fetal pole, perform a second scan a minimum of 7\xa0days after the first before making a diagnosis. Further scans may be needed before a diagnosis can be made. \n\nIf the mean gestational sac diameter is 25.0\xa0mm or more using a transvaginal ultrasound scan and there is no visible fetal pole:\n\nseek a second opinion on the viability of the pregnancy and/or\n\nperform a second scan a minimum of 7\xa0days after the first before making a diagnosis. \n\nIf there is no visible fetal pole and the mean gestational sac diameter is measured using a transabdominal ultrasound scan:\n\nrecord the size of the mean gestational sac diameter and\n\nperform a second scan a minimum of 14\xa0days after the first before making a diagnosis. \n\nDo not use gestational age from the last menstrual period alone to determine whether a fetal heartbeat should be visible. \n\nInform women that the date of their last menstrual period may not give an accurate representation of gestational age because of variability in the menstrual cycle. \n\nInform women what to expect while waiting for a repeat scan and that waiting for a repeat scan has no detrimental effects on the outcome of the pregnancy. \n\nGive women a 24‑hour contact telephone number so that they can speak to someone with experience of caring for women with early pregnancy complications who understands their needs and can advise on appropriate care. See also recommendation 1.1.3 for details of further information that should be provided. \n\nWhen diagnosing complete miscarriage on an ultrasound scan, in the absence of a previous scan confirming an intrauterine pregnancy, always be aware of the possibility of a pregnancy of unknown location. Advise these women to return for follow‑up (for example, hCG levels, ultrasound scans) until a definitive diagnosis is obtained. (See also recommendations on human chorionic gonadotrophin measurements in women with pregnancy of unknown location.) [2012, amended 2019]\n\n## Using ultrasound scans for diagnosis of tubal ectopic pregnancy\n\nWhen carrying out a transvaginal ultrasound scan in early pregnancy, look for these signs indicating there is a tubal ectopic pregnancy:\n\nan adnexal mass, moving separate to the ovary (sometimes called the 'sliding sign'), comprising a gestational sac containing a yolk sac or\n\nan adnexal mass, moving separately to the ovary, comprising a gestational sac and fetal pole (with or without fetal heartbeat). \n\nWhen carrying out a transvaginal ultrasound scan in early pregnancy, look for these signs indicating a high probability of a tubal ectopic pregnancy:\n\nan adnexal mass, moving separately to the ovary (sometimes called the 'sliding sign'), with an empty gestational sac (sometimes described as a 'tubal ring' or 'bagel sign') or\n\na complex, inhomogeneous adnexal mass, moving separate to the ovary.If these features are present, take into account other intrauterine and adnexal features on the scan, the woman's clinical presentation and serum hCG levels before making a diagnosis. \n\nWhen carrying out a transvaginal ultrasound scan in early pregnancy, look for these signs indicating a possible ectopic pregnancy:\n\nan empty uterus or\n\na collection of fluid within the uterine cavity (sometimes described as a pseudo-sac; this collection of fluid must be differentiated from an early intrauterine sac, which is identified by the presence of an eccentrically located hypoechoic structure with a double decidual sign [gestational sac surrounded by 2 concentric echogenic rings] in the endometrium).If these features are present, take into account other intrauterine and adnexal features on the scan, the woman's clinical presentation and serum hCG levels before making a diagnosis. (See also recommendations on human chorionic gonadotrophin measurements in women with pregnancy of unknown location.) \n\nWhen carrying out a transabdominal or transvaginal ultrasound scan in early pregnancy, look for a moderate to large amount of free fluid in the peritoneal cavity or Pouch of Douglas, which might represent haemoperitoneum. If this is present, take into account other intrauterine and adnexal features on the scan, the woman's clinical presentation and hCG levels before making a diagnosis. \n\nWhen carrying out a transabdominal or transvaginal ultrasound scan during early pregnancy, scan the uterus and adnexae to see if there is a heterotopic pregnancy. \n\nAll ultrasound scans should be performed or directly supervised and reviewed by appropriately qualified healthcare professionals with training in, and experience of, diagnosing ectopic pregnancies. [2012, amended 2019]\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on using ultrasound for diagnosis of a tubal ectopic pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: diagnostic accuracy of ultrasound features for tubal ectopic pregnancy.\n\nLoading. Please wait.\n\n## Human chorionic gonadotrophin measurements in women with pregnancy of unknown location\n\nBe aware that women with a pregnancy of unknown location could have an ectopic pregnancy until the location is determined. \n\nDo not use serum hCG measurements to determine the location of the pregnancy. \n\nIn a woman with a pregnancy of unknown location, place more importance on clinical symptoms than on serum hCG results, and review the woman's condition if any of her symptoms change, regardless of previous results and assessments. \n\nUse serum hCG measurements only for assessing trophoblastic proliferation to help to determine subsequent management. \n\nTake 2 serum hCG measurements as near as possible to 48\xa0hours apart (but no earlier) to determine subsequent management of a pregnancy of unknown location. Take further measurements only after review by a senior healthcare professional. \n\nRegardless of serum hCG levels, give women with a pregnancy of unknown location written information about what to do if they experience any new or worsening symptoms, including details about how to access emergency care 24\xa0hours a day. Advise women to return if there are new symptoms or if existing symptoms worsen. \n\nFor a woman with an increase in serum hCG levels greater than 63% after 48\xa0hours:\n\nInform her that she is likely to have a developing intrauterine pregnancy (although the possibility of an ectopic pregnancy cannot be excluded).\n\nOffer her a transvaginal ultrasound scan to determine the location of the pregnancy between 7\xa0and 14\xa0days later. Consider an earlier scan for women with a serum hCG level greater than or equal to 1,500\xa0IU/litre.\n\n\n\nIf a viable intrauterine pregnancy is confirmed, offer her routine antenatal care. See the NICE guideline on antenatal care.\n\nIf a viable intrauterine pregnancy is not confirmed, refer her for immediate clinical review by a senior gynaecologist. \n\n\n\nFor a woman with a decrease in serum hCG levels greater than 50% after 48\xa0hours:\n\ninform her that the pregnancy is unlikely to continue but that this is not confirmed and\n\nprovide her with oral and written information about where she can access support and counselling services; see also recommendation 1.1.3 for details of further information that should be provided\n\nask her to take a urine pregnancy test 14\xa0days after the second serum hCG test, and explain that:\n\n\n\nif the test is negative, no further action is necessary\n\nif the test is positive, she should return to the early pregnancy assessment service for clinical review within 24\xa0hours. \n\n\n\nFor a woman with a decrease in serum hCG levels less than 50%, or an increase less than 63%, refer her for clinical review in the early pregnancy assessment service within 24\xa0hours. [2012, amended 2019]\n\nFor women with a pregnancy of unknown location, when using serial serum hCG measurements, do not use serum progesterone measurements as an adjunct to diagnose either viable intrauterine pregnancy or ectopic pregnancy. \n\n# Management of miscarriage\n\n## Threatened miscarriage\n\nAdvise a woman with a confirmed intrauterine pregnancy with a fetal heartbeat who presents with vaginal bleeding, but has no history of previous miscarriage, that:\n\nif her bleeding gets worse, or persists beyond 14\xa0days, she should return for further assessment\n\nif the bleeding stops, she should start or continue routine antenatal care. [2012, amended 2021]\n\nOffer vaginal micronised progesterone 400\xa0mg twice daily to women with an intrauterine pregnancy confirmed by a scan, if they have vaginal bleeding and have previously had a miscarriage. \n\nIf a fetal heartbeat is confirmed, continue progesterone until 16\xa0completed weeks of pregnancy. In November\xa02021, this was an off-label use of vaginal micronised progesterone. See NICE's information on prescribing medicines.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on progestogens for preventing miscarriage\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: progestogens for preventing miscarriage.\n\nLoading. Please wait.\n\n## Expectant management\n\nUse expectant management for 7\xa0to 14\xa0days as the first-line management strategy for women with a confirmed diagnosis of miscarriage. Explore management options other than expectant management if:\n\nthe woman is at increased risk of haemorrhage (for example, she is in the late first trimester) or\n\nshe has previous adverse and/or traumatic experience associated with pregnancy (for example, stillbirth, miscarriage or antepartum haemorrhage) or\n\nshe is at increased risk from the effects of haemorrhage (for example, if she has coagulopathies or is unable to have a blood transfusion) or\n\nthere is evidence of infection. \n\nOffer medical management to women with a confirmed diagnosis of miscarriage if expectant management is not acceptable to the woman. \n\nExplain what expectant management involves and that most women will need no further treatment. Also provide women with oral and written information about further treatment options. \n\nGive all women undergoing expectant management of miscarriage oral and written information about what to expect throughout the process, advice on pain relief and where and when to get help in an emergency. See also recommendation\xa01.1.3 for details of further information that should be provided. \n\nIf the resolution of bleeding and pain indicate that the miscarriage has completed during 7\xa0to 14\xa0days of expectant management, advise the woman to take a urine pregnancy test after 3\xa0weeks, and to return for individualised care if it is positive. \n\nOffer a repeat scan if after the period of expectant management, the bleeding and pain:\n\nhave not started (suggesting that the process of miscarriage has not begun) or\n\nare persisting and/or increasing (suggesting incomplete miscarriage).Discuss all treatment options (continued expectant management, medical management and surgical management) with the woman to allow her to make an informed choice. \n\nReview the condition of a woman who opts for continued expectant management of miscarriage at a minimum of 14\xa0days after the first follow‑up appointment. \n\n## Medical management\n\nIn April\xa02019, the use of misoprostol in recommendations 1.5.12, 1.5.3 and 1.5.15 was off label. See NICE's information on prescribing medicines.\n\nDo not offer mifepristone as a treatment for missed or incomplete miscarriage. \n\nOffer vaginal misoprostol for the medical treatment of missed or incomplete miscarriage. Oral administration is an acceptable alternative if this is the woman's preference. \n\nFor women with a missed miscarriage, use a single dose of 800\xa0micrograms of misoprostol. \n\nAdvise the woman that if bleeding has not started 24\xa0hours after treatment, she should contact her healthcare professional to determine ongoing individualised care. \n\nFor women with an incomplete miscarriage, use a single dose of 600\xa0micrograms of misoprostol. (800\xa0micrograms can be used as an alternative to allow alignment of treatment protocols for both missed and incomplete miscarriage.) \n\nOffer all women receiving medical management of miscarriage pain relief and anti-emetics as needed. \n\nInform women undergoing medical management of miscarriage about what to expect throughout the process, including the length and extent of bleeding and the potential side effects of treatment including pain, diarrhoea and vomiting. \n\nProvide women with a urine pregnancy test to carry out at home 3\xa0weeks after medical management of miscarriage unless they experience worsening symptoms, in which case advise them to return to the healthcare professional responsible for providing their medical management. [2012, amended 2021]\n\nAdvise women with a positive urine pregnancy test after 3\xa0weeks to return for a review by a healthcare professional to ensure that there is no molar or ectopic pregnancy. \n\n## Surgical management\n\nWhere clinically appropriate, offer women undergoing a miscarriage a choice of:\n\nmanual vacuum aspiration under local anaesthetic in an outpatient or clinic setting or\n\nsurgical management in a theatre under general anaesthetic. \n\nProvide oral and written information to all women undergoing surgical management of miscarriage about the treatment options available and what to expect during and after the procedure. See also recommendation 1.1.3 for details of further information that should be provided. \n\n# Management of tubal ectopic pregnancy\n\nGive all women with an ectopic pregnancy oral and written information about:\n\nthe treatment options and what to expect during and after treatment\n\nhow they can contact a healthcare professional for advice after treatment if needed, and who this will be\n\nwhere and when to get help in an emergency. See also recommendation\xa01.1.3 for details of further information that should be provided. [2012, amended 2019]\n\nInform women who have had an ectopic pregnancy that they can self-refer to an early pregnancy assessment service in future pregnancies if they have any early concerns. \n\n## Expectant management\n\nOffer expectant management as an option to women who:\n\nare clinically stable and pain free and\n\nhave a tubal ectopic pregnancy measuring less than 35\xa0mm with no visible heartbeat on transvaginal ultrasound scan and\n\nhave serum hCG levels of 1,000\xa0IU/L or less and\n\nare able to return for follow-up. \n\nConsider expectant management as an option for women who:\n\nare clinically stable and pain free and\n\nhave a tubal ectopic pregnancy measuring less than 35\xa0mm with no visible heartbeat on transvaginal ultrasound scan and\n\nhave serum hCG levels above 1,000\xa0IU/L and below 1,500\xa0IU/L and\n\nare able to return for follow-up. \n\nFor women with a tubal ectopic pregnancy being managed expectantly, repeat hCG levels on days\xa02, 4\xa0and\xa07 after the original test and:\n\nif hCG levels drop by 15% or more from the previous value on days\xa02, 4\xa0and\xa07, then repeat weekly until a negative result (less than 20\xa0IU/L) is obtained or\n\nif hCG levels do not fall by 15%, stay the same or rise from the previous value, review the woman's clinical condition and seek senior advice to help decide further management. \n\nAdvise women that, based on limited evidence, there seems to be no difference following expectant or medical management in:\n\nthe rate of ectopic pregnancies ending naturally\n\nthe risk of tubal rupture\n\nthe need for additional treatment, but that they might need to be admitted urgently if their condition deteriorates\n\nhealth status, depression or anxiety scores. \n\nAdvise women that the time taken for ectopic pregnancies to resolve and future fertility outcomes are likely to be the same with either expectant or medical management. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on expectant management of tubal ectopic pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: expectant versus medical management of ectopic pregnancy.\n\nLoading. Please wait.\n\n## Medical and surgical management\n\nIn April 2019, the use of methotrexate in recommendations 1.6.8 to 1.6.11 was off label. See NICE's information on prescribing medicines.\n\nOffer systemic methotrexate to women who:\n\nhave no significant pain and\n\nhave an unruptured tubal ectopic pregnancy with an adnexal mass smaller than 35\xa0mm with no visible heartbeat and\n\nhave a serum hCG level less than 1,500\xa0IU/litre and\n\ndo not have an intrauterine pregnancy (as confirmed on an ultrasound scan) and\n\nare able to return for follow-up.Methotrexate should only be offered on a first visit when there is a definitive diagnosis of an ectopic pregnancy, and a viable intrauterine pregnancy has been excluded. Offer surgery where treatment with methotrexate is not acceptable to the woman. [2012, amended 2019]\n\nOffer surgery as a first-line treatment to women who are unable to return for follow-up after methotrexate treatment or who have any of the following:\n\nan ectopic pregnancy and significant pain\n\nan ectopic pregnancy with an adnexal mass of 35\xa0mm or larger\n\nan ectopic pregnancy with a fetal heartbeat visible on an ultrasound scan\n\nan ectopic pregnancy and a serum hCG level of 5,000\xa0IU/litre or more. \n\nOffer the choice of either methotrexate or surgical management to women with an ectopic pregnancy who have a serum hCG level of at least 1,500\xa0IU/litre and less than 5,000\xa0IU/litre, who are able to return for follow‑up and who meet all of the following criteria:\n\nno significant pain\n\nan unruptured ectopic pregnancy with an adnexal mass smaller than 35\xa0mm with no visible heartbeat\n\nno intrauterine pregnancy (as confirmed on an ultrasound scan). Advise women who choose methotrexate that their chance of needing further intervention is increased and they may need to be urgently admitted if their condition deteriorates. \n\nFor women with ectopic pregnancy who have had methotrexate, take 2\xa0serum hCG measurements in the first week (days\xa04\xa0and\xa07) after treatment and then 1\xa0serum hCG measurement per week until a negative result is obtained. If hCG levels plateau or rise, reassess the woman's condition for further treatment. \n\n## Performing laparoscopy\n\nWhen surgical treatment is indicated for women with an ectopic pregnancy, it should be performed laparoscopically whenever possible, taking into account the condition of the woman and the complexity of the surgical procedure. \n\nSurgeons providing care to women with ectopic pregnancy should be competent to perform laparoscopic surgery. \n\nCommissioners and managers should ensure that equipment for laparoscopic surgery is available. \n\n## Salpingectomy and salpingotomy\n\nOffer a salpingectomy to women undergoing surgery for an ectopic pregnancy unless they have other risk factors for infertility. \n\nConsider salpingotomy as an alternative to salpingectomy for women with risk factors for infertility such as contralateral tube damage. \n\nInform women having a salpingotomy that up to 1\xa0in\xa05\xa0women may need further treatment. This treatment may include methotrexate and/or a salpingectomy. \n\nFor women who have had a salpingotomy, take 1\xa0serum hCG measurement at 7\xa0days after surgery, then 1\xa0serum hCG measurement per week until a negative result is obtained. \n\nAdvise women who have had a salpingectomy that they should take a urine pregnancy test after 3\xa0weeks. Advise women to return for further assessment if the test is positive. \n\n# Anti-D immunoglobulin prophylaxis\n\nOffer anti-D immunoglobulin prophylaxis at a dose of 250\xa0IU (50\xa0micrograms) to all rhesus-negative women who have a surgical procedure to manage an ectopic pregnancy or a miscarriage. \n\nDo not offer anti‑D immunoglobulin prophylaxis to women who:\n\nreceive solely medical management for an ectopic pregnancy or miscarriage or\n\nhave a threatened miscarriage or\n\nhave a complete miscarriage or\n\nhave a pregnancy of unknown location. \n\nDo not use a Kleihauer test for quantifying feto-maternal haemorrhage. \n\n# Terms used in this guideline\n\n## Early pregnancy\n\nPregnancy in the first trimester (that is, up to 13\xa0completed weeks of pregnancy).\n\n## Expectant management\n\nA management approach, also called 'wait and watch', when no medical or surgical treatment is given. The aim is to see if the condition will resolve naturally.\n\n## Pregnancy of unknown location\n\nWhen a woman has a positive pregnancy test, but no intrauterine or extrauterine pregnancy can be seen with a transvaginal ultrasound scan.", 'Recommendations for research': "The guideline committee has made the following recommendations for research based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of recommendations for research is detailed in the full guideline.\n\n# Early pregnancy assessment units\n\nA national evaluation of early pregnancy assessment unit service provision should be carried out to identify factors affecting outcomes. Factors should include whether care is provided in a dedicated unit, staffing configuration and opening hours of dedicated services. Outcomes should include both process (service) outcomes and pregnancy-related outcomes. Data collected should be used to analyse the cost effectiveness of early pregnancy assessment units compared with other models of care.\n\n## Why this is important\n\nThe first report of an early pregnancy assessment unit in England was published over 20\xa0years ago, and prompted the rapid development of centres for the management of problems in early pregnancy. Today there are an estimated 150\xa0early pregnancy assessment units in England and Wales (Association of Early Pregnancy Units, 2012). However, there is considerable variation between centres in access to services and levels of care provided. In addition, there has been very little good quality research on the effectiveness of early pregnancy assessment units in improving physical and emotional health compared with services provided outside of a dedicated unit.\n\nA national audit of early pregnancy assessment services would help to make up for this lack of information. Such an audit should be along the lines of the National Caesarean Section Sentinel Audit, a cross-sectional national survey of service configuration and outcomes. Data recorded would include service location, opening hours and the healthcare professionals involved. Outcomes would include time of attendance, length of stay, admission rates, time to treatment and women's experience. Obtaining some of this information would involve early pregnancy services carrying out more formal follow‑up of women than they might do currently, for the duration of the audit. The evaluation should be structured to allow for comparisons between different models of care.\n\nComparative outcome data collected would be used to conduct an analysis of the cost effectiveness of early pregnancy assessment units compared with other models of care.\n\n# Ultrasound for determining a viable intrauterine pregnancy\n\nHow does the timing and frequency of ultrasound examination affect diagnosis and outcomes of early pregnancy complications, including women's experience and cost effectiveness?\n\n## Why this is important\n\nThe rationale behind the frequency of ultrasound to improve diagnosis and outcomes of early pregnancy complications addresses the problems associated with pregnancy of unknown location and intrauterine pregnancy of uncertain viability. The evidence base for the timing and frequency of scanning in early pregnancy is limited, and the number of scans is organised by individual units according to capacity and demand. Some healthcare professionals choose to wait 5\xa0days between scans whereas others will wait 10\xa0to\xa014\xa0days. These decisions are driven by resource availability as well as clinical considerations, but in particular, the effect of different strategies on cost and women's experience is not clear. The literature suggests that there is no clear consensus, but there is general agreement that by 14\xa0days a diagnosis will be clear. To establish the most appropriate time for scans, the efficacy of scans taken after 14\xa0days could be compared with scans taken after 7\xa0days for diagnosis of ectopic pregnancy or viability.\n\n# Effectiveness of progestogens in women with recurrent miscarriage\n\nWhat is the clinical and cost effectiveness of progesterone for improving outcomes in women with unexplained recurrent miscarriage?\n\n## Why this is important\n\nWomen with previous pregnancy losses have an increased risk of miscarriage in subsequent pregnancies. Progesterone is essential for maintaining a healthy pregnancy, and there is evidence that it is safe for both women and fetuses.\n\nA recent randomised controlled trial assessed the effectiveness of micronised vaginal progesterone supplementation in women with 3 or more first-trimester losses and did not show a benefit with progesterone therapy use during the first trimester, concluding that there is not enough evidence to support its use in women with unexplained recurrent miscarriage. However, this trial was designed to look for a 10% difference in live birth outcomes in those who received progesterone versus those who did not receive it. A larger randomised controlled trial is needed to determine if there is a smaller difference (for example 2.5% to 5%) which would still lead to a meaningful increase in live births and reduce the trauma of a further miscarriage for a number of women.\n\n# Effectiveness of different progestogens in women at risk of miscarriage\n\nWhat is the clinical and cost effectiveness of vaginal micronised progesterone versus other progesterone preparations in improving outcomes in women at risk of miscarriage?\n\n## Why this is important\n\nEvidence from a recent randomised controlled trial showed a small but important benefit for the outcome of live birth when vaginal micronised progesterone was given to women with early pregnancy bleeding and a history of one or more previous miscarriages. However, there was not enough evidence available to assess whether other formulations of progesterone would lead to other beneficial outcomes in this group of women. Research is needed to identify whether there is a difference in the effectiveness of micronised versus non-micronised progesterone therapy in women with early pregnancy bleeding and a history of one or more previous miscarriages.\n\n# Management of miscarriage\n\nIn women with confirmed miscarriage, does the type of management strategy (expectant, medical and surgical) impact on women's experience, including psychological and emotional outcomes?\n\n## Why this is important\n\nThe management of miscarriage in the UK has changed in many ways over the past 2\xa0decades, particularly in the shift from inpatient to outpatient or day case care and the introduction of medical and expectant management as alternatives to surgery.\n\nDespite these changes there is a lack of research into the effects of these different approaches from the woman's perspective, in particular their psychological and emotional impact. Miscarriage is distressing for most women, and the type of management itself might affect women's need for counselling, with a resulting cost to the NHS. Because of this it is an important area for research.\n\nThe deficiency in the literature could be addressed by a comparative study of women having the different management strategies (expectant, medical or surgical) and in a variety of clinical settings (for example, early pregnancy assessment unit, gynaecological ward or gynaecological emergency unit). The data collected could be both quantitative (using validated psychological health questionnaires) and qualitative (focusing particularly on women's experience of the particular type and setting of care).\n\n# Comparison between expectant, medical or surgical management of ectopic pregnancy\n\nIn women with ectopic pregnancy, does the type of intervention impact on women's experience, including psychological and emotional outcomes?\n\n## Why this is important\n\nCurrently there is no evidence exploring the psychological impact of the different treatments for ectopic pregnancy. However, the emotional impact of the condition can be significant, in some circumstances leading to post-traumatic stress disorder. A qualitative comparative study should be carried out to assess how this impact can be reduced. This would help to maximise women's emotional recovery in the short and long term, enable women and clinicians to decide the optimum treatment method and identify what support is needed for women during and after the process. It could also reduce the cost to the NHS of providing long-term counselling for affected women.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Using ultrasound for diagnosis of a tubal ectopic pregnancy\n\nRecommendations 1.4.17 to 1.4.21\n\n## Why the committee made the recommendations\n\nThere was good evidence that, when seen on ultrasound, the presence of an adnexal mass with features of an early pregnancy (a gestational sac containing a yolk sac or fetal pole, with or without a heartbeat) was a reliable indicator for ectopic pregnancy.\n\nOther features such as a complex inhomogeneous adnexal mass, adnexal mass with an empty gestational sac, empty uterus, a collection of fluid in the uterine cavity or free peritoneal fluid might indicate a suspicion of an ectopic pregnancy, but the evidence showed they are not reliable enough features on their own to diagnose an ectopic pregnancy. The committee used their knowledge and experience to recommend that other scan features, clinical presentation and serum human chorionic gonadotrophin (hCG) levels should therefore be used as well to confirm or rule out the diagnosis of ectopic pregnancy.\n\n## How the recommendations might affect practice\n\nThe recommendations will not change the amount of ultrasound scanning that is carried out but will standardise practice across the NHS. By defining the features that should be used to indicate the presence of an ectopic pregnancy, or a suspicion of an ectopic pregnancy (which can then be investigated further), the diagnosis of ectopic pregnancy should be improved and so risks to women will be reduced.\n\nReturn to recommendations\n\n# Progestogens for preventing miscarriage\n\nRecommendations 1.5.2 and 1.5.3\n\n## Why the committee made the recommendations\n\nThere was good evidence that 400\xa0mg twice daily of micronised vaginal progesterone increases the number of live births in women with early pregnancy bleeding and a previous miscarriage. There was no evidence of benefit for any other preparations or doses of progesterone, so the committee made a recommendation for research.\n\nThere was evidence of no benefit in women with early pregnancy bleeding but no previous miscarriage, nor in women with previous miscarriage but no early pregnancy bleeding in the current pregnancy. The committee made a recommendation for research to further assess the use of progesterone in women with recurrent miscarriage. There was no evidence of harm to the mother or baby from the use of progesterone, although the evidence is insufficient to rule out the possibility of rare events.\n\nTo reduce the risk of women with a pregnancy of unknown location or an ectopic pregnancy being given progesterone, the committee agreed that, as in the clinical studies, progesterone should only be given to women with intrauterine pregnancy confirmed with a scan. To avoid delay in starting treatment the committee agreed that progesterone could be started before a fetal heartbeat is detected. The evidence on which the recommendations were based had continued the progesterone treatment until 16 weeks of pregnancy so the committee used this duration of treatment in their recommendations.\n\nThe committee discussed that as a scan was needed to confirm the intrauterine pregnancy it would be appropriate for the initial prescription for progesterone to be provided by the Early Pregnancy Unit, with prescribing continued to 16 weeks (if a fetal heartbeat was detected) by the woman's GP. However, the committee were aware that shared care prescribing arrangements are usually agreed locally and so did not include this detail in their recommendations.\n\nThe committee confirmed that the recommendations for the use of progesterone are only for women with early pregnancy bleeding and a history of miscarriage. The recommendations are not applicable in other circumstances, such as after the use of mifepristone.\n\n## How the recommendations might affect practice\n\nThe recommendations will increase the use of progestogens to prevent miscarriage but this is cost effective. The recommendations will standardise the preparation of progesterone used to treat threatened miscarriage.\n\nReturn to recommendations\n\n# Expectant management of tubal ectopic pregnancy\n\nRecommendations 1.6.3 to 1.6.7\n\n## Why the committee made the recommendations\n\nThe evidence showed no significant differences in the number of ectopic pregnancies ending naturally, the need for additional treatment, the incidence of tubal rupture or the effect on health-related quality of life between expectant management and medical management, so the committee recommended that expectant management could be offered to clinically stable women with small ectopic pregnancies and low hCG levels, and should be considered for clinically stable women with small ectopic pregnancies and slightly higher hCG levels, as an alternative to medical management.\n\nThere was no evidence for the time taken for ectopic pregnancies to end naturally or the effects on future fertility but the committee agreed, based on their expertise and experience, that these outcomes were likely to be the same with expectant management compared with medical management.\n\n## How the recommendations might affect practice\n\nThese recommendations will standardise the management of ectopic pregnancy and make expectant management available for women when it is clinically appropriate. More women might have expectant management of ectopic pregnancy as a result. This could result in cost savings through a reduction in drug use and treatment of associated side effects. Local protocols will be needed for assessment, monitoring and follow-up of women choosing expectant management.\n\nReturn to recommendations", 'Context': 'Ectopic pregnancy and miscarriage have an adverse effect on the quality of life of many women. Approximately 20% of pregnancies miscarry, and miscarriages can cause considerable distress. Early pregnancy loss accounts for over 50,000 admissions in the UK annually. The rate of ectopic pregnancy is 11 per 1,000 pregnancies, with a maternal mortality of 0.2 per 1,000 estimated ectopic pregnancies. About two-thirds of these deaths are associated with substandard care.\n\nWomen who do not access medical help readily (such as women who are recent migrants, asylum seekers, refugees, or women who have difficulty reading or speaking English) are particularly vulnerable. Improvement in the diagnosis and management of early pregnancy loss is therefore of vital importance, in order to reduce the incidence of the associated psychological morbidity and avoid the unnecessary deaths of women with ectopic pregnancies.'}
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https://www.nice.org.uk/guidance/ng126
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This guideline covers diagnosing and managing ectopic pregnancy and miscarriage in women with complications, such as pain and bleeding, in early pregnancy (that is, up to 13 completed weeks of pregnancy). It aims to improve how early pregnancy loss is diagnosed, and the support women are given, to limit the psychological impact of their loss.
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9bae8fda2975a32b200162434422954d517122a0
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nice
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Chronic kidney disease: assessment and management
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Chronic kidney disease: assessment and management
This guideline covers care and treatment for people with, or at risk of, chronic kidney disease (CKD). It aims to prevent or delay the progression, and reduce the risk of complications and cardiovascular disease. It also covers managing anaemia and hyperphosphataemia associated with CKD.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
Adults, children and young people
Some recommendations in this guideline apply to adults only, and we have specified 'adults' in these individual recommendations. When a recommendation applies to children and young people only, we have also specified this in the recommendation. When recommendations apply to adults, children and young people we have specified this in recommendations at the beginning of a section. But for brevity, we have used 'people' for later recommendations. When a recommendation refers to 'people', this means adults, children and young people.
# Investigations for chronic kidney disease
## Measuring kidney function
Whenever a request for serum creatinine measurement is made, clinical laboratories should report an estimate of (eGFRcreatinine) using a prediction equation (see recommendation 1.1.2) in addition to reporting the serum creatinine result.eGFRcreatinine may be less reliable in certain situations (for example, acute kidney injury, pregnancy, oedematous states, muscle wasting disorders, and in adults who are malnourished, who have higher muscle mass or use protein supplements, or who have had an amputation) and has not been well validated in certain ethnic groups (for example, black, Asian and other minority ethnic groups with CKD living in the UK).
Clinical laboratories should:
use the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to estimate GFRcreatinine for adults, using creatinine assays with calibration traceable to standardised reference material
use creatinine assays that are specific (for example, enzymatic assays) and zero-biased compared with isotope dilution mass spectrometry (IDMS)
participate in a UK national external quality assessment scheme for creatinine.
The committee reviewed the evidence on creatinine-based estimation of glomerular filtration rate (GFR) in 2021. For a short explanation of why they did not make new recommendations, see the rationale and impact section on creatinine-based estimate of GFR .
Full details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of eGFR calculations in adults, children, and young people from black, Asian and other minority ethnic groups with CKD.
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Interpret eGFRcreatinine with caution in adults with extremes of muscle mass, for example, in bodybuilders, people who have had an amputation or people with muscle wasting disorders. (Reduced muscle mass will lead to overestimation and increased muscle mass to underestimation of the GFR.)
Advise adults not to eat any meat in the 12 hours before having a blood test for eGFRcreatinine. Avoid delaying the despatch of blood samples to ensure that they are received and processed by the laboratory within 12 hours of venepuncture.
Clinical laboratories should report eGFR either as a whole number if it is 90 ml/min/1.73 m2 or less, or as 'greater than 90 ml/min/1.73 m2'.
If eGFR is greater than 90 ml/min/1.73 m2, use an increase in serum creatinine concentration of more than 20% to infer significant reduction in kidney function.
Interpret eGFR values of 60 ml/min/1.73 m2 or more with caution, bearing in mind that estimates of GFR become less accurate as the true GFR increases.
Confirm an eGFR result of less than 60 ml/min/1.73 m2 in an adult not previously tested by repeating the test within 2 weeks. Allow for biological and analytical variability of serum creatinine (±5%) when interpreting changes in eGFR.
If a highly accurate measure of GFR is needed, for example, during monitoring of chemotherapy and in the evaluation of kidney function in potential living donors, consider a reference standard measure (inulin, 51Cr‑EDTA, 125I‑iothalamate or iohexol).
## Investigations for proteinuria
Do not use reagent strips to identify proteinuria in children and young people.
Do not use reagent strips to identify proteinuria in adults unless they are capable of specifically measuring albumin at low concentrations and expressing the result as an albumin:creatinine ratio (ACR).
For the initial detection of proteinuria in adults, children and young people:
use urine ACR rather than protein:creatinine ratio (PCR) because of the greater sensitivity for low levels of proteinuria
check an ACR between 3 mg/mmol and 70 mg/mmol in a subsequent early morning sample to confirm the result.A repeat sample is not needed if the initial ACR is 70 mg/mmol or more.
Regard a confirmed ACR of 3 mg/mmol or more as clinically important proteinuria.
Measure proteinuria with urine ACR in the following groups:
adults, children and young people with diabetes (type 1 or type 2)
adults with an eGFR of less than 60 ml/min/1.73 m2
adults with an eGFR of 60 ml/min/1.73 m2 or more if there is a strong suspicion of CKD
children and young people without diabetes and with creatinine above the upper limit of the age-appropriate reference range.When ACR is 70 mg/mmol or more, PCR can be used as an alternative to ACR.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on investigations for proteinuria .
Full details of the evidence and the committee's discussion are in evidence review B: accuracy of albumin:creatinine ratio versus protein:creatinine ratio measurements to quantify proteinuria in children and young people with CKD.
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If unexplained proteinuria is an incidental finding on a reagent strip, offer testing for CKD using eGFRcreatinine and ACR.
## Haematuria
Use reagent strips to test for haematuria in adults, children and young people (see recommendation 1.1.14 for people who should be tested for haematuria):
Evaluate further for results of 1+ or higher.
Do not use urine microscopy to confirm a positive result.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reagent strips for proteinuria and haematuria .
Full details of the evidence and the committee's discussion are in evidence review C: accuracy of reagent strips for detecting protein and blood in urine in children and young people with CKD.
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## Managing isolated invisible haematuria
When there is the need to differentiate persistent invisible haematuria in the absence of proteinuria from transient haematuria, regard 2 out of 3 positive reagent strip tests as confirmation of persistent invisible haematuria.
Persistent invisible haematuria, with or without proteinuria, should prompt investigation for urinary tract malignancy in appropriate age groups (see NICE's guideline on suspected cancer: recognition and referral).
Persistent invisible haematuria in the absence of proteinuria should be followed up annually with repeat testing for haematuria (see recommendations 1.1.17 and 1.1.18), proteinuria or albuminuria, GFR and blood pressure monitoring as long as the haematuria persists.
## Who should be tested for CKD
Monitor GFR at least annually in adults, children and young people who are taking medicines that can adversely affect kidney function, such as calcineurin inhibitors (for example, ciclosporin or tacrolimus), lithium or non-steroidal anti-inflammatory drugs (long-term chronic use of NSAIDs).
Offer testing for CKD using eGFRcreatinine and ACR to adults with any of the following risk factors:
diabetes
hypertension
previous episode of acute kidney injury
cardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease or cerebral vascular disease)
structural renal tract disease, recurrent renal calculi or prostatic hypertrophy
multisystem diseases with potential kidney involvement, for example, systemic lupus erythematosus
gout
family history of end-stage renal disease (GFR category G5) or hereditary kidney disease
incidental detection of haematuria or proteinuria.
Offer testing for CKD using eGFRcreatinine and ACR to children and young people with any of the following risk factors:
previous episode of acute kidney injury
solitary functioning kidney.
Consider testing for CKD using eGFRcreatinine and ACR in children and young people with any of the following risk factors:
low birth weight (2,500 g or lower)
diabetes
hypertension
cardiac disease
structural renal tract disease or recurrent renal calculi
multisystem diseases with potential kidney involvement, for example, systemic lupus erythematosus
family history of end-stage renal disease (GFR category G5) or hereditary kidney disease
incidental detection of haematuria or proteinuria.
Do not use any of the following as risk factors indicating testing for CKD in adults, children and young people:
age
gender
ethnicity
-besity in the absence of metabolic syndrome, diabetes or hypertension.
Monitor adults, children and young people for the development or progression of CKD for at least 3 years after acute kidney injury (longer for people with acute kidney injury stage 3) even if eGFR has returned to baseline.
For guidance on ACR monitoring for children and young people with diabetes, see the NICE guideline on diabetes in children:
monitoring for complications and associated conditions of type 1 diabetes
monitoring for complications and associated conditions of type 2 diabetes.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on who should be tested for CKD .
Full details of the evidence and the committee's discussion are in evidence review D: children and young people who should be tested for CKD.
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# Classification of CKD in adults
Classify CKD in adults using a combination of GFR and ACR categories (as described in table 1). Be aware that:
increased ACR is associated with increased risk of adverse outcomes
decreased GFR is associated with increased risk of adverse outcomes
increased ACR and decreased GFR in combination multiply the risk of adverse outcomes.
Do not determine management of CKD solely by age.
ACR category A1: normal to mildly increased (less than 3 mg/mmol)
ACR category A2: moderately increased (3 to 30 mg/mmol)
ACR category A3: severely increased (over 30 mg/mmol)
GFR category G1: normal and high (90 ml/min/1.73 m2 or over)
Low risk
No CKD if there are no other markers of kidney damage
Moderate risk
High risk
GFR category G2: mild reduction related to normal range for a young adult (60 to 89 ml/min/1.73 m2)
Low risk
No CKD if there are no other markers of kidney damage
Moderate risk
High risk
GFR category G3a: mild to moderate reduction (45 to 59 ml/min/1.73 m2)
Moderate risk
High risk
Very high risk
GFR category G3b: moderate to severe reduction (30 to 44 ml/min/1.73 m2)
High risk
Very high risk
Very high risk
GFR category G4: severe reduction (15 to 29 ml/min/1.73 m2)
Very high risk
Very high risk
Very high risk
GFR category G5: kidney failure (under 15 ml/min/1.73 m2)
Very high risk
Very high risk
Very high risk
Adapted with permission from the KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
Abbreviations: ACR, albumin creatinine ratio; CKD, chronic kidney disease; GFR, glomerular filtration rate.
## Investigating the cause of CKD and determining the risk of adverse outcomes
Agree a plan to establish the cause of CKD during an informed discussion with the person with CKD, particularly if the cause may be treatable (for example, urinary tract obstruction, medicines that can adversely affect kidney function or glomerular disease).
Use the person's GFR and ACR categories (see table 1) to indicate their risk of adverse outcomes (for example, CKD progression, acute kidney injury, all-cause mortality and cardiovascular events) and discuss this with them.
## Indications for renal ultrasound in adults
Offer a renal ultrasound scan to all adults with CKD who:
have accelerated progression of CKD (see recommendation 1.3.5)
have visible or persistent invisible haematuria
have symptoms of urinary tract obstruction
have a family history of polycystic kidney disease and are older than 20
have a GFR of less than 30 ml/min/1.73 m2 (GFR category G4 or G5)
are considered by a nephrologist to need a renal biopsy.
Advise adults with a family history of hereditary kidney disease about the implications of an abnormal result before a renal ultrasound scan is arranged for them.
# Frequency of monitoring
If an adult, child or young person has CKD, or is at risk of it, agree the frequency of monitoring (eGFRcreatinine and ACR) with them (and their family members or carers, as appropriate), bearing in mind that CKD is not progressive in many people.
When agreeing the frequency of monitoring, follow:
the recommendations on patient views and preferences in NICE's guideline on patient experience in adult NHS services
NICE's guideline on shared decision making.
See the recommendations on when to refer adults (recommendation 1.5.5) and children and young people (recommendation 1.5.6) for specialist assessment.
Use table 2 to guide the minimum frequency of eGFRcreatinine monitoring, but tailor it according to:
the underlying cause of CKD
the rate of decline in eGFR or increase in ACR (but be aware that CKD progression is often non-linear)
-ther risk factors, including heart failure, diabetes and hypertension
changes to their treatment (such as renin–angiotensin–aldosterone system antagonists, NSAIDs and diuretics)
intercurrent illness (for example acute kidney injury)
whether they have chosen conservative management of CKD.
Note: ACR monitoring should be individualised based on a person's individual characteristics, risk of progression and whether a change in ACR is likely to lead to a change in management.
ACR category A1: normal to mildly increased (less than 3 mg/mmol)
ACR category A2: moderately increased (3 to 30 mg/mmol)
ACR category A3: severely increased (over 30 mg/mmol)
GFR category G1: normal and high (90 ml/min/1.73 m2 or over)
to 1
-r more
GFR category G2: mild reduction related to normal range for a young adult (60 to 89 ml/min/1.73 m2)
to 1
-r more
GFR category G3a: mild to moderate reduction (45 to 59 ml/min/1.73 m2)
GFR category G3b: moderate to severe reduction (30 to 44 ml/min/1.73 m2)
to 2
-r more
GFR category G4: severe reduction (15 to 29 ml/min/1.73 m2)
GFR category G5: kidney failure (under 15 ml/min/1.73 m2)
-r more
-r more
Abbreviations: ACR, albumin creatinine ratio; GFR, glomerular filtration rate.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on frequency of monitoring .
Full details of the evidence and the committee's discussion are in evidence review E: optimal monitoring frequency and evidence review N: defining clinically significant decline in eGFR in terms of risk of kidney disease progression.
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## Defining progression in adults
Define accelerated progression of CKD in adults as:
a sustained decrease in GFR of 25% or more and a change in GFR category within 12 months or
a sustained decrease in GFR of 15 ml/min/1.73 m2 per year.
Take the following steps to identify the rate of progression of CKD:
Obtain a minimum of 3 GFR estimations over a period of not less than 90 days.
In adults with a new finding of reduced GFR, repeat the GFR within 2 weeks to exclude causes of acute deterioration of GFR. For example, acute kidney injury or starting renin–angiotensin system antagonist therapy.
Be aware that adults with CKD are at increased risk of progression to end-stage renal disease if they have either of the following:
a sustained decrease in GFR of 25% or more over 12 months or
a sustained decrease in GFR of 15 ml/min/1.73 m2 or more over 12 months.
When assessing CKD progression, extrapolate the current rate of decline of GFR and take this into account when planning intervention strategies, particularly if it suggests that the person might need renal replacement therapy in their lifetime.
## Risk factors associated with CKD progression in adults
Work with adults who have any of the following risk factors for CKD progression to optimise their health:
cardiovascular disease
proteinuria
previous episode of acute kidney injury
hypertension
diabetes
smoking
African, African-Caribbean or Asian family origin
chronic use of NSAIDs
untreated urinary outflow tract obstruction.
In adults with CKD the chronic use of NSAIDs may be associated with progression and acute use is associated with a reversible decrease in GFR. Exercise caution when giving NSAIDs to people with CKD over prolonged periods of time. Monitor the effects on GFR, particularly in people with a low baseline GFR and/or in the presence of other risks for progression.
# Information and education for people with CKD
Offer people with CKD (and their family members or carers, as appropriate) education and information tailored to the severity and cause of CKD, the associated complications and the risk of progression. For more guidance, see:
the information on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services
NICE's guideline on shared decision making
the section on shared decision making in NICE's guideline on babies, children and young people's experience of healthcare.
When developing information or education programmes, involve adults with CKD in their development from the outset. The following topics are suggested.
What is CKD and how does it affect people?
What questions should people ask about their kidneys?
What treatments are available for CKD, what are their advantages and disadvantages, and what complications or side effects may occur as a result of treatment or medication?
What can people do to manage and influence their own condition?
In what ways could CKD and its treatment affect people's daily life, social activities, work opportunities and financial situation, including benefits and allowances available?
How can people cope with and adjust to CKD and what sources of psychological support are available?
Information about renal replacement therapy (such as the frequency and length of time of dialysis treatment sessions or exchanges and pre-emptive transplantation) and the preparation needed (such as having a fistula or peritoneal catheter), if appropriate for the person. See NICE's guideline on renal replacement therapy and conservative management.
Conservative management and when it may be considered.
Offer adults with CKD (and their family members or carers, as appropriate) high-quality information or education programmes as appropriate to the severity of their condition to allow time for them to fully understand and make informed choices about their treatment.
Ensure healthcare professionals providing information and education programmes have specialist knowledge about CKD and the necessary skills to facilitate learning.
Take account of the psychological aspects of coping with CKD and offer adults with CKD access to support, for example, support groups, counselling or a specialist nurse.
## Lifestyle advice
Encourage adults with CKD to take exercise, achieve a healthy weight and stop smoking.
Offer dietary advice about potassium, phosphate, calorie and salt intake appropriate to the severity of CKD.
If dietary intervention is agreed, provide it alongside education, detailed dietary assessment and supervision to ensure malnutrition is prevented.
Do not offer low-protein diets (dietary protein intake less than 0.6 to 0.8 g/kg/day) to adults with CKD.
## Self-management
Ensure that systems are in place to:
inform adults with CKD (and their family members or carers, as appropriate) of their diagnosis
enable adults with CKD (and their family members or carers, as appropriate) to share in decision making about their care
support self-management (this includes providing information about blood pressure, smoking cessation, exercise, diet and medicines) and enable adults with CKD to make informed choices.
Give adults access to their medical data (including diagnosis, comorbidities, test results, treatments and correspondence) through information systems, such as Renal PatientView, to encourage and help them to self-manage their CKD.
# Risk assessment, referral criteria and shared care
## Risk assessment
Give adults with CKD and their family members or carers (as appropriate) information about their 5-year risk of needing renal replacement therapy (measured using the 4-variable Kidney Failure Risk Equation).Follow NICE's guideline on shared decision making when communicating risk.
Use every day, jargon-free language to communicate information on risk. If technical and medical terms are used, explain them clearly.
Set aside enough time during the consultation to give information on risk assessment and to answer any questions. Arrange another appointment for more discussion if this is needed.
Document the discussion on risk assessment and any decisions the person makes.
## Referral criteria
Refer adults with CKD for specialist assessment (taking into account their wishes and comorbidities) if they have any of the following:
a 5-year risk of needing renal replacement therapy of greater than 5% (measured using the 4-variable Kidney Failure Risk Equation)
an ACR of 70 mg/mmol or more, unless known to be caused by diabetes and already appropriately treated (see recommendations 1.6.6 and 1.6.7)
an ACR of more than 30 mg/mmol (ACR category A3), together with haematuria
a sustained decrease in eGFR of 25% or more and a change in eGFR category within 12 months
a sustained decrease in eGFR of 15 ml/min/1.73 m2 or more per year
hypertension that remains poorly controlled (above the person's individual target) despite the use of at least 4 antihypertensive medicines at therapeutic doses (see also NICE's guideline on hypertension in adults)
known or suspected rare or genetic causes of CKD
suspected renal artery stenosis.
Refer children and young people with CKD for specialist assessment if they have any of the following:
an ACR of 3 mg/mmol or more, confirmed on a repeat early morning urine sample
haematuria
any decrease in eGFR
hypertension
known or suspected rare or genetic causes of CKD
suspected renal artery stenosis
renal outflow obstruction.
Consider discussing management with a specialist by letter, email, telephone, or virtual meeting, if there are concerns but the person with CKD does not need to see a specialist.
Refer people with CKD and renal outflow obstruction to urological services, unless urgent treatment is needed (for example, for hyperkalaemia, severe uraemia, acidosis or fluid overload).
## Shared care
After referral:
Agree, document and date a care plan with the person with CKD or their family member or carer (as appropriate). Follow:
the recommendations on patient views and preferences in NICE's guideline on patient experience in adult NHS services
NICE's guideline on shared decision making.
Consider routine follow up at the GP surgery or with a paediatrician rather than in a specialist clinic.
Specify criteria for future referral and re-referral if GP follow up is agreed. For children and young people, these criteria should be agreed between the GP and secondary care services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment, referral criteria and shared care .
Full details of the evidence and the committee's discussion are in evidence review F: the best combination of measures to identify increased risk of progression in adults, children and young people.
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# Pharmacotherapy
## Blood pressure control
See NICE's guideline on hypertension in adults for advice on blood pressure control in people with frailty and multimorbidity.
NICE's guideline on hypertension in adults recommends using clinic blood pressure for monitoring response to lifestyle changes or medical treatment (see recommendation 1.4.15).
In adults with CKD and an ACR under 70 mg/mmol, aim for a clinic systolic blood pressure below 140 mmHg (target range 120 to 139 mmHg) and a clinic diastolic blood pressure below 90 mmHg.
In adults with CKD and an ACR of 70 mg/mmol or more, aim for a clinic systolic blood pressure below 130 mmHg (target range 120 to 129 mmHg) and a clinic diastolic blood pressure below 80 mmHg.
In children and young people with CKD and an ACR of 70 mg/mol or more, aim for a clinic systolic blood pressure below the 50th percentile for height.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacotherapy for blood pressure control .
Full details of the evidence and the committee's discussion are in evidence review G: optimal blood pressure targets
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## Pharmacotherapy for hypertension
Follow the recommendations on treating hypertension in NICE's guideline on hypertension in adults for adults with CKD, hypertension and an ACR of 30 mg/mmol or less (ACR categories A1 and A2).
Offer an angiotensin-receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor (titrated to the highest licensed dose that the person can tolerate) to adults, children and young people with CKD who have hypertension and an ACR over 30 mg/mmol (ACR category A3 or above).
## Pharmacotherapy for CKD in adults, children, and young people with related persistent proteinuria
For advice on blood glucose control, see:
NICE's guideline on type 1 diabetes in adults
NICE's guideline on type 2 diabetes in adults
NICE's guideline on type 1 and type 2 diabetes in children and young people.
For adults with CKD and diabetes (type 1 or type 2) offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that the person can tolerate) if ACR is 3 mg/mmol or more.
For guidance on SGLT2 inhibitors for adults with CKD and type 2 diabetes, see chronic kidney disease in NICE's guideline on type 2 diabetes in adults.
For guidance on dapagliflozin for adults with CKD, with or without type 2 diabetes, see NICE's technology appraisal guidance on dapagliflozin for treating chronic kidney disease.
For adults with CKD but without diabetes:
refer for nephrology assessment and offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), if ACR is 70 mg/mmol or more
monitor in line with recommendations 1.3.1 and 1.3.4 if ACR is above 30 but below 70 mg/mmol; consider discussing with a nephrologist if eGFR declines or ACR increases.
For children and young people with CKD and diabetes (type 1 or 2), offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate) if ACR is 3 mg/mmol or more.
For children and young people with CKD but without diabetes:
-ffer an ARB or an ACE inhibitor if ACR (titrated to the highest licensed dose that they can tolerate) is 70 mg/mol or more
monitor in line with recommendations 1.3.1 and 1.3.4 if ACR is above 30 but below 70 mg/mmol; consider discussing with a nephrologist if eGFR declines or ACR increases.
When offering medicines to lower proteinuria to people with frailty, comorbidities or who are taking many other prescribed medicines, follow the recommendations in NICE's guideline on medicines optimisation to ensure the best possible outcomes. Seek specialist advice if needed, for example from a consultant in care of the elderly, or from a kidney physician if the person asks about contraception.
For a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on pharmacotherapy for proteinuria and choice of antihypertensive agent .
Full details of the evidence and the committee's discussion are in evidence review H: interventions to lower proteinuria.
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## Renin–angiotensin system antagonists
Do not offer a combination of renin–angiotensin system antagonists to adults with CKD.
Explain to adults with CKD (and their family members or carers, as appropriate) who are prescribed renin–angiotensin system antagonists about the importance of:
achieving the optimal tolerated dose of renin–angiotensin system antagonists and
monitoring eGFR and serum potassium in achieving this safely.
Measure serum potassium concentrations and estimate the GFR before starting renin–angiotensin system antagonists in people with CKD. Repeat these measurements between 1 and 2 weeks after starting renin–angiotensin system antagonists and after each dose increase.
Do not routinely offer a renin–angiotensin system antagonist to adults with CKD if their pretreatment serum potassium concentration is greater than 5.0 mmol/litre.
If an adult cannot use renin–angiotensin system antagonists because of hyperkalaemia:
assess for and treat any other factors that promote hyperkalaemia and
recheck serum potassium concentration.
Be aware that more frequent monitoring of serum potassium concentration may be needed if medicines known to promote hyperkalaemia are prescribed for use in people alongside renin–angiotensin system antagonists.
Stop renin–angiotensin system antagonists in adults if the serum potassium concentration increases to 6.0 mmol/litre or more and other medicines known to promote hyperkalaemia have been discontinued.
For recommendations on hyperkalaemia treatment in adults with categories G3b to G5 chronic kidney disease, see NICE's technology appraisals on sodium zirconium cyclosilicate and patiromer.
After introducing or increasing the dose of renin–angiotensin system antagonists in adults, do not modify the dose if either:
the GFR decrease from pretreatment baseline is less than 25% or
the serum creatinine increase from baseline is less than 30%.
If there is a decrease in eGFR or increase in serum creatinine after starting or increasing the dose of renin–angiotensin system antagonists, but it is less than 25% (eGFR) or 30% (serum creatinine) of baseline, repeat the test in 1 to 2 weeks. Do not modify the renin–angiotensin system antagonist dose if the change in eGFR is less than 25% or the change in serum creatinine is less than 30%.
If an adult's eGFR change is 25% or more, or the change in serum creatinine is 30% or more:
investigate other causes of a deterioration in kidney function, such as volume depletion or concurrent medication (for example, NSAIDs)
if no other cause for the deterioration in kidney function is found, stop the renin–angiotensin system antagonist or reduce the dose to a previously tolerated lower dose, and add an alternative antihypertensive medication if needed.
## Statins for adults
Follow the recommendations in NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification for the use of statins in adults with CKD.
## Oral antiplatelets and anticoagulants for adults
Offer antiplatelet medicines to adults with CKD for the secondary prevention of cardiovascular disease, but be aware of the increased risk of bleeding.
For guidance on oral anticoagulants for people with CKD, see NICE's guidelines on atrial fibrillation and venous thromboembolic diseases.
# Diagnosing and assessing anaemia
## Diagnostic role of haemoglobin levels
Consider investigating and managing anaemia in adults, children and young people with CKD if:
their haemoglobin (Hb) level falls to 110 g/litre or less (or 105 g/litre or less if younger than 2 years) or
they develop symptoms attributable to anaemia (such as tiredness, shortness of breath, lethargy and palpitations).
## Diagnostic role of glomerular filtration rate
In adults, children and young people with anaemia (see recommendation 1.7.3):
If eGFR is above 60 ml/min/1.73 m2, investigate other causes of anaemia as it is unlikely to be caused by CKD.
If eGFR is between 30 and 60 ml/min/1.73 m2:
investigate other causes of anaemia, but
use clinical judgement to decide how extensive this investigation should be, because the anaemia may be caused by CKD.
If eGFR is below 30 ml/min/1.73 m2, think about other causes of anaemia but note that anaemia is often caused by CKD.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on diagnostic role of glomerular filtration rate .
Full details of the evidence and the committee's discussion are in evidence review I: eGFR threshold for the investigation of anaemia due to CKD.
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## Diagnostic tests to determine iron status and predict response to iron therapy
Carry out testing to diagnose iron deficiency and determine potential responsiveness to iron therapy and long‑term iron requirements every 3 months (every 1 to 3 months for people having haemodialysis).
Use percentage of hypochromic red blood cells (% HRC; more than 6%), but only if processing of blood sample is possible within 6 hours.
If using percentage of hypochromic red blood cells is not possible, use reticulocyte Hb content (CHr; less than 29 pg) or equivalent tests – for example, reticulocyte Hb equivalent.
If these tests are not available or the person has thalassaemia or thalassaemia trait, use a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100 micrograms/litre).
Do not request transferrin saturation or serum ferritin measurement alone to assess iron deficiency status in people with anaemia of CKD.
Do not routinely measure erythropoietin levels for the diagnosis or management of anaemia in people with anaemia of CKD.
# Managing anaemia
NICE has published technology appraisal guidance on treating anaemia in people with chronic kidney disease.
## Starting erythropoietic stimulating agent therapy in iron‑deficiency
ESA (erythropoietic stimulating agent) therapy should not be started in the presence of absolute iron deficiency without also managing the iron deficiency.
## Maximum iron levels in people with anaemia of CKD
In adults, children and young people treated with iron, serum ferritin levels should not rise above 800 micrograms/litre. In order to prevent this, review the dose of iron when serum ferritin levels reach 500 micrograms/litre.
## Clinical utility of ESA therapy in people with sufficient iron
Discuss the pros and cons of a trial of anaemia management with the person with anaemia of CKD, and their families and carers if agreed.
ESAs need not be administered if the presence of comorbidities, or the prognosis, is likely to negate the benefits of correcting the anaemia.
Start a trial of anaemia correction when there is uncertainty over whether the presence of comorbidities, or the prognosis, would negate benefit from correcting the anaemia with ESAs.
If a trial of ESA therapy is carried out, assess the effectiveness of the trial after an agreed interval. Agree with the person with anaemia of CKD (and their families and carers, if appropriate) whether or not to continue ESA therapy.
Review treatment in all people started on ESA therapy after an agreed interval to decide whether or not to continue using ESAs.
## Nutritional supplements
Do not prescribe supplements of vitamin C, folic acid or carnitine as adjuvants specifically for the treatment of anaemia of CKD.
## Androgens
Do not use androgens to treat anaemia in people with anaemia of CKD.
## Hyperparathyroidism
Treat clinically relevant hyperparathyroidism in adults, children and young people with CKD to improve the management of the anaemia.
## Person-centred care and ESAs
Give adults, children and young people offered ESA therapy and their GPs information about why ESA therapy is needed, how it works and what benefits and side effects may be experienced.
When managing the treatment of anaemia of CKD, there should be agreed protocols defining roles and responsibilities of healthcare professionals in primary and secondary care.
Explain to people receiving ESA therapy about the importance of concordance with therapy and the consequences of poor adherence.
When prescribing ESA therapy, take into account the person's preferences about supervised‑ or self‑administration, dose frequency, pain on injection, method of supplying ESA and storage.
In order for people to self‑administer their ESA in a way that is clinically effective and safe, make arrangements to provide ready, reasonable and uninterrupted access to supplies.
## Patient education programmes
Offer culturally and age‑appropriate patient education programmes to all adults, children and young people diagnosed with anaemia of CKD (and their families and carers). These should be repeated as requested, and according to the person's changing circumstances. They should include the following key areas:
Practical information about how anaemia of CKD is managed.
Knowledge (for example, about symptoms, iron management, causes of anaemia, associated medications, phases of treatment).
Professional support (for example, contact information, community services, continuity of care, monitoring, feedback on progress of results).
Lifestyle (for example, diet, physical exercise, maintaining normality, meeting other people with the condition).
Adaptation to chronic disease (for example, previous information and expectations, resolution of symptoms).
# Assessing and optimising erythropoiesis in people with anaemia
## Benefits of treatment with ESAs
Offer treatment with ESAs to adults, children and young people with anaemia of CKD who are likely to benefit in terms of quality of life and physical function.
## Blood transfusions
Avoid blood transfusions if possible in people with anaemia of CKD in whom kidney transplant is a treatment option.
If a transfusion is indicated clinically in a person with anaemia of CKD, follow NICE's guideline on blood transfusion.
## Comparisons of ESAs
Discuss the choice of ESA with the person with anaemia of CKD when starting treatment and at subsequent review, taking into account:
the person's dialysis status
the route of administration
the local availability of ESAs
the lack of evidence comparing the efficacy of ESAs.
## Coordinating care
Ensure people with anaemia of CKD have access to a designated contact person or people who have principal responsibility for their anaemia management and who have skills in the following activities:
Monitoring and managing a caseload in line with locally agreed protocols.
Providing information, education and support to empower people and their families and carers to participate in their care.
Coordinating an anaemia service for people with CKD, working between secondary and primary care and providing a single point of contact, to ensure people receive a seamless service of the highest standard.
Prescribing medicines related to anaemia management and monitoring their effectiveness.
## Providing ESAs
Agree a treatment plan between the prescriber and the person with anaemia of CKD that ensures ESA therapy is clinically effective, consistent and safe. The plan should be person‑centred and include:
continuity of medicine supply
flexibility of where the medicine is delivered and administered
the person's lifestyle and preferences
cost of medicine supply
desire for self‑care if appropriate
regular review of the plan in light of changing needs.
## ESAs: optimal route of administration
Agree the route of administration of ESAs between the person with anaemia of CKD and the prescriber, and revise as appropriate. Take into account the following factors:
patient population (for example, people having haemodialysis)
pain of injection
frequency of administration
the person's lifestyle and preferences
efficacy (for example, subcutaneous compared with intravenous administration, or long‑acting compared with short‑acting preparations)
cost of medicine supply.
The prescriber should take into account that when using short‑acting ESAs, subcutaneous injection allows the use of lower doses of medicines than intravenous administration.
## ESAs: dose and frequency
When correcting anaemia of CKD, the dose and frequency of ESA should be:
determined by the duration of action and route of administration of the ESA
adjusted to keep the rate of Hb increase between 10 and 20 g/litre/month.
## Optimal Hb levels
When determining individual aspirational Hb ranges for people with anaemia of CKD, take into account:
their preferences
symptoms and comorbidities
the necessary treatment.
Do not routinely correct Hb to normal levels with ESAs in adults, children and young people with anaemia of CKD.
Typically maintain the aspirational Hb range between 100 and 120 g/litre for adults, young people and children aged 2 years and over, and between 95 and 115 g/litre for children under 2 years, reflecting the lower normal range in that age group.
To keep the Hb level within the aspirational range, do not wait until Hb levels are outside the aspirational range before adjusting treatment (for example, take action when Hb levels are within 5 g/litre of the range's limits). Follow the MHRA safety advice on recombinant human erythropoietins, particularly the advice to avoid Hb levels above 120 g/litre because of the increased risk of death and serious adverse cardiovascular events in people with CKD. People should have close monitoring to ensure that the lowest approved dose of ESA is used to provide adequate control of the anaemia symptoms.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on optimal Hb levels .
Full details of the evidence and the committee's discussion are in evidence review J: aspirational haemoglobin target range for children and young people with CKD.
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Consider accepting Hb levels below the agreed aspirational range if:
high doses of ESAs are needed to achieve the aspirational range or
the aspirational range is not achieved despite escalating ESA doses. High doses are more than 175 IU/kg per week for people having haemodialysis; more than 125 IU/kg per week for people having peritoneal dialysis; more than 100 IU/kg per week for people not having dialysis.
Do not use age alone to determine treatment of anaemia of CKD.
## Adjusting ESA treatment
Optimise iron status before or at the same time as starting ESAs and during maintenance treatment with ESAs.
Use of ACE inhibitors or angiotensin type II receptor antagonists is not precluded, but if they are used, an increase in ESA therapy should be considered.
Take into account Hb measurements when determining the dose and frequency of ESA administration.
Investigate the cause of an unexpected change in Hb level (that is, intercurrent illness or bleeding) to enable intervention and optimise iron status.
Increase or decrease ESA dose and/or frequency when Hb measurements fall outside action thresholds (usually below 105 g/litre or above 115 g/litre), or for example when the rate of change of Hb suggests an established trend (for example, greater than 10 g/litre/month).
## Correcting iron deficiency
Offer iron therapy to adults, children and young people with anaemia of CKD who are receiving ESAs to achieve:
percentage of hypochromic red blood cells less than 6% (unless ferritin is greater than 800 micrograms/litre)
reticulocyte Hb count or equivalent tests above 29 pg (unless serum ferritin is greater than 800 micrograms/litre).If these tests are not available or the person has thalassaemia or thalassaemia trait, iron therapy should maintain transferrin saturation greater than 20% and serum ferritin level greater than 100 micrograms/litre (unless serum ferritin is greater than 800 micrograms/litre).Most adults will need 500 to 1,000 mg of iron (equivalent doses for children) in a single or divided dose depending on the preparation. Intravenous iron should be administered in a setting with facilities for resuscitation. In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.
Offer a high-dose intravenous iron regimen to adults, children and young people with stage 5 CKD on in-centre (hospital or satellite unit) haemodialysis, if they have iron deficiency (see recommendation 1.7.3).See table 3 for an example of a high-dose intravenous iron regimen for adults or use a bioequivalent dose of iron. For children and young people, use the maximum dosing regimen in the British National Formulary for Children (BNFc) unless serum ferritin is greater than 800 micrograms/litre when the dose should be withheld. In August 2021, this was an off-label use of intravenous iron products for some children and young people. See NICE's information on prescribing medicines.
Iron status
Intravenous iron sucrose (high-dose regimen)
First month
mg divided equally over 3 haemodialysis sessions
Second month onwards if ferritin 700 micrograms/litre or less
mg during each of the first 2 dialysis sessions
Second month onwards if ferritin over 700 micrograms/litre and/or transferrin saturation 40% or more and/or C-reactive protein (CRP) over 50 mg/litre
Withhold iron dose
Intravenous iron sucrose based on the high-dose iron regimen in the PIVOTAL trial (Macdougall 2019), which included people with serum ferritin below 400 micrograms/litre, a transferrin saturation below 30% and a CRP below 50 mg/litre and on ESA.
For a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on correcting iron deficiency .
Full details of the evidence and the committee's discussion are in evidence review K: anaemia – IV iron.
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## Maintaining iron levels after a deficiency is corrected
Once the percentage of hypochromic red blood cells is less than 6%, reticulocyte Hb count or equivalent tests are above 29 pg, or transferrin saturation is greater than 20% and serum ferritin level is greater than 100 micrograms/litre, offer maintenance iron to people with anaemia of CKD who are receiving ESAs.The dosing regimen will depend on modality, for example people having haemodialysis will need the equivalent of 50 to 60 mg intravenous iron per week (or an equivalent dose in children of 1 mg/kg/week). In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.
## Monitoring iron status during ESA treatment
Offer iron therapy to adults, children and young people receiving ESA maintenance therapy to keep their:
percentage of hypochromic red blood cells less than 6% (unless serum ferritin is greater than 800 micrograms/litre)
reticulocyte Hb count or equivalent tests above 29 pg (unless serum ferritin is greater than 800 micrograms/litre)
transferrin saturation level above 20% and serum ferritin level above 100 micrograms/litre (unless serum ferritin is greater than 800 micrograms/litre).The marker of iron status should be monitored every 1 to 3 months in people having haemodialysis.In people who are pre-dialysis or receiving peritoneal dialysis, levels are typically monitored every 3 months. If these people have a normal full blood count there is little benefit in checking iron status. In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.
## Iron therapy for people who are iron deficient and not on ESA therapy
Offer iron therapy to adults, children and young people with anaemia of CKD who are iron deficient and who are not receiving ESA therapy, before discussing ESA therapy. (In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines).
Discuss the risks and benefits of treatment options. Take into account the person's choice.
For people who are not having haemodialysis, consider a trial of oral iron before offering intravenous iron therapy. If they are intolerant of oral iron or target Hb levels are not reached within 3 months (see recommendation 1.9.11), offer intravenous iron therapy.
For people who are having haemodialysis, offer intravenous iron therapy. Offer oral iron therapy to people who are having haemodialysis only if:
intravenous iron therapy is contraindicated or
the person chooses not to have intravenous iron therapy after discussing the relative efficacy and side effects of oral and intravenous iron therapy.
Discuss the results of the iron therapy with the person or, if appropriate, with their family or carers and offer ESA therapy if needed (see recommendation 1.9.1).
## Iron therapy for people who are iron deficient and receiving ESA therapy
Offer iron therapy to adults, children and young people with anaemia of CKD who are iron deficient and who are receiving ESA therapy. (In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines).
Discuss the risks and benefits of treatment options. Take into account the person's choice.
For adults and young people, offer intravenous iron therapy.
For children who are having haemodialysis, offer intravenous iron therapy.
For children who are not having haemodialysis, consider oral iron. If the child is intolerant of oral iron or target Hb levels are not reached within 3 months (see recommendation 1.9.11), offer intravenous iron therapy.
Offer oral iron therapy to adults and young people who are receiving ESA therapy only if:
intravenous iron therapy is contraindicated or
the person chooses not to have intravenous iron therapy after discussing the relative efficacy and side effects of oral and intravenous iron therapy.
When offering intravenous iron therapy to people not having haemodialysis, consider high‑dose low‑frequency intravenous iron as the treatment of choice for adults and young people when trying to achieve iron repletion. Take into account all of the following:
preferences of the person with anaemia of CKD or, if appropriate, their family or carers
nursing and administration costs
cost of local medicine supply
provision of resuscitation facilities.High-dose and low-frequency iron is a maximum of 2 infusions, with a minimum of 500 mg of iron in each infusion for adults. Low dose and high frequency is more than 2 infusions with 100 mg to 200 mg of iron in each infusion for adults. In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.
# Monitoring anaemia treatment
## Monitoring iron status
Do not check iron levels earlier than 1 week after administering intravenous iron in adults, children and young people with anaemia of CKD. The length of time to monitoring of iron status is dependent on the product used and the amount of iron given.
Carry out routine monitoring of iron stores to prevent iron overload using serum ferritin at intervals of 1 to 3 months.
## Monitoring Hb levels
In adults, children and young people with anaemia of CKD, monitor Hb:
every 2 to 4 weeks in the induction phase of ESA therapy
every 1 to 3 months in the maintenance phase of ESA therapy
more frequently after an ESA dose adjustment
in a clinical setting chosen in discussion with the person, taking into account their convenience and local healthcare systems.
## Detecting ESA resistance
After other causes of anaemia, such as intercurrent illness or chronic blood loss have been excluded, regard people with anaemia of CKD as resistant to ESAs when:
an aspirational Hb range is not achieved despite treatment with 300 IU/kg/week or more of subcutaneous epoetin or 450 IU/kg/week or more of intravenous epoetin or 1.5 micrograms/kg/week of darbepoetin or
there is a continued need for the administration of high doses of ESAs to maintain the aspirational Hb range.
In people with CKD, pure red cell aplasia (PRCA) is indicated by a low reticulocyte count, together with anaemia and the presence of neutralising antibodies. Confirm PRCA by the presence of anti‑erythropoietin antibodies together with a lack of pro‑erythroid progenitor cells in the bone marrow.
In people with anaemia of CKD, aluminium toxicity should be considered as a potential cause of a reduced response to ESAs after other causes, such as intercurrent illness and chronic blood loss, have been excluded.
## Managing ESA resistance
If aluminium toxicity is suspected in an adult, child or young person with anaemia of CKD having haemodialysis, perform a desferrioxamine test and review the management of their condition accordingly.
Consider specialist referral for people with ESA‑induced PRCA.
## Role of blood transfusion in managing ESA resistance
Consider referring adults, children and young people with ESA resistance to a haematology service, particularly if an underlying haematological disorder is suspected.
Evaluate and discuss the risks and benefits of red cell transfusion with the person or, if appropriate, with their family or carers.
Take into account the person's symptoms, quality of life, underlying conditions and the chance of a future successful kidney transplant, in addition to Hb levels, when thinking about the need for red cell transfusion.
Review the rate of red cell transfusion and consider a trial period of stopping ESA in people who have ESA resistance (typically on haemodialysis and on high‑dose ESA) and are having frequent transfusions when:
all reversible causes of ESA resistance have been taken into account and excluded and
the person's condition is otherwise stable (without intercurrent illness such as infection) and
the person is receiving adequate dialysis.Review the rate of red cell transfusion between 1 and 3 months after stopping ESA therapy. If the rate of transfusion has increased, consider restarting ESA therapy.
# Hyperphosphataemia in people with CKD stage 4 or 5
## Dietary management for adults, children and young people
A specialist renal dietitian, supported by healthcare professionals with the necessary skills and competencies, should carry out a dietary assessment and give individualised information and advice on dietary phosphate management.
Tailor advice on dietary phosphate management to the person's learning needs and preferences, rather than using a generalised or complex multicomponent programme of delivery.
Give information about controlling intake of phosphate-rich foods (in particular, foods with a high phosphate content per gram of protein, as well as food and drinks with high levels of phosphate additives) to control serum phosphate, while avoiding malnutrition by maintaining a protein intake at or above the minimum recommended level. For people on dialysis, take into account possible dialysate protein losses.
If a nutritional supplement is needed to maintain protein intake in children and young people with hyperphosphataemia, offer a supplement with a lower phosphate content, taking into account the person's preference and other nutritional requirements.
## Before starting phosphate binders for adults, children and young people
Before starting phosphate binders for adults, children and young people with CKD stage 4 or 5, optimise:
diet (see recommendations 1.4.7 to 1.4.9 for adults)
dialysis, for people who are having this.
When offering a phosphate binder, explain to them and their family members or carers (as appropriate):
the reason for offering phosphate binders
the risks if they are not taken
the side effects linked to phosphate binders
when and how they have to be taken (depending on the type of binder), including the exact timing (before, with or after food) and the need to take them with food containing phosphate (including, for example, high-protein snacks).
Take into account the person's preferences on phosphate binders.
If the person has problems taking the first phosphate binder offered, consider switching to the next recommended one (see recommendations 1.11.9 to 1.11.15).
## Phosphate binders for children and young people
Offer children and young people with CKD stage 4 or 5 and hyperphosphataemia a calcium-based phosphate binder to control serum phosphate levels. In August 2021, this was an off-label use of some calcium-based phosphate binders in people not on dialysis. See NICE's information on prescribing medicines.
If serum calcium increases towards, or above, the age-adjusted upper normal limit:
investigate possible causes other than the phosphate binder
consider reducing the dose of the calcium-based phosphate binder and adding sevelamer carbonate or switching to sevelamer carbonate alone. In August 2021, this was an off-label use of sevelamer carbonate. See NICE's information on prescribing medicines.
For all children and young people who are taking more than 1 phosphate binder, titrate the dosage to achieve the best possible control of serum phosphate while keeping serum calcium levels below the upper normal limit.
## Phosphate binders for adults
Offer adults with CKD stage 4 or 5 and hyperphosphataemia calcium acetate to control serum phosphate levels. In August 2021, this was an off-label use of calcium acetate in people not on dialysis. See NICE's information on prescribing medicines.
Offer sevelamer carbonate if calcium acetate is not indicated (for example, because of hypercalcaemia or low serum parathyroid hormone levels) or not tolerated. In August 2021, this was an off-label use of sevelamer carbonate. See NICE's information on prescribing medicines.
If calcium acetate and sevelamer carbonate cannot be used, consider:
sucroferric oxyhydroxide, for adults on dialysis if a calcium-based phosphate binder is not needed or
calcium carbonate, if a calcium-based phosphate binder is needed. In August 2021, this was an off-label use of these phosphate binders in people not on dialysis. See NICE's information on prescribing medicines.
Only consider lanthanum carbonate for adults with CKD stage 4 or 5 if other phosphate binders cannot be used. In August 2021, this was an off-label use of lanthanum carbonate phosphate binders in people not on dialysis and with serum phosphate levels less than 1.78 mmol/l. See NICE's information on prescribing medicines.
If adults with CKD stage 4 or 5 remain hyperphosphataemic after taking the maximum dose recommended in the BNF (or the maximum dose they can tolerate if that is lower), of a calcium-based phosphate binder:
check they are taking it as prescribed
consider combining a calcium-based phosphate binder with a non-calcium-based phosphate binder.
For all adults who are taking more than 1 phosphate binder, titrate the dosage to achieve the best possible control of serum phosphate while keeping serum calcium levels below the upper normal limit.
## Review of treatments in adults, children and young people
At every routine clinical review, assess the person's serum phosphate control, taking into account:
diet
whether they are taking the phosphate binders as prescribed
-ther relevant factors, such as vitamin D levels, serum parathyroid hormone levels, alkaline phosphatase, serum calcium, medications that might affect serum phosphate, or dialysis.
For a short explanation of why the committee made these 2021 recommendations and how they might affect practice, see the rationale and impact section on hyperphosphataemia in people with CKD stage 4 or 5 .
Full details of the evidence and the committee's discussion are in evidence review L: use of phosphate binders.
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# Other complications in adults
## Bone metabolism and osteoporosis
Do not routinely measure calcium, phosphate, parathyroid hormone and vitamin D levels in adults with a GFR of 30 ml/min/1.73 m2 or more (GFR category G1, G2 or G3).
Measure serum calcium, phosphate and parathyroid hormone concentrations in adults with a GFR of less than 30 ml/min/1.73 m2 (GFR category G4 or G5). Determine the subsequent frequency of testing by the measured values and the clinical circumstances. If doubt exists, seek specialist opinion.
Offer bisphosphonates if indicated for the prevention and treatment of osteoporosis in adults with a GFR of 30 ml/min/1.73 m2 or more (GFR category G1, G2 or G3).
Detailed advice on the management of CKD–mineral and bone disorders is beyond the scope of this guideline. If uncertain, seek advice from your local renal service.
Do not routinely offer vitamin D supplementation to manage or prevent CKD–mineral and bone disorders.
Offer colecalciferol or ergocalciferol to treat vitamin D deficiency in people with CKD and vitamin D deficiency.
If vitamin D deficiency has been corrected and symptoms of CKD–mineral and bone disorders persist, offer alfacalcidol (1‑alpha‑hydroxycholecalciferol) or calcitriol (1‑25‑dihydroxycholecalciferol) to people with a GFR of less than 30 ml/min/1.73 m2 (GFR category G4 or G5).
Monitor serum calcium and phosphate concentrations in people receiving alfacalcidol or calcitriol supplements.
## Oral bicarbonate supplements in the management of metabolic acidosis
Detailed advice on the management of metabolic acidosis is beyond the scope of this guideline. If uncertain, seek advice from your local renal service.
Consider oral sodium bicarbonate supplementation for adults with both:
a GFR less than 30 ml/min/1.73 m2 (GFR category G4 or G5) and
a serum bicarbonate concentration of less than 20 mmol/litre.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.
## Chronic kidney disease (CKD)
Abnormalities of kidney function or structure present for more than 3 months, with implications for health. This includes all people with markers of kidney damage and those with a glomerular filtration rate (GFR) of less than 60 ml/min/1.73 m2 on at least 2 occasions separated by a period of at least 90 days (with or without markers of kidney damage).
## Classification of CKD
CKD is classified according to estimated GFR (eGFR) and albumin:creatinine ratio (ACR) (see table 1), using 'G' to denote the GFR category (G1 to G5, which have the same GFR thresholds as the CKD stages 1 to 5 recommended previously) and 'A' for the ACR category (A1 to A3), for example:
A person with an eGFR of 25 ml/min/1.73 m2 and an ACR of 15 mg/mmol has CKD G4A2.
A person with an eGFR of 50 ml/min/1.73 m2 and an ACR of 35 mg/mmol has CKD G3aA3.
An eGFR of less than 15 ml/min/1.73 m2 (GFR category G5) is referred to as kidney failure.
## Glomerular filtration rate (GFR)
This is abbreviated in the following way in this guideline:
GFR: either a measured or an estimated GFR
eGFR: estimated GFR (without indicating the method of estimation)
eGFRcreatinine: an estimation of GFR using serum creatinine
## -variable Kidney Failure Risk Equation
A person's 5-year risk of needing renal replacement therapy (defined as the need for dialysis or transplant) is estimated, as in Major 2019, as:
In the above, eGFR is reported in ml/min/1.73 m2 and ACR in mg/mmol. Where the term 'male' is used, this should be replaced by a 1 if the person being assessed is male, and a 0 if they are female. This equation and its coefficients are validated in a UK population, and it is important to use this version, and not a version validated in another country.
## Markers of kidney damage
These include albuminuria (ACR more than 3 mg/mmol), urine sediment abnormalities, electrolyte and other abnormalities due to tubular disorders, abnormalities detected by histology, structural abnormalities detected by imaging, and a history of kidney transplantation.
## Pre-dialysis
Usually regarded to be CKD stages 4 and 5, although there is no accepted definition. Pre-dialysis includes people with a failing transplant and people having conservative management.
## Renal replacement therapy (RRT)
Life-supporting treatments for severe acute kidney injury or stage 5 CKD. This includes haemodialysis, haemofiltration, haemodiafiltration, peritoneal dialysis and kidney transplantation.
## Renin–angiotensin–aldosterone system antagonist
A medicine that blocks or inhibits the renin–angiotensin–aldosterone system, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), direct renin inhibitors and aldosterone antagonists.
## Renin–angiotensin system antagonist
A medicine that blocks or inhibits the renin–angiotensin system, including ACE inhibitors, ARBs and direct renin inhibitors. This group of medicines does not include aldosterone antagonists.# Recommendations for research
As part of the 2021 update, the guideline committee made 18 recommendations for research on chronic kidney disease (CKD). They prioritised 5 key recommendations for research. They also retained some recommendations for research from previous guidelines.
# Key recommendations for research
## Creatinine-based estimate of eGFR – existing calculations
In adults, children and young people from black, Asian and other minority ethnic groups with CKD living in the UK, which existing eGFR calculations are the most accurate?
## Creatinine-based estimate of eGFR – improving accuracy of calculations
In adults, children and young people from black, Asian and other minority ethnic groups with CKD living in the UK, what biomarkers or factors, other than ethnicity, improve the diagnostic accuracy of eGFR calculations?
For a short explanation of why the committee made these recommendations for research, see the rationale on creatinine-based estimate of GFR .
Full details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of eGFR calculations in adults, children, and young people from black, Asian and other minority ethnic groups with CKD.
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## Risk assessment for black, Asian and minority ethnic groups
What is the accuracy of the 4-variable Kidney Failure Risk Equation in adults, children and young people with CKD from black, Asian and minority ethnic groups living in the UK?
For a short explanation of why the committee made this recommendation for research, see the rationale on risk assessment, referral criteria and shared care .
Full details of the evidence and the committee's discussion are in evidence review F: the best combination of measures to identify increased risk of progression in adults, children and young people.
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## Managing anaemia – optimal Hb levels for children and young people
What is the efficacy and safety of different aspirational haemoglobin (Hb) targets for children and young people with CKD undergoing treatment for anaemia?
For a short explanation of why the committee made this recommendation for research, see the rationale on optimal Hb levels .
Full details of the evidence and the committee's discussion are in evidence review J: aspirational haemoglobin target range for children and young people with CKD.
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## Hyperphosphatemia in people with CKD stage 4 or 5
What are people with CKD and their family members and carers views and beliefs about taking oral phosphate binders?
For a short explanation of why the committee made this recommendation for research, see the rationale on hyperphosphataemia in people with CKD stage 4 or 5 .
Full details of the evidence and the committee's discussion are in evidence review L: use of phosphate binders.
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# Other recommendations for research
## Cystatin-C equations
What is the diagnostic accuracy of cystatin-C equations to estimate GFR as a measurement of kidney function in adults, young people and children in the UK?
## Investigations for proteinuria
In children and young people, what is the accuracy of reagent strips for detecting albumin in urine?
What is the effect of measuring proteinuria with albumin:creatinine ratio compared with protein:creatinine ratio on the timing of treatment changes in children and young people with CKD?
## Frequency of monitoring
For adults, children and young people with CKD, what is the optimal monitoring frequency for albumin:creatinine ratio?
## Risk assessment, referral criteria and shared care
What is the association between risk factors and CKD outcomes in children and young people?
What is the accuracy of the 4-variable Kidney Failure Risk Equation in children and young people living in the UK?
## Frequency of review
What is the most clinical and cost-effective frequency of review for children and young people with CKD?
## Managing anaemia
For adults, children and young people with CKD and anaemia, what is the diagnostic accuracy of eGFR thresholds of 60, 45, and 30 ml/min/1.73 m2 for determining whether the anaemia is due to CKD?
For adults, children and young people with CKD and anaemia who are on peritoneal dialysis, what amount of intravenous (IV) iron is most clinically and cost effective in managing anaemia and its associated outcomes (including quality of life)?
What are the long-term consequences of high ferritin levels (above 800 micrograms/litre) in children and young people with CKD?
## Phosphate binders
Which binders are the most clinically and cost effective in controlling serum phosphate in adults, children and young people with stage 4 or 5 CKD who are not on dialysis?
In adults with stage 4 or 5 CKD, including those on dialysis, what is the clinical and cost effectiveness and safety of long-term calcium acetate combined with magnesium carbonate for controlling serum phosphate?
## Self-management of CKD
Does the provision of educational and supportive interventions to people with CKD by healthcare professionals increase the person's skills and confidence in managing their conditions and improve clinical outcomes?
## Antiplatelet therapy
For people with CKD at the highest risk of cardiovascular disease, what is the clinical effectiveness of low-dose aspirin compared with placebo for primary prevention of cardiovascular disease?
## Renin–angiotensin–aldosterone system antagonists
For people aged over 75 years with CKD, what is the clinical effectiveness of renin–angiotensin–aldosterone system (RAAS) antagonists?
## Vitamin D supplements in the management of CKD–mineral and bone disorders
In people with hyperparathyroidism secondary to CKD, does treatment with vitamin D or vitamin D analogues improve patient-related outcomes?
## Management of anaemia of CKD with concurrent illness
What is the optimal management (in terms of clinical and cost effectiveness) of anaemia of CKD in people who are receiving erythropoietic stimulating agents (ESAs) and have a significant concurrent acute infectious illness?
## Treatment of ESA resistance in people on haemodialysis
What is the most effective type of intervention to treat people on haemodialysis with ESA‑resistant anaemia? # Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Creatinine-based estimate of glomerular filtration rate (GFR)
## Why the committee did not make recommendations
Evidence on the specific eGFR equations or ethnicity adjustments seen by the committee was not from UK studies so may not be applicable to UK black, Asian and minority ethnic groups. None of the studies included children and young people. The committee was also concerned about the value of P30 as a measure of accuracy (P30 is the probability that the measured value is within 30% of the true value), the broad range of P30 values found across equations and the relative value or accuracy of ethnicity adjustments to eGFR equations in different ethnic groups. The committee agreed that adding an ethnicity adjustment to eGFR equations for different ethnicities may not be valid or accurate. Categorisations based on ethnicity lump together people with a diverse range of family backgrounds and differences in eGFR across ethnicities are likely to at least partly arise because of differences in average muscle mass between ethnic groups. However, muscle mass also differs from person to person within the same ethnicity and so making an adjustment based on ethnicity may be inaccurate for some people. Therefore, the committee agreed to remove the 2014 recommendation on how to adjust the CKD-EPI creatinine equation for adults of African-Caribbean or African family origin. The committee highlighted the 2008 recommendation, which states that caution should be used when interpreting eGFR and in adults with extremes of muscle mass and on those who consume protein supplements (this was added to recommendation 1.1.1). The committee made recommendations for research on appropriate eGFR equations for black, Asian and minority ethnic groups (adults, children and young people) in the UK (see recommendations for research 1 and 2). They agreed that factors other than ethnicity should also be explored as biomarkers.
The committee agreed that in the absence of good evidence for their accuracy, the 2014 recommendations that cystatin-c equations should be considered during diagnosis in certain circumstances, should be removed. In particular, they noted that although using cystatin-c equations may reduce false-positive results, it is likely to also increase false-negative results. This will avoid potentially misleading tests being conducted and the costs associated with these. They made a recommendation for research for a large study using UK data to evaluate the accuracy of cystatin-c equations (see other recommendations for research).
## Impact on practice
There will be an impact on practice, as the adjustment of the CKD-EPI creatinine equation for adults of African-Caribbean or African family origin has been removed from the guideline. Only a small number of centres in the UK currently use cystatin-c equations regularly, so most should not be affected by the removal of the cystatin-c recommendations.
Return to recommendations
# Investigations for proteinuria
Recommendations 1.1.10 to 1.1.14
## Why the committee made the recommendations
For children and young people with CKD, there was no evidence for the accuracy of measuring albumin:creatinine ratio (ACR) compared with protein:creatinine ratio (PCR) to quantify proteinuria. The committee discussed the recommendations for adults and agreed that, overall, these fit well with current practice and can be recommended for children and young people as well.
The committee discussed the eGFR threshold recommended for quantifying urinary albumin or urinary protein loss in adults without diabetes. They agreed that this threshold is not appropriate for children and young people because any reduction in GFR in this population would prompt measuring proteinuria. Therefore, for children and young people they set the threshold for creatinine as above the upper limit of the age-appropriate reference range.
The committee agreed to make a recommendation for research to identify the effect of measuring proteinuria with ACR compared with PCR on the timing of treatment changes in children and young people with CKD and the consequences of the delay in treatment changes on different levels of proteinuria. (See other recommendations for research.)
## How the recommendations might affect practice
The recommendations are in line with current practice, so no additional resources should be needed.
Return to recommendations
# Reagent strips for proteinuria and haematuria
Recommendations 1.1.15 to 1.1.16
## Why the committee made the recommendations
The evidence showed that reagent strips were less useful to rule out than to rule in proteinuria. The committee highlighted that ruling out proteinuria with confidence was the main goal when using reagent strips. Therefore, they agreed that reagent strips should not be used to identify proteinuria in children and young people. The evidence was not reviewed for adults and so the committee agreed to retain the 2014 recommendation not to use reagent strips to identify proteinuria in adults unless the strips are capable of specifically measuring albumin at low concentrations and expressing the result as an ACR. The committee also highlighted that these tests are commonly used in clinical practice and agreed to make a further recommendation for further investigations in adults, children and young people with an incidental finding of unexplained proteinuria on reagent strips. Further testing is needed to confirm CKD by identifying other markers of kidney damage (such as ACR or glomerular filtration rate).
There was limited evidence on the accuracy of reagent strips for albuminuria, so the committee did not feel able to make recommendations. There were only 2 studies, and only 1 showed that reagent strips could be useful.
There was no evidence on the accuracy of reagent strips for haematuria in children and young people. The 2014 guideline (which did not cover children and young people) recommended reagent strips for detecting haematuria in adults. The committee agreed to extend this recommendation to children and young people, because the evidence for adults is likely to be applicable to this population.
## How the recommendations might affect practice
The recommendations are in line with current practice, so no additional resources should be needed. The committee noted that if all dipstick tests are confirmed by laboratory testing anyway, there would be extra costs attached to using dipsticks as a first step, which were not justified by the benefits.
Return to recommendations
# Who should be tested for CKD
Recommendations 1.1.20 to 1.1.25
## Why the committee made the recommendations
For children and young people, the evidence showed that acute kidney injury and solitary functioning kidney were clinically significant risk factors for developing CKD. The committee highlighted that solitary functioning kidney was not due to kidney donation but to nephrectomy secondary to congenital anomalies of the kidney and urinary tract or to a lack of a kidney at birth or a non-functioning kidney.
The committee highlighted that there were other important risk factors for developing CKD in children and young people, but that no evidence was found for these. Based on their clinical knowledge and experience, they added 'gout' as a risk factor for adults and 'low birth weight' as a risk factor for children and young people.
The committee agreed that the frequency of monitoring (for developing CKD or progression) should be individualised for adults, children and young people. This is to address the different characteristics and risks that each person will have.
The committee agreed that more research on risk factors for developing CKD in children and young people would help to strengthen current guidance, so they made a recommendation for research. (See other recommendations for research.)
## How the recommendations might affect practice
The recommendations are in line with current practice, so no additional resources should be needed.
Return to recommendations
# Frequency of monitoring
Recommendations 1.3.1 to 1.3.4
## Why the committee made the recommendations
Most of the evidence showed that with eGFR decline, the risk of kidney disease progression and mortality increases, and this risk increases with the rate of eGFR decline. The committee agreed this is observed in clinical practice and any person presenting with an increase in eGFR decline would be monitored more frequently. The committee reviewed the recommendations and agreed that they are consistent with the evidence and clinical practice. They agreed to clarify monitoring by stating that repeat assessment is to be agreed with each person with or at risk of CKD.
The committee agreed that the frequency of monitoring they recommended was a minimum level and that more frequent monitoring would be appropriate for some patients. This should also be guided by rate of change in eGFR or ACR and specific comorbidities, including diabetes. ACR monitoring should be individualised. For example, ACR might be monitored more frequently in people with high ACR (categories A2 or A3), or if a change in ACR would affect management.
The committee made a recommendation for research to identify the optimal frequency of ACR monitoring in adults, children and young people with CKD. (See other recommendations for research.)
The committee discussed whether specific recommendations are needed for children and young people with CKD and decline in eGFR, but agreed that this population would be referred to specialist care.
## How the recommendations might affect practice
The committee noted that no changes had been made to the previous suggested monitoring schedule, and they believed it was relatively well implemented in clinical practice. Therefore, they were confident there should not be a substantial impact on practice from the new recommendations.
Return to recommendations
# Risk assessment, referral criteria and shared care
Recommendation 1.5.1 to 1.5.9
## Why the committee made the recommendations
New evidence found a UK validation of the 4-variable Kidney Failure Risk Equation for adults, which can be used as one of the referral criteria (5-year risk of needing renal replacement therapy greater than 5%). The results of both the validation study and cost-effectiveness modelling undertaken for the guideline showed using this equation and threshold as a referral criteria (rather than an eGFR threshold) was likely to be both more sensitive and more specific than the criteria in the 2014 NICE guideline, meaning people who will progress to needing renal replacement therapy are identified earlier, and there are fewer unnecessary referrals to secondary care.
The benefits of this approach over using an eGFR threshold (as in the 2014 NICE guideline) were not large, but the committee agreed they were meaningful. They also agreed there were additional potential benefits of using the 4-variable Kidney Failure Risk Equation, including the ability to provide people with an individual risk assessment, which could help them to proactively manage their own risk, and inform the management plans in secondary care.
However, validation of the risk equation was only in adults, so the committee made a separate recommendation for children and young people. Black people were under-represented in the study and, although there was a sizeable proportion of people of Asian family origin, the location of the study suggests that people of east Asian family origin were likely to be under-represented. Therefore, the committee agreed to make recommendation for research 3 for validation of the risk equation in adults, children and young people from black, Asian and other minority ethnic groups living in the UK.
The committee agreed that it is important to discuss with a person with CKD what risk means. They added additional recommendations on providing information about risk, using jargon-free language, allowing enough time for discussions and documenting any decisions made.
## How the recommendations might affect practice
If the 4-variable Kidney Failure Risk Equation can be built into laboratory computer systems, as part of how eGFR and ACR results are returned to GPs, there should be no difficulty in implementing the recommendations. Because the calculation requires both an eGFR and ACR value, it can only be produced if the GP requests both those measurements. These recommendations are intended to provide additional information to supplement eGFR and ACR values, rather than changing how often these values are requested by GPs.
There may be particular difficulties for laboratories that store eGFR and ACR values on separate systems that cannot automatically communicate. In this situation, calculations may have to be done manually. However, this is still likely to be a more efficient system than calculations being carried out routinely by GPs. Overall, the referral criteria are predicted to slightly reduce monitoring costs but, excluding costs associated with dialysis, overall there should be no substantial impact on resource use.
There may be an implementation period before the risk equation results are available to all GPs. Until then, some GPs may have to continue to base referral decisions on eGFR and ACR values independently, as is currently done, without providing patients with a quantitative assessment of their risk of needing renal replacement therapy. The faster these recommendations can be routinely adopted the less time it will be necessary for these 2 parallel approaches to both be in use.
Return to recommendations
# Pharmacotherapy for blood pressure control
Recommendations 1.6.1 to 1.6.3
## Why the committee made the recommendations
Results from a meta-analysis (including the SPRINT trial) showed no meaningful difference between standard and more intensive blood pressure targets for adults with CKD. The 2014 guideline recommended maintaining systolic blood pressure below 140 mmHg and diastolic blood pressure below 90 mmHg. This is consistent with clinical practice and with the NICE guideline on managing hypertension. The committee noted that although there is limited evidence on blood pressure targets in people with CKD and proteinuria, it is important to maintain a systolic blood pressure below 130 mmHg and a diastolic pressure below 80 mmHg.
The committee agreed that none of the evidence they had seen warranted changing the recommendations. They also noted that intensive blood pressure targets only result in a marginal reduction in stroke and kidney failure, but put a large burden on patients in terms of polypharmacy and associated risks and side effects (such as falls).
The committee agreed that a useful target for blood pressure in children and young people with CKD and proteinuria is a systolic blood pressure below the 50th percentile for height.
The committee agreed that particular care had to be taken with people who were frail or who had multiple morbidities. However, the NICE guideline on hypertension already covers this group, so the committee did not make new recommendations.
## How the recommendations might affect practice
The recommendations for adults are consistent with current practice and should not have an impact on resources. The recommendation for blood pressure targets in children and young people may have some cost implications, although the committee did not think they would be significant.
Return to recommendations
# Pharmacotherapy for proteinuria and choice of antihypertensive agent
Recommendations 1.6.5 to 1.6.12
## Why the committee made the recommendations
The interventions recommended are intended to improve a range of outcomes, including rates of progression to end-stage renal disease. There was evidence for adults, but not for children and young people. Paediatric experts on the committee agreed that the evidence for adults was also applicable to children and young people. Therefore, the committee did not make separate recommendations for different age groups.
The evidence for adults covered people with proteinuria or albuminuria, and included people with diabetes. This allowed the committee to make separate recommendations for people with and without diabetes. In the committee's experience, many people with diabetes and CKD are frail, or are taking a lot of medicines, so they made a recommendation to address this.
The evidence showed that, compared with placebo, ACE inhibitors reduced the risk of end-stage renal disease in people without diabetes. ARBs did not show the same effect. However, the committee did not believe the evidence was sufficiently robust to show that ACE inhibitors were better than ARBs. In addition, for people with type 2 diabetes, ARBs did reduce the risk of end-stage renal disease and heart failure. Based on the limitations of the evidence and the evidence available for people with type 2 diabetes, the committee recommended both ACE inhibitors and ARBs.
For people with type 2 diabetes, ARBs reduced the risk of end-stage renal disease and heart failure. The committee also recommended ACE inhibitors because the evidence did not show a clear difference between ACE inhibitors and ARBs on the following outcomes:
reduction of proteinuria
end-stage renal disease
all-cause mortality
cardiovascular mortality
non-fatal cardiovascular events
adverse events (hypotension)
hospitalisation.
There was no evidence comparing ACE inhibitors with placebo in people with type 2 diabetes. The evidence for people without diabetes did show that ACE inhibitors reduced the risk of end-stage renal disease, compared with placebo. The committee used this evidence to make the recommendation for people with diabetes.
## How the recommendations might affect practice
The recommendations reflect current practice, so no additional resources should be needed.
Return to recommendations
# Diagnostic role of glomerular filtration rate
Recommendation 1.7.2
## Why the committee made the recommendation
There was limited evidence showing that eGFR thresholds below 60 ml/min/1.73 m2 could be used to identify anaemia as being due to CKD. The committee questioned the applicability of this evidence because the studies did not rule out other causes of anaemia (which is usually done in practice).
The limited evidence meant that the committee was unable to recommend specific thresholds or probabilities. Instead, they used the available evidence and their expertise to specify ranges of GFR indicating that anaemia is more or less likely to be caused by CKD.
When anaemia may have other causes (such as gastrointestinal bleeding and certain cancers), investigating further will increase the chance of the real cause being identified and treated.
Clinical judgement is needed on how extensively to look for other causes when eGFR is between 30 and 60 ml/min/1.73 m2. Healthcare professionals will need to balance the risks of:
putting people through extensive and unnecessary investigations when their anaemia is caused by CKD
missing the real cause of their anaemia by assuming it is caused by CKD.
The committee agreed that when eGFR is below 30 ml/min/1.73 m2, anaemia is more likely to be caused by CKD. However, healthcare professionals should still use their clinical judgement and think about people's circumstances when deciding whether further assessment is needed.
Only 1 study included people with diabetes, and no studies included children and young people. However, the recommendations still apply to these populations, because other causes of anaemia would be ruled out before attributing the anaemia to CKD.
The committee noted a need for further research on the diagnostic test accuracy of different eGFR thresholds, particularly for eGFR thresholds of 30 and 60 ml/min/1.73 m2. They highlighted that in clinical practice, an eGFR threshold of 45 ml/min/1.73 m2 can also trigger investigation into anaemia due to CKD, but limited evidence was identified for the diagnostic accuracy of this threshold. The committee made a recommendation for research on the diagnostic accuracy of these specific eGFR thresholds for determining the likelihood of anaemia being CKD related. (See other recommendations for research.)
## How the recommendations might affect practice
These recommendations should not increase the cost to primary care, because they reflect current practice and act as cautions for healthcare professionals to explore the cause of anaemia. They may reduce costs by ensuring that the correct cause of anaemia is identified more quickly with appropriate investigations.
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# Optimal Hb levels
Recommendation 1.9.11
## Why the committee made the recommendation
In the 2015 guideline, an aspirational Hb range between 100 and 120 g/litre was recommended for adults, young people and children aged 2 years and over. For children under 2 years, the Hb range was between 95 and 115 g/litre. These were based on evidence for adults. In 2020, the committee reviewed the evidence specifically for children and young people. The only evidence for this population came from a single small low-quality study, comparing the effects of a high and low Hb target on left ventricular mass index. No difference in effect was found. Given the lack of evidence, the committee agreed that the recommendations made in 2015 should not be changed.
The 2015 guideline recommended using the same target Hb range as adults for children and young people over 2 years, and a slightly lower level in children under 2. However, children and young people have different coagulation risks than adults, and are more prone to reductions in Hb from blood loss in haemodialysis circuits. In practice, higher Hb targets (up to 130 g/litre) are often used for children and young people. Because of the lack of evidence in this age group, the committee agreed that research is needed to inform future guidance (see recommendation for research 4).
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# Correcting iron deficiency
Recommendation 1.9.18
## Why the committee made the recommendation
For people with stage 5 CKD who are on in-centre haemodialysis, the evidence showed that high-dose intravenous iron was better than a low-dose regimen at increasing levels of serum ferritin and haemoglobin as well as increasing the haematocrit. The committee agreed that the type of intravenous iron was not relevant and that there was no reason to recommend a specific preparation. They also highlighted that there are differences between iron preparations that affect their bioequivalence. Therefore, pharmacist advice is likely to be needed when choosing iron preparations. An example regimen for adults using iron sucrose was taken from the evidence to help guide practice. Ultimately, the choice of preparation should be based on local availability and policies. The committee agreed that children and young people should be given a high dose as set out in the BNFc, although they noted that use of intravenous iron preparations in children under 14 years was off label.
The committee was aware of a MHRA alert on intravenous iron and serious hypersensitivity reactions. The alert states that 'intravenous iron products should only be administered when staff trained to evaluate and manage anaphylactic or anaphylactoid reactions – as well as resuscitation facilities – are immediately available.' The committee agreed that intravenous iron should not be administered at home but recognised that this has a significant impact on people on home dialysis.
Most of the evidence was from studies with participants on haemodialysis. The committee agreed that more research would help to inform future guidance on intravenous iron for people with stage 5 CKD who are on peritoneal dialysis.
## How the recommendations might affect practice
The recommendations are unlikely to lead to a substantial change in costs, as intravenous iron is relatively inexpensive, and there was evidence found in adults that use of high-dose iron leads to lower doses of erythropoiesis-stimulating agents being used, thereby offsetting any extra costs.
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# Hyperphosphataemia in people with CKD stage 4 or 5
Recommendations 1.11.5 to 1.11.18
## Why the committee made the recommendations
There was a significant amount of evidence (of varying quality) for adults with stage 5 CKD who are having dialysis. However, evidence was limited for adults not on dialysis, and for children and young people. The committee agreed to extrapolate from the evidence for adults with stage 5 CKD on dialysis, so they could make recommendations for the other groups.
People's preferences need to be taken into account when offering phosphate binders, because this could have an impact on adherence. The differences in phosphate binder formulations (for example, chewable and non-chewable) and the effect this has on how they are taken (before, with or after food) mean that people will often prefer one phosphate binder over the others. Oral phosphate binders are also unpleasant to take, and this might affect adherence as well. It is important to involve people in the choice of phosphate binder as far as possible, to ensure they are prescribed one they are happy with and can take as recommended.
The committee highlighted several factors that renal physicians assess at clinical reviews for people who are taking phosphate binders (including parathyroid hormone, vitamin D and serum calcium).
The committee reviewed the recommendations from the 2013 guideline in the light of limited new evidence. For children and young people with high serum calcium, they agreed to recommend sevelamer carbonate instead of sevelamer hydrochloride. This is because sevelamer carbonate offers a better balance of benefits and costs. The committee highlighted that in growing children and young people, calcium is often maintained close to, but not above the upper limit of the age-related reference range. Calcium is essential for bone development in children.
The committee reviewed the evidence for phosphate binders both in adults on dialysis and adults not having dialysis. Although the evidence for those not on dialysis was limited, it did reflect the evidence for adults on dialysis in every area apart from sucroferric oxyhydroxide. As there was no evidence on sucroferric oxyhydroxide in adults not on dialysis, the committee did not recommend it for this group.
The evidence showed that the most cost-effective treatment strategy is to start with calcium acetate, and switch to sevelamer carbonate if the person gets hypercalcaemia. This is because:
calcium acetate as a first-line treatment provides the best balance of benefits, harms and costs
calcium carbonate is cheaper than calcium acetate, but is more likely to cause high serum calcium levels and associated adverse outcomes
sevelamer carbonate and sevelamer hydrochloride are more expensive than calcium acetate, and do not provide enough benefit as a first-line treatment to justify the extra expense
when people have high serum calcium levels and cannot take calcium acetate, sevelamer carbonate is the best alternative; it is cheaper than sevelamer hydrochloride, and provides similar benefits, however, it still costs more than calcium acetate and, for first-line treatment, it does not provide enough benefit to justify this extra expense
sucroferric oxyhydroxide is not cost effective as a first-line treatment, but is a reasonable choice for people who cannot take calcium acetate or sevelamer carbonate
lanthanum carbonate is much more expensive than calcium acetate and sevelamer carbonate and may provide less benefit than other non-calcium-based phosphate binders.
Based on this evidence, the committee recommended a treatment sequence and alternatives for different situations.
The committee also agreed that diet and dialysis (when appropriate) had a large impact on serum phosphate levels. Therefore, before offering phosphate binders it is important to provide dietary advice and ensure people are on the dialysis regime that works best for them.
The committee made recommendation for research 5 to address the lack of evidence in adults not on dialysis.
## How the recommendations might affect practice
Replacing sevelamer hydrochloride with sevelamer carbonate may result in lower resource use, because there is a cheap generic version of sevelamer carbonate available.
There is currently variation across the UK in use of sucroferric oxyhydroxide. The recommendation on this phosphate binder may increase costs. However, this increase is unlikely to be substantial, because sucroferric oxyhydroxide is only recommended as a third-line option.
Return to recommendations# Context
Chronic kidney disease (CKD) describes abnormal kidney function or structure. It is common and often occurs with other conditions (such as cardiovascular disease and diabetes). Moderate to severe CKD is also associated with an increased risk of acute kidney injury, falls, frailty and mortality. The risk of developing CKD increases with age.
CKD is usually asymptomatic, but it is detectable, and tests for CKD are simple and available. There is evidence that treatment can prevent or delay the progression of CKD, reduce or prevent the development of complications, and reduce the risk of cardiovascular disease. However, CKD is often unrecognised or diagnosed at an advanced stage. Late presentation of people with kidney failure increases morbidity, mortality and associated healthcare costs.
As kidney disease progresses, some coexisting conditions become more common and increase in severity. Hyperphosphataemia is an example of this, occurring because of insufficient filtering of phosphate from the blood by poorly functioning kidneys. This means that a certain amount of the phosphate does not leave the body in the urine, instead remaining in the blood at abnormally high levels.
High serum phosphate levels can directly and indirectly increase parathyroid hormone secretion, leading to the development of secondary hyperparathyroidism. Left untreated, secondary hyperparathyroidism increases morbidity and mortality and may lead to renal bone disease, with people experiencing bone and muscular pain, fracture, bone and joint abnormalities, and vascular and soft tissue calcification.
Many people with CKD or established renal failure also develop associated anaemia. The prevalence of anaemia associated with CKD increases progressively with the stage of CKD, especially when the person reaches stage 4 or 5. Anaemia of CKD contributes significantly to the burden of CKD. However, it is potentially reversible and manageable with appropriate identification and treatment.
The Health Survey for England (2016) found that 13% of adults (16 years and over) had any CKD (stages 1 to 5). The prevalence of stages 3 to 5 was 5% for all adults, rising to 34% in people aged 75 and over. At the end of 2018 there were 826 children and young people and 66,612 adults receiving renal replacement therapy in the UK according to the UK Renal Registry annual report.
Since publication of the previous guidelines, new evidence was identified for several areas. The following areas of the guideline have been updated:
investigations for CKD
classification of CKD
frequency of monitoring for CKD
blood pressure control for people with CKD
phosphate binders to manage mineral and bone disorder in CKD
glomerular filtration rate for diagnosing anaemia associated with CKD
intravenous iron for treating anaemia associated with CKD.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nAdults, children and young people\n\nSome recommendations in this guideline apply to adults only, and we have specified 'adults' in these individual recommendations. When a recommendation applies to children and young people only, we have also specified this in the recommendation. When recommendations apply to adults, children and young people we have specified this in recommendations at the beginning of a section. But for brevity, we have used 'people' for later recommendations. When a recommendation refers to 'people', this means adults, children and young people.\n\n# Investigations for chronic kidney disease\n\n## Measuring kidney function\n\nWhenever a request for serum creatinine measurement is made, clinical laboratories should report an estimate of (eGFRcreatinine) using a prediction equation (see recommendation\xa01.1.2) in addition to reporting the serum creatinine result.eGFRcreatinine may be less reliable in certain situations (for example, acute kidney injury, pregnancy, oedematous states, muscle wasting disorders, and in adults who are malnourished, who have higher muscle mass or use protein supplements, or who have had an amputation) and has not been well validated in certain ethnic groups (for example, black, Asian and other minority ethnic groups with CKD living in the UK). \n\nClinical laboratories should:\n\nuse the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to estimate GFRcreatinine for adults, using creatinine assays with calibration traceable to standardised reference material\n\nuse creatinine assays that are specific (for example, enzymatic assays) and zero-biased compared with isotope dilution mass spectrometry (IDMS)\n\nparticipate in a UK national external quality assessment scheme for creatinine. \n\nThe committee reviewed the evidence on creatinine-based estimation of glomerular filtration rate (GFR) in 2021. For a short explanation of why they did not make new recommendations, see the rationale and impact section on creatinine-based estimate of GFR\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of eGFR calculations in adults, children, and young people from black, Asian and other minority ethnic groups with CKD.\n\nLoading. Please wait.\n\nInterpret eGFRcreatinine with caution in adults with extremes of muscle mass, for example, in bodybuilders, people who have had an amputation or people with muscle wasting disorders. (Reduced muscle mass will lead to overestimation and increased muscle mass to underestimation of the GFR.) \n\nAdvise adults not to eat any meat in the 12\xa0hours before having a blood test for eGFRcreatinine. Avoid delaying the despatch of blood samples to ensure that they are received and processed by the laboratory within 12\xa0hours of venepuncture. \n\nClinical laboratories should report eGFR either as a whole number if it is 90\xa0ml/min/1.73\xa0m2 or less, or as 'greater than 90\xa0ml/min/1.73\xa0m2'. \n\nIf eGFR is greater than 90\xa0ml/min/1.73\xa0m2, use an increase in serum creatinine concentration of more than 20% to infer significant reduction in kidney function. \n\nInterpret eGFR values of 60\xa0ml/min/1.73\xa0m2 or more with caution, bearing in mind that estimates of GFR become less accurate as the true GFR increases. \n\nConfirm an eGFR result of less than 60\xa0ml/min/1.73\xa0m2 in an adult not previously tested by repeating the test within 2\xa0weeks. Allow for biological and analytical variability of serum creatinine (±5%) when interpreting changes in eGFR. \n\nIf a highly accurate measure of GFR is needed, for example, during monitoring of chemotherapy and in the evaluation of kidney function in potential living donors, consider a reference standard measure (inulin, 51Cr‑EDTA, 125I‑iothalamate or iohexol). \n\n## Investigations for proteinuria\n\nDo not use reagent strips to identify proteinuria in children and young people. \n\nDo not use reagent strips to identify proteinuria in adults unless they are capable of specifically measuring albumin at low concentrations and expressing the result as an albumin:creatinine ratio (ACR). \n\nFor the initial detection of proteinuria in adults, children and young people:\n\nuse urine ACR rather than protein:creatinine ratio (PCR) because of the greater sensitivity for low levels of proteinuria\n\ncheck an ACR between 3\xa0mg/mmol and 70\xa0mg/mmol in a subsequent early morning sample to confirm the result.A repeat sample is not needed if the initial ACR is 70\xa0mg/mmol or more. \n\nRegard a confirmed ACR of 3\xa0mg/mmol or more as clinically important proteinuria. \n\nMeasure proteinuria with urine ACR in the following groups:\n\nadults, children and young people with diabetes (type 1 or type 2)\n\nadults with an eGFR of less than 60\xa0ml/min/1.73\xa0m2\n\nadults with an eGFR of 60\xa0ml/min/1.73\xa0m2 or more if there is a strong suspicion of CKD\n\nchildren and young people without diabetes and with creatinine above the upper limit of the age-appropriate reference range.When ACR is 70\xa0mg/mmol or more, PCR can be used as an alternative to ACR. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on investigations for proteinuria\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review B: accuracy of albumin:creatinine ratio versus protein:creatinine ratio measurements to quantify proteinuria in children and young people with CKD.\n\nLoading. Please wait.\n\nIf unexplained proteinuria is an incidental finding on a reagent strip, offer testing for CKD using eGFRcreatinine and ACR. \n\n## Haematuria\n\nUse reagent strips to test for haematuria in adults, children and young people (see recommendation 1.1.14 for people who should be tested for haematuria):\n\nEvaluate further for results of 1+ or higher.\n\nDo not use urine microscopy to confirm a positive result. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on reagent strips for proteinuria and haematuria\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review C: accuracy of reagent strips for detecting protein and blood in urine in children and young people with CKD.\n\nLoading. Please wait.\n\n## Managing isolated invisible haematuria\n\nWhen there is the need to differentiate persistent invisible haematuria in the absence of proteinuria from transient haematuria, regard 2 out of 3 positive reagent strip tests as confirmation of persistent invisible haematuria. \n\nPersistent invisible haematuria, with or without proteinuria, should prompt investigation for urinary tract malignancy in appropriate age groups (see NICE's guideline on suspected cancer: recognition and referral). \n\nPersistent invisible haematuria in the absence of proteinuria should be followed up annually with repeat testing for haematuria (see recommendations 1.1.17 and 1.1.18), proteinuria or albuminuria, GFR and blood pressure monitoring as long as the haematuria persists. \n\n## Who should be tested for CKD\n\nMonitor GFR at least annually in adults, children and young people who are taking medicines that can adversely affect kidney function, such as calcineurin inhibitors (for example, ciclosporin or tacrolimus), lithium or non-steroidal anti-inflammatory drugs (long-term chronic use of NSAIDs). \n\nOffer testing for CKD using eGFRcreatinine and ACR to adults with any of the following risk factors:\n\ndiabetes\n\nhypertension\n\nprevious episode of acute kidney injury\n\ncardiovascular disease (ischaemic heart disease, chronic heart failure, peripheral vascular disease or cerebral vascular disease)\n\nstructural renal tract disease, recurrent renal calculi or prostatic hypertrophy\n\nmultisystem diseases with potential kidney involvement, for example, systemic lupus erythematosus\n\ngout\n\nfamily history of end-stage renal disease (GFR category G5) or hereditary kidney disease\n\nincidental detection of haematuria or proteinuria. \n\nOffer testing for CKD using eGFRcreatinine and ACR to children and young people with any of the following risk factors:\n\nprevious episode of acute kidney injury\n\nsolitary functioning kidney. \n\nConsider testing for CKD using eGFRcreatinine and ACR in children and young people with any of the following risk factors:\n\nlow birth weight (2,500\xa0g or lower)\n\ndiabetes\n\nhypertension\n\ncardiac disease\n\nstructural renal tract disease or recurrent renal calculi\n\nmultisystem diseases with potential kidney involvement, for example, systemic lupus erythematosus\n\nfamily history of end-stage renal disease (GFR category G5) or hereditary kidney disease\n\nincidental detection of haematuria or proteinuria. \n\nDo not use any of the following as risk factors indicating testing for CKD in adults, children and young people:\n\nage\n\ngender\n\nethnicity\n\nobesity in the absence of metabolic syndrome, diabetes or hypertension. \n\nMonitor adults, children and young people for the development or progression of CKD for at least 3\xa0years after acute kidney injury (longer for people with acute kidney injury stage 3) even if eGFR has returned to baseline. \n\nFor guidance on ACR monitoring for children and young people with diabetes, see the NICE guideline on diabetes in children:\n\nmonitoring for complications and associated conditions of type 1 diabetes\n\nmonitoring for complications and associated conditions of type 2 diabetes. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on who should be tested for CKD\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review D: children and young people who should be tested for CKD.\n\nLoading. Please wait.\n\n# Classification of CKD in adults\n\nClassify CKD in adults using a combination of GFR and ACR categories (as described in table 1). Be aware that:\n\nincreased ACR is associated with increased risk of adverse outcomes\n\ndecreased GFR is associated with increased risk of adverse outcomes\n\nincreased ACR and decreased GFR in combination multiply the risk of adverse outcomes. \n\nDo not determine management of CKD solely by age. \n\n\n\nACR category A1: normal to mildly increased (less than 3 mg/mmol)\n\nACR category A2: moderately increased (3 to 30 mg/mmol)\n\nACR category A3: severely increased (over 30 mg/mmol)\n\nGFR category G1: normal and high (90 ml/min/1.73 m2 or over)\n\nLow risk\n\nNo CKD if there are no other markers of kidney damage\n\nModerate risk\n\nHigh risk\n\nGFR category G2: mild reduction related to normal range for a young adult (60 to 89 ml/min/1.73 m2)\n\nLow risk\n\nNo CKD if there are no other markers of kidney damage\n\nModerate risk\n\nHigh risk\n\nGFR category G3a: mild to moderate reduction (45 to 59 ml/min/1.73 m2)\n\nModerate risk\n\nHigh risk\n\nVery high risk\n\nGFR category G3b: moderate to severe reduction (30 to 44 ml/min/1.73 m2)\n\nHigh risk\n\nVery high risk\n\nVery high risk\n\nGFR category G4: severe reduction (15 to 29 ml/min/1.73 m2)\n\nVery high risk\n\nVery high risk\n\nVery high risk\n\nGFR category G5: kidney failure (under 15 ml/min/1.73 m2)\n\nVery high risk\n\nVery high risk\n\nVery high risk\n\nAdapted with permission from the KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.\n\nAbbreviations: ACR, albumin creatinine ratio; CKD, chronic kidney disease; GFR, glomerular filtration rate.\n\n## Investigating the cause of CKD and determining the risk of adverse outcomes\n\nAgree a plan to establish the cause of CKD during an informed discussion with the person with CKD, particularly if the cause may be treatable (for example, urinary tract obstruction, medicines that can adversely affect kidney function or glomerular disease). \n\nUse the person's GFR and ACR categories (see table 1) to indicate their risk of adverse outcomes (for example, CKD progression, acute kidney injury, all-cause mortality and cardiovascular events) and discuss this with them. \n\n## Indications for renal ultrasound in adults\n\nOffer a renal ultrasound scan to all adults with CKD who:\n\nhave accelerated progression of CKD (see recommendation 1.3.5)\n\nhave visible or persistent invisible haematuria\n\nhave symptoms of urinary tract obstruction\n\nhave a family history of polycystic kidney disease and are older than 20\n\nhave a GFR of less than 30\xa0ml/min/1.73\xa0m2 (GFR category G4 or G5)\n\nare considered by a nephrologist to need a renal biopsy. [2008, amended 2014]\n\nAdvise adults with a family history of hereditary kidney disease about the implications of an abnormal result before a renal ultrasound scan is arranged for them. \n\n# Frequency of monitoring\n\nIf an adult, child or young person has CKD, or is at risk of it, agree the frequency of monitoring (eGFRcreatinine and ACR) with them (and their family members or carers, as appropriate), bearing in mind that CKD is not progressive in many people. \n\nWhen agreeing the frequency of monitoring, follow:\n\nthe recommendations on patient views and preferences in NICE's guideline on patient experience in adult NHS services\n\nNICE's guideline on shared decision making. \n\nSee the recommendations on when to refer adults (recommendation 1.5.5) and children and young people (recommendation 1.5.6) for specialist assessment. \n\nUse table 2 to guide the minimum frequency of eGFRcreatinine monitoring, but tailor it according to:\n\nthe underlying cause of CKD\n\nthe rate of decline in eGFR or increase in ACR (but be aware that CKD progression is often non-linear)\n\nother risk factors, including heart failure, diabetes and hypertension\n\nchanges to their treatment (such as renin–angiotensin–aldosterone system [RAAS] antagonists, NSAIDs and diuretics)\n\nintercurrent illness (for example acute kidney injury)\n\nwhether they have chosen conservative management of CKD. \n\nNote: ACR monitoring should be individualised based on a person's individual characteristics, risk of progression and whether a change in ACR is likely to lead to a change in management.\n\n\n\nACR category A1: normal to mildly increased (less than 3 mg/mmol)\n\nACR category A2: moderately increased (3 to 30 mg/mmol)\n\nACR category A3: severely increased (over 30 mg/mmol)\n\nGFR category G1: normal and high (90 ml/min/1.73 m2 or over)\n\nto 1\n\n\n\nor more\n\nGFR category G2: mild reduction related to normal range for a young adult (60 to 89 ml/min/1.73 m2)\n\nto 1\n\n\n\nor more\n\nGFR category G3a: mild to moderate reduction (45 to 59 ml/min/1.73 m2)\n\n\n\n\n\n\n\nGFR category G3b: moderate to severe reduction (30 to 44 ml/min/1.73 m2)\n\nto 2\n\n\n\nor more\n\nGFR category G4: severe reduction (15 to 29 ml/min/1.73 m2)\n\n\n\n\n\n\n\nGFR category G5: kidney failure (under 15 ml/min/1.73 m2)\n\n\n\nor more\n\nor more\n\nAbbreviations: ACR, albumin creatinine ratio; GFR, glomerular filtration rate.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on frequency of monitoring\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review E: optimal monitoring frequency and evidence review N: defining clinically significant decline in eGFR in terms of risk of kidney disease progression.\n\nLoading. Please wait.\n\n## Defining progression in adults\n\nDefine accelerated progression of CKD in adults as:\n\na sustained decrease in GFR of 25% or more and a change in GFR category within 12\xa0months or\n\na sustained decrease in GFR of 15\xa0ml/min/1.73\xa0m2 per year. \n\nTake the following steps to identify the rate of progression of CKD:\n\nObtain a minimum of 3 GFR estimations over a period of not less than 90\xa0days.\n\nIn adults with a new finding of reduced GFR, repeat the GFR within 2\xa0weeks to exclude causes of acute deterioration of GFR. For example, acute kidney injury or starting renin–angiotensin system antagonist therapy. [2008, amended 2014]\n\nBe aware that adults with CKD are at increased risk of progression to end-stage renal disease if they have either of the following:\n\na sustained decrease in GFR of 25% or more over 12\xa0months or\n\na sustained decrease in GFR of 15\xa0ml/min/1.73\xa0m2 or more over 12\xa0months. [2008, amended 2014]\n\nWhen assessing CKD progression, extrapolate the current rate of decline of GFR and take this into account when planning intervention strategies, particularly if it suggests that the person might need renal replacement therapy in their lifetime. [2008, amended 2014]\n\n## Risk factors associated with CKD progression in adults\n\nWork with adults who have any of the following risk factors for CKD progression to optimise their health:\n\ncardiovascular disease\n\nproteinuria\n\nprevious episode of acute kidney injury\n\nhypertension\n\ndiabetes\n\nsmoking\n\nAfrican, African-Caribbean or Asian family origin\n\nchronic use of NSAIDs\n\nuntreated urinary outflow tract obstruction. \n\nIn adults with CKD the chronic use of NSAIDs may be associated with progression and acute use is associated with a reversible decrease in GFR. Exercise caution when giving NSAIDs to people with CKD over prolonged periods of time. Monitor the effects on GFR, particularly in people with a low baseline GFR and/or in the presence of other risks for progression. \n\n# Information and education for people with CKD\n\nOffer people with CKD (and their family members or carers, as appropriate) education and information tailored to the severity and cause of CKD, the associated complications and the risk of progression. For more guidance, see:\n\nthe information on enabling patients to actively participate in their care in NICE's guideline on patient experience in adult NHS services\n\nNICE's guideline on shared decision making\n\nthe section on shared decision making in NICE's guideline on babies, children and young people's experience of healthcare. \n\nWhen developing information or education programmes, involve adults with CKD in their development from the outset. The following topics are suggested.\n\nWhat is CKD and how does it affect people?\n\nWhat questions should people ask about their kidneys?\n\nWhat treatments are available for CKD, what are their advantages and disadvantages, and what complications or side effects may occur as a result of treatment or medication?\n\nWhat can people do to manage and influence their own condition?\n\nIn what ways could CKD and its treatment affect people's daily life, social activities, work opportunities and financial situation, including benefits and allowances available?\n\nHow can people cope with and adjust to CKD and what sources of psychological support are available?\n\nInformation about renal replacement therapy (such as the frequency and length of time of dialysis treatment sessions or exchanges and pre-emptive transplantation) and the preparation needed (such as having a fistula or peritoneal catheter), if appropriate for the person. See NICE's guideline on renal replacement therapy and conservative management.\n\nConservative management and when it may be considered. \n\nOffer adults with CKD (and their family members or carers, as appropriate) high-quality information or education programmes as appropriate to the severity of their condition to allow time for them to fully understand and make informed choices about their treatment. \n\nEnsure healthcare professionals providing information and education programmes have specialist knowledge about CKD and the necessary skills to facilitate learning. \n\nTake account of the psychological aspects of coping with CKD and offer adults with CKD access to support, for example, support groups, counselling or a specialist nurse. \n\n## Lifestyle advice\n\nEncourage adults with CKD to take exercise, achieve a healthy weight and stop smoking. \n\nOffer dietary advice about potassium, phosphate, calorie and salt intake appropriate to the severity of CKD. [2008, amended 2014]\n\nIf dietary intervention is agreed, provide it alongside education, detailed dietary assessment and supervision to ensure malnutrition is prevented. \n\nDo not offer low-protein diets (dietary protein intake less than 0.6 to 0.8\xa0g/kg/day) to adults with CKD. \n\n## Self-management\n\nEnsure that systems are in place to:\n\ninform adults with CKD (and their family members or carers, as appropriate) of their diagnosis\n\nenable adults with CKD (and their family members or carers, as appropriate) to share in decision making about their care\n\nsupport self-management (this includes providing information about blood pressure, smoking cessation, exercise, diet and medicines) and enable adults with CKD to make informed choices. \n\nGive adults access to their medical data (including diagnosis, comorbidities, test results, treatments and correspondence) through information systems, such as Renal PatientView, to encourage and help them to self-manage their CKD. \n\n# Risk assessment, referral criteria and shared care\n\n## Risk assessment\n\nGive adults with CKD and their family members or carers (as appropriate) information about their 5-year risk of needing renal replacement therapy (measured using the 4-variable Kidney Failure Risk Equation).Follow NICE's guideline on shared decision making when communicating risk. \n\nUse every day, jargon-free language to communicate information on risk. If technical and medical terms are used, explain them clearly. \n\nSet aside enough time during the consultation to give information on risk assessment and to answer any questions. Arrange another appointment for more discussion if this is needed. \n\nDocument the discussion on risk assessment and any decisions the person makes. \n\n## Referral criteria\n\nRefer adults with CKD for specialist assessment (taking into account their wishes and comorbidities) if they have any of the following:\n\na 5-year risk of needing renal replacement therapy of greater than 5% (measured using the 4-variable Kidney Failure Risk Equation)\n\nan ACR of 70\xa0mg/mmol or more, unless known to be caused by diabetes and already appropriately treated (see recommendations 1.6.6 and 1.6.7)\n\nan ACR of more than 30\xa0mg/mmol (ACR category A3), together with haematuria\n\na sustained decrease in eGFR of 25% or more and a change in eGFR category within 12\xa0months\n\na sustained decrease in eGFR of 15\xa0ml/min/1.73\xa0m2 or more per year\n\nhypertension that remains poorly controlled (above the person's individual target) despite the use of at least 4 antihypertensive medicines at therapeutic doses (see also NICE's guideline on hypertension in adults)\n\nknown or suspected rare or genetic causes of CKD\n\nsuspected renal artery stenosis. \n\nRefer children and young people with CKD for specialist assessment if they have any of the following:\n\nan ACR of 3\xa0mg/mmol or more, confirmed on a repeat early morning urine sample\n\nhaematuria\n\nany decrease in eGFR\n\nhypertension\n\nknown or suspected rare or genetic causes of CKD\n\nsuspected renal artery stenosis\n\nrenal outflow obstruction. \n\nConsider discussing management with a specialist by letter, email, telephone, or virtual meeting, if there are concerns but the person with CKD does not need to see a specialist. \n\nRefer people with CKD and renal outflow obstruction to urological services, unless urgent treatment is needed (for example, for hyperkalaemia, severe uraemia, acidosis or fluid overload). \n\n## Shared care\n\nAfter referral:\n\nAgree, document and date a care plan with the person with CKD or their family member or carer (as appropriate). Follow:\n\n\n\nthe recommendations on patient views and preferences in NICE's guideline on patient experience in adult NHS services\n\nNICE's guideline on shared decision making.\n\n\n\nConsider routine follow up at the GP surgery or with a paediatrician rather than in a specialist clinic.\n\nSpecify criteria for future referral and re-referral if GP follow up is agreed. For children and young people, these criteria should be agreed between the GP and secondary care services. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on risk assessment, referral criteria and shared care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: the best combination of measures to identify increased risk of progression in adults, children and young people.\n\nLoading. Please wait.\n\n# Pharmacotherapy\n\n## Blood pressure control\n\nSee NICE's guideline on hypertension in adults for advice on blood pressure control in people with frailty and multimorbidity.\n\nNICE's guideline on hypertension in adults recommends using clinic blood pressure for monitoring response to lifestyle changes or medical treatment (see recommendation 1.4.15).\n\nIn adults with CKD and an ACR under 70\xa0mg/mmol, aim for a clinic systolic blood pressure below 140\xa0mmHg (target range 120 to 139\xa0mmHg) and a clinic diastolic blood pressure below 90\xa0mmHg. \n\nIn adults with CKD and an ACR of 70\xa0mg/mmol or more, aim for a clinic systolic blood pressure below 130\xa0mmHg (target range 120 to 129\xa0mmHg) and a clinic diastolic blood pressure below 80\xa0mmHg. \n\nIn children and young people with CKD and an ACR of 70\xa0mg/mol or more, aim for a clinic systolic blood pressure below the 50th percentile for height. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pharmacotherapy for blood pressure control\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review G: optimal blood pressure targets\n\nLoading. Please wait.\n\n## Pharmacotherapy for hypertension\n\nFollow the recommendations on treating hypertension in NICE's guideline on hypertension in adults for adults with CKD, hypertension and an ACR of 30\xa0mg/mmol or less (ACR categories A1 and A2). [2014, amended 2021]\n\nOffer an angiotensin-receptor blocker (ARB) or an angiotensin-converting enzyme (ACE) inhibitor (titrated to the highest licensed dose that the person can tolerate) to adults, children and young people with CKD who have hypertension and an ACR over 30\xa0mg/mmol (ACR category A3 or above). \n\n## Pharmacotherapy for CKD in adults, children, and young people with related persistent proteinuria\n\nFor advice on blood glucose control, see:\n\nNICE's guideline on type 1 diabetes in adults\n\nNICE's guideline on type 2 diabetes in adults\n\nNICE's guideline on type 1 and type 2 diabetes in children and young people.\n\nFor adults with CKD and diabetes (type 1 or type 2) offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that the person can tolerate) if ACR is 3\xa0mg/mmol or more. \n\nFor guidance on SGLT2 inhibitors for adults with CKD and type\xa02 diabetes, see chronic kidney disease in NICE's guideline on type 2 diabetes in adults. \n\nFor guidance on dapagliflozin for adults with CKD, with or without type\xa02 diabetes, see NICE's technology appraisal guidance on dapagliflozin for treating chronic kidney disease. \n\nFor adults with CKD but without diabetes:\n\nrefer for nephrology assessment and offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate), if ACR is 70\xa0mg/mmol or more\n\nmonitor in line with recommendations 1.3.1 and 1.3.4 if ACR is above 30 but below 70\xa0mg/mmol; consider discussing with a nephrologist if eGFR declines or ACR increases. \n\nFor children and young people with CKD and diabetes (type 1 or 2), offer an ARB or an ACE inhibitor (titrated to the highest licensed dose that they can tolerate) if ACR is 3\xa0mg/mmol or more. \n\nFor children and young people with CKD but without diabetes:\n\noffer an ARB or an ACE inhibitor if ACR (titrated to the highest licensed dose that they can tolerate) is 70\xa0mg/mol or more\n\nmonitor in line with recommendations 1.3.1 and 1.3.4 if ACR is above 30 but below 70\xa0mg/mmol; consider discussing with a nephrologist if eGFR declines or ACR increases. \n\nWhen offering medicines to lower proteinuria to people with frailty, comorbidities or who are taking many other prescribed medicines, follow the recommendations in NICE's guideline on medicines optimisation to ensure the best possible outcomes. Seek specialist advice if needed, for example from a consultant in care of the elderly, or from a kidney physician if the person asks about contraception. \n\nFor a short explanation of why the committee made the 2021 recommendations and how they might affect practice, see the rationale and impact section on pharmacotherapy for proteinuria and choice of antihypertensive agent\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review H: interventions to lower proteinuria.\n\nLoading. Please wait.\n\n## Renin–angiotensin system antagonists\n\nDo not offer a combination of renin–angiotensin system antagonists to adults with CKD. \n\nExplain to adults with CKD (and their family members or carers, as appropriate) who are prescribed renin–angiotensin system antagonists about the importance of:\n\nachieving the optimal tolerated dose of renin–angiotensin system antagonists and\n\nmonitoring eGFR and serum potassium in achieving this safely. \n\nMeasure serum potassium concentrations and estimate the GFR before starting renin–angiotensin system antagonists in people with CKD. Repeat these measurements between 1 and 2\xa0weeks after starting renin–angiotensin system antagonists and after each dose increase. \n\nDo not routinely offer a renin–angiotensin system antagonist to adults with CKD if their pretreatment serum potassium concentration is greater than 5.0\xa0mmol/litre. [2008, amended 2014]\n\nIf an adult cannot use renin–angiotensin system antagonists because of hyperkalaemia:\n\nassess for and treat any other factors that promote hyperkalaemia and\n\nrecheck serum potassium concentration. \n\nBe aware that more frequent monitoring of serum potassium concentration may be needed if medicines known to promote hyperkalaemia are prescribed for use in people alongside renin–angiotensin system antagonists. \n\nStop renin–angiotensin system antagonists in adults if the serum potassium concentration increases to 6.0\xa0mmol/litre or more and other medicines known to promote hyperkalaemia have been discontinued. \n\nFor recommendations on hyperkalaemia treatment in adults with categories G3b to G5 chronic kidney disease, see NICE's technology appraisals on sodium zirconium cyclosilicate and patiromer. \n\nAfter introducing or increasing the dose of renin–angiotensin system antagonists in adults, do not modify the dose if either:\n\nthe GFR decrease from pretreatment baseline is less than 25% or\n\nthe serum creatinine increase from baseline is less than 30%. \n\nIf there is a decrease in eGFR or increase in serum creatinine after starting or increasing the dose of renin–angiotensin system antagonists, but it is less than 25% (eGFR) or 30% (serum creatinine) of baseline, repeat the test in 1 to 2\xa0weeks. Do not modify the renin–angiotensin system antagonist dose if the change in eGFR is less than 25% or the change in serum creatinine is less than 30%. \n\nIf an adult's eGFR change is 25% or more, or the change in serum creatinine is 30% or more:\n\ninvestigate other causes of a deterioration in kidney function, such as volume depletion or concurrent medication (for example, NSAIDs)\n\nif no other cause for the deterioration in kidney function is found, stop the renin–angiotensin system antagonist or reduce the dose to a previously tolerated lower dose, and add an alternative antihypertensive medication if needed. \n\n## Statins for adults\n\nFollow the recommendations in NICE's guideline on cardiovascular disease: risk assessment and reduction, including lipid modification for the use of statins in adults with CKD. \n\n## Oral antiplatelets and anticoagulants for adults\n\nOffer antiplatelet medicines to adults with CKD for the secondary prevention of cardiovascular disease, but be aware of the increased risk of bleeding. \n\nFor guidance on oral anticoagulants for people with CKD, see NICE's guidelines on atrial fibrillation and venous thromboembolic diseases. [2014, amended 2021]\n\n# Diagnosing and assessing anaemia\n\n## Diagnostic role of haemoglobin levels\n\nConsider investigating and managing anaemia in adults, children and young people with CKD if:\n\ntheir haemoglobin (Hb) level falls to 110\xa0g/litre or less (or 105\xa0g/litre or less if younger than 2\xa0years) or\n\nthey develop symptoms attributable to anaemia (such as tiredness, shortness of breath, lethargy and palpitations). \n\n## Diagnostic role of glomerular filtration rate\n\nIn adults, children and young people with anaemia (see recommendation 1.7.3):\n\nIf eGFR is above 60\xa0ml/min/1.73\xa0m2, investigate other causes of anaemia as it is unlikely to be caused by CKD.\n\nIf eGFR is between 30 and 60\xa0ml/min/1.73\xa0m2:\n\n\n\ninvestigate other causes of anaemia, but\n\nuse clinical judgement to decide how extensive this investigation should be, because the anaemia may be caused by CKD.\n\n\n\nIf eGFR is below 30\xa0ml/min/1.73\xa0m2, think about other causes of anaemia but note that anaemia is often caused by CKD. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on diagnostic role of glomerular filtration rate\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review I: eGFR threshold for the investigation of anaemia due to CKD.\n\nLoading. Please wait.\n\n## Diagnostic tests to determine iron status and predict response to iron therapy\n\nCarry out testing to diagnose iron deficiency and determine potential responsiveness to iron therapy and long‑term iron requirements every 3\xa0months (every 1 to 3\xa0months for people having haemodialysis).\n\nUse percentage of hypochromic red blood cells (% HRC; more than 6%), but only if processing of blood sample is possible within 6\xa0hours.\n\nIf using percentage of hypochromic red blood cells is not possible, use reticulocyte Hb content (CHr; less than 29\xa0pg) or equivalent tests – for example, reticulocyte Hb equivalent.\n\nIf these tests are not available or the person has thalassaemia or thalassaemia trait, use a combination of transferrin saturation (less than 20%) and serum ferritin measurement (less than 100\xa0micrograms/litre). \n\nDo not request transferrin saturation or serum ferritin measurement alone to assess iron deficiency status in people with anaemia of CKD. \n\nDo not routinely measure erythropoietin levels for the diagnosis or management of anaemia in people with anaemia of CKD. \n\n# Managing anaemia\n\nNICE has published technology appraisal guidance on treating anaemia in people with chronic kidney disease.\n\n## Starting erythropoietic stimulating agent therapy in iron‑deficiency\n\nESA (erythropoietic stimulating agent) therapy should not be started in the presence of absolute iron deficiency without also managing the iron deficiency. \n\n## Maximum iron levels in people with anaemia of CKD\n\nIn adults, children and young people treated with iron, serum ferritin levels should not rise above 800\xa0micrograms/litre. In order to prevent this, review the dose of iron when serum ferritin levels reach 500\xa0micrograms/litre. \n\n## Clinical utility of ESA therapy in people with sufficient iron\n\nDiscuss the pros and cons of a trial of anaemia management with the person with anaemia of CKD, and their families and carers if agreed. \n\nESAs need not be administered if the presence of comorbidities, or the prognosis, is likely to negate the benefits of correcting the anaemia. \n\nStart a trial of anaemia correction when there is uncertainty over whether the presence of comorbidities, or the prognosis, would negate benefit from correcting the anaemia with ESAs. \n\nIf a trial of ESA therapy is carried out, assess the effectiveness of the trial after an agreed interval. Agree with the person with anaemia of CKD (and their families and carers, if appropriate) whether or not to continue ESA therapy. \n\nReview treatment in all people started on ESA therapy after an agreed interval to decide whether or not to continue using ESAs. \n\n## Nutritional supplements\n\nDo not prescribe supplements of vitamin\xa0C, folic acid or carnitine as adjuvants specifically for the treatment of anaemia of CKD. \n\n## Androgens\n\nDo not use androgens to treat anaemia in people with anaemia of CKD. \n\n## Hyperparathyroidism\n\nTreat clinically relevant hyperparathyroidism in adults, children and young people with CKD to improve the management of the anaemia. \n\n## Person-centred care and ESAs\n\nGive adults, children and young people offered ESA therapy and their GPs information about why ESA therapy is needed, how it works and what benefits and side effects may be experienced. \n\nWhen managing the treatment of anaemia of CKD, there should be agreed protocols defining roles and responsibilities of healthcare professionals in primary and secondary care. \n\nExplain to people receiving ESA therapy about the importance of concordance with therapy and the consequences of poor adherence. \n\nWhen prescribing ESA therapy, take into account the person's preferences about supervised‑ or self‑administration, dose frequency, pain on injection, method of supplying ESA and storage. \n\nIn order for people to self‑administer their ESA in a way that is clinically effective and safe, make arrangements to provide ready, reasonable and uninterrupted access to supplies. \n\n## Patient education programmes\n\nOffer culturally and age‑appropriate patient education programmes to all adults, children and young people diagnosed with anaemia of CKD (and their families and carers). These should be repeated as requested, and according to the person's changing circumstances. They should include the following key areas:\n\nPractical information about how anaemia of CKD is managed.\n\nKnowledge (for example, about symptoms, iron management, causes of anaemia, associated medications, phases of treatment).\n\nProfessional support (for example, contact information, community services, continuity of care, monitoring, feedback on progress of results).\n\nLifestyle (for example, diet, physical exercise, maintaining normality, meeting other people with the condition).\n\nAdaptation to chronic disease (for example, previous information and expectations, resolution of symptoms). \n\n# Assessing and optimising erythropoiesis in people with anaemia\n\n## Benefits of treatment with ESAs\n\nOffer treatment with ESAs to adults, children and young people with anaemia of CKD who are likely to benefit in terms of quality of life and physical function. \n\n## Blood transfusions\n\nAvoid blood transfusions if possible in people with anaemia of CKD in whom kidney transplant is a treatment option. \n\nIf a transfusion is indicated clinically in a person with anaemia of CKD, follow NICE's guideline on blood transfusion. [2006, amended 2015]\n\n## Comparisons of ESAs\n\nDiscuss the choice of ESA with the person with anaemia of CKD when starting treatment and at subsequent review, taking into account:\n\nthe person's dialysis status\n\nthe route of administration\n\nthe local availability of ESAs\n\nthe lack of evidence comparing the efficacy of ESAs. \n\n## Coordinating care\n\nEnsure people with anaemia of CKD have access to a designated contact person or people who have principal responsibility for their anaemia management and who have skills in the following activities:\n\nMonitoring and managing a caseload in line with locally agreed protocols.\n\nProviding information, education and support to empower people and their families and carers to participate in their care.\n\nCoordinating an anaemia service for people with CKD, working between secondary and primary care and providing a single point of contact, to ensure people receive a seamless service of the highest standard.\n\nPrescribing medicines related to anaemia management and monitoring their effectiveness. \n\n## Providing ESAs\n\nAgree a treatment plan between the prescriber and the person with anaemia of CKD that ensures ESA therapy is clinically effective, consistent and safe. The plan should be person‑centred and include:\n\ncontinuity of medicine supply\n\nflexibility of where the medicine is delivered and administered\n\nthe person's lifestyle and preferences\n\ncost of medicine supply\n\ndesire for self‑care if appropriate\n\nregular review of the plan in light of changing needs. \n\n## ESAs: optimal route of administration\n\nAgree the route of administration of ESAs between the person with anaemia of CKD and the prescriber, and revise as appropriate. Take into account the following factors:\n\npatient population (for example, people having haemodialysis)\n\npain of injection\n\nfrequency of administration\n\nthe person's lifestyle and preferences\n\nefficacy (for example, subcutaneous compared with intravenous administration, or long‑acting compared with short‑acting preparations)\n\ncost of medicine supply. \n\nThe prescriber should take into account that when using short‑acting ESAs, subcutaneous injection allows the use of lower doses of medicines than intravenous administration. \n\n## ESAs: dose and frequency\n\nWhen correcting anaemia of CKD, the dose and frequency of ESA should be:\n\ndetermined by the duration of action and route of administration of the ESA\n\nadjusted to keep the rate of Hb increase between 10 and 20\xa0g/litre/month. \n\n## Optimal Hb levels\n\nWhen determining individual aspirational Hb ranges for people with anaemia of CKD, take into account:\n\ntheir preferences\n\nsymptoms and comorbidities\n\nthe necessary treatment. \n\nDo not routinely correct Hb to normal levels with ESAs in adults, children and young people with anaemia of CKD.\n\nTypically maintain the aspirational Hb range between 100 and 120\xa0g/litre for adults, young people and children aged 2\xa0years and over, and between 95 and 115\xa0g/litre for children under 2\xa0years, reflecting the lower normal range in that age group.\n\nTo keep the Hb level within the aspirational range, do not wait until Hb levels are outside the aspirational range before adjusting treatment (for example, take action when Hb levels are within 5\xa0g/litre of the range's limits). Follow the MHRA safety advice on recombinant human erythropoietins, particularly the advice to avoid Hb levels above 120\xa0g/litre because of the increased risk of death and serious adverse cardiovascular events in people with CKD. People should have close monitoring to ensure that the lowest approved dose of ESA is used to provide adequate control of the anaemia symptoms. \n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on optimal Hb levels\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: aspirational haemoglobin target range for children and young people with CKD.\n\nLoading. Please wait.\n\nConsider accepting Hb levels below the agreed aspirational range if:\n\nhigh doses of ESAs are needed to achieve the aspirational range or\n\nthe aspirational range is not achieved despite escalating ESA doses. High doses are more than 175\xa0IU/kg per week for people having haemodialysis; more than 125\xa0IU/kg per week for people having peritoneal dialysis; more than 100\xa0IU/kg per week for people not having dialysis. \n\nDo not use age alone to determine treatment of anaemia of CKD. \n\n## Adjusting ESA treatment\n\nOptimise iron status before or at the same time as starting ESAs and during maintenance treatment with ESAs. [2006, amended 2011]\n\nUse of ACE inhibitors or angiotensin type II receptor antagonists is not precluded, but if they are used, an increase in ESA therapy should be considered. \n\nTake into account Hb measurements when determining the dose and frequency of ESA administration.\n\nInvestigate the cause of an unexpected change in Hb level (that is, intercurrent illness or bleeding) to enable intervention and optimise iron status.\n\nIncrease or decrease ESA dose and/or frequency when Hb measurements fall outside action thresholds (usually below 105\xa0g/litre or above 115\xa0g/litre), or for example when the rate of change of Hb suggests an established trend (for example, greater than 10\xa0g/litre/month). [2006, amended 2011]\n\n## Correcting iron deficiency\n\nOffer iron therapy to adults, children and young people with anaemia of CKD who are receiving ESAs to achieve:\n\npercentage of hypochromic red blood cells less than 6% (unless ferritin is greater than 800\xa0micrograms/litre)\n\nreticulocyte Hb count or equivalent tests above 29\xa0pg (unless serum ferritin is greater than 800 micrograms/litre).If these tests are not available or the person has thalassaemia or thalassaemia trait, iron therapy should maintain transferrin saturation greater than 20% and serum ferritin level greater than 100\xa0micrograms/litre (unless serum ferritin is greater than 800\xa0micrograms/litre).Most adults will need 500 to 1,000\xa0mg of iron (equivalent doses for children) in a single or divided dose depending on the preparation. Intravenous iron should be administered in a setting with facilities for resuscitation. In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.\n\nOffer a high-dose intravenous iron regimen to adults, children and young people with stage 5 CKD on in-centre (hospital or satellite unit) haemodialysis, if they have iron deficiency (see recommendation 1.7.3).See table\xa03 for an example of a high-dose intravenous iron regimen for adults or use a bioequivalent dose of iron. For children and young people, use the maximum dosing regimen in the British National Formulary for Children (BNFc) unless serum ferritin is greater than 800\xa0micrograms/litre when the dose should be withheld. In August 2021, this was an off-label use of intravenous iron products for some children and young people. See NICE's information on prescribing medicines. \n\nIron status\n\nIntravenous iron sucrose (high-dose regimen)\n\nFirst month\n\nmg divided equally over 3 haemodialysis sessions\n\nSecond month onwards if ferritin 700\xa0micrograms/litre or less\n\nmg during each of the first 2 dialysis sessions\n\nSecond month onwards if ferritin over 700\xa0micrograms/litre and/or transferrin saturation 40% or more and/or C-reactive protein (CRP) over 50\xa0mg/litre\n\nWithhold iron dose\n\nIntravenous iron sucrose based on the high-dose iron regimen in the PIVOTAL trial (Macdougall 2019), which included people with serum ferritin below 400\xa0micrograms/litre, a transferrin saturation below 30% and a CRP below 50\xa0mg/litre and on ESA.\n\nFor a short explanation of why the committee made the 2021 recommendation and how it might affect practice, see the rationale and impact section on correcting iron deficiency\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review K: anaemia – IV iron.\n\nLoading. Please wait.\n\n## Maintaining iron levels after a deficiency is corrected\n\nOnce the percentage of hypochromic red blood cells is less than 6%, reticulocyte Hb count or equivalent tests are above 29\xa0pg, or transferrin saturation is greater than 20% and serum ferritin level is greater than 100\xa0micrograms/litre, offer maintenance iron to people with anaemia of CKD who are receiving ESAs.The dosing regimen will depend on modality, for example people having haemodialysis will need the equivalent of 50 to 60\xa0mg intravenous iron per week (or an equivalent dose in children of 1\xa0mg/kg/week). In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.\n\n## Monitoring iron status during ESA treatment\n\nOffer iron therapy to adults, children and young people receiving ESA maintenance therapy to keep their:\n\npercentage of hypochromic red blood cells less than 6% (unless serum ferritin is greater than 800\xa0micrograms/litre)\n\nreticulocyte Hb count or equivalent tests above 29\xa0pg (unless serum ferritin is greater than 800\xa0micrograms/litre)\n\ntransferrin saturation level above 20% and serum ferritin level above 100\xa0micrograms/litre (unless serum ferritin is greater than 800\xa0micrograms/litre).The marker of iron status should be monitored every 1 to 3\xa0months in people having haemodialysis.In people who are pre-dialysis or receiving peritoneal dialysis, levels are typically monitored every 3\xa0months. If these people have a normal full blood count there is little benefit in checking iron status. In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.\n\n## Iron therapy for people who are iron deficient and not on ESA therapy\n\nOffer iron therapy to adults, children and young people with anaemia of CKD who are iron deficient and who are not receiving ESA therapy, before discussing ESA therapy. (In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines).\n\nDiscuss the risks and benefits of treatment options. Take into account the person's choice.\n\nFor people who are not having haemodialysis, consider a trial of oral iron before offering intravenous iron therapy. If they are intolerant of oral iron or target Hb levels are not reached within 3\xa0months (see recommendation 1.9.11), offer intravenous iron therapy.\n\nFor people who are having haemodialysis, offer intravenous iron therapy. Offer oral iron therapy to people who are having haemodialysis only if:\n\n\n\nintravenous iron therapy is contraindicated or\n\nthe person chooses not to have intravenous iron therapy after discussing the relative efficacy and side effects of oral and intravenous iron therapy. \n\n\n\nDiscuss the results of the iron therapy with the person or, if appropriate, with their family or carers and offer ESA therapy if needed (see recommendation 1.9.1). \n\n## Iron therapy for people who are iron deficient and receiving ESA therapy\n\nOffer iron therapy to adults, children and young people with anaemia of CKD who are iron deficient and who are receiving ESA therapy. (In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines).\n\nDiscuss the risks and benefits of treatment options. Take into account the person's choice.\n\nFor adults and young people, offer intravenous iron therapy.\n\nFor children who are having haemodialysis, offer intravenous iron therapy.\n\nFor children who are not having haemodialysis, consider oral iron. If the child is intolerant of oral iron or target Hb levels are not reached within 3\xa0months (see recommendation\xa01.9.11), offer intravenous iron therapy. \n\nOffer oral iron therapy to adults and young people who are receiving ESA therapy only if:\n\nintravenous iron therapy is contraindicated or\n\nthe person chooses not to have intravenous iron therapy after discussing the relative efficacy and side effects of oral and intravenous iron therapy. \n\nWhen offering intravenous iron therapy to people not having haemodialysis, consider high‑dose low‑frequency intravenous iron as the treatment of choice for adults and young people when trying to achieve iron repletion. Take into account all of the following:\n\npreferences of the person with anaemia of CKD or, if appropriate, their family or carers\n\nnursing and administration costs\n\ncost of local medicine supply\n\nprovision of resuscitation facilities.High-dose and low-frequency iron is a maximum of 2\xa0infusions, with a minimum of 500\xa0mg of iron in each infusion for adults. Low dose and high frequency is more than 2 infusions with 100\xa0mg to 200\xa0mg of iron in each infusion for adults. In August 2021, this was an off-label use of intravenous iron products for some ages of children and young people. See NICE's information on prescribing medicines.\n\n# Monitoring anaemia treatment\n\n## Monitoring iron status\n\nDo not check iron levels earlier than 1\xa0week after administering intravenous iron in adults, children and young people with anaemia of CKD. The length of time to monitoring of iron status is dependent on the product used and the amount of iron given. \n\nCarry out routine monitoring of iron stores to prevent iron overload using serum ferritin at intervals of 1 to 3\xa0months. [2006, amended 2015]\n\n## Monitoring Hb levels\n\nIn adults, children and young people with anaemia of CKD, monitor Hb:\n\nevery 2 to 4\xa0weeks in the induction phase of ESA therapy\n\nevery 1 to 3\xa0months in the maintenance phase of ESA therapy\n\nmore frequently after an ESA dose adjustment\n\nin a clinical setting chosen in discussion with the person, taking into account their convenience and local healthcare systems. \n\n## Detecting ESA resistance\n\nAfter other causes of anaemia, such as intercurrent illness or chronic blood loss have been excluded, regard people with anaemia of CKD as resistant to ESAs when:\n\nan aspirational Hb range is not achieved despite treatment with 300\xa0IU/kg/week or more of subcutaneous epoetin or 450\xa0IU/kg/week or more of intravenous epoetin or 1.5\xa0micrograms/kg/week of darbepoetin or\n\nthere is a continued need for the administration of high doses of ESAs to maintain the aspirational Hb range. \n\nIn people with CKD, pure red cell aplasia (PRCA) is indicated by a low reticulocyte count, together with anaemia and the presence of neutralising antibodies. Confirm PRCA by the presence of anti‑erythropoietin antibodies together with a lack of pro‑erythroid progenitor cells in the bone marrow. \n\nIn people with anaemia of CKD, aluminium toxicity should be considered as a potential cause of a reduced response to ESAs after other causes, such as intercurrent illness and chronic blood loss, have been excluded. \n\n## Managing ESA resistance\n\nIf aluminium toxicity is suspected in an adult, child or young person with anaemia of CKD having haemodialysis, perform a desferrioxamine test and review the management of their condition accordingly. \n\nConsider specialist referral for people with ESA‑induced PRCA. [2006, amended 2011]\n\n## Role of blood transfusion in managing ESA resistance\n\nConsider referring adults, children and young people with ESA resistance to a haematology service, particularly if an underlying haematological disorder is suspected. \n\nEvaluate and discuss the risks and benefits of red cell transfusion with the person or, if appropriate, with their family or carers. \n\nTake into account the person's symptoms, quality of life, underlying conditions and the chance of a future successful kidney transplant, in addition to Hb levels, when thinking about the need for red cell transfusion. \n\nReview the rate of red cell transfusion and consider a trial period of stopping ESA in people who have ESA resistance (typically on haemodialysis and on high‑dose ESA) and are having frequent transfusions when:\n\nall reversible causes of ESA resistance have been taken into account and excluded and\n\nthe person's condition is otherwise stable (without intercurrent illness such as infection) and\n\nthe person is receiving adequate dialysis.Review the rate of red cell transfusion between 1\xa0and 3\xa0months after stopping ESA therapy. If the rate of transfusion has increased, consider restarting ESA therapy. \n\n# Hyperphosphataemia in people with CKD stage 4 or 5\n\n## Dietary management for adults, children and young people\n\nA specialist renal dietitian, supported by healthcare professionals with the necessary skills and competencies, should carry out a dietary assessment and give individualised information and advice on dietary phosphate management. \n\nTailor advice on dietary phosphate management to the person's learning needs and preferences, rather than using a generalised or complex multicomponent programme of delivery. \n\nGive information about controlling intake of phosphate-rich foods (in particular, foods with a high phosphate content per gram of protein, as well as food and drinks with high levels of phosphate additives) to control serum phosphate, while avoiding malnutrition by maintaining a protein intake at or above the minimum recommended level. For people on dialysis, take into account possible dialysate protein losses. \n\nIf a nutritional supplement is needed to maintain protein intake in children and young people with hyperphosphataemia, offer a supplement with a lower phosphate content, taking into account the person's preference and other nutritional requirements. \n\n## Before starting phosphate binders for adults, children and young people\n\nBefore starting phosphate binders for adults, children and young people with CKD stage 4 or 5, optimise:\n\ndiet (see recommendations 1.4.7 to 1.4.9 for adults)\n\ndialysis, for people who are having this. \n\nWhen offering a phosphate binder, explain to them and their family members or carers (as appropriate):\n\nthe reason for offering phosphate binders\n\nthe risks if they are not taken\n\nthe side effects linked to phosphate binders\n\nwhen and how they have to be taken (depending on the type of binder), including the exact timing (before, with or after food) and the need to take them with food containing phosphate (including, for example, high-protein snacks). \n\nTake into account the person's preferences on phosphate binders. \n\nIf the person has problems taking the first phosphate binder offered, consider switching to the next recommended one (see recommendations 1.11.9 to 1.11.15). \n\n## Phosphate binders for children and young people\n\nOffer children and young people with CKD stage 4 or 5 and hyperphosphataemia a calcium-based phosphate binder to control serum phosphate levels. In August 2021, this was an off-label use of some calcium-based phosphate binders in people not on dialysis. See NICE's information on prescribing medicines.\n\nIf serum calcium increases towards, or above, the age-adjusted upper normal limit:\n\ninvestigate possible causes other than the phosphate binder\n\nconsider reducing the dose of the calcium-based phosphate binder and adding sevelamer carbonate or switching to sevelamer carbonate alone. In August 2021, this was an off-label use of sevelamer carbonate. See NICE's information on prescribing medicines.\n\nFor all children and young people who are taking more than 1 phosphate binder, titrate the dosage to achieve the best possible control of serum phosphate while keeping serum calcium levels below the upper normal limit. \n\n## Phosphate binders for adults\n\nOffer adults with CKD stage 4 or 5 and hyperphosphataemia calcium acetate to control serum phosphate levels. In August 2021, this was an off-label use of calcium acetate in people not on dialysis. See NICE's information on prescribing medicines.\n\nOffer sevelamer carbonate if calcium acetate is not indicated (for example, because of hypercalcaemia or low serum parathyroid hormone levels) or not tolerated. In August 2021, this was an off-label use of sevelamer carbonate. See NICE's information on prescribing medicines.\n\nIf calcium acetate and sevelamer carbonate cannot be used, consider:\n\nsucroferric oxyhydroxide, for adults on dialysis if a calcium-based phosphate binder is not needed or\n\ncalcium carbonate, if a calcium-based phosphate binder is needed. In August 2021, this was an off-label use of these phosphate binders in people not on dialysis. See NICE's information on prescribing medicines. \n\nOnly consider lanthanum carbonate for adults with CKD stage 4 or 5 if other phosphate binders cannot be used. In August 2021, this was an off-label use of lanthanum carbonate phosphate binders in people not on dialysis and with serum phosphate levels less than 1.78\xa0mmol/l. See NICE's information on prescribing medicines. \n\nIf adults with CKD stage 4 or 5 remain hyperphosphataemic after taking the maximum dose recommended in the BNF (or the maximum dose they can tolerate if that is lower), of a calcium-based phosphate binder:\n\ncheck they are taking it as prescribed\n\nconsider combining a calcium-based phosphate binder with a non-calcium-based phosphate binder. \n\nFor all adults who are taking more than 1 phosphate binder, titrate the dosage to achieve the best possible control of serum phosphate while keeping serum calcium levels below the upper normal limit. \n\n## Review of treatments in adults, children and young people\n\nAt every routine clinical review, assess the person's serum phosphate control, taking into account:\n\ndiet\n\nwhether they are taking the phosphate binders as prescribed\n\nother relevant factors, such as vitamin D levels, serum parathyroid hormone levels, alkaline phosphatase, serum calcium, medications that might affect serum phosphate, or dialysis. \n\nFor a short explanation of why the committee made these 2021 recommendations and how they might affect practice, see the rationale and impact section on hyperphosphataemia in people with CKD stage 4 or 5\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: use of phosphate binders.\n\nLoading. Please wait.\n\n# Other complications in adults\n\n## Bone metabolism and osteoporosis\n\nDo not routinely measure calcium, phosphate, parathyroid hormone and vitamin\xa0D levels in adults with a GFR of 30\xa0ml/min/1.73\xa0m2 or more (GFR category G1, G2 or G3). \n\nMeasure serum calcium, phosphate and parathyroid hormone concentrations in adults with a GFR of less than 30\xa0ml/min/1.73\xa0m2 (GFR category G4 or G5). Determine the subsequent frequency of testing by the measured values and the clinical circumstances. If doubt exists, seek specialist opinion. \n\nOffer bisphosphonates if indicated for the prevention and treatment of osteoporosis in adults with a GFR of 30\xa0ml/min/1.73\xa0m2 or more (GFR category G1, G2 or G3). \n\nDetailed advice on the management of CKD–mineral and bone disorders is beyond the scope of this guideline. If uncertain, seek advice from your local renal service.\n\nDo not routinely offer vitamin\xa0D supplementation to manage or prevent CKD–mineral and bone disorders. \n\nOffer colecalciferol or ergocalciferol to treat vitamin\xa0D deficiency in people with CKD and vitamin\xa0D deficiency. \n\nIf vitamin D deficiency has been corrected and symptoms of CKD–mineral and bone disorders persist, offer alfacalcidol (1‑alpha‑hydroxycholecalciferol) or calcitriol (1‑25‑dihydroxycholecalciferol) to people with a GFR of less than 30\xa0ml/min/1.73\xa0m2 (GFR category G4 or G5). \n\nMonitor serum calcium and phosphate concentrations in people receiving alfacalcidol or calcitriol supplements. \n\n## Oral bicarbonate supplements in the management of metabolic acidosis\n\nDetailed advice on the management of metabolic acidosis is beyond the scope of this guideline. If uncertain, seek advice from your local renal service.\n\nConsider oral sodium bicarbonate supplementation for adults with both:\n\na GFR less than 30\xa0ml/min/1.73\xa0m2 (GFR category G4 or G5) and\n\na serum bicarbonate concentration of less than 20\xa0mmol/litre. \n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary.\n\n## Chronic kidney disease (CKD)\n\nAbnormalities of kidney function or structure present for more than 3\xa0months, with implications for health. This includes all people with markers of kidney damage and those with a glomerular filtration rate (GFR) of less than 60\xa0ml/min/1.73\xa0m2 on at least 2 occasions separated by a period of at least 90\xa0days (with or without markers of kidney damage).\n\n## Classification of CKD\n\nCKD is classified according to estimated GFR (eGFR) and albumin:creatinine ratio (ACR) (see table\xa01), using 'G' to denote the GFR category (G1 to G5, which have the same GFR thresholds as the CKD stages 1 to 5 recommended previously) and 'A' for the ACR category (A1 to A3), for example:\n\nA person with an eGFR of 25\xa0ml/min/1.73\xa0m2 and an ACR of 15\xa0mg/mmol has CKD G4A2.\n\nA person with an eGFR of 50\xa0ml/min/1.73\xa0m2 and an ACR of 35\xa0mg/mmol has CKD G3aA3.\n\nAn eGFR of less than 15\xa0ml/min/1.73\xa0m2 (GFR category G5) is referred to as kidney failure.\n\n## Glomerular filtration rate (GFR)\n\nThis is abbreviated in the following way in this guideline:\n\nGFR: either a measured or an estimated GFR\n\neGFR: estimated GFR (without indicating the method of estimation)\n\neGFRcreatinine: an estimation of GFR using serum creatinine\n\n## -variable Kidney Failure Risk Equation\n\nA person's 5-year risk of needing renal replacement therapy (defined as the need for dialysis or transplant) is estimated, as in Major 2019, as:\n\nIn the above, eGFR is reported in ml/min/1.73\xa0m2 and ACR in mg/mmol. Where the term 'male' is used, this should be replaced by a 1 if the person being assessed is male, and a 0 if they are female. This equation and its coefficients are validated in a UK population, and it is important to use this version, and not a version validated in another country.\n\n## Markers of kidney damage\n\nThese include albuminuria (ACR more than 3\xa0mg/mmol), urine sediment abnormalities, electrolyte and other abnormalities due to tubular disorders, abnormalities detected by histology, structural abnormalities detected by imaging, and a history of kidney transplantation.\n\n## Pre-dialysis\n\nUsually regarded to be CKD stages 4 and 5, although there is no accepted definition. Pre-dialysis includes people with a failing transplant and people having conservative management.\n\n## Renal replacement therapy (RRT)\n\nLife-supporting treatments for severe acute kidney injury or stage 5 CKD. This includes haemodialysis, haemofiltration, haemodiafiltration, peritoneal dialysis and kidney transplantation.\n\n## Renin–angiotensin–aldosterone system antagonist\n\nA medicine that blocks or inhibits the renin–angiotensin–aldosterone system, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs), direct renin inhibitors and aldosterone antagonists.\n\n## Renin–angiotensin system antagonist\n\nA medicine that blocks or inhibits the renin–angiotensin system, including ACE inhibitors, ARBs and direct renin inhibitors. This group of medicines does not include aldosterone antagonists.", 'Recommendations for research': "As part of the 2021 update, the guideline committee made 18 recommendations for research on chronic kidney disease (CKD). They prioritised 5 key recommendations for research. They also retained some recommendations for research from previous guidelines.\n\n# Key recommendations for research\n\n## Creatinine-based estimate of eGFR – existing calculations\n\nIn adults, children and young people from black, Asian and other minority ethnic groups with CKD living in the UK, which existing eGFR calculations are the most accurate? \n\n## Creatinine-based estimate of eGFR – improving accuracy of calculations\n\nIn adults, children and young people from black, Asian and other minority ethnic groups with CKD living in the UK, what biomarkers or factors, other than ethnicity, improve the diagnostic accuracy of eGFR calculations? \n\nFor a short explanation of why the committee made these recommendations for research, see the rationale on creatinine-based estimate of GFR\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review A: diagnostic accuracy of eGFR calculations in adults, children, and young people from black, Asian and other minority ethnic groups with CKD.\n\nLoading. Please wait.\n\n## Risk assessment for black, Asian and minority ethnic groups\n\nWhat is the accuracy of the 4-variable Kidney Failure Risk Equation in adults, children and young people with CKD from black, Asian and minority ethnic groups living in the UK? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on risk assessment, referral criteria and shared care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review F: the best combination of measures to identify increased risk of progression in adults, children and young people.\n\nLoading. Please wait.\n\n## Managing anaemia – optimal Hb levels for children and young people\n\nWhat is the efficacy and safety of different aspirational haemoglobin (Hb) targets for children and young people with CKD undergoing treatment for anaemia? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on optimal Hb levels\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review J: aspirational haemoglobin target range for children and young people with CKD.\n\nLoading. Please wait.\n\n## Hyperphosphatemia in people with CKD stage 4 or 5\n\nWhat are people with CKD and their family members and carers views and beliefs about taking oral phosphate binders? \n\nFor a short explanation of why the committee made this recommendation for research, see the rationale on hyperphosphataemia in people with CKD stage 4 or 5\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review L: use of phosphate binders.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Cystatin-C equations\n\nWhat is the diagnostic accuracy of cystatin-C equations to estimate GFR as a measurement of kidney function in adults, young people and children in the UK? \n\n## Investigations for proteinuria\n\nIn children and young people, what is the accuracy of reagent strips for detecting albumin in urine? \n\nWhat is the effect of measuring proteinuria with albumin:creatinine ratio compared with protein:creatinine ratio on the timing of treatment changes in children and young people with CKD? \n\n## Frequency of monitoring\n\nFor adults, children and young people with CKD, what is the optimal monitoring frequency for albumin:creatinine ratio? \n\n## Risk assessment, referral criteria and shared care\n\nWhat is the association between risk factors and CKD outcomes in children and young people? \n\nWhat is the accuracy of the 4-variable Kidney Failure Risk Equation in children and young people living in the UK? \n\n## Frequency of review\n\nWhat is the most clinical and cost-effective frequency of review for children and young people with CKD? \n\n## Managing anaemia\n\nFor adults, children and young people with CKD and anaemia, what is the diagnostic accuracy of eGFR thresholds of 60, 45, and 30\xa0ml/min/1.73\xa0m2 for determining whether the anaemia is due to CKD? \n\nFor adults, children and young people with CKD and anaemia who are on peritoneal dialysis, what amount of intravenous (IV) iron is most clinically and cost effective in managing anaemia and its associated outcomes (including quality of life)? \n\nWhat are the long-term consequences of high ferritin levels (above 800\xa0micrograms/litre) in children and young people with CKD? \n\n## Phosphate binders\n\nWhich binders are the most clinically and cost effective in controlling serum phosphate in adults, children and young people with stage 4 or 5 CKD who are not on dialysis? \n\nIn adults with stage 4 or 5 CKD, including those on dialysis, what is the clinical and cost effectiveness and safety of long-term calcium acetate combined with magnesium carbonate for controlling serum phosphate? \n\n## Self-management of CKD\n\nDoes the provision of educational and supportive interventions to people with CKD by healthcare professionals increase the person's skills and confidence in managing their conditions and improve clinical outcomes? \n\n## Antiplatelet therapy\n\nFor people with CKD at the highest risk of cardiovascular disease, what is the clinical effectiveness of low-dose aspirin compared with placebo for primary prevention of cardiovascular disease? \n\n## Renin–angiotensin–aldosterone system antagonists\n\nFor people aged over 75\xa0years with CKD, what is the clinical effectiveness of renin–angiotensin–aldosterone system (RAAS) antagonists? \n\n## Vitamin D supplements in the management of CKD–mineral and bone disorders\n\nIn people with hyperparathyroidism secondary to CKD, does treatment with vitamin\xa0D or vitamin\xa0D analogues improve patient-related outcomes? \n\n## Management of anaemia of CKD with concurrent illness\n\nWhat is the optimal management (in terms of clinical and cost effectiveness) of anaemia of CKD in people who are receiving erythropoietic stimulating agents (ESAs) and have a significant concurrent acute infectious illness? \n\n## Treatment of ESA resistance in people on haemodialysis\n\nWhat is the most effective type of intervention to treat people on haemodialysis with ESA‑resistant anaemia? ", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Creatinine-based estimate of glomerular filtration rate (GFR)\n\n## Why the committee did not make recommendations\n\nEvidence on the specific eGFR equations or ethnicity adjustments seen by the committee was not from UK studies so may not be applicable to UK black, Asian and minority ethnic groups. None of the studies included children and young people. The committee was also concerned about the value of P30 as a measure of accuracy (P30 is the probability that the measured value is within 30% of the true value), the broad range of P30 values found across equations and the relative value or accuracy of ethnicity adjustments to eGFR equations in different ethnic groups. The committee agreed that adding an ethnicity adjustment to eGFR equations for different ethnicities may not be valid or accurate. Categorisations based on ethnicity lump together people with a diverse range of family backgrounds and differences in eGFR across ethnicities are likely to at least partly arise because of differences in average muscle mass between ethnic groups. However, muscle mass also differs from person to person within the same ethnicity and so making an adjustment based on ethnicity may be inaccurate for some people. Therefore, the committee agreed to remove the 2014 recommendation on how to adjust the CKD-EPI creatinine equation for adults of African-Caribbean or African family origin. The committee highlighted the 2008 recommendation, which states that caution should be used when interpreting eGFR and in adults with extremes of muscle mass and on those who consume protein supplements (this was added to recommendation 1.1.1). The committee made recommendations for research on appropriate eGFR equations for black, Asian and minority ethnic groups (adults, children and young people) in the UK (see recommendations for research 1 and 2). They agreed that factors other than ethnicity should also be explored as biomarkers.\n\nThe committee agreed that in the absence of good evidence for their accuracy, the 2014 recommendations that cystatin-c equations should be considered during diagnosis in certain circumstances, should be removed. In particular, they noted that although using cystatin-c equations may reduce false-positive results, it is likely to also increase false-negative results. This will avoid potentially misleading tests being conducted and the costs associated with these. They made a recommendation for research for a large study using UK data to evaluate the accuracy of cystatin-c equations (see other recommendations for research).\n\n## Impact on practice\n\nThere will be an impact on practice, as the adjustment of the CKD-EPI creatinine equation for adults of African-Caribbean or African family origin has been removed from the guideline. Only a small number of centres in the UK currently use cystatin-c equations regularly, so most should not be affected by the removal of the cystatin-c recommendations.\n\nReturn to recommendations\n\n# Investigations for proteinuria\n\nRecommendations 1.1.10 to 1.1.14\n\n## Why the committee made the recommendations\n\nFor children and young people with CKD, there was no evidence for the accuracy of measuring albumin:creatinine ratio (ACR) compared with protein:creatinine ratio (PCR) to quantify proteinuria. The committee discussed the recommendations for adults and agreed that, overall, these fit well with current practice and can be recommended for children and young people as well.\n\nThe committee discussed the eGFR threshold recommended for quantifying urinary albumin or urinary protein loss in adults without diabetes. They agreed that this threshold is not appropriate for children and young people because any reduction in GFR in this population would prompt measuring proteinuria. Therefore, for children and young people they set the threshold for creatinine as above the upper limit of the age-appropriate reference range.\n\nThe committee agreed to make a recommendation for research to identify the effect of measuring proteinuria with ACR compared with PCR on the timing of treatment changes in children and young people with CKD and the consequences of the delay in treatment changes on different levels of proteinuria. (See other recommendations for research.)\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice, so no additional resources should be needed.\n\nReturn to recommendations\n\n# Reagent strips for proteinuria and haematuria\n\nRecommendations 1.1.15 to 1.1.16\n\n## Why the committee made the recommendations\n\nThe evidence showed that reagent strips were less useful to rule out than to rule in proteinuria. The committee highlighted that ruling out proteinuria with confidence was the main goal when using reagent strips. Therefore, they agreed that reagent strips should not be used to identify proteinuria in children and young people. The evidence was not reviewed for adults and so the committee agreed to retain the 2014 recommendation not to use reagent strips to identify proteinuria in adults unless the strips are capable of specifically measuring albumin at low concentrations and expressing the result as an ACR. The committee also highlighted that these tests are commonly used in clinical practice and agreed to make a further recommendation for further investigations in adults, children and young people with an incidental finding of unexplained proteinuria on reagent strips. Further testing is needed to confirm CKD by identifying other markers of kidney damage (such as ACR or glomerular filtration rate).\n\nThere was limited evidence on the accuracy of reagent strips for albuminuria, so the committee did not feel able to make recommendations. There were only 2 studies, and only 1 showed that reagent strips could be useful.\n\nThere was no evidence on the accuracy of reagent strips for haematuria in children and young people. The 2014 guideline (which did not cover children and young people) recommended reagent strips for detecting haematuria in adults. The committee agreed to extend this recommendation to children and young people, because the evidence for adults is likely to be applicable to this population.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice, so no additional resources should be needed. The committee noted that if all dipstick tests are confirmed by laboratory testing anyway, there would be extra costs attached to using dipsticks as a first step, which were not justified by the benefits.\n\nReturn to recommendations\n\n# Who should be tested for CKD\n\nRecommendations 1.1.20 to 1.1.25\n\n## Why the committee made the recommendations\n\nFor children and young people, the evidence showed that acute kidney injury and solitary functioning kidney were clinically significant risk factors for developing CKD. The committee highlighted that solitary functioning kidney was not due to kidney donation but to nephrectomy secondary to congenital anomalies of the kidney and urinary tract or to a lack of a kidney at birth or a non-functioning kidney.\n\nThe committee highlighted that there were other important risk factors for developing CKD in children and young people, but that no evidence was found for these. Based on their clinical knowledge and experience, they added 'gout' as a risk factor for adults and 'low birth weight' as a risk factor for children and young people.\n\nThe committee agreed that the frequency of monitoring (for developing CKD or progression) should be individualised for adults, children and young people. This is to address the different characteristics and risks that each person will have.\n\nThe committee agreed that more research on risk factors for developing CKD in children and young people would help to strengthen current guidance, so they made a recommendation for research. (See other recommendations for research.)\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice, so no additional resources should be needed.\n\nReturn to recommendations\n\n# Frequency of monitoring\n\nRecommendations 1.3.1 to 1.3.4\n\n## Why the committee made the recommendations\n\nMost of the evidence showed that with eGFR decline, the risk of kidney disease progression and mortality increases, and this risk increases with the rate of eGFR decline. The committee agreed this is observed in clinical practice and any person presenting with an increase in eGFR decline would be monitored more frequently. The committee reviewed the recommendations and agreed that they are consistent with the evidence and clinical practice. They agreed to clarify monitoring by stating that repeat assessment is to be agreed with each person with or at risk of CKD.\n\nThe committee agreed that the frequency of monitoring they recommended was a minimum level and that more frequent monitoring would be appropriate for some patients. This should also be guided by rate of change in eGFR or ACR and specific comorbidities, including diabetes. ACR monitoring should be individualised. For example, ACR might be monitored more frequently in people with high ACR (categories A2 or A3), or if a change in ACR would affect management.\n\nThe committee made a recommendation for research to identify the optimal frequency of ACR monitoring in adults, children and young people with CKD. (See other recommendations for research.)\n\nThe committee discussed whether specific recommendations are needed for children and young people with CKD and decline in eGFR, but agreed that this population would be referred to specialist care.\n\n## How the recommendations might affect practice\n\nThe committee noted that no changes had been made to the previous suggested monitoring schedule, and they believed it was relatively well implemented in clinical practice. Therefore, they were confident there should not be a substantial impact on practice from the new recommendations.\n\nReturn to recommendations\n\n# Risk assessment, referral criteria and shared care\n\nRecommendation 1.5.1 to 1.5.9\n\n## Why the committee made the recommendations\n\nNew evidence found a UK validation of the 4-variable Kidney Failure Risk Equation for adults, which can be used as one of the referral criteria (5-year risk of needing renal replacement therapy greater than 5%). The results of both the validation study and cost-effectiveness modelling undertaken for the guideline showed using this equation and threshold as a referral criteria (rather than an eGFR threshold) was likely to be both more sensitive and more specific than the criteria in the 2014 NICE guideline, meaning people who will progress to needing renal replacement therapy are identified earlier, and there are fewer unnecessary referrals to secondary care.\n\nThe benefits of this approach over using an eGFR threshold (as in the 2014 NICE guideline) were not large, but the committee agreed they were meaningful. They also agreed there were additional potential benefits of using the 4-variable Kidney Failure Risk Equation, including the ability to provide people with an individual risk assessment, which could help them to proactively manage their own risk, and inform the management plans in secondary care.\n\nHowever, validation of the risk equation was only in adults, so the committee made a separate recommendation for children and young people. Black people were under-represented in the study and, although there was a sizeable proportion of people of Asian family origin, the location of the study suggests that people of east Asian family origin were likely to be under-represented. Therefore, the committee agreed to make recommendation for research 3 for validation of the risk equation in adults, children and young people from black, Asian and other minority ethnic groups living in the UK.\n\nThe committee agreed that it is important to discuss with a person with CKD what risk means. They added additional recommendations on providing information about risk, using jargon-free language, allowing enough time for discussions and documenting any decisions made.\n\n## How the recommendations might affect practice\n\nIf the 4-variable Kidney Failure Risk Equation can be built into laboratory computer systems, as part of how eGFR and ACR results are returned to GPs, there should be no difficulty in implementing the recommendations. Because the calculation requires both an eGFR and ACR value, it can only be produced if the GP requests both those measurements. These recommendations are intended to provide additional information to supplement eGFR and ACR values, rather than changing how often these values are requested by GPs.\n\nThere may be particular difficulties for laboratories that store eGFR and ACR values on separate systems that cannot automatically communicate. In this situation, calculations may have to be done manually. However, this is still likely to be a more efficient system than calculations being carried out routinely by GPs. Overall, the referral criteria are predicted to slightly reduce monitoring costs but, excluding costs associated with dialysis, overall there should be no substantial impact on resource use.\n\nThere may be an implementation period before the risk equation results are available to all GPs. Until then, some GPs may have to continue to base referral decisions on eGFR and ACR values independently, as is currently done, without providing patients with a quantitative assessment of their risk of needing renal replacement therapy. The faster these recommendations can be routinely adopted the less time it will be necessary for these 2 parallel approaches to both be in use.\n\nReturn to recommendations\n\n# Pharmacotherapy for blood pressure control\n\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\n\nResults from a meta-analysis (including the SPRINT trial) showed no meaningful difference between standard and more intensive blood pressure targets for adults with CKD. The 2014 guideline recommended maintaining systolic blood pressure below 140\xa0mmHg and diastolic blood pressure below 90\xa0mmHg. This is consistent with clinical practice and with the NICE guideline on managing hypertension. The committee noted that although there is limited evidence on blood pressure targets in people with CKD and proteinuria, it is important to maintain a systolic blood pressure below 130\xa0mmHg and a diastolic pressure below 80\xa0mmHg.\n\nThe committee agreed that none of the evidence they had seen warranted changing the recommendations. They also noted that intensive blood pressure targets only result in a marginal reduction in stroke and kidney failure, but put a large burden on patients in terms of polypharmacy and associated risks and side effects (such as falls).\n\nThe committee agreed that a useful target for blood pressure in children and young people with CKD and proteinuria is a systolic blood pressure below the 50th percentile for height.\n\nThe committee agreed that particular care had to be taken with people who were frail or who had multiple morbidities. However, the NICE guideline on hypertension already covers this group, so the committee did not make new recommendations.\n\n## How the recommendations might affect practice\n\nThe recommendations for adults are consistent with current practice and should not have an impact on resources. The recommendation for blood pressure targets in children and young people may have some cost implications, although the committee did not think they would be significant.\n\nReturn to recommendations\n\n# Pharmacotherapy for proteinuria and choice of antihypertensive agent\n\nRecommendations 1.6.5 to 1.6.12\n\n## Why the committee made the recommendations\n\nThe interventions recommended are intended to improve a range of outcomes, including rates of progression to end-stage renal disease. There was evidence for adults, but not for children and young people. Paediatric experts on the committee agreed that the evidence for adults was also applicable to children and young people. Therefore, the committee did not make separate recommendations for different age groups.\n\nThe evidence for adults covered people with proteinuria or albuminuria, and included people with diabetes. This allowed the committee to make separate recommendations for people with and without diabetes. In the committee's experience, many people with diabetes and CKD are frail, or are taking a lot of medicines, so they made a recommendation to address this.\n\nThe evidence showed that, compared with placebo, ACE inhibitors reduced the risk of end-stage renal disease in people without diabetes. ARBs did not show the same effect. However, the committee did not believe the evidence was sufficiently robust to show that ACE inhibitors were better than ARBs. In addition, for people with type\xa02 diabetes, ARBs did reduce the risk of end-stage renal disease and heart failure. Based on the limitations of the evidence and the evidence available for people with type\xa02 diabetes, the committee recommended both ACE inhibitors and ARBs.\n\nFor people with type\xa02 diabetes, ARBs reduced the risk of end-stage renal disease and heart failure. The committee also recommended ACE inhibitors because the evidence did not show a clear difference between ACE inhibitors and ARBs on the following outcomes:\n\nreduction of proteinuria\n\nend-stage renal disease\n\nall-cause mortality\n\ncardiovascular mortality\n\nnon-fatal cardiovascular events\n\nadverse events (hypotension)\n\nhospitalisation.\n\nThere was no evidence comparing ACE inhibitors with placebo in people with type\xa02 diabetes. The evidence for people without diabetes did show that ACE inhibitors reduced the risk of end-stage renal disease, compared with placebo. The committee used this evidence to make the recommendation for people with diabetes.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice, so no additional resources should be needed.\n\nReturn to recommendations\n\n# Diagnostic role of glomerular filtration rate\n\nRecommendation 1.7.2\n\n## Why the committee made the recommendation\n\nThere was limited evidence showing that eGFR thresholds below 60\xa0ml/min/1.73\xa0m2 could be used to identify anaemia as being due to CKD. The committee questioned the applicability of this evidence because the studies did not rule out other causes of anaemia (which is usually done in practice).\n\nThe limited evidence meant that the committee was unable to recommend specific thresholds or probabilities. Instead, they used the available evidence and their expertise to specify ranges of GFR indicating that anaemia is more or less likely to be caused by CKD.\n\nWhen anaemia may have other causes (such as gastrointestinal bleeding and certain cancers), investigating further will increase the chance of the real cause being identified and treated.\n\nClinical judgement is needed on how extensively to look for other causes when eGFR is between 30 and 60\xa0ml/min/1.73\xa0m2. Healthcare professionals will need to balance the risks of:\n\nputting people through extensive and unnecessary investigations when their anaemia is caused by CKD\n\nmissing the real cause of their anaemia by assuming it is caused by CKD.\n\nThe committee agreed that when eGFR is below 30\xa0ml/min/1.73\xa0m2, anaemia is more likely to be caused by CKD. However, healthcare professionals should still use their clinical judgement and think about people's circumstances when deciding whether further assessment is needed.\n\nOnly 1 study included people with diabetes, and no studies included children and young people. However, the recommendations still apply to these populations, because other causes of anaemia would be ruled out before attributing the anaemia to CKD.\n\nThe committee noted a need for further research on the diagnostic test accuracy of different eGFR thresholds, particularly for eGFR thresholds of 30 and 60\xa0ml/min/1.73\xa0m2. They highlighted that in clinical practice, an eGFR threshold of 45\xa0ml/min/1.73\xa0m2 can also trigger investigation into anaemia due to CKD, but limited evidence was identified for the diagnostic accuracy of this threshold. The committee made a recommendation for research on the diagnostic accuracy of these specific eGFR thresholds for determining the likelihood of anaemia being CKD related. (See other recommendations for research.)\n\n## How the recommendations might affect practice\n\nThese recommendations should not increase the cost to primary care, because they reflect current practice and act as cautions for healthcare professionals to explore the cause of anaemia. They may reduce costs by ensuring that the correct cause of anaemia is identified more quickly with appropriate investigations.\n\nReturn to recommendations\n\n# Optimal Hb levels\n\nRecommendation 1.9.11\n\n## Why the committee made the recommendation\n\nIn the 2015 guideline, an aspirational Hb range between 100 and 120\xa0g/litre was recommended for adults, young people and children aged 2\xa0years and over. For children under 2\xa0years, the Hb range was between 95 and 115\xa0g/litre. These were based on evidence for adults. In 2020, the committee reviewed the evidence specifically for children and young people. The only evidence for this population came from a single small low-quality study, comparing the effects of a high and low Hb target on left ventricular mass index. No difference in effect was found. Given the lack of evidence, the committee agreed that the recommendations made in 2015 should not be changed.\n\nThe 2015 guideline recommended using the same target Hb range as adults for children and young people over 2\xa0years, and a slightly lower level in children under\xa02. However, children and young people have different coagulation risks than adults, and are more prone to reductions in Hb from blood loss in haemodialysis circuits. In practice, higher Hb targets (up to 130\xa0g/litre) are often used for children and young people. Because of the lack of evidence in this age group, the committee agreed that research is needed to inform future guidance (see recommendation for research 4).\n\nReturn to recommendations\n\n# Correcting iron deficiency\n\nRecommendation 1.9.18\n\n## Why the committee made the recommendation\n\nFor people with stage\xa05 CKD who are on in-centre haemodialysis, the evidence showed that high-dose intravenous iron was better than a low-dose regimen at increasing levels of serum ferritin and haemoglobin as well as increasing the haematocrit. The committee agreed that the type of intravenous iron was not relevant and that there was no reason to recommend a specific preparation. They also highlighted that there are differences between iron preparations that affect their bioequivalence. Therefore, pharmacist advice is likely to be needed when choosing iron preparations. An example regimen for adults using iron sucrose was taken from the evidence to help guide practice. Ultimately, the choice of preparation should be based on local availability and policies. The committee agreed that children and young people should be given a high dose as set out in the BNFc, although they noted that use of intravenous iron preparations in children under 14\xa0years was off label.\n\nThe committee was aware of a MHRA alert on intravenous iron and serious hypersensitivity reactions. The alert states that 'intravenous iron products should only be administered when staff trained to evaluate and manage anaphylactic or anaphylactoid reactions – as well as resuscitation facilities – are immediately available.' The committee agreed that intravenous iron should not be administered at home but recognised that this has a significant impact on people on home dialysis.\n\nMost of the evidence was from studies with participants on haemodialysis. The committee agreed that more research would help to inform future guidance on intravenous iron for people with stage\xa05 CKD who are on peritoneal dialysis.\n\n## How the recommendations might affect practice\n\nThe recommendations are unlikely to lead to a substantial change in costs, as intravenous iron is relatively inexpensive, and there was evidence found in adults that use of high-dose iron leads to lower doses of erythropoiesis-stimulating agents being used, thereby offsetting any extra costs.\n\nReturn to recommendations\n\n# Hyperphosphataemia in people with CKD stage 4 or 5\n\nRecommendations 1.11.5 to 1.11.18\n\n## Why the committee made the recommendations\n\nThere was a significant amount of evidence (of varying quality) for adults with stage\xa05 CKD who are having dialysis. However, evidence was limited for adults not on dialysis, and for children and young people. The committee agreed to extrapolate from the evidence for adults with stage\xa05 CKD on dialysis, so they could make recommendations for the other groups.\n\nPeople's preferences need to be taken into account when offering phosphate binders, because this could have an impact on adherence. The differences in phosphate binder formulations (for example, chewable and non-chewable) and the effect this has on how they are taken (before, with or after food) mean that people will often prefer one phosphate binder over the others. Oral phosphate binders are also unpleasant to take, and this might affect adherence as well. It is important to involve people in the choice of phosphate binder as far as possible, to ensure they are prescribed one they are happy with and can take as recommended.\n\nThe committee highlighted several factors that renal physicians assess at clinical reviews for people who are taking phosphate binders (including parathyroid hormone, vitamin D and serum calcium).\n\nThe committee reviewed the recommendations from the 2013 guideline in the light of limited new evidence. For children and young people with high serum calcium, they agreed to recommend sevelamer carbonate instead of sevelamer hydrochloride. This is because sevelamer carbonate offers a better balance of benefits and costs. The committee highlighted that in growing children and young people, calcium is often maintained close to, but not above the upper limit of the age-related reference range. Calcium is essential for bone development in children.\n\nThe committee reviewed the evidence for phosphate binders both in adults on dialysis and adults not having dialysis. Although the evidence for those not on dialysis was limited, it did reflect the evidence for adults on dialysis in every area apart from sucroferric oxyhydroxide. As there was no evidence on sucroferric oxyhydroxide in adults not on dialysis, the committee did not recommend it for this group.\n\nThe evidence showed that the most cost-effective treatment strategy is to start with calcium acetate, and switch to sevelamer carbonate if the person gets hypercalcaemia. This is because:\n\ncalcium acetate as a first-line treatment provides the best balance of benefits, harms and costs\n\ncalcium carbonate is cheaper than calcium acetate, but is more likely to cause high serum calcium levels and associated adverse outcomes\n\nsevelamer carbonate and sevelamer hydrochloride are more expensive than calcium acetate, and do not provide enough benefit as a first-line treatment to justify the extra expense\n\nwhen people have high serum calcium levels and cannot take calcium acetate, sevelamer carbonate is the best alternative; it is cheaper than sevelamer hydrochloride, and provides similar benefits, however, it still costs more than calcium acetate and, for first-line treatment, it does not provide enough benefit to justify this extra expense\n\nsucroferric oxyhydroxide is not cost effective as a first-line treatment, but is a reasonable choice for people who cannot take calcium acetate or sevelamer carbonate\n\nlanthanum carbonate is much more expensive than calcium acetate and sevelamer carbonate and may provide less benefit than other non-calcium-based phosphate binders.\n\nBased on this evidence, the committee recommended a treatment sequence and alternatives for different situations.\n\nThe committee also agreed that diet and dialysis (when appropriate) had a large impact on serum phosphate levels. Therefore, before offering phosphate binders it is important to provide dietary advice and ensure people are on the dialysis regime that works best for them.\n\nThe committee made recommendation for research 5 to address the lack of evidence in adults not on dialysis.\n\n## How the recommendations might affect practice\n\nReplacing sevelamer hydrochloride with sevelamer carbonate may result in lower resource use, because there is a cheap generic version of sevelamer carbonate available.\n\nThere is currently variation across the UK in use of sucroferric oxyhydroxide. The recommendation on this phosphate binder may increase costs. However, this increase is unlikely to be substantial, because sucroferric oxyhydroxide is only recommended as a third-line option.\n\nReturn to recommendations", 'Context': 'Chronic kidney disease (CKD) describes abnormal kidney function or structure. It is common and often occurs with other conditions (such as cardiovascular disease and diabetes). Moderate to severe CKD is also associated with an increased risk of acute kidney injury, falls, frailty and mortality. The risk of developing CKD increases with age.\n\nCKD is usually asymptomatic, but it is detectable, and tests for CKD are simple and available. There is evidence that treatment can prevent or delay the progression of CKD, reduce or prevent the development of complications, and reduce the risk of cardiovascular disease. However, CKD is often unrecognised or diagnosed at an advanced stage. Late presentation of people with kidney failure increases morbidity, mortality and associated healthcare costs.\n\nAs kidney disease progresses, some coexisting conditions become more common and increase in severity. Hyperphosphataemia is an example of this, occurring because of insufficient filtering of phosphate from the blood by poorly functioning kidneys. This means that a certain amount of the phosphate does not leave the body in the urine, instead remaining in the blood at abnormally high levels.\n\nHigh serum phosphate levels can directly and indirectly increase parathyroid hormone secretion, leading to the development of secondary hyperparathyroidism. Left untreated, secondary hyperparathyroidism increases morbidity and mortality and may lead to renal bone disease, with people experiencing bone and muscular pain, fracture, bone and joint abnormalities, and vascular and soft tissue calcification.\n\nMany people with CKD or established renal failure also develop associated anaemia. The prevalence of anaemia associated with CKD increases progressively with the stage of CKD, especially when the person reaches stage 4 or 5. Anaemia of CKD contributes significantly to the burden of CKD. However, it is potentially reversible and manageable with appropriate identification and treatment.\n\nThe Health Survey for England (2016) found that 13% of adults (16\xa0years and over) had any CKD (stages 1 to 5). The prevalence of stages 3 to 5 was 5% for all adults, rising to 34% in people aged 75 and over. At the end of 2018 there were 826 children and young people and 66,612 adults receiving renal replacement therapy in the UK according to the UK Renal Registry annual report.\n\nSince publication of the previous guidelines, new evidence was identified for several areas. The following areas of the guideline have been updated:\n\ninvestigations for CKD\n\nclassification of CKD\n\nfrequency of monitoring for CKD\n\nblood pressure control for people with CKD\n\nphosphate binders to manage mineral and bone disorder in CKD\n\nglomerular filtration rate for diagnosing anaemia associated with CKD\n\nintravenous iron for treating anaemia associated with CKD.'}
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https://www.nice.org.uk/guidance/ng203
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This guideline covers care and treatment for people with, or at risk of, chronic kidney disease (CKD). It aims to prevent or delay the progression, and reduce the risk of complications and cardiovascular disease. It also covers managing anaemia and hyperphosphataemia associated with CKD.
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257a4390d468685393c78f6aa6ac4c198afb29e5
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nice
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Coronary sinus narrowing device implantation for refractory angina
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Coronary sinus narrowing device implantation for refractory angina
Evidence-based recommendations on coronary sinus narrowing device implantation for refractory angina in adults. This involves putting a device into the coronary sinus to narrow it with the aim of improving the flow of oxygenated blood throughout the heart muscle.
# Recommendations
Evidence on the safety of coronary sinus narrowing device implantation for refractory angina shows well-recognised complications. Evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wanting to do coronary sinus narrowing device implantation for refractory angina should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by a multidisciplinary team.
The procedure should only be done in specialist centres by interventional cardiologists with specific training in the technique.
Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.
NICE encourages further research into coronary sinus narrowing device implantation for refractory angina. This should report details of patient selection and long-term patient outcomes, including survival.# The condition, current treatments and procedure
# The condition
Angina is pain or constricting discomfort that typically occurs in the front of the chest (but may radiate to the neck, shoulders, jaw or arms). It is brought on by physical exertion or emotional stress. Some people can have atypical symptoms, such as gastrointestinal discomfort, breathlessness or nausea. Angina is the main symptom of myocardial ischaemia. It is usually caused by atherosclerotic obstructive coronary artery disease restricting blood flow and therefore oxygen delivery to the heart muscle. Being diagnosed with angina can have a significant effect on a person's quality of life, restricting daily work and leisure activities.
# Current treatments
NICE's guideline on stable angina describes recommendations on managing stable angina. Options include lifestyle advice, drug treatment and revascularisation using percutaneous or surgical techniques.
Coronary sinus narrowing device implantation is indicated for angina when other treatment options (medical or surgical) have failed or are not possible (refractory angina). The aim is to reduce symptoms and to improve quality of life.
# The procedure
The coronary sinus is a large venous structure formed by the merging of veins that drain blood away from the myocardium. It receives most of the cardiac venous blood, which then flows into the right atrium (along with deoxygenated blood from the superior and inferior venae cavae).
This procedure uses a percutaneously inserted, balloon-expandable device to narrow the coronary sinus. In current practice, an hourglass-shaped device made of stainless steel mesh is used. The device is put into the main vessel of the coronary sinus by a catheter in the right side of the heart, typically through the right or left jugular vein. To define and measure the most suitable position for the device, injected contrast is used to visualise the anatomy of the coronary sinus. A guiding catheter is then used to advance the device to the implantation site. The device is mounted on a balloon, which is inflated to expand it. Once the device is correctly placed, the balloon is deflated and the catheter pulled back. Imaging is used to confirm that there is 'hour-glass' device expansion in the coronary sinus.
Over time, endothelialisation occurs, which creates a functional stenosis. This leads to an increase in postcapillary venous pressure and redistribution of blood from the less ischaemic epicardium to the more ischaemic endocardium.
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{'Recommendations': "Evidence on the safety of coronary sinus narrowing device implantation for refractory angina shows well-recognised complications. Evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do coronary sinus narrowing device implantation for refractory angina should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team.\n\nThe procedure should only be done in specialist centres by interventional cardiologists with specific training in the technique.\n\nReport any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nNICE encourages further research into coronary sinus narrowing device implantation for refractory angina. This should report details of patient selection and long-term patient outcomes, including survival.", 'The condition, current treatments and procedure': "# The condition\n\nAngina is pain or constricting discomfort that typically occurs in the front of the chest (but may radiate to the neck, shoulders, jaw or arms). It is brought on by physical exertion or emotional stress. Some people can have atypical symptoms, such as gastrointestinal discomfort, breathlessness or nausea. Angina is the main symptom of myocardial ischaemia. It is usually caused by atherosclerotic obstructive coronary artery disease restricting blood flow and therefore oxygen delivery to the heart muscle. Being diagnosed with angina can have a significant effect on a person's quality of life, restricting daily work and leisure activities.\n\n# Current treatments\n\nNICE's guideline on stable angina describes recommendations on managing stable angina. Options include lifestyle advice, drug treatment and revascularisation using percutaneous or surgical techniques.\n\nCoronary sinus narrowing device implantation is indicated for angina when other treatment options (medical or surgical) have failed or are not possible (refractory angina). The aim is to reduce symptoms and to improve quality of life.\n\n# The procedure\n\nThe coronary sinus is a large venous structure formed by the merging of veins that drain blood away from the myocardium. It receives most of the cardiac venous blood, which then flows into the right atrium (along with deoxygenated blood from the superior and inferior venae cavae).\n\nThis procedure uses a percutaneously inserted, balloon-expandable device to narrow the coronary sinus. In current practice, an hourglass-shaped device made of stainless steel mesh is used. The device is put into the main vessel of the coronary sinus by a catheter in the right side of the heart, typically through the right or left jugular vein. To define and measure the most suitable position for the device, injected contrast is used to visualise the anatomy of the coronary sinus. A guiding catheter is then used to advance the device to the implantation site. The device is mounted on a balloon, which is inflated to expand it. Once the device is correctly placed, the balloon is deflated and the catheter pulled back. Imaging is used to confirm that there is 'hour-glass' device expansion in the coronary sinus.\n\nOver time, endothelialisation occurs, which creates a functional stenosis. This leads to an increase in postcapillary venous pressure and redistribution of blood from the less ischaemic epicardium to the more ischaemic endocardium."}
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https://www.nice.org.uk/guidance/ipg712
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Evidence-based recommendations on coronary sinus narrowing device implantation for refractory angina in adults. This involves putting a device into the coronary sinus to narrow it with the aim of improving the flow of oxygenated blood throughout the heart muscle.
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829b2f127404ebc95b696355ddf5787686a0fb9e
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nice
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SeHCAT (tauroselcholic [75 selenium] acid) for diagnosing bile acid diarrhoea
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SeHCAT (tauroselcholic [75 selenium] acid) for diagnosing bile acid diarrhoea
Evidence-based recommendations on SeHCAT (tauroselcholic [75 selenium] acid) for diagnosing bile acid diarrhoea.
# Recommendations
There is not enough evidence to recommend routine adoption of SeHCAT (tauroselcholic acid) for diagnosing bile acid diarrhoea in people with:
chronic diarrhoea with an unknown cause, suspected or diagnosed diarrhoea-predominant irritable bowel syndrome (IBS‑D) or functional diarrhoea
Crohn's disease without ileal resection who have chronic diarrhoea.
Centres already using SeHCAT for diagnosing bile acid diarrhoea may continue to do so but must collect further data or do further research (see section 5).
Further data collection and research are recommended (see section 5) on:
how SeHCAT test results affect decisions about treatment and clinical outcomes
how well tolerated and effective treatments for bile acid diarrhoea are
the health-related quality of life of people with bile acid diarrhoea.
Why the committee made these recommendations
SeHCAT is a test for diagnosing bile acid diarrhoea. Having bile acid diarrhoea can affect quality of life and limit daily activities, such as the ability to work. There is an unmet clinical need for a test to diagnose bile acid diarrhoea. Having a test is important to explain the person's symptoms and offer treatment.
Despite additional research since NICE diagnostics guidance on SeHCAT in 2012, clinical evidence on SeHCAT remains limited in quantity and quality. Most studies are small and give results only for people who had a positive SeHCAT test result. It is unclear how the test results are used to guide management of bile acid diarrhoea, and how well people tolerate treatment. So, it is uncertain how having a diagnosis affects clinical outcomes, particularly in the longer term.
The lack of data on the link between the SeHCAT test and longer-term clinical outcomes means that the economic model includes many assumptions, so its results are not reliable. Because of this, SeHCAT's cost effectiveness cannot be determined, so it cannot be recommended for routine adoption. So, although SeHCAT shows promise, further data collection and research are needed.# The diagnostic tests
# Clinical need and practice
In bile acid diarrhoea, a form of chronic diarrhoea, the body does not recycle bile acids properly. It is most commonly caused when bile acids are overproduced in people who have no damage to the bile acid recycling system. Bile acid diarrhoea can also be a secondary condition if the small bowel or another part of the bile acid recycling system is damaged, for example by disease or surgery.
Symptoms of bile acid diarrhoea are usually managed with bile acid sequestrant medication. Three products are available: colestyramine, colestipol and colesevelam.
# The intervention
## SeHCAT
SeHCAT (tauroselcholic acid) is a diagnostic radiopharmaceutical capsule used to measure how well the body absorbs bile acids. It contains 75 selenium (a gamma emitter) and a synthetic bile acid (tauroselcholic acid). When swallowed, the body absorbs SeHCAT like a natural bile acid. It can be detected in the body by a scan using a gamma camera.
A SeHCAT test involves 2 outpatient appointments in a hospital's nuclear medicine department. At the first appointment (day 1), the person swallows a SeHCAT capsule, waits for up to 3 hours and has a baseline scan. At the second appointment (day 8), they have a follow-up scan. People may need to stop antidiarrhoeal medication for the duration of the test because it may affect the result.
The test result shows how much SeHCAT remains in the body. To calculate this, the amount of radioactivity detected in the follow-up scan is divided by the amount of radioactivity detected in the baseline scan. Bile acid diarrhoea is usually diagnosed when around 15% or less SeHCAT remains in the body.
# The comparators
The comparators are:
no SeHCAT testing and no bile acid sequestrants
no SeHCAT testing and a trial of bile acid sequestrants.# Evidence
The diagnostics advisory committee considered evidence on SeHCAT (tauroselcholic acid) for investigating bile acid diarrhoea from several sources. Full details of all the evidence are in the project documents on the NICE website.
The clinical and cost effectiveness of SeHCAT for investigating bile acid diarrhoea was assessed in people with:
chronic diarrhoea with an unknown cause, suspected or diagnosed diarrhoea-predominant irritable bowel syndrome (IBS‑D) or functional diarrhoea (primary bile acid diarrhoea)
Crohn's disease without ileal resection who have chronic diarrhoea (secondary bile acid diarrhoea).
# Clinical effectiveness
A systematic review of clinical-effectiveness evidence by the external assessment group (EAG) identified 24 observational studies relevant to this assessment. No randomised controlled trials were identified. Of the 24 studies, 21 described outcomes only for some of the people who had a positive SeHCAT test result. The remaining 3 studies assessed how well the SeHCAT test predicts response to bile acid treatment (predictive accuracy). Heterogeneity between the studies was high and the quality of the studies was considered low.
## Predictive accuracy of SeHCAT in suspected or diagnosed IBS-D or functional diarrhoea
The 3 small studies evaluating the predictive accuracy of SeHCAT were included in the previous assessment. They assessed the relationship between the SeHCAT test result and response to colestyramine treatment. Table 1 summarises the predictive accuracy estimates for the different SeHCAT thresholds that the studies reported. Because of the small number of studies, and differences in study characteristics and test thresholds, a pooled estimate of predictive accuracy was not calculated.
Study
Study size
Threshold
Sensitivity
% confidence interval (CI)
Specificity
% CI
Merrick et al. (1985)
to 0.957
to 0.999
Merrick et al. (1985)
to 1.000
to 0.981
Sciaretta et al. (1986)
to 0.996
to 1.000
Sciaretta et al. (1987)
to 0.999
to 0.999
## Response to bile acid sequestrants after a positive SeHCAT test in suspected or diagnosed IBS-D or functional diarrhoea
In total, 8 studies evaluated the probability of response to bile acid sequestrants after a positive SeHCAT test at a 15% threshold. Only 2 of these were new studies found through the searches in this assessment. The median response rate in these 8 studies was 68% (range 38% to 86%). Between 70% and 100% of people had bile acid sequestrant treatment after a positive SeHCAT test. Because of the substantial differences between studies, meta-analysis of the response rate was considered inappropriate.
## Effects of treatment on bowel symptoms in suspected or diagnosed IBS-D or functional diarrhoea
In addition to reporting the probability of response to treatment after a positive SeHCAT test, 3 of the studies described the effects of bile acid sequestrants on bowel symptoms. In these studies, colestyramine was described as improving stool consistency, reducing daily bowel movements and stool frequency, and removing the urgency of needing the toilet.
## Tolerability of bile acid sequestrants in suspected or diagnosed IBS-D or functional diarrhoea
There were 8 studies reporting the proportion of people who found bile acid sequestrants difficult to tolerate or stopped their treatment for unclear reasons. Rates of intolerance and discontinuation were generally high (median 15%, range 4% to 27%). There was not enough information to determine whether these rates varied between the different types of bile acid sequestrants.
## Health-related quality of life of people with suspected or diagnosed IBS-D or functional diarrhoea
There were 2 studies reporting changes in health-related quality of life in people who had bile acid sequestrants after a positive SeHCAT test result. One study evaluated quality of life using the SF‑36 questionnaire after 8 weeks of cholestyramine. There were improvements in the general pain domain in people with mild bile acid diarrhoea (defined as a positive SeHCAT test result at a threshold between 11% and 15%, p<0.05). There were also improvements across other domains (including emotional problems, energy or fatigue, emotional wellbeing, social functioning, general health and health change) in people with more severe bile acid diarrhoea (threshold 5% or less, p<0.05). Another study reported improvements in activity levels subscore (p=0.00998) using the EQ‑5D questionnaire in people who had colestyramine or colesevelam. This study did not report either the threshold used to define a positive SeHCAT test result or the duration of follow up.
## Evidence in Crohn's disease
No evidence was found for the predictive accuracy of SeHCAT or for patient-reported outcomes in people with Crohn's disease without ileal resection who have chronic diarrhoea.
Only 1 small study (Smith et al. 2000) evaluated the probability of response to bile acid sequestrants (colestyramine or colestipol) after a positive SeHCAT test in 44 people with Crohn's disease. This study was included in the previous assessment. The threshold used to define a positive SeHCAT test was 10%. In this study, 24 (55%) people had a positive SeHCAT test result at a 10% threshold. But only 9 of these 24 (38%) people had bile acid sequestrants. This treatment was considered to work for 8 of these 9 people (89%).
# Cost effectiveness
## Economic model
The EAG developed 2 de novo economic models to assess SeHCAT's cost effectiveness for investigating and diagnosing bile acid diarrhoea in the populations in the scope of this assessment. The models used a lifetime (50 years) time horizon to estimate outcomes in terms of quality-adjusted life years (QALYs) and costs from an NHS perspective.
The models included:
a short-term decision analytic model that captured the diagnostic pathway and initial response to treatment (first 6 months)
a long-term Markov model that estimated the lifetime costs and effects for people having treatment.
SeHCAT testing, using a 15% threshold value for a positive test, was compared with these strategies:
no SeHCAT testing and no bile acid sequestrants
no SeHCAT testing and a trial of bile acid sequestrants.
## Model inputs for suspected or diagnosed IBS-D or functional diarrhoea
When possible, model inputs were based on the clinical effectiveness systematic review or other published literature. When such evidence was not available, expert opinion was used. This was obtained from a questionnaire the EAG sent to the clinical expert specialist committee members for this assessment.
The probability of a positive SeHCAT test result in the base case was a pooled estimate of 45.4%, calculated from the 8 studies in the systematic review that used SeHCAT at a 15% threshold.
People who were offered bile acid sequestrants had either colestyramine or colesevelam. Based on the responses to the EAG's questionnaire, it was assumed that 50% of people in the SeHCAT strategy and 85% of people in the trial of treatment strategy started colestyramine.
The probability of response to bile acid sequestrants after a positive SeHCAT test result was a pooled estimate of 63.8%, from the 8 studies using SeHCAT at a 15% threshold. In the trial of treatment strategy, based on expert opinion, the treatment response was estimated as 30%. Based on the available evidence, it was not possible to distinguish between the response to colestyramine and colesevelam.
Expert opinion suggested that colestyramine may be difficult to tolerate so people may be offered colesevelam instead. In both the SeHCAT strategy and the trial of treatment strategy, the probability of switching from colestyramine to colesevelam was estimated to be 50% based on expert opinion.
The probability of having a colonoscopy in the model was estimated based on expert opinion:
For people who had a negative SeHCAT test result or when bile acid sequestrant treatment after a positive SeHCAT test did not work, the probability was 49%.
For people who had not had a SeHCAT test or a trial of bile acid sequestrants, the probability was 74%.
For people who had a trial of bile acid sequestrants that had not worked, the probability was 90%.
The probability of being diagnosed with inflammatory bowel disease (IBD) after colonoscopy was likely to be very low. This was supported by expert opinion and a study (Patel et al. 2015) that reported the number of people with IBS‑D‑like symptoms who were eventually diagnosed with IBD. Based on this, the proportion of people who would be diagnosed with IBD after colonoscopy was estimated to be 5.3%. Based on expert opinion, the probability of response to IBD treatment was estimated to be 72%.
The estimated probabilities of having a colonoscopy and a diagnosis of IBD (5.3% of the people having a colonoscopy) meant that most people, about 96%, would be offered IBS‑D treatment. The probability of IBS‑D treatment response, after a colonoscopy that ruled out IBD, was estimated based on expert opinion:
For people who had a negative SeHCAT test result, the probability was 56%.
For people who had not had a SeHCAT test or a trial of bile acid sequestrants, the probability was 46%.
For people whose bile acid sequestrant treatment had not worked, the probability was 50%.Based on these estimates, the EAG calculated that the probability of IBS‑D treatment response would be slightly lower for people who had not had a colonoscopy to rule out IBD:
For people who had a negative SeHCAT test result, the probability was 53%.
For people who had not had a SeHCAT test or a trial of bile acid sequestrant, the probability was 44%.
For people whose bile acid sequestrant treatment had not worked, the probability was 47%.
The long-term Markov model included health states for 'diarrhoea', 'no diarrhoea' and 'death'. Assumptions about people moving between the 'diarrhoea' and 'no diarrhoea' health states were informed by expert opinion. This suggested that, in general, the response to bile acid sequestrants and to IBS‑D treatment is expected to last without relapses. So, no movement from the 'no diarrhoea' to the 'diarrhoea' health state in the long term should be expected. With IBD treatment, the experts noted that relapses are expected to occur after the initial response to treatment. Therefore, in the long-term Markov model it was assumed that people having IBD treatment would move between the 'diarrhoea' and 'no diarrhoea' health states. Based on expert opinion, the EAG assumed that people having IBD treatment have an average of 1 relapse every 5 years. So, the base-case probability of people having IBD treatment moving from the 'no diarrhoea' to 'diarrhoea' health state was estimated as 0.45%.
The base case assumed that no excess mortality was associated with bile acid diarrhoea.
## Health-related quality of life in suspected or diagnosed IBS-D or functional diarrhoea
The utility values used were the same as in the previous assessment (see table 2). Because colestyramine can be difficult to tolerate, it was assumed that people for whom colestyramine worked had a slightly lower (75%) utility gain from their treatment. The model did not include utility loss for colonoscopy.
Health state
Subpopulation
Utility value
Source
No diarrhoea
People for whom colesevelam, diarrhoea-predominant irritable bowel syndrome (IBS-D) or inflammatory bowel disease (IBD) treatment works (treatment response)
Pooled estimate from Mearin et al. (2004) and Spiegel et al. (2009)
No diarrhoea
People for whom colestyramine treatment works (treatment response)
Assumption
Diarrhoea
People for whom bile acid sequestrant, IBS-D or IBD treatment does not work (no treatment response)
Pooled estimate from Mearin et al. (2004) and Spiegel et al. (2009)
## Costs for suspected or diagnosed IBS-D or functional diarrhoea
The company's cost for SeHCAT was £195 per capsule. The cost of administering it in the NHS was £282 per test, taken from the NHS national tariff for 2021 to 2022. Therefore, the total cost of a SeHCAT test in the base case was £477 per test.
Other costs considered in the model included the costs of bile acid sequestrants, IBS‑D treatment, IBD treatment and colonoscopy (see table 3).
Resource
Cost per person per day
Sources
Bile acid sequestrants: colestyramine
BNF, expert opinion
Bile acid sequestrants: colesevelam
BNF, expert opinion
IBS-D treatment: medication
BNF, expert opinion
IBS-D treatment: diet therapy
NHS national tariff, expert opinion
IBS-D treatment: psychological therapy
NHS national tariff, expert opinion
IBD treatment: medication
BNF, expert opinion
IBD treatment: diet therapy
NHS national tariff, expert opinion
IBD treatment: psychological therapy
NHS national tariff, expert opinion
Colonoscopy
NHS national tariff, expert opinion (90% conventional colonoscopy and 10% CT colonoscopy)
## Base-case assumptions in suspected or diagnosed IBS-D or functional diarrhoea
These key assumptions were applied in the base-case analysis:
People whose condition responds to bile acid sequestrant treatment have bile acid diarrhoea.
Treatment for bile acid diarrhoea includes only bile acid sequestrants, either colestyramine or colesevelam.
Some people will switch to colesevelam early in the treatment because colestyramine may be difficult to tolerate.
People for whom bile acid sequestrant or IBS‑D treatment works in the short term will continue and will benefit from it for the rest of their life.
People who take colesevelam will have better quality of life than people who take colestyramine.
Some people who have not had a SeHCAT test, or who have a negative SeHCAT test result, or for whom bile acid sequestrants have not worked in the short term, will have a colonoscopy to detect IBD.
Some people for whom IBD treatment works in the short term will have relapses throughout their life.
People for whom none of the treatments offered have worked in the short term are assumed to take loperamide for the rest of their life.
All the resource-use estimates are based on expert opinion.
## Model inputs for Crohn's disease
The clinical effectiveness systematic review found only 1 study that reported the probability of a positive SeHCAT test in people with Crohn's disease without ileal resection who have chronic diarrhoea. This probability of 55% was used in the base case.
People who were offered bile acid sequestrants started either colestyramine or colesevelam. Based on expert opinion, it was assumed that 63% of people in the SeHCAT strategy and 58% of people in the trial of treatment strategy started colestyramine.
The probability of response to treatment after a positive SeHCAT test result at a 15% threshold was estimated as 89% in the base case. This came from the same small study that provided data for the probability of a positive SeHCAT test result. It was higher than the maximum 70% probability of response estimated by the clinical experts. In the trial of treatment strategy, based on expert opinion, the treatment response was estimated as 33%. Based on the available evidence, it was not possible to distinguish between the response to colestyramine and colesevelam.
In both the SeHCAT and the trial of treatment strategies, the probability of switching from colestyramine to colesevelam because of poor tolerability was estimated to be 44%, based on expert opinion.
Treatment options for diarrhoea in Crohn's disease may vary depending on whether they treat diarrhoea because of relapse or prevent diarrhoea during remission. Because of this, it was not possible to find evidence on how well diarrhoea treatment in Crohn's disease might work. Therefore, the probability of Crohn's disease treatment response was estimated based on expert opinion:
For people who had a negative SeHCAT test result, the probability was 42%.
For people who had not had a SeHCAT test or a trial of bile acid sequestrants, the probability was 40%.
For people whose bile acid sequestrant treatment had not worked, the probability was 41%.
Assumptions about people moving between the 'diarrhoea' and 'no diarrhoea' health states were informed by expert opinion. This suggested that, in general, the response to bile acid sequestrants is expected to last. So, no relapses and no movement from the 'no diarrhoea' to the 'diarrhoea' health state in the long term should be expected. For diarrhoea treatment for Crohn's disease, the experts expected that relapses would occur after the initial response to treatment. Therefore, in the long-term Markov model it was assumed that people having this treatment would move between the 'diarrhoea' and 'no diarrhoea' health states. As with people having IBD treatment in the IBS‑D or functional diarrhoea model, it was assumed that people having diarrhoea treatment for Crohn's disease would have an average of 1 relapse every 5 years. So, the base-case probability of people on this treatment moving from the 'no diarrhoea' to 'diarrhoea' health state was estimated as 0.575%.
The base case assumed that no excess mortality was associated with bile acid diarrhoea. A pooled standardised mortality ratio estimate from a meta-analysis of mortality in Crohn's disease by Canavan et al. (2007) was applied to the overall UK mortality estimates.
## Health-related quality of life in Crohn's disease
No studies on health-related quality of life in people with Crohn's disease and diarrhoea were found. The estimate from a study providing utilities for people with active Crohn's disease (Buxton et al. 2007) was assumed to also reflect quality of life in the diarrhoea health state. To estimate the utility gain for people for whom the treatment worked, it was assumed that the utility loss because of diarrhoea was the same as for people with IBS‑D or functional diarrhoea. As in the IBS‑D or functional diarrhoea model, it was assumed that the utility gain from colestyramine would be slightly lower than from the other treatments. Table 4 summarises the utility values used.
Health state
Subpopulation
Utility value
Source
No diarrhoea
People for whom colesevelam or treatment of diarrhoea in Crohn's disease works (treatment response)
Assumption
No diarrhoea
People for whom colestyramine treatment works (treatment response)
Assumption
Diarrhoea
People for whom bile acid sequestrants or treatment of diarrhoea in Crohn's disease does not work (no treatment response)
Estimate from Buxton et al. (2007)
## Costs for Crohn's disease
The total cost of SeHCAT in the base-case model was £477 per test, the same as in the IBS‑D or functional diarrhoea model.
The costs of treating bile acid diarrhoea with bile acid sequestrants were £0.35 per person per day for colestyramine and £2.56 per person per day for colesevelam. These were the same as in the IBS‑D or functional diarrhoea model.
The cost of the medication for treating diarrhoea in Crohn's disease was £5.76 per person per day. This was estimated using BNF prices, and the average dosages and proportion of people having different types of medication reported by the experts in the previous assessment.
## Base-case assumptions in Crohn's disease
Except for the assumption about colonoscopy, the key assumptions used in the base-case analysis for people with suspected or diagnosed IBS‑D or functional diarrhoea were also applied in the base-case analysis for people with Crohn's disease without ileal resection who have chronic diarrhoea.
These key assumptions were also applied:
Everyone has had a colonoscopy to diagnose Crohn's disease.
People who have not had a SeHCAT test, or who have a negative SeHCAT test result, or whose bile acid sequestrant treatment has not worked in the short term, will be offered treatment for diarrhoea in Crohn's disease.
Some people with Crohn's disease for whom the diarrhoea treatment works in the short term will have relapses throughout their life.
## Base-case results in suspected or diagnosed IBS-D or functional diarrhoea
The SeHCAT strategy was more effective and less expensive (dominant) than the strategy of offering a trial of bile acid sequestrants. It was also more effective but more expensive than the strategy in which bile acid diarrhoea was not investigated or treated. The incremental cost-effectiveness ratio (ICER) for the SeHCAT strategy compared with this strategy was £9,661 per QALY gained (probabilistic base-case analysis).
In the short term, the SeHCAT strategy had the lowest rate of colonoscopies and the lowest cost per avoided colonoscopy. It also had the highest rate of treatment response (any type of treatment). The initial costs of the SeHCAT strategy were the highest because of the costs of the SeHCAT test. The results of the deterministic and probabilistic analyses were similar.
## Secondary analysis in suspected or diagnosed IBS-D or functional diarrhoea
In this analysis, it was assumed that colonoscopy was not offered to people:
who had no SeHCAT test
who had a negative SeHCAT test result
whose bile acid sequestrant treatment did not work.
As with the base-case analysis, the SeHCAT strategy provided the highest QALYs. But in this analysis, it was more expensive than the strategy in which no testing and no bile acid sequestrant was offered and the strategy in which a trial of treatment was offered. The ICER for the SeHCAT strategy compared with the trial of treatment strategy was £21,036 per QALY gained (probabilistic base-case analysis).
In the short term, as in the base-case scenario, the SeHCAT strategy had the highest rate of treatment response. Initial costs of the SeHCAT strategy were again the highest because of the costs of the SeHCAT test. The results of the deterministic and probabilistic analyses were similar.
## Analysis of alternative scenarios in suspected or diagnosed IBS-D or functional diarrhoea
Robustness of the cost-effectiveness results to alternative model assumptions was considered in several scenario analyses. In nearly all the scenarios, the cost-effectiveness results were similar to the base case, or the SeHCAT strategy produced ICERs around or below £20,000 per QALY gained. In the scenarios in which another strategy could be considered the most cost-effective option (when the probability of colonoscopy is set to 0, and the probability of response to IBS‑D treatment is lower in the SeHCAT arm), the model assumptions were likely to be unrealistic.
## Base-case results in Crohn's disease
In both the deterministic and probabilistic base-case analyses, the SeHCAT strategy was the most cost effective. In the deterministic analysis, it was more expensive but also more effective than the strategy of offering a trial of a bile acid sequestrant. The ICER for the SeHCAT strategy compared with this strategy was £1,727 per QALY gained (deterministic base-case analysis). In the probabilistic analysis, it was both more effective and less expensive than the trial of treatment strategy. In both analyses, the strategy in which bile acid diarrhoea was not investigated or treated was more expensive and less effective than the other strategies. The total costs of all the strategies in the probabilistic analysis were higher than the total costs in the deterministic analysis. This was because it was assumed in the probabilistic analysis that, within the possible cost range, the costs would more often be higher than lower.
In the short term, the SeHCAT strategy had the highest treatment response rate to any type of medication. But the initial costs were higher than in the trial of treatment strategy because of the costs of the SeHCAT test. Cost per response was the lowest for the trial of treatment strategy.
## Analysis of alternative scenarios in Crohn's disease
Robustness of the cost-effectiveness results to alternative model assumptions and parameters was considered in several scenario analyses. In nearly all the scenarios, the cost-effectiveness results were similar to the base case or SeHCAT-produced ICERs at below £9,500 per QALY gained. In the scenarios in which another strategy could be considered the most cost-effective option, the model assumptions were likely to be unrealistic.# Committee discussion
# Clinical need
## Bile acid diarrhoea is now better recognised as a condition
The clinical experts explained that since NICE published guidance on SeHCAT (tauroselcholic acid) in 2012, awareness of bile acid diarrhoea as a condition has increased. They estimated that 1 in 20 people referred to a gastroenterology clinic because of chronic diarrhoea may have bile acid diarrhoea. Testing means that this condition can be identified and distinguished from diarrhoea-predominant irritable bowel syndrome (IBS‑D), and treatment offered. Clinicians now agree that it is important to be able to test for bile acid diarrhoea and to treat it.
## Having a diagnosis of bile acid diarrhoea is helpful
The patient experts explained that having bile acid diarrhoea can affect quality of life and limit daily activities such as the ability to work. Diagnosing bile acid diarrhoea is important because it explains the person's symptoms and means they can have treatment. Also, it can support a request for reasonable adjustments at work. The committee considered how having a diagnosis affects treatment with bile acid sequestrants. These are unpleasant to take, and many people do not adhere to treatment. The clinical experts explained that people who have a diagnosis of bile acid diarrhoea may be more motivated to continue them than people who start them as a trial of treatment. The committee recognised that having a diagnosis of bile acid diarrhoea is helpful.
# Clinical effectiveness
## Evidence on the effects of SeHCAT testing in Crohn's disease is very limited
The external assessment group's (EAG) systematic review on the clinical effectiveness of SeHCAT testing (see section 3) found only 1 study in people with Crohn's disease. The committee concluded that SeHCAT testing in this population could be useful but there is not enough data available to understand its benefits and harms. It recommended that further research is done to show the clinical effectiveness of SeHCAT testing in people with Crohn's disease (see sections 5.1 to 5.4).
## Evidence on the effects of SeHCAT testing in people with primary bile acid diarrhoea is limited in quality
There were 9 new studies published since NICE's original guidance in 2012. So, 24 studies in total were available for the primary bile acid diarrhoea population. Most of these provided data on response to treatment after a positive test result. The committee noted that the populations in these studies did not reflect the people who would be seen in NHS clinical practice. This is because people with chronic diarrhoea in the NHS are likely to be offered tests to identify other conditions with similar symptoms first, before SeHCAT testing. The populations in the studies were not likely to have had faecal immunochemical tests and faecal calprotectin tests before SeHCAT because the studies predate their introduction. Also, the committee noted that the studies were often small and had methodological limitations. Most only described limited short-term outcomes. It recommended that further research is done to show the clinical effectiveness of SeHCAT testing in people with primary bile acid diarrhoea (see sections 5.1 to 5.4).
## It is uncertain how SeHCAT test results affect decisions about treatment
The committee noted that, although most studies described response to treatment after a positive SeHCAT test result, not everyone with a positive test result was offered bile acid sequestrants. Between 70% and 100% of people who had a positive SeHCAT test at a 15% threshold had bile acid sequestrants. The studies provided no information on how treatment decisions were made, and it was unclear whether some people with negative test results would also have treatment. The committee concluded that research was needed to better understand how the test results affect treatment decisions (see section 5.1).
## The longer-term outcomes for people having SeHCAT testing are not clear
The committee noted that, based on the evidence, it was not possible to estimate the effectiveness of the different bile acid sequestrants for treating bile acid diarrhoea. No evidence was found on the long-term effects of the bile acid sequestrants. It was unclear whether they have a sustained effect on bile acid diarrhoea and if they have any negative effects such as reducing vitamin absorption. The patient experts highlighted how important it is to better understand the tolerability of different bile acid sequestrants. The committee noted that many studies reported high rates of treatment discontinuation, but it was not clear whether the rates were the same for the different bile acid sequestrants. The evidence described outcomes only for people who had a positive SeHCAT test result. The committee recognised that although the SeHCAT test is safe, the potential benefits and risks of testing for people who have a negative test result are not clear. The committee concluded that further research is needed to assess tolerability and effectiveness of the treatment options for bile acid diarrhoea (see section 5.3). It further concluded that to fully understand the benefits and risks of the SeHCAT test, evidence from people with a negative test result is needed (see section 5.2).
## How severity of bile acid diarrhoea affects health-related quality of life is not clear
The committee noted that there was very limited evidence on the health-related quality of life of people with bile acid diarrhoea and whether treatment would improve this. The patient experts explained that the severity of symptoms and how much bile acid sequestrants improve symptoms may vary. The more severe the symptoms, the more effect treatment is likely to have. However, they explained that treatment is unlikely to completely resolve symptoms. This is because many people have flare-ups despite long-term treatment, especially when they have bile acid diarrhoea and irritable bowel syndrome. The committee noted that severe symptoms are more likely to be associated with reduced quality of life than less severe symptoms, but how much more likely is unknown. Further research on how severity of bile acid diarrhoea affects health-related quality of life and how this may change over time with and without treatment is needed (see section 5.4).
# Cost effectiveness
## Modelling the use of SeHCAT at a 15% threshold for a positive test result is appropriate
The EAG assumed that a threshold of 15% retention of SeHCAT would be used to define a positive test result in its model. The committee discussed whether this threshold was appropriate. The evidence was too limited to estimate how bile acid sequestrants might benefit people who have a positive test result at different SeHCAT thresholds. But it noted that in most studies a 15% threshold was used to define a positive SeHCAT test result. The clinical experts explained that the threshold used in practice varies. Treatment may also work for people with a positive test at higher thresholds, but 15% was a widely used and accepted threshold. The clinical experts noted that the 15% threshold was also supported by 2 recent surveys of SeHCAT use. The committee concluded that although the evidence did not allow the optimal threshold to be explored, it was reasonable to assume a 15% threshold in the model.
## The resource impact of preventing colonoscopies when SeHCAT is used is captured in the analyses
Since NICE published the original guidance in 2012, the place of SeHCAT in the care pathway has changed. The EAG included the possibility of having a colonoscopy after SeHCAT testing in the model for people with suspected or diagnosed IBS‑D or functional diarrhoea. The committee considered whether this reflected current practice and whether using SeHCAT could help reduce the number of colonoscopies done. The clinical experts explained that most colonoscopies are avoided because blood and stool tests are used to exclude inflammation before a SeHCAT test (see section 4.4). They noted that clinical practice varies but variation in the timing of colonoscopies (before or after SeHCAT testing) was adequately reflected in the modelling. The committee noted that the cost of colonoscopy was included in the model. It concluded that the resource impact of preventing colonoscopies was adequately captured. The committee questioned whether the model should have also included disutility associated with colonoscopy. The EAG explained that the disutility was not included because of a lack of data. But it noted that the model assumes colonoscopy occurs only in the 6 months immediately after a SeHCAT test. So, the committee concluded that it was unlikely that including a disutility for colonoscopy would change the overall conclusions of the cost-effectiveness analyses.
## The model is unlikely to capture the full costs of providing SeHCAT testing
The committee discussed whether all the relevant costs involved in providing SeHCAT testing had been included in the model. The clinical experts explained that because the level of radioactivity in SeHCAT is low, other investigations using radioactivity could interfere with the test results. So, nuclear medicine departments cannot do other investigations when doing SeHCAT testing. The committee concluded that the cost of providing SeHCAT testing was unlikely to be fully captured in the model.
## The model does not reflect the variable severity of bile acid diarrhoea
The long-term Markov model included a health state for people who have diarrhoea (because the treatment did not work) and a health state for people who do not have diarrhoea (because the treatment worked). The committee recalled its discussion on the severity of bile acid diarrhoea and how this could affect quality of life (see section 4.8). It concluded that the model did not capture the effects of variable diarrhoea severity and treatment response.
## The relative value of SeHCAT testing may be overestimated in the model
The committee discussed whether it was appropriate to assume that response to bile acid sequestrants in the trial of treatment strategy was lower than in the SeHCAT strategy. This assumption was based on expert opinion. It recalled that the clinical experts highlighted that they were not confident of their answers to the questionnaire used to obtain values for the model. Assuming a lower probability of treatment response in the trial of treatment strategy would bias the model results towards SeHCAT and make it appear more cost effective. The committee concluded that using expert opinion without accounting for the discrepancies in treatment response for each of the strategies affected the internal validity of the model. As a result, this affected the comparison between the modelled strategies.
## How SeHCAT testing affects clinical outcomes is uncertain
The committee considered the assumptions used in the economic model. It noted that, because of the lack of clinical outcome data, most of the model inputs were estimated based on expert opinion from a small group of clinicians. The clinical experts explained that they were not confident that their estimates captured the variability of bile acid diarrhoea seen in practice. The committee was not certain that the analyses presented had fully quantified the uncertainty caused by the lack of clinical outcome data that links the results of testing to treatment outcomes. It concluded that, in the absence of key clinical outcome data, the results of the economic model cannot be used to inform recommendations about whether SeHCAT can be adopted.
## SeHCAT cannot be recommended for routine adoption in the NHS
The committee considered that there is an unmet clinical need for a test to diagnose bile acid diarrhoea. It recognised the value of having a diagnosis and access to treatment, but acknowledged that the evidence to support both the use of the test and the treatment is highly uncertain. So, the full benefits and potential harms of widespread use of SeHCAT testing cannot be reliably quantified. The committee recognised that the British Society of Gastroenterology clinical guidelines for the investigation of chronic diarrhoea in adults recommend the use of SeHCAT testing. It considered that this NICE assessment aimed to evaluate the test as well as its link to longer-term clinical outcomes to show whether it was cost effective. There is no robust data on this link and so the clinical utility of SeHCAT testing, that is:
how well it predicts response to treatment
how it influences clinical decision making
the longer-term clinical outcomes with treatment.Without this, SeHCAT's cost effectiveness cannot be adequately assessed. The committee concluded that it was unable to recommend the routine adoption of SeHCAT testing. It strongly encouraged further data collection and research to address the limitations in the evidence.
# Research considerations
## Data to support the use of SeHCAT testing in the NHS is urgently needed
There is a lack of robust data on the link between the SeHCAT test and longer-term clinical outcomes preventing the test from being recommended for routine adoption in the NHS (see section 4.14). Because of the unmet clinical need for a test to diagnose bile acid diarrhoea, the committee emphasised that there is an urgent need for further data collection and research to:
support future evaluations of the test and
improve outcomes for people with bile acid diarrhoea. The committee's recommendations for further data collection and research are described in section 5.# Recommendations for further research
Further data collection and research are recommended to understand how SeHCAT (tauroselcholic acid) test results affect clinical decision making.
Further data collection and research are recommended to assess clinical outcomes after positive and negative SeHCAT test results. This research should focus on clinical outcomes relevant to people with chronic diarrhoea, such as severity of symptoms, including urgency. Clinical outcomes should be measured in the short and long term.
Further data collection and research are recommended to assess the effectiveness of treatment options for bile acid diarrhoea. Consideration should be given to how well the treatments are tolerated and how they affect the severity of symptoms in the longer term.
Further data collection and research are recommended to better understand the health-related quality of life in people with bile acid diarrhoea. Consideration should be given to how quality of life differs before and after a positive or negative test and diagnosis, and how it is affected by treatment and symptom severity.
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{'Recommendations': "There is not enough evidence to recommend routine adoption of SeHCAT (tauroselcholic [75 selenium] acid) for diagnosing bile acid diarrhoea in people with:\n\nchronic diarrhoea with an unknown cause, suspected or diagnosed diarrhoea-predominant irritable bowel syndrome (IBS‑D) or functional diarrhoea\n\nCrohn's disease without ileal resection who have chronic diarrhoea.\n\nCentres already using SeHCAT for diagnosing bile acid diarrhoea may continue to do so but must collect further data or do further research (see section\xa05).\n\nFurther data collection and research are recommended (see section\xa05) on:\n\nhow SeHCAT test results affect decisions about treatment and clinical outcomes\n\nhow well tolerated and effective treatments for bile acid diarrhoea are\n\nthe health-related quality of life of people with bile acid diarrhoea.\n\nWhy the committee made these recommendations\n\nSeHCAT is a test for diagnosing bile acid diarrhoea. Having bile acid diarrhoea can affect quality of life and limit daily activities, such as the ability to work. There is an unmet clinical need for a test to diagnose bile acid diarrhoea. Having a test is important to explain the person's symptoms and offer treatment.\n\nDespite additional research since NICE diagnostics guidance on SeHCAT in 2012, clinical evidence on SeHCAT remains limited in quantity and quality. Most studies are small and give results only for people who had a positive SeHCAT test result. It is unclear how the test results are used to guide management of bile acid diarrhoea, and how well people tolerate treatment. So, it is uncertain how having a diagnosis affects clinical outcomes, particularly in the longer term.\n\nThe lack of data on the link between the SeHCAT test and longer-term clinical outcomes means that the economic model includes many assumptions, so its results are not reliable. Because of this, SeHCAT's cost effectiveness cannot be determined, so it cannot be recommended for routine adoption. So, although SeHCAT shows promise, further data collection and research are needed.", 'The diagnostic tests': "# Clinical need and practice\n\nIn bile acid diarrhoea, a form of chronic diarrhoea, the body does not recycle bile acids properly. It is most commonly caused when bile acids are overproduced in people who have no damage to the bile acid recycling system. Bile acid diarrhoea can also be a secondary condition if the small bowel or another part of the bile acid recycling system is damaged, for example by disease or surgery.\n\nSymptoms of bile acid diarrhoea are usually managed with bile acid sequestrant medication. Three products are available: colestyramine, colestipol and colesevelam.\n\n# The intervention\n\n## SeHCAT\n\nSeHCAT (tauroselcholic [75\xa0selenium] acid) is a diagnostic radiopharmaceutical capsule used to measure how well the body absorbs bile acids. It contains 75\xa0selenium (a gamma emitter) and a synthetic bile acid (tauroselcholic acid). When swallowed, the body absorbs SeHCAT like a natural bile acid. It can be detected in the body by a scan using a gamma camera.\n\nA SeHCAT test involves 2\xa0outpatient appointments in a hospital's nuclear medicine department. At the first appointment (day\xa01), the person swallows a SeHCAT capsule, waits for up to 3\xa0hours and has a baseline scan. At the second appointment (day\xa08), they have a follow-up scan. People may need to stop antidiarrhoeal medication for the duration of the test because it may affect the result.\n\nThe test result shows how much SeHCAT remains in the body. To calculate this, the amount of radioactivity detected in the follow-up scan is divided by the amount of radioactivity detected in the baseline scan. Bile acid diarrhoea is usually diagnosed when around 15% or less SeHCAT remains in the body.\n\n# The comparators\n\nThe comparators are:\n\nno SeHCAT testing and no bile acid sequestrants\n\nno SeHCAT testing and a trial of bile acid sequestrants.", 'Evidence': "The diagnostics advisory committee considered evidence on SeHCAT (tauroselcholic [75 selenium] acid) for investigating bile acid diarrhoea from several sources. Full details of all the evidence are in the project documents on the NICE website.\n\nThe clinical and cost effectiveness of SeHCAT for investigating bile acid diarrhoea was assessed in people with:\n\nchronic diarrhoea with an unknown cause, suspected or diagnosed diarrhoea-predominant irritable bowel syndrome (IBS‑D) or functional diarrhoea (primary bile acid diarrhoea)\n\nCrohn's disease without ileal resection who have chronic diarrhoea (secondary bile acid diarrhoea).\n\n# Clinical effectiveness\n\nA systematic review of clinical-effectiveness evidence by the external assessment group (EAG) identified 24\xa0observational studies relevant to this assessment. No randomised controlled trials were identified. Of the 24\xa0studies, 21 described outcomes only for some of the people who had a positive SeHCAT test result. The remaining 3\xa0studies assessed how well the SeHCAT test predicts response to bile acid treatment (predictive accuracy). Heterogeneity between the studies was high and the quality of the studies was considered low.\n\n## Predictive accuracy of SeHCAT in suspected or diagnosed IBS-D or functional diarrhoea\n\nThe 3\xa0small studies evaluating the predictive accuracy of SeHCAT were included in the previous assessment. They assessed the relationship between the SeHCAT test result and response to colestyramine treatment. Table\xa01 summarises the predictive accuracy estimates for the different SeHCAT thresholds that the studies reported. Because of the small number of studies, and differences in study characteristics and test thresholds, a pooled estimate of predictive accuracy was not calculated.\n\nStudy\n\nStudy size\n\nThreshold\n\nSensitivity\n\n% confidence interval (CI)\n\nSpecificity\n\n% CI\n\nMerrick et al. (1985)\n\n\n\n<8%\n\n\n\nto 0.957\n\n\n\nto 0.999\n\nMerrick et al. (1985)\n\n\n\n≤15%\n\n\n\nto 1.000\n\n\n\nto 0.981\n\nSciaretta et al. (1986)\n\n\n\n<5%\n\n\n\nto 0.996\n\n\n\nto 1.000\n\nSciaretta et al. (1987)\n\n\n\n<8%\n\n\n\nto 0.999\n\n\n\nto 0.999\n\n## Response to bile acid sequestrants after a positive SeHCAT test in suspected or diagnosed IBS-D or functional diarrhoea\n\nIn total, 8\xa0studies evaluated the probability of response to bile acid sequestrants after a positive SeHCAT test at a 15% threshold. Only 2\xa0of these were new studies found through the searches in this assessment. The median response rate in these 8\xa0studies was 68% (range 38% to 86%). Between 70% and 100% of people had bile acid sequestrant treatment after a positive SeHCAT test. Because of the substantial differences between studies, meta-analysis of the response rate was considered inappropriate.\n\n## Effects of treatment on bowel symptoms in suspected or diagnosed IBS-D or functional diarrhoea\n\nIn addition to reporting the probability of response to treatment after a positive SeHCAT test, 3\xa0of the studies described the effects of bile acid sequestrants on bowel symptoms. In these studies, colestyramine was described as improving stool consistency, reducing daily bowel movements and stool frequency, and removing the urgency of needing the toilet.\n\n## Tolerability of bile acid sequestrants in suspected or diagnosed IBS-D or functional diarrhoea\n\nThere were 8\xa0studies reporting the proportion of people who found bile acid sequestrants difficult to tolerate or stopped their treatment for unclear reasons. Rates of intolerance and discontinuation were generally high (median 15%, range 4% to 27%). There was not enough information to determine whether these rates varied between the different types of bile acid sequestrants.\n\n## Health-related quality of life of people with suspected or diagnosed IBS-D or functional diarrhoea\n\nThere were 2\xa0studies reporting changes in health-related quality of life in people who had bile acid sequestrants after a positive SeHCAT test result. One study evaluated quality of life using the SF‑36 questionnaire after 8\xa0weeks of cholestyramine. There were improvements in the general pain domain in people with mild bile acid diarrhoea (defined as a positive SeHCAT test result at a threshold between 11% and 15%, p<0.05). There were also improvements across other domains (including emotional problems, energy or fatigue, emotional wellbeing, social functioning, general health and health change) in people with more severe bile acid diarrhoea (threshold 5% or less, p<0.05). Another study reported improvements in activity levels subscore (p=0.00998) using the EQ‑5D questionnaire in people who had colestyramine or colesevelam. This study did not report either the threshold used to define a positive SeHCAT test result or the duration of follow up.\n\n## Evidence in Crohn's disease\n\nNo evidence was found for the predictive accuracy of SeHCAT or for patient-reported outcomes in people with Crohn's disease without ileal resection who have chronic diarrhoea.\n\nOnly 1\xa0small study (Smith et al. 2000) evaluated the probability of response to bile acid sequestrants (colestyramine or colestipol) after a positive SeHCAT test in 44\xa0people with Crohn's disease. This study was included in the previous assessment. The threshold used to define a positive SeHCAT test was 10%. In this study, 24\xa0(55%) people had a positive SeHCAT test result at a 10% threshold. But only 9\xa0of these 24\xa0(38%) people had bile acid sequestrants. This treatment was considered to work for 8\xa0of these 9\xa0people (89%).\n\n# Cost effectiveness\n\n## Economic model\n\nThe EAG developed 2\xa0de novo economic models to assess SeHCAT's cost effectiveness for investigating and diagnosing bile acid diarrhoea in the populations in the scope of this assessment. The models used a lifetime (50\xa0years) time horizon to estimate outcomes in terms of quality-adjusted life years (QALYs) and costs from an NHS perspective.\n\nThe models included:\n\na short-term decision analytic model that captured the diagnostic pathway and initial response to treatment (first 6\xa0months)\n\na long-term Markov model that estimated the lifetime costs and effects for people having treatment.\n\nSeHCAT testing, using a 15% threshold value for a positive test, was compared with these strategies:\n\nno SeHCAT testing and no bile acid sequestrants\n\nno SeHCAT testing and a trial of bile acid sequestrants.\n\n## Model inputs for suspected or diagnosed IBS-D or functional diarrhoea\n\nWhen possible, model inputs were based on the clinical effectiveness systematic review or other published literature. When such evidence was not available, expert opinion was used. This was obtained from a questionnaire the EAG sent to the clinical expert specialist committee members for this assessment.\n\nThe probability of a positive SeHCAT test result in the base case was a pooled estimate of 45.4%, calculated from the 8\xa0studies in the systematic review that used SeHCAT at a 15% threshold.\n\nPeople who were offered bile acid sequestrants had either colestyramine or colesevelam. Based on the responses to the EAG's questionnaire, it was assumed that 50% of people in the SeHCAT strategy and 85% of people in the trial of treatment strategy started colestyramine.\n\nThe probability of response to bile acid sequestrants after a positive SeHCAT test result was a pooled estimate of 63.8%, from the 8\xa0studies using SeHCAT at a 15% threshold. In the trial of treatment strategy, based on expert opinion, the treatment response was estimated as 30%. Based on the available evidence, it was not possible to distinguish between the response to colestyramine and colesevelam.\n\nExpert opinion suggested that colestyramine may be difficult to tolerate so people may be offered colesevelam instead. In both the SeHCAT strategy and the trial of treatment strategy, the probability of switching from colestyramine to colesevelam was estimated to be 50% based on expert opinion.\n\nThe probability of having a colonoscopy in the model was estimated based on expert opinion:\n\nFor people who had a negative SeHCAT test result or when bile acid sequestrant treatment after a positive SeHCAT test did not work, the probability was 49%.\n\nFor people who had not had a SeHCAT test or a trial of bile acid sequestrants, the probability was 74%.\n\nFor people who had a trial of bile acid sequestrants that had not worked, the probability was 90%.\n\nThe probability of being diagnosed with inflammatory bowel disease (IBD) after colonoscopy was likely to be very low. This was supported by expert opinion and a study (Patel et al. 2015) that reported the number of people with IBS‑D‑like symptoms who were eventually diagnosed with IBD. Based on this, the proportion of people who would be diagnosed with IBD after colonoscopy was estimated to be 5.3%. Based on expert opinion, the probability of response to IBD treatment was estimated to be 72%.\n\nThe estimated probabilities of having a colonoscopy and a diagnosis of IBD (5.3% of the people having a colonoscopy) meant that most people, about 96%, would be offered IBS‑D treatment. The probability of IBS‑D treatment response, after a colonoscopy that ruled out IBD, was estimated based on expert opinion:\n\nFor people who had a negative SeHCAT test result, the probability was 56%.\n\nFor people who had not had a SeHCAT test or a trial of bile acid sequestrants, the probability was 46%.\n\nFor people whose bile acid sequestrant treatment had not worked, the probability was 50%.Based on these estimates, the EAG calculated that the probability of IBS‑D treatment response would be slightly lower for people who had not had a colonoscopy to rule out IBD:\n\nFor people who had a negative SeHCAT test result, the probability was 53%.\n\nFor people who had not had a SeHCAT test or a trial of bile acid sequestrant, the probability was 44%.\n\nFor people whose bile acid sequestrant treatment had not worked, the probability was 47%.\n\nThe long-term Markov model included health states for 'diarrhoea', 'no diarrhoea' and 'death'. Assumptions about people moving between the 'diarrhoea' and 'no diarrhoea' health states were informed by expert opinion. This suggested that, in general, the response to bile acid sequestrants and to IBS‑D treatment is expected to last without relapses. So, no movement from the 'no diarrhoea' to the 'diarrhoea' health state in the long term should be expected. With IBD treatment, the experts noted that relapses are expected to occur after the initial response to treatment. Therefore, in the long-term Markov model it was assumed that people having IBD treatment would move between the 'diarrhoea' and 'no diarrhoea' health states. Based on expert opinion, the EAG assumed that people having IBD treatment have an average of 1\xa0relapse every 5\xa0years. So, the base-case probability of people having IBD treatment moving from the 'no diarrhoea' to 'diarrhoea' health state was estimated as 0.45%.\n\nThe base case assumed that no excess mortality was associated with bile acid diarrhoea.\n\n## Health-related quality of life in suspected or diagnosed IBS-D or functional diarrhoea\n\nThe utility values used were the same as in the previous assessment (see table\xa02). Because colestyramine can be difficult to tolerate, it was assumed that people for whom colestyramine worked had a slightly lower (75%) utility gain from their treatment. The model did not include utility loss for colonoscopy.\n\nHealth state\n\nSubpopulation\n\nUtility value\n\nSource\n\nNo diarrhoea\n\nPeople for whom colesevelam, diarrhoea-predominant irritable bowel syndrome (IBS-D) or inflammatory bowel disease (IBD) treatment works (treatment response)\n\n\n\nPooled estimate from Mearin et al. (2004) and Spiegel et al. (2009)\n\nNo diarrhoea\n\nPeople for whom colestyramine treatment works (treatment response)\n\n\n\nAssumption\n\nDiarrhoea\n\nPeople for whom bile acid sequestrant, IBS-D or IBD treatment does not work (no treatment response)\n\n\n\nPooled estimate from Mearin et al. (2004) and Spiegel et al. (2009)\n\n## Costs for suspected or diagnosed IBS-D or functional diarrhoea\n\nThe company's cost for SeHCAT was £195 per capsule. The cost of administering it in the NHS was £282 per test, taken from the NHS national tariff for 2021\xa0to 2022. Therefore, the total cost of a SeHCAT test in the base case was £477 per test.\n\nOther costs considered in the model included the costs of bile acid sequestrants, IBS‑D treatment, IBD treatment and colonoscopy (see table\xa03).\n\nResource\n\nCost per person per day\n\nSources\n\nBile acid sequestrants: colestyramine\n\n£0.35\n\nBNF, expert opinion\n\nBile acid sequestrants: colesevelam\n\n£2.56\n\nBNF, expert opinion\n\nIBS-D treatment: medication\n\n£0.06\n\nBNF, expert opinion\n\nIBS-D treatment: diet therapy\n\n£12.24\n\nNHS national tariff, expert opinion\n\nIBS-D treatment: psychological therapy\n\n£35.74\n\nNHS national tariff, expert opinion\n\nIBD treatment: medication\n\n£21.73\n\nBNF, expert opinion\n\nIBD treatment: diet therapy\n\n£149.00\n\nNHS national tariff, expert opinion\n\nIBD treatment: psychological therapy\n\n£289.33\n\nNHS national tariff, expert opinion\n\nColonoscopy\n\n£175.75\n\nNHS national tariff, expert opinion (90% conventional colonoscopy and 10% CT colonoscopy)\n\n## Base-case assumptions in suspected or diagnosed IBS-D or functional diarrhoea\n\nThese key assumptions were applied in the base-case analysis:\n\nPeople whose condition responds to bile acid sequestrant treatment have bile acid diarrhoea.\n\nTreatment for bile acid diarrhoea includes only bile acid sequestrants, either colestyramine or colesevelam.\n\nSome people will switch to colesevelam early in the treatment because colestyramine may be difficult to tolerate.\n\nPeople for whom bile acid sequestrant or IBS‑D treatment works in the short term will continue and will benefit from it for the rest of their life.\n\nPeople who take colesevelam will have better quality of life than people who take colestyramine.\n\nSome people who have not had a SeHCAT test, or who have a negative SeHCAT test result, or for whom bile acid sequestrants have not worked in the short term, will have a colonoscopy to detect IBD.\n\nSome people for whom IBD treatment works in the short term will have relapses throughout their life.\n\nPeople for whom none of the treatments offered have worked in the short term are assumed to take loperamide for the rest of their life.\n\nAll the resource-use estimates are based on expert opinion.\n\n## Model inputs for Crohn's disease\n\nThe clinical effectiveness systematic review found only 1\xa0study that reported the probability of a positive SeHCAT test in people with Crohn's disease without ileal resection who have chronic diarrhoea. This probability of 55% was used in the base case.\n\nPeople who were offered bile acid sequestrants started either colestyramine or colesevelam. Based on expert opinion, it was assumed that 63% of people in the SeHCAT strategy and 58% of people in the trial of treatment strategy started colestyramine.\n\nThe probability of response to treatment after a positive SeHCAT test result at a 15% threshold was estimated as 89% in the base case. This came from the same small study that provided data for the probability of a positive SeHCAT test result. It was higher than the maximum 70% probability of response estimated by the clinical experts. In the trial of treatment strategy, based on expert opinion, the treatment response was estimated as 33%. Based on the available evidence, it was not possible to distinguish between the response to colestyramine and colesevelam.\n\nIn both the SeHCAT and the trial of treatment strategies, the probability of switching from colestyramine to colesevelam because of poor tolerability was estimated to be 44%, based on expert opinion.\n\nTreatment options for diarrhoea in Crohn's disease may vary depending on whether they treat diarrhoea because of relapse or prevent diarrhoea during remission. Because of this, it was not possible to find evidence on how well diarrhoea treatment in Crohn's disease might work. Therefore, the probability of Crohn's disease treatment response was estimated based on expert opinion:\n\nFor people who had a negative SeHCAT test result, the probability was 42%.\n\nFor people who had not had a SeHCAT test or a trial of bile acid sequestrants, the probability was 40%.\n\nFor people whose bile acid sequestrant treatment had not worked, the probability was 41%.\n\nAssumptions about people moving between the 'diarrhoea' and 'no diarrhoea' health states were informed by expert opinion. This suggested that, in general, the response to bile acid sequestrants is expected to last. So, no relapses and no movement from the 'no diarrhoea' to the 'diarrhoea' health state in the long term should be expected. For diarrhoea treatment for Crohn's disease, the experts expected that relapses would occur after the initial response to treatment. Therefore, in the long-term Markov model it was assumed that people having this treatment would move between the 'diarrhoea' and 'no diarrhoea' health states. As with people having IBD treatment in the IBS‑D or functional diarrhoea model, it was assumed that people having diarrhoea treatment for Crohn's disease would have an average of 1\xa0relapse every 5\xa0years. So, the base-case probability of people on this treatment moving from the 'no diarrhoea' to 'diarrhoea' health state was estimated as 0.575%.\n\nThe base case assumed that no excess mortality was associated with bile acid diarrhoea. A pooled standardised mortality ratio estimate from a meta-analysis of mortality in Crohn's disease by Canavan et al. (2007) was applied to the overall UK mortality estimates.\n\n## Health-related quality of life in Crohn's disease\n\nNo studies on health-related quality of life in people with Crohn's disease and diarrhoea were found. The estimate from a study providing utilities for people with active Crohn's disease (Buxton et al. 2007) was assumed to also reflect quality of life in the diarrhoea health state. To estimate the utility gain for people for whom the treatment worked, it was assumed that the utility loss because of diarrhoea was the same as for people with IBS‑D or functional diarrhoea. As in the IBS‑D or functional diarrhoea model, it was assumed that the utility gain from colestyramine would be slightly lower than from the other treatments. Table\xa04 summarises the utility values used.\n\nHealth state\n\nSubpopulation\n\nUtility value\n\nSource\n\nNo diarrhoea\n\nPeople for whom colesevelam or treatment of diarrhoea in Crohn's disease works (treatment response)\n\n\n\nAssumption\n\nNo diarrhoea\n\nPeople for whom colestyramine treatment works (treatment response)\n\n\n\nAssumption\n\nDiarrhoea\n\nPeople for whom bile acid sequestrants or treatment of diarrhoea in Crohn's disease does not work (no treatment response)\n\n\n\nEstimate from Buxton et al. (2007)\n\n## Costs for Crohn's disease\n\nThe total cost of SeHCAT in the base-case model was £477 per test, the same as in the IBS‑D or functional diarrhoea model.\n\nThe costs of treating bile acid diarrhoea with bile acid sequestrants were £0.35 per person per day for colestyramine and £2.56 per person per day for colesevelam. These were the same as in the IBS‑D or functional diarrhoea model.\n\nThe cost of the medication for treating diarrhoea in Crohn's disease was £5.76 per person per day. This was estimated using BNF prices, and the average dosages and proportion of people having different types of medication reported by the experts in the previous assessment.\n\n## Base-case assumptions in Crohn's disease\n\nExcept for the assumption about colonoscopy, the key assumptions used in the base-case analysis for people with suspected or diagnosed IBS‑D or functional diarrhoea were also applied in the base-case analysis for people with Crohn's disease without ileal resection who have chronic diarrhoea.\n\nThese key assumptions were also applied:\n\nEveryone has had a colonoscopy to diagnose Crohn's disease.\n\nPeople who have not had a SeHCAT test, or who have a negative SeHCAT test result, or whose bile acid sequestrant treatment has not worked in the short term, will be offered treatment for diarrhoea in Crohn's disease.\n\nSome people with Crohn's disease for whom the diarrhoea treatment works in the short term will have relapses throughout their life.\n\n## Base-case results in suspected or diagnosed IBS-D or functional diarrhoea\n\nThe SeHCAT strategy was more effective and less expensive (dominant) than the strategy of offering a trial of bile acid sequestrants. It was also more effective but more expensive than the strategy in which bile acid diarrhoea was not investigated or treated. The incremental cost-effectiveness ratio (ICER) for the SeHCAT strategy compared with this strategy was £9,661 per QALY gained (probabilistic base-case analysis).\n\nIn the short term, the SeHCAT strategy had the lowest rate of colonoscopies and the lowest cost per avoided colonoscopy. It also had the highest rate of treatment response (any type of treatment). The initial costs of the SeHCAT strategy were the highest because of the costs of the SeHCAT test. The results of the deterministic and probabilistic analyses were similar.\n\n## Secondary analysis in suspected or diagnosed IBS-D or functional diarrhoea\n\nIn this analysis, it was assumed that colonoscopy was not offered to people:\n\nwho had no SeHCAT test\n\nwho had a negative SeHCAT test result\n\nwhose bile acid sequestrant treatment did not work.\n\nAs with the base-case analysis, the SeHCAT strategy provided the highest QALYs. But in this analysis, it was more expensive than the strategy in which no testing and no bile acid sequestrant was offered and the strategy in which a trial of treatment was offered. The ICER for the SeHCAT strategy compared with the trial of treatment strategy was £21,036 per QALY gained (probabilistic base-case analysis).\n\nIn the short term, as in the base-case scenario, the SeHCAT strategy had the highest rate of treatment response. Initial costs of the SeHCAT strategy were again the highest because of the costs of the SeHCAT test. The results of the deterministic and probabilistic analyses were similar.\n\n## Analysis of alternative scenarios in suspected or diagnosed IBS-D or functional diarrhoea\n\nRobustness of the cost-effectiveness results to alternative model assumptions was considered in several scenario analyses. In nearly all the scenarios, the cost-effectiveness results were similar to the base case, or the SeHCAT strategy produced ICERs around or below £20,000 per QALY gained. In the scenarios in which another strategy could be considered the most cost-effective option (when the probability of colonoscopy is set to 0, and the probability of response to IBS‑D treatment is lower in the SeHCAT arm), the model assumptions were likely to be unrealistic.\n\n## Base-case results in Crohn's disease\n\nIn both the deterministic and probabilistic base-case analyses, the SeHCAT strategy was the most cost effective. In the deterministic analysis, it was more expensive but also more effective than the strategy of offering a trial of a bile acid sequestrant. The ICER for the SeHCAT strategy compared with this strategy was £1,727 per QALY gained (deterministic base-case analysis). In the probabilistic analysis, it was both more effective and less expensive than the trial of treatment strategy. In both analyses, the strategy in which bile acid diarrhoea was not investigated or treated was more expensive and less effective than the other strategies. The total costs of all the strategies in the probabilistic analysis were higher than the total costs in the deterministic analysis. This was because it was assumed in the probabilistic analysis that, within the possible cost range, the costs would more often be higher than lower.\n\nIn the short term, the SeHCAT strategy had the highest treatment response rate to any type of medication. But the initial costs were higher than in the trial of treatment strategy because of the costs of the SeHCAT test. Cost per response was the lowest for the trial of treatment strategy.\n\n## Analysis of alternative scenarios in Crohn's disease\n\nRobustness of the cost-effectiveness results to alternative model assumptions and parameters was considered in several scenario analyses. In nearly all the scenarios, the cost-effectiveness results were similar to the base case or SeHCAT-produced ICERs at below £9,500 per QALY gained. In the scenarios in which another strategy could be considered the most cost-effective option, the model assumptions were likely to be unrealistic.", 'Committee discussion': "# Clinical need\n\n## Bile acid diarrhoea is now better recognised as a condition\n\nThe clinical experts explained that since NICE published guidance on SeHCAT (tauroselcholic [75 selenium] acid) in 2012, awareness of bile acid diarrhoea as a condition has increased. They estimated that 1\xa0in 20\xa0people referred to a gastroenterology clinic because of chronic diarrhoea may have bile acid diarrhoea. Testing means that this condition can be identified and distinguished from diarrhoea-predominant irritable bowel syndrome (IBS‑D), and treatment offered. Clinicians now agree that it is important to be able to test for bile acid diarrhoea and to treat it.\n\n## Having a diagnosis of bile acid diarrhoea is helpful\n\nThe patient experts explained that having bile acid diarrhoea can affect quality of life and limit daily activities such as the ability to work. Diagnosing bile acid diarrhoea is important because it explains the person's symptoms and means they can have treatment. Also, it can support a request for reasonable adjustments at work. The committee considered how having a diagnosis affects treatment with bile acid sequestrants. These are unpleasant to take, and many people do not adhere to treatment. The clinical experts explained that people who have a diagnosis of bile acid diarrhoea may be more motivated to continue them than people who start them as a trial of treatment. The committee recognised that having a diagnosis of bile acid diarrhoea is helpful.\n\n# Clinical effectiveness\n\n## Evidence on the effects of SeHCAT testing in Crohn's disease is very limited\n\nThe external assessment group's (EAG) systematic review on the clinical effectiveness of SeHCAT testing (see section\xa03) found only 1\xa0study in people with Crohn's disease. The committee concluded that SeHCAT testing in this population could be useful but there is not enough data available to understand its benefits and harms. It recommended that further research is done to show the clinical effectiveness of SeHCAT testing in people with Crohn's disease (see sections\xa05.1 to 5.4).\n\n## Evidence on the effects of SeHCAT testing in people with primary bile acid diarrhoea is limited in quality\n\nThere were 9\xa0new studies published since NICE's original guidance in 2012. So, 24\xa0studies in total were available for the primary bile acid diarrhoea population. Most of these provided data on response to treatment after a positive test result. The committee noted that the populations in these studies did not reflect the people who would be seen in NHS clinical practice. This is because people with chronic diarrhoea in the NHS are likely to be offered tests to identify other conditions with similar symptoms first, before SeHCAT testing. The populations in the studies were not likely to have had faecal immunochemical tests and faecal calprotectin tests before SeHCAT because the studies predate their introduction. Also, the committee noted that the studies were often small and had methodological limitations. Most only described limited short-term outcomes. It recommended that further research is done to show the clinical effectiveness of SeHCAT testing in people with primary bile acid diarrhoea (see sections\xa05.1 to 5.4).\n\n## It is uncertain how SeHCAT test results affect decisions about treatment\n\nThe committee noted that, although most studies described response to treatment after a positive SeHCAT test result, not everyone with a positive test result was offered bile acid sequestrants. Between 70% and 100% of people who had a positive SeHCAT test at a 15% threshold had bile acid sequestrants. The studies provided no information on how treatment decisions were made, and it was unclear whether some people with negative test results would also have treatment. The committee concluded that research was needed to better understand how the test results affect treatment decisions (see section\xa05.1).\n\n## The longer-term outcomes for people having SeHCAT testing are not clear\n\nThe committee noted that, based on the evidence, it was not possible to estimate the effectiveness of the different bile acid sequestrants for treating bile acid diarrhoea. No evidence was found on the long-term effects of the bile acid sequestrants. It was unclear whether they have a sustained effect on bile acid diarrhoea and if they have any negative effects such as reducing vitamin absorption. The patient experts highlighted how important it is to better understand the tolerability of different bile acid sequestrants. The committee noted that many studies reported high rates of treatment discontinuation, but it was not clear whether the rates were the same for the different bile acid sequestrants. The evidence described outcomes only for people who had a positive SeHCAT test result. The committee recognised that although the SeHCAT test is safe, the potential benefits and risks of testing for people who have a negative test result are not clear. The committee concluded that further research is needed to assess tolerability and effectiveness of the treatment options for bile acid diarrhoea (see section\xa05.3). It further concluded that to fully understand the benefits and risks of the SeHCAT test, evidence from people with a negative test result is needed (see section\xa05.2).\n\n## How severity of bile acid diarrhoea affects health-related quality of life is not clear\n\nThe committee noted that there was very limited evidence on the health-related quality of life of people with bile acid diarrhoea and whether treatment would improve this. The patient experts explained that the severity of symptoms and how much bile acid sequestrants improve symptoms may vary. The more severe the symptoms, the more effect treatment is likely to have. However, they explained that treatment is unlikely to completely resolve symptoms. This is because many people have flare-ups despite long-term treatment, especially when they have bile acid diarrhoea and irritable bowel syndrome. The committee noted that severe symptoms are more likely to be associated with reduced quality of life than less severe symptoms, but how much more likely is unknown. Further research on how severity of bile acid diarrhoea affects health-related quality of life and how this may change over time with and without treatment is needed (see section\xa05.4).\n\n# Cost effectiveness\n\n## Modelling the use of SeHCAT at a 15% threshold for a positive test result is appropriate\n\nThe EAG assumed that a threshold of 15% retention of SeHCAT would be used to define a positive test result in its model. The committee discussed whether this threshold was appropriate. The evidence was too limited to estimate how bile acid sequestrants might benefit people who have a positive test result at different SeHCAT thresholds. But it noted that in most studies a 15% threshold was used to define a positive SeHCAT test result. The clinical experts explained that the threshold used in practice varies. Treatment may also work for people with a positive test at higher thresholds, but 15% was a widely used and accepted threshold. The clinical experts noted that the 15% threshold was also supported by 2\xa0recent surveys of SeHCAT use. The committee concluded that although the evidence did not allow the optimal threshold to be explored, it was reasonable to assume a 15% threshold in the model.\n\n## The resource impact of preventing colonoscopies when SeHCAT is used is captured in the analyses\n\nSince NICE published the original guidance in 2012, the place of SeHCAT in the care pathway has changed. The EAG included the possibility of having a colonoscopy after SeHCAT testing in the model for people with suspected or diagnosed IBS‑D or functional diarrhoea. The committee considered whether this reflected current practice and whether using SeHCAT could help reduce the number of colonoscopies done. The clinical experts explained that most colonoscopies are avoided because blood and stool tests are used to exclude inflammation before a SeHCAT test (see section\xa04.4). They noted that clinical practice varies but variation in the timing of colonoscopies (before or after SeHCAT testing) was adequately reflected in the modelling. The committee noted that the cost of colonoscopy was included in the model. It concluded that the resource impact of preventing colonoscopies was adequately captured. The committee questioned whether the model should have also included disutility associated with colonoscopy. The EAG explained that the disutility was not included because of a lack of data. But it noted that the model assumes colonoscopy occurs only in the 6\xa0months immediately after a SeHCAT test. So, the committee concluded that it was unlikely that including a disutility for colonoscopy would change the overall conclusions of the cost-effectiveness analyses.\n\n## The model is unlikely to capture the full costs of providing SeHCAT testing\n\nThe committee discussed whether all the relevant costs involved in providing SeHCAT testing had been included in the model. The clinical experts explained that because the level of radioactivity in SeHCAT is low, other investigations using radioactivity could interfere with the test results. So, nuclear medicine departments cannot do other investigations when doing SeHCAT testing. The committee concluded that the cost of providing SeHCAT testing was unlikely to be fully captured in the model.\n\n## The model does not reflect the variable severity of bile acid diarrhoea\n\nThe long-term Markov model included a health state for people who have diarrhoea (because the treatment did not work) and a health state for people who do not have diarrhoea (because the treatment worked). The committee recalled its discussion on the severity of bile acid diarrhoea and how this could affect quality of life (see section\xa04.8). It concluded that the model did not capture the effects of variable diarrhoea severity and treatment response.\n\n## The relative value of SeHCAT testing may be overestimated in the model\n\nThe committee discussed whether it was appropriate to assume that response to bile acid sequestrants in the trial of treatment strategy was lower than in the SeHCAT strategy. This assumption was based on expert opinion. It recalled that the clinical experts highlighted that they were not confident of their answers to the questionnaire used to obtain values for the model. Assuming a lower probability of treatment response in the trial of treatment strategy would bias the model results towards SeHCAT and make it appear more cost effective. The committee concluded that using expert opinion without accounting for the discrepancies in treatment response for each of the strategies affected the internal validity of the model. As a result, this affected the comparison between the modelled strategies.\n\n## How SeHCAT testing affects clinical outcomes is uncertain\n\nThe committee considered the assumptions used in the economic model. It noted that, because of the lack of clinical outcome data, most of the model inputs were estimated based on expert opinion from a small group of clinicians. The clinical experts explained that they were not confident that their estimates captured the variability of bile acid diarrhoea seen in practice. The committee was not certain that the analyses presented had fully quantified the uncertainty caused by the lack of clinical outcome data that links the results of testing to treatment outcomes. It concluded that, in the absence of key clinical outcome data, the results of the economic model cannot be used to inform recommendations about whether SeHCAT can be adopted.\n\n## SeHCAT cannot be recommended for routine adoption in the NHS\n\nThe committee considered that there is an unmet clinical need for a test to diagnose bile acid diarrhoea. It recognised the value of having a diagnosis and access to treatment, but acknowledged that the evidence to support both the use of the test and the treatment is highly uncertain. So, the full benefits and potential harms of widespread use of SeHCAT testing cannot be reliably quantified. The committee recognised that the British Society of Gastroenterology clinical guidelines for the investigation of chronic diarrhoea in adults recommend the use of SeHCAT testing. It considered that this NICE assessment aimed to evaluate the test as well as its link to longer-term clinical outcomes to show whether it was cost effective. There is no robust data on this link and so the clinical utility of SeHCAT testing, that is:\n\nhow well it predicts response to treatment\n\nhow it influences clinical decision making\n\nthe longer-term clinical outcomes with treatment.Without this, SeHCAT's cost effectiveness cannot be adequately assessed. The committee concluded that it was unable to recommend the routine adoption of SeHCAT testing. It strongly encouraged further data collection and research to address the limitations in the evidence.\n\n# Research considerations\n\n## Data to support the use of SeHCAT testing in the NHS is urgently needed\n\nThere is a lack of robust data on the link between the SeHCAT test and longer-term clinical outcomes preventing the test from being recommended for routine adoption in the NHS (see section\xa04.14). Because of the unmet clinical need for a test to diagnose bile acid diarrhoea, the committee emphasised that there is an urgent need for further data collection and research to:\n\nsupport future evaluations of the test and\n\nimprove outcomes for people with bile acid diarrhoea. The committee's recommendations for further data collection and research are described in section\xa05.", 'Recommendations for further research': 'Further data collection and research are recommended to understand how SeHCAT (tauroselcholic [75 selenium] acid) test results affect clinical decision making.\n\nFurther data collection and research are recommended to assess clinical outcomes after positive and negative SeHCAT test results. This research should focus on clinical outcomes relevant to people with chronic diarrhoea, such as severity of symptoms, including urgency. Clinical outcomes should be measured in the short and long term.\n\nFurther data collection and research are recommended to assess the effectiveness of treatment options for bile acid diarrhoea. Consideration should be given to how well the treatments are tolerated and how they affect the severity of symptoms in the longer term.\n\nFurther data collection and research are recommended to better understand the health-related quality of life in people with bile acid diarrhoea. Consideration should be given to how quality of life differs before and after a positive or negative test and diagnosis, and how it is affected by treatment and symptom severity.'}
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https://www.nice.org.uk/guidance/dg44
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Evidence-based recommendations on SeHCAT (tauroselcholic [75 selenium] acid) for diagnosing bile acid diarrhoea.
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06d1859543765cb4157e7205717c71be28be2a3b
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nice
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Acute heart failure: diagnosis and management
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Acute heart failure: diagnosis and management
This guideline covers diagnosing and managing acute heart failure or possible acute heart failure in people aged 18 and over. It aims to improve the immediate care of someone who is acutely unwell as a result of heart failure.
# Introduction
Heart failure is a condition in which the heart does not pump enough blood to meet all the needs of the body. It is caused by dysfunction of the heart due to muscle damage (systolic or diastolic dysfunction), valvular dysfunction, arrhythmias or other rare causes. Acute heart failure can present as new‑onset heart failure in people without known cardiac dysfunction, or as acute decompensation of chronic heart failure.
Acute heart failure is a common cause of admission to hospital (over 67,000 admissions in England and Wales per year) and is the leading cause of hospital admission in people 65 years or older in the UK.
This guideline includes important aspects of the diagnosis and management of acute heart failure that are not addressed by the NICE guideline on chronic heart failure. The guideline on chronic heart failure focuses on long‑term management rather than on the immediate care of someone who is acutely unwell as a result of heart failure.
This guideline covers the care of adults (aged 18 years or older) who have a diagnosis of acute heart failure, have possible acute heart failure, or are being investigated for acute heart failure. It includes the following key clinical areas:
the role of early natriuretic peptide testing and echocardiography
the role of specialist management units
the use of ventilatory support, pharmacological therapy and ultrafiltration
treatment after stabilisation, including selected surgical interventions and initiation of the pharmacological therapies that are used in the management of chronic heart failure.
# Drug recommendations
The guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.
In memory of Christopher Jones, patient member of the GDG who ensured that the patient voice was heard during the development of this guideline.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
The following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.
# Organisation of care
All hospitals admitting people with suspected acute heart failure should provide a specialist heart failure team that is based on a cardiology ward and provides outreach services.
Ensure that all people being admitted to hospital with suspected acute heart failure have early and continuing input from a dedicated specialist heart failure team.
Plan the following with people with acute heart failure in line with the NICE guideline on chronic heart failure:
discharge from hospital after the acute phase and
subsequent management in primary care, including ongoing monitoring and care provided by the multidisciplinary team and
information and communication about their condition, its treatment and prognosis.
A follow‑up clinical assessment should be undertaken by a member of the specialist heart failure team within 2 weeks of the person being discharged from hospital.
# Diagnosis, assessment and monitoring
Take a history, perform a clinical examination and undertake standard investigations – for example, electrocardiography, chest X‑ray and blood tests – in line with the NICE guideline on chronic heart failure.
In people presenting with new suspected acute heart failure, use a single measurement of serum natriuretic peptides (B‑type natriuretic peptide or N‑terminal pro‑B‑type natriuretic peptide ) and the following thresholds to rule out the diagnosis of heart failure:
BNP less than 100 ng/litre
NT‑proBNP less than 300 ng/litre.
In people presenting with new suspected acute heart failure with raised natriuretic peptide levels (see recommendation 1.2.2), perform transthoracic Doppler 2D echocardiography to establish the presence or absence of cardiac abnormalities.
In people presenting with new suspected acute heart failure, consider performing transthoracic Doppler 2D echocardiography within 48 hours of admission to guide early specialist management.
Do not routinely offer pulmonary artery catheterisation to people with acute heart failure.
# Initial pharmacological treatment
For guidance on patient consent and capacity follow recommendations on consent and capacity in the NICE guideline on patient experience in adult NHS services.
Do not routinely offer opiates to people with acute heart failure.
Offer intravenous diuretic therapy to people with acute heart failure. Start treatment using either a bolus or infusion strategy.
For people already taking a diuretic, consider a higher dose of diuretic than that on which the person was admitted unless there are serious concerns with patient adherence to diuretic therapy before admission.
Closely monitor the person's renal function, weight and urine output during diuretic therapy.
Discuss with the person the best strategies of coping with an increased urine output.
Do not routinely offer nitrates to people with acute heart failure.
If intravenous nitrates are used in specific circumstances, such as for people with concomitant myocardial ischaemia, severe hypertension or regurgitant aortic or mitral valve disease, monitor blood pressure closely in a setting where at least level 2 care can be provided.
Do not offer sodium nitroprusside to people with acute heart failure.
Do not routinely offer inotropes or vasopressors to people with acute heart failure.
Consider inotropes or vasopressors in people with acute heart failure with potentially reversible cardiogenic shock. Administer these treatments in a cardiac care unit or high dependency unit or an alternative setting where at least level 2 care can be provided.Level 2 care is for people needing more detailed observation or intervention, including support for a single failing organ system or postoperative care and for those stepping down from higher levels of care. From levels of critical care for adult patients.
# Initial non-pharmacological treatment
Do not routinely use non‑invasive ventilation (continuous positive airways pressure or non‑invasive positive pressure ventilation ) in people with acute heart failure and cardiogenic pulmonary oedema.
If a person has cardiogenic pulmonary oedema with severe dyspnoea and acidaemia consider starting non‑invasive ventilation without delay:
at acute presentation or
as an adjunct to medical therapy if the person's condition has failed to respond.
Consider invasive ventilation in people with acute heart failure that, despite treatment, is leading to or is complicated by:
respiratory failure or
reduced consciousness or physical exhaustion.
Do not routinely offer ultrafiltration to people with acute heart failure.
Consider ultrafiltration for people with confirmed diuretic resistance.Diuretic resistance is defined as dose escalation beyond a person's previously recognised dose ceiling or a dose approaching the maximum recommended daily dose without incremental improvement in diuresis. From diuretics and ultrafiltration in acute decompensated heart failure.
# Treatment after stabilisation
In a person presenting with acute heart failure who is already taking beta‑blockers, continue the beta‑blocker treatment unless they have a heart rate less than 50 beats per minute, second or third degree atrioventricular block, or shock.
Start or restart beta‑blocker treatment during hospital admission in people with acute heart failure due to left ventricular systolic dysfunction, once their condition has been stabilised – for example, when intravenous diuretics are no longer needed.
Ensure that the person's condition is stable for typically 48 hours after starting or restarting beta‑blockers and before discharging from hospital.
Offer an angiotensin‑converting enzyme inhibitor (or angiotensin receptor blocker if there are intolerable side effects) and an aldosterone antagonist during hospital admission to people with acute heart failure and reduced left ventricular ejection fraction. If the angiotensin‑converting enzyme inhibitor (or angiotensin receptor blocker) is not tolerated an aldosterone antagonist should still be offered.In February 2016, the Medicines and Healthcare products Regulatory Agency (MHRA) published advice on the concomitant use of spironolactone and renin-angiotensin system drugs in heart failure concerning the risk of potentially fatal hyperkalaemia. See the MHRA advice for more information.
Closely monitor the person's renal function, electrolytes, heart rate, blood pressure and overall clinical status during treatment with beta‑blockers, aldosterone antagonists or angiotensin‑converting enzyme inhibitors.
# Valvular surgery and percutaneous intervention
The recommendations on valvular surgery and percutaneous intervention have been replaced by the NICE guideline on heart valve disease.
# Mechanical assist devices
At an early stage, the specialist should have a discussion with a centre providing mechanical circulatory support about:
people with potentially reversible severe acute heart failure or
people who are potential candidates for transplantation.# Recommendations for research
The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.
# Dopamine
In people with acute heart failure, congestion and worsening renal function, does the addition of low‑dose dopamine to standard therapy lead to greater diuresis and renal protection compared with adding placebo to standard therapy?
## Why this is important
A randomised controlled trial should be conducted to investigate whether the addition of low‑dose dopamine to standard therapy leads to more clinically and cost effective decongestion in people admitted to hospital for treatment of decompensated heart failure. The study should aim to investigate the diuretic effect of dopamine as well as effects on renal function.
One of the most common and difficult to manage problems arising during the initial treatment of people with acute heart failure is an inadequate response to intravenous diuretic therapy (that is, failure to relieve congestion), which is often associated with worsening renal function. This combination frequently leads to a prolonged inpatient stay and is associated with higher inpatient mortality rates and higher post‑discharge mortality and re‑admission rates. The best treatment for this combination of problems is unknown. However, theoretical and experimental evidence indicates that low‑dose dopamine may improve renal blood flow, as well as enhance sodium and water excretion. Clinical trials have not yet resolved whether in some patients, the use of low‑dose dopamine actually results in improved decongestion and shorter hospital stays.
# Thiazide
In people with acute heart failure and persistent congestion, does the addition of a thiazide diuretic to standard therapy lead to greater diuresis compared with adding placebo to standard therapy?
## Why this is important
A randomised controlled trial should be conducted to investigate whether the addition of a thiazide diuretic to standard therapy leads to more clinically and cost effective decongestion in people admitted to hospital for treatment of decompensated heart failure.
One of the most common and difficult to manage problems arising during the initial treatment of people with acute heart failure is an inadequate response to intravenous diuretic therapy. This frequently leads to a prolonged inpatient stay and is associated with higher inpatient mortality and higher post‑discharge mortality and re‑admission rates. The best treatment for this problem is unknown. However, there is some inconsistent and non‑robust evidence that addition of a thiazide or thiazide‑like diuretic (metolazone) may be beneficial. The proposed study would aim to resolve this uncertainty and guide the management of a difficult clinical problem.
# Intra-aortic balloon counter‑pulsation
In people with acute heart failure and hypoperfusion syndrome, is the use of intra‑aortic balloon counter‑pulsation pump (IABP) better than the use of intravenous inotropes?
## Why this is important
A randomised controlled trial should be conducted in people with decompensated heart failure due to left ventricular systolic dysfunction and systemic hypoperfusion comparing the use of IABP with the use of inotropes/vasopressors. This would determine which strategy is more clinically and cost effective in this cohort.
IABP is used in the hospital setting as an adjuvant in people with critical coronary ischaemia and in people with mechanical complications of acute myocardial infarction. It has also been used in people who develop cardiogenic shock after acute myocardial infarction. However, it is uncertain whether it can provide clinical benefit in the critically unwell patients with acute heart failure due to left ventricular systolic dysfunction and systemic hypoperfusion.
# Ultrafiltration
In people with decompensated heart failure, fluid congestion and diuretic resistance, does ultrafiltration lead to more rapid and effective decongestion compared with continuing diuretic treatment?
## Why this is important
A randomised controlled trial should be undertaken to determine whether ultrafiltration is more clinically and cost effective than conventional diuretic therapy for people admitted to hospital with decompensated heart failure. The study should not only investigate several clinical outcomes but also consider the impact of treatments on quality of life and provide data on safety.
People who have fluid retention that is resistant to conventional diuretic therapy, with or without renal dysfunction, make up a high proportion of hospital admissions due to heart failure. Such admissions are often prolonged and therefore have important budgetary implications for the NHS. The few, relatively small scale, randomised trials of ultrafiltration performed so far have been conducted in healthcare settings very different from the UK, with less fluid retention than is usually seen in UK practice, and where length of stay is usually much shorter than in UK (and European) practice. Although technically feasible, the evidence for benefit on heart failure outcomes is inconsistent and difficult to generalise to UK practice. Therefore, a UK‑based study of sufficient quality is needed.
|
{'Introduction ': "Heart failure is a condition in which the heart does not pump enough blood to meet all the needs of the body. It is caused by dysfunction of the heart due to muscle damage (systolic or diastolic dysfunction), valvular dysfunction, arrhythmias or other rare causes. Acute heart failure can present as new‑onset heart failure in people without known cardiac dysfunction, or as acute decompensation of chronic heart failure.\n\nAcute heart failure is a common cause of admission to hospital (over 67,000\xa0admissions in England and Wales per year) and is the leading cause of hospital admission in people 65\xa0years or older in the UK.\n\nThis guideline includes important aspects of the diagnosis and management of acute heart failure that are not addressed by the NICE guideline on chronic heart failure. The guideline on chronic heart failure focuses on long‑term management rather than on the immediate care of someone who is acutely unwell as a result of heart failure.\n\nThis guideline covers the care of adults (aged 18\xa0years or older) who have a diagnosis of acute heart failure, have possible acute heart failure, or are being investigated for acute heart failure. It includes the following key clinical areas:\n\nthe role of early natriuretic peptide testing and echocardiography\n\nthe role of specialist management units\n\nthe use of ventilatory support, pharmacological therapy and ultrafiltration\n\ntreatment after stabilisation, including selected surgical interventions and initiation of the pharmacological therapies that are used in the management of chronic heart failure.\n\n# Drug recommendations\n\nThe guideline will assume that prescribers will use a drug's summary of product characteristics to inform decisions made with individual patients.\n\nIn memory of Christopher Jones, patient member of the GDG who ensured that the patient voice was heard during the development of this guideline.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThe following guidance is based on the best available evidence. The full guideline gives details of the methods and the evidence used to develop the guidance.\n\n# Organisation of care\n\nAll hospitals admitting people with suspected acute heart failure should provide a specialist heart failure team that is based on a cardiology ward and provides outreach services.\n\nEnsure that all people being admitted to hospital with suspected acute heart failure have early and continuing input from a dedicated specialist heart failure team.\n\nPlan the following with people with acute heart failure in line with the NICE guideline on chronic heart failure:\n\ndischarge from hospital after the acute phase and\n\nsubsequent management in primary care, including ongoing monitoring and care provided by the multidisciplinary team and\n\ninformation and communication about their condition, its treatment and prognosis.\n\nA follow‑up clinical assessment should be undertaken by a member of the specialist heart failure team within 2\xa0weeks of the person being discharged from hospital.\n\n# Diagnosis, assessment and monitoring\n\nTake a history, perform a clinical examination and undertake standard investigations – for example, electrocardiography, chest X‑ray and blood tests – in line with the NICE guideline on chronic heart failure.\n\nIn people presenting with new suspected acute heart failure, use a single measurement of serum natriuretic peptides (B‑type natriuretic peptide [BNP] or N‑terminal pro‑B‑type natriuretic peptide [NT‑proBNP]) and the following thresholds to rule out the diagnosis of heart failure:\n\nBNP less than 100\xa0ng/litre\n\nNT‑proBNP less than 300\xa0ng/litre.\n\nIn people presenting with new suspected acute heart failure with raised natriuretic peptide levels (see recommendation 1.2.2), perform transthoracic Doppler 2D echocardiography to establish the presence or absence of cardiac abnormalities.\n\nIn people presenting with new suspected acute heart failure, consider performing transthoracic Doppler 2D echocardiography within 48\xa0hours of admission to guide early specialist management.\n\nDo not routinely offer pulmonary artery catheterisation to people with acute heart failure.\n\n# Initial pharmacological treatment\n\nFor guidance on patient consent and capacity follow recommendations on consent and capacity in the NICE guideline on patient experience in adult NHS services.\n\nDo not routinely offer opiates to people with acute heart failure.\n\nOffer intravenous diuretic therapy to people with acute heart failure. Start treatment using either a bolus or infusion strategy.\n\nFor people already taking a diuretic, consider a higher dose of diuretic than that on which the person was admitted unless there are serious concerns with patient adherence to diuretic therapy before admission.\n\nClosely monitor the person's renal function, weight and urine output during diuretic therapy.\n\nDiscuss with the person the best strategies of coping with an increased urine output.\n\nDo not routinely offer nitrates to people with acute heart failure.\n\nIf intravenous nitrates are used in specific circumstances, such as for people with concomitant myocardial ischaemia, severe hypertension or regurgitant aortic or mitral valve disease, monitor blood pressure closely in a setting where at least level\xa02 care can be provided.\n\nDo not offer sodium nitroprusside to people with acute heart failure.\n\nDo not routinely offer inotropes or vasopressors to people with acute heart failure.\n\nConsider inotropes or vasopressors in people with acute heart failure with potentially reversible cardiogenic shock. Administer these treatments in a cardiac care unit or high dependency unit or an alternative setting where at least level\xa02 care can be provided.Level 2 care is for people needing more detailed observation or intervention, including support for a single failing organ system or postoperative care and for those stepping down from higher levels of care. From levels of critical care for adult patients.\n\n# Initial non-pharmacological treatment\n\nDo not routinely use non‑invasive ventilation (continuous positive airways pressure [CPAP] or non‑invasive positive pressure ventilation [NIPPV]) in people with acute heart failure and cardiogenic pulmonary oedema.\n\nIf a person has cardiogenic pulmonary oedema with severe dyspnoea and acidaemia consider starting non‑invasive ventilation without delay:\n\nat acute presentation or\n\nas an adjunct to medical therapy if the person's condition has failed to respond.\n\nConsider invasive ventilation in people with acute heart failure that, despite treatment, is leading to or is complicated by:\n\nrespiratory failure or\n\nreduced consciousness or physical exhaustion.\n\nDo not routinely offer ultrafiltration to people with acute heart failure.\n\nConsider ultrafiltration for people with confirmed diuretic resistance.Diuretic resistance is defined as dose escalation beyond a person's previously recognised dose ceiling or a dose approaching the maximum recommended daily dose without incremental improvement in diuresis. From diuretics and ultrafiltration in acute decompensated heart failure.\n\n# Treatment after stabilisation\n\nIn a person presenting with acute heart failure who is already taking beta‑blockers, continue the beta‑blocker treatment unless they have a heart rate less than 50\xa0beats per minute, second or third degree atrioventricular block, or shock.\n\nStart or restart beta‑blocker treatment during hospital admission in people with acute heart failure due to left ventricular systolic dysfunction, once their condition has been stabilised – for example, when intravenous diuretics are no longer needed.\n\nEnsure that the person's condition is stable for typically 48\xa0hours after starting or restarting beta‑blockers and before discharging from hospital.\n\nOffer an angiotensin‑converting enzyme inhibitor (or angiotensin receptor blocker if there are intolerable side effects) and an aldosterone antagonist during hospital admission to people with acute heart failure and reduced left ventricular ejection fraction. If the angiotensin‑converting enzyme inhibitor (or angiotensin receptor blocker) is not tolerated an aldosterone antagonist should still be offered.In February 2016, the Medicines and Healthcare products Regulatory Agency (MHRA) published advice on the concomitant use of spironolactone and renin-angiotensin system drugs in heart failure concerning the risk of potentially fatal hyperkalaemia. See the MHRA advice for more information.\n\nClosely monitor the person's renal function, electrolytes, heart rate, blood pressure and overall clinical status during treatment with beta‑blockers, aldosterone antagonists or angiotensin‑converting enzyme inhibitors.\n\n# Valvular surgery and percutaneous intervention\n\nThe recommendations on valvular surgery and percutaneous intervention have been replaced by the NICE guideline on heart valve disease.\n\n# Mechanical assist devices\n\nAt an early stage, the specialist should have a discussion with a centre providing mechanical circulatory support about:\n\npeople with potentially reversible severe acute heart failure or\n\npeople who are potential candidates for transplantation.", 'Recommendations for research': 'The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.\n\n# Dopamine\n\nIn people with acute heart failure, congestion and worsening renal function, does the addition of low‑dose dopamine to standard therapy lead to greater diuresis and renal protection compared with adding placebo to standard therapy?\n\n## Why this is important\n\nA randomised controlled trial should be conducted to investigate whether the addition of low‑dose dopamine to standard therapy leads to more clinically and cost effective decongestion in people admitted to hospital for treatment of decompensated heart failure. The study should aim to investigate the diuretic effect of dopamine as well as effects on renal function.\n\nOne of the most common and difficult to manage problems arising during the initial treatment of people with acute heart failure is an inadequate response to intravenous diuretic therapy (that is, failure to relieve congestion), which is often associated with worsening renal function. This combination frequently leads to a prolonged inpatient stay and is associated with higher inpatient mortality rates and higher post‑discharge mortality and re‑admission rates. The best treatment for this combination of problems is unknown. However, theoretical and experimental evidence indicates that low‑dose dopamine may improve renal blood flow, as well as enhance sodium and water excretion. Clinical trials have not yet resolved whether in some patients, the use of low‑dose dopamine actually results in improved decongestion and shorter hospital stays.\n\n# Thiazide\n\nIn people with acute heart failure and persistent congestion, does the addition of a thiazide diuretic to standard therapy lead to greater diuresis compared with adding placebo to standard therapy?\n\n## Why this is important\n\nA randomised controlled trial should be conducted to investigate whether the addition of a thiazide diuretic to standard therapy leads to more clinically and cost effective decongestion in people admitted to hospital for treatment of decompensated heart failure.\n\nOne of the most common and difficult to manage problems arising during the initial treatment of people with acute heart failure is an inadequate response to intravenous diuretic therapy. This frequently leads to a prolonged inpatient stay and is associated with higher inpatient mortality and higher post‑discharge mortality and re‑admission rates. The best treatment for this problem is unknown. However, there is some inconsistent and non‑robust evidence that addition of a thiazide or thiazide‑like diuretic (metolazone) may be beneficial. The proposed study would aim to resolve this uncertainty and guide the management of a difficult clinical problem.\n\n# Intra-aortic balloon counter‑pulsation\n\nIn people with acute heart failure and hypoperfusion syndrome, is the use of intra‑aortic balloon counter‑pulsation pump (IABP) better than the use of intravenous inotropes?\n\n## Why this is important\n\nA randomised controlled trial should be conducted in people with decompensated heart failure due to left ventricular systolic dysfunction and systemic hypoperfusion comparing the use of IABP with the use of inotropes/vasopressors. This would determine which strategy is more clinically and cost effective in this cohort.\n\nIABP is used in the hospital setting as an adjuvant in people with critical coronary ischaemia and in people with mechanical complications of acute myocardial infarction. It has also been used in people who develop cardiogenic shock after acute myocardial infarction. However, it is uncertain whether it can provide clinical benefit in the critically unwell patients with acute heart failure due to left ventricular systolic dysfunction and systemic hypoperfusion.\n\n# Ultrafiltration\n\nIn people with decompensated heart failure, fluid congestion and diuretic resistance, does ultrafiltration lead to more rapid and effective decongestion compared with continuing diuretic treatment?\n\n## Why this is important\n\nA randomised controlled trial should be undertaken to determine whether ultrafiltration is more clinically and cost effective than conventional diuretic therapy for people admitted to hospital with decompensated heart failure. The study should not only investigate several clinical outcomes but also consider the impact of treatments on quality of life and provide data on safety.\n\nPeople who have fluid retention that is resistant to conventional diuretic therapy, with or without renal dysfunction, make up a high proportion of hospital admissions due to heart failure. Such admissions are often prolonged and therefore have important budgetary implications for the NHS. The few, relatively small scale, randomised trials of ultrafiltration performed so far have been conducted in healthcare settings very different from the UK, with less fluid retention than is usually seen in UK practice, and where length of stay is usually much shorter than in UK (and European) practice. Although technically feasible, the evidence for benefit on heart failure outcomes is inconsistent and difficult to generalise to UK practice. Therefore, a UK‑based study of sufficient quality is needed.'}
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https://www.nice.org.uk/guidance/cg187
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This guideline covers diagnosing and managing acute heart failure or possible acute heart failure in people aged 18 and over. It aims to improve the immediate care of someone who is acutely unwell as a result of heart failure.
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Heart valve disease presenting in adults: investigation and management
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Heart valve disease presenting in adults: investigation and management
This guideline covers investigation and management of heart valve disease presenting in adults. It aims to improve quality of life and survival for people with heart valve disease through timely diagnosis and appropriate intervention.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Referral for echocardiography and specialist assessment
## Referral for echocardiography
Consider an echocardiogram for adults with a murmur and no other signs or symptoms if valve disease is suspected based on:
the nature of the murmur
family history
age (especially if over 75), or
medical history (for example, a history of atrial fibrillation).
Offer an echocardiogram to adults with a murmur if valve disease is suspected (based on the nature of the murmur, family history, age or medical history) and they have:
signs (such as peripheral oedema) or symptoms (such as angina or breathlessness) or an abnormal ECG, or
an ejection systolic murmur with a reduced second heart sound but no other signs or symptoms.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for echocardiography .
Full details of the evidence and the committee's discussion are in evidence review A: symptoms and signs indicating need for echocardiography or direct referral to a specialist.
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## Referral for urgent specialist assessment or urgent echocardiography
If valve disease is suspected (based on the nature of the murmur, family history, age or medical history):
Offer urgent (within 2 weeks) specialist assessment that includes echocardiogram or if not available an urgent echocardiogram alone to adults with a systolic murmur and exertional syncope.
Consider urgent (within 2 weeks) specialist assessment that includes echocardiogram for adults with a murmur and severe symptoms (angina or breathlessness on minimal exertion or at rest) thought to be related to valvular heart disease.
For guidance on referral and assessment for adults with murmur and non-exertional syncope, follow the recommendations in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s.
For guidance on referral and assessment for adults with breathlessness but no murmur, follow the recommendations in the NICE guideline on chronic heart failure in adults.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for urgent specialist assessment or urgent echocardiography .
Full details of the evidence and the committee's discussion are in evidence review A: symptoms and signs indicating need for echocardiography or direct referral to a specialist.
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## Referral to a specialist after echocardiography
Be aware that mild valve disease is common and rarely progresses to become clinically significant.
Offer referral to a specialist to:
adults with moderate or severe valve disease of any type
adults with bicuspid aortic valve disease of any severity (including mild valve disease).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral to a specialist after echocardiography .
Full details of the evidence and the committee's discussion are in evidence review B: indications for referral to a specialist following echocardiography.
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## Information, referral and specialist assessment for pregnant women and women considering pregnancy
Be aware that most women with valve disease can have a pregnancy without complications.
Offer advice on the implications of treatment choices on any future pregnancy to women who need heart valve intervention.
Offer advice on family planning to women with severe valve disease, particularly aortic and mitral stenosis.
Refer pregnant women or women who are considering a pregnancy to a cardiologist with expertise in the care of pregnant women, if they have any of the following:
moderate or severe valve disease
bicuspid aortic valve disease of any severity (including mild disease) and associated aortopathy
a prosthetic valve.Refer whether they have symptoms or not.
Consider seeking specialist advice on the choice of replacement valve if heart valve replacement surgery is being considered for women of childbearing potential.
For guidance on intrapartum care, follow the recommendations on heart disease in the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information, referral and specialist assessment for pregnant women and women considering a pregnancy .
Full details of the evidence and the committee's discussion are in evidence review A: symptoms and signs indicating need for echocardiography or direct referral to a specialist.
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# Pharmacological management
## Management of heart failure in people with valve disease
Consider a beta-blocker for adults with moderate to severe mitral stenosis and heart failure.
When adults with heart valve conditions and heart failure also have left ventricular dysfunction, refer to the NICE guideline on chronic heart failure in adults.
For a short explanation of why the committee made these recommendations and how they might affect practice, see rationale and impact section on pharmacological management of heart failure in heart valve disease .
Full details of the evidence and the committee's discussion are in evidence review C: pharmacological management.
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# Indications for interventions
Offer an intervention to adults with symptomatic severe heart valve disease.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on indications for interventions .
Full details of the evidence and the committee's discussion are in evidence review H: transcatheter intervention, surgery or conservative management in heart valve disease.
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## Aortic stenosis
Consider referring adults with asymptomatic severe aortic stenosis for intervention, if suitable, if they have any of the following:
Vmax (peak aortic jet velocity) more than 5 m/s on echocardiography
aortic valve area less than 0.6 cm2 on echocardiography
left ventricular ejection fraction (LVEF) less than 55%
B‑type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) level more than twice the upper limit of normal
symptoms unmasked on exercise testing.
Consider referring adults with symptomatic low‑gradient aortic stenosis with LVEF less than 50% for intervention if during dobutamine stress echocardiography the aortic stenosis is shown to be severe by:
a mean gradient across the aortic valve that increases to more than 40 mmHg and
an aortic valve area that remains less than 1 cm2.
Consider measuring aortic valve calcium score on cardiac CT if the severity of symptomatic aortic stenosis is uncertain.
Offer enhanced follow up (for example, more frequent reviews) and further assessment (for example, stress echocardiography) to monitor the need for intervention if mid‑wall fibrosis is detected on cardiac MRI in adults with severe aortic stenosis.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for interventions for adults with aortic stenosis .
Full details of the evidence and the committee's discussion are in:
evidence review D: indications for intervention
evidence review E: stress testing and stress echocardiography in determining need for intervention
evidence review F: CT and MRI indications for intervention.
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## Aortic regurgitation
Consider referring adults with asymptomatic severe aortic regurgitation for intervention, if suitable, if they have either of the following:
LVEF less than 55% or
end systolic diameter (ESD) of more than 50 mm or end systolic diameter index (ESDI) more than 24 mm/m2 on echocardiography.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on indications for interventions for adults with aortic regurgitation .
Full details of the evidence and the committee's discussion are in evidence review D: indications for intervention.
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## Mitral regurgitation
Consider referring adults with asymptomatic severe primary mitral regurgitation for intervention, if suitable, if they have any of the following:
LVEF less than 60%
ESD more than 45 mm or ESDI more than 22 mm/m2 on echocardiography or
an increase of systolic pulmonary artery pressure to more than 60 mmHg on exercise testing.When making decisions about referral for surgery, take into account the suitability of the valve for repair and the presence of atrial fibrillation or systolic pulmonary artery pressure of more than 50 mmHg on echocardiography at rest.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on indications for intervention for adults with mitral regurgitation .
Full details of the evidence and the committee's discussion are in evidence review D: indications for intervention and evidence review E: stress testing and stress echocardiography in determining need for intervention.
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# Monitoring when there is no current need for intervention
Offer clinical review every 6 to 12 months, with an echocardiogram, to adults with asymptomatic severe valve disease if an intervention is suitable but not currently needed. Base the frequency of the review on echocardiography findings and shared decision making with the patient.
Consider echocardiographic assessment every 3 to 5 years for adults with mild aortic or mitral stenosis.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring where there is no current need for intervention .
Full details of the evidence and the committee's discussion are in evidence review G: monitoring of people with heart valve disease and no current indication for intervention.
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# Interventions
See the recommendations on indications for interventions.
## Decisions about interventions
Discuss the possible benefits and risks of interventions with adults who have an indication for valve intervention. Include in the discussion:
the benefits to quality of life (both in the short and long term)
prosthetic valve durability
the risks associated with the procedures
the type of access for surgery (median sternotomy, minimally invasive surgery or, for people at high surgical risk, transcatheter)
the possible need for other cardiac procedures in the future.Follow the recommendations in the NICE guidelines on shared decision making and patient experience in adult NHS services and base decisions on the type of intervention on patient characteristics and preferences.
When surgery is agreed, base the decision on the type of surgery (median sternotomy or minimally invasive surgery) on patient characteristics and preferences. If minimally invasive surgery is the agreed option and is not available locally, refer the person to another centre.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on decisions about interventions .
Full details of the evidence and the committee's discussion are in evidence review H: transcatheter intervention, surgery or conservative management in heart valve disease.
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## Aortic valve disease
For NHS England and NHS Improvement's position on transcatheter aortic valve implantation for people at low or intermediate surgical risk, see the implementation strategy for transcatheter aortic valve implantation.
Offer surgery, if suitable (by median sternotomy or minimally invasive surgery), as first-line intervention for adults with severe aortic stenosis, aortic regurgitation or mixed aortic valve disease and an indication for surgery who are at low or intermediate surgical risk. TAVI is not cost effective for people at low or intermediate surgical risk at the current list price.
Offer TAVI, if suitable, to adults with non-bicuspid severe aortic stenosis who are at high surgical risk or if surgery is unsuitable.
See the recommendations on using TAVI in the NICE interventional procedures guidance on transcatheter aortic valve implantation for aortic stenosis, including entering the details of all people undergoing TAVI into the UK TAVI registry. See also the NICE interventional procedures guidance on sutureless aortic valve replacement in aortic stenosis and balloon valvuloplasty for aortic valve stenosis.
See NHS England's clinical commissioning policy on transcatheter aortic valve implantation for aortic stenosis.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for aortic valve disease .
Full details of the evidence and the committee's discussion are in evidence review H: transcatheter intervention, surgery or conservative management in heart valve disease.
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## Mitral stenosis
Consider transcatheter valvotomy for adults with rheumatic severe mitral stenosis, if the valve is suitable for this procedure.
Offer surgical mitral valve replacement to adults with rheumatic severe mitral stenosis if transcatheter valvotomy is unsuitable.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for mitral stenosis .
Full details of the evidence and the committee's discussion are in evidence review H: transcatheter intervention, surgery or conservative management in heart valve disease.
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## Mitral regurgitation
Offer surgical mitral valve repair (by median sternotomy or minimally invasive surgery) to adults with severe primary mitral regurgitation and an indication for repair, if surgery is suitable.
Offer surgical mitral valve replacement (by median sternotomy or minimally invasive surgery) to adults with severe primary mitral regurgitation and an indication for surgery, if the valve is not suitable for repair and surgery is suitable.
Consider transcatheter edge-to-edge repair, if suitable, for adults with severe primary mitral regurgitation and symptoms, if surgery is unsuitable.
See NHS England's clinical commissioning policy on percutaneous mitral valve leaflet repair for primary degenerative mitral regurgitation in adults and the NICE interventional procedures guidance on percutaneous mitral valve leaflet repair for mitral regurgitation and thoracoscopically assisted mitral valve surgery.
Consider surgical mitral valve repair (by median sternotomy or minimally invasive surgery) for adults with severe secondary mitral regurgitation who are having cardiac surgery for another indication, if surgery is suitable.
Consider surgical mitral valve replacement (by median sternotomy or minimally invasive surgery) for adults with severe secondary mitral regurgitation who are having cardiac surgery for another indication, if the valve is not suitable for repair and surgery is suitable.
Offer medical management to adults with heart failure and severe secondary mitral regurgitation, if surgery is unsuitable.
Consider transcatheter mitral edge-to-edge repair for adults with heart failure and severe secondary mitral regurgitation, if surgery is unsuitable and they remain symptomatic on medical management.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for mitral regurgitation .
Full details of the evidence and the committee's discussion are in evidence review H: transcatheter intervention, surgery or conservative management in heart valve disease.
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Consider surgical tricuspid valve repair at the time of mitral valve surgery when tricuspid regurgitation is moderate or severe.
Consider surgical tricuspid valve repair at the time of aortic valve surgery when tricuspid regurgitation is severe.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for tricuspid regurgitation .
Full details of the evidence and the committee's discussion are in evidence review H: transcatheter intervention, surgery or conservative management in heart valve disease.
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# Repeat intervention
Consider transcatheter or redo surgical intervention for adults with severe aortic degeneration of a biological prosthetic valve and symptoms. Take into account the following factors to inform a shared decision about the choice of intervention:
the short- and long-term benefits
type of valve dysfunction and prosthesis
the risks associated with the procedure
the possible need for other cardiac procedures in the future.See the NICE interventional procedures guidance on using transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis, transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair and valve-in-valve TAVI for aortic bioprosthetic dysfunction.
For a short explanation of why the committee made this recommendation and how it might affect practice, see rationale and impact section on repeat intervention .
Full details of the evidence and the committee's discussion are in evidence review I: repeat intervention for failure of biological or repaired valves.
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# Anticoagulation and antiplatelet therapy
Do not offer anticoagulation after surgical biological valve replacement unless there are other indications for anticoagulation.
Consider aspirin, or clopidogrel if aspirin is not tolerated, after TAVI.
If people have other indications for anticoagulation or antiplatelet therapy, follow the recommendations in the NICE guidelines on atrial fibrillation and acute coronary syndromes.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anticoagulation and antiplatelet therapy .
Full details of the evidence and the committee's discussion are in evidence review J: anticoagulant and/or antiplatelet therapy for biological prosthetic valves and after valve repair.
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# Monitoring after an intervention
Base decisions on the frequency and type of monitoring for adults who have had an intervention (valve repair or replacement) for valve disease on:
durability of the prosthetic valve or durability of the repair
the presence of another condition, including other heart disease
residual valve abnormality or consequences of the procedure, for example, paravalvular leak
concerns about abnormal function of the prosthetic valve
the patient's wishes.Advise people and their family members or carers (as appropriate) to seek advice if the heart condition deteriorates.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on monitoring after an intervention .
Full details of the evidence and the committee's discussion are in evidence review K: monitoring in people with repaired or replaced heart valves.
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# Information and advice
Follow the NICE guideline on shared decision making and the recommendations in the NICE guideline on patient experience in adult NHS services on:
involvement of family members and carers
communication
information
tailoring healthcare services.
Consider providing a point of contact for accessing specialist advice between appointments.
Be aware of the psychological impact on the person receiving a diagnosis of valve disease, whether or not they have symptoms. Consider the person's needs for additional information and support.
Provide information and advice to adults with valve disease about:
the expected progression and prognosis of their condition, including the likely length of an asymptomatic stage
any need for intervention, including the type of intervention
pregnancy, if appropriate
the possible effects of other conditions on long-term outcomes
rehabilitation and long‑term outcomes
palliative care, if appropriate, including how to access this.
Provide information and support to young adults about transition from paediatric to adult services, in line with the NICE guideline on transition from children's to adults' services for young people using health or social care services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and advice .
Full details of the evidence and the committee's discussion are in evidence review L: information and advice.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline.
## Degenerated
Degenerated covers progressive degeneration and does not include failure of the valve due to endocarditis or thrombosis.
## Risk of surgery
This is calculated using EuroSCORE II. People have low surgical risk if they score less than 4%, intermediate risk if they score between 4% and 8% and high risk if they score more than 8%.
## Severe valve disease
Severity of valve disease is defined in line with the British Society of Echocardiography guidelines on the assessment of aortic stenosis, the tricuspid and pulmonary valves, and mitral valve disease.
## Specialist assessment and advice
This could include assessment and advice from a cardiologist with expertise in heart valve disease, a multidisciplinary team or a heart valve clinic.
## Suitability for transcatheter aortic valve implantation
Suitability for transcatheter aortic valve implantation (TAVI) depends on:
an appropriate access for inserting the TAVI catheter
the morphology of the valve, aortic root and ascending aorta
the degree and distribution of calcium in the aortic valve.
It is an option for:
All people expected to have an unacceptably high risk of mortality or morbidity as a result of surgery (for example, because of a risk of infection in people who are immunosuppressed). See also the definition of high risk of surgery according to EuroSCORE II.
All people expected to have unacceptably strenuous and prolonged recovery from surgery and an extended need for rehabilitation because of frailty, reduced mobility, or musculoskeletal conditions.
All people with low life expectancy, either because of their age or because they have life-limiting comorbidities.
## Suitability for transcatheter edge-to-edge repair
Suitability for transcatheter edge-to-edge repair depends on:
the morphology of the person's valve
the feasibility of using transoesophageal echocardiography to guide the procedure
the person's fitness for general anaesthesia.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Monitoring when there is no current need for intervention
What is the most clinically and cost-effective monitoring (type and frequency of test) for adults with asymptomatic mild or moderate heart valve disease (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation and tricuspid regurgitation) and no current need for intervention?
For a short explanation of why the committee made the recommendation for research, see the rationale on monitoring where there is no current need for intervention .
Full details of the evidence and the committee's discussion are in evidence review G: monitoring of people with heart valve disease and no current indication for intervention.
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## Interventions for tricuspid regurgitation
What is the most clinically and cost-effective management strategy for adults with tricuspid regurgitation?
For a short explanation of why the committee made the recommendation for research, see the rationale on interventions for tricuspid regurgitation .
Full details of the evidence and the committee's discussion are in evidence review H: transcatheter intervention, surgery or conservative management in heart valve disease.
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## Interventions for a failed valve
What is the clinical and cost effectiveness of transcatheter intervention compared with surgical redo intervention for adults with failing biological prosthetic tricuspid valves or failing repaired native tricuspid valves when either procedure is suitable?
For a short explanation of why the committee made the recommendation for research, see the rationale on repeat intervention .
Full details of the evidence and the committee's discussion are in evidence review I: repeat intervention for failure of biological or repaired valves.
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## Monitoring after an intervention
What is the most clinically and cost‑effective timing, nature and frequency of follow up for different types of valve interventions, including repair and replacement with tissue or mechanical valves?
For a short explanation of why the committee made the recommendation for research, see rationale on monitoring after an intervention .
Full details of the evidence and the committee's discussion are in evidence review K: monitoring in people with repaired or replaced heart valves.
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## Information and advice
What are the information and advice needs of all adult age groups with heart valve disease of all severities and stages?
For a short explanation of why the committee made the recommendation for research, see the rationale on information and advice .
Full details of the evidence and the committee's discussion are in evidence review L: information and advice.
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# Other recommendations for research
## Indications for interventions – stress testing or echocardiography
What is the prognostic value of severe mitral regurgitation unmasked on exercise echocardiography in adults with symptomatic non‑severe mitral regurgitation at rest?
What is the prognostic value of parameters observed on exercise stress testing and exercise stress echocardiography in asymptomatic severe aortic regurgitation?
## Indications for interventions – CT or MRI
In adults with aortic or primary mitral regurgitation in whom the need for intervention is unclear after echocardiography, what is the prognostic value and cost effectiveness of cardiac MRI to assess the severity of valvular regurgitation?
In adults with aortic or mitral regurgitation in whom the need for intervention is unclear after echocardiography, what is the prognostic value and cost effectiveness of left ventricular ejection fraction (LVEF) measured on cardiac MRI to assess the need for intervention?
In adults with asymptomatic severe aortic stenosis what is the prognostic value and cost effectiveness of LVEF measured on cardiac MRI to assess the need for intervention?
In adults with asymptomatic severe tricuspid regurgitation what is the prognostic value and cost effectiveness of cardiac MRI for assessment of the right ventricle to assess the need for intervention?
## Indications for interventions – global longitudinal strain
In adults with severe heart valve disease what is the prognostic value and cost effectiveness of global longitudinal strain to assess the need for intervention?
In adults with asymptomatic, severe aortic regurgitation or mitral regurgitation what is the prognostic value and cost effectiveness of B‑type natriuretic peptide (BNP) to assess the need for intervention?
## Pharmacological management for adults with heart valve disease
What is the clinical and cost effectiveness of ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers and diuretics for adults with severe aortic stenosis?
What is the clinical and cost effectiveness of ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers and calcium channel blockers, including compared with placebo, for adults with aortic regurgitation?
What is the clinical and cost effectiveness of ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers and diuretics for adults with primary severe mitral regurgitation?
What is the clinical and cost effectiveness of beta‑blockers for adults over 75 years with non‑rheumatic/calcific mitral stenosis, in both sinus rhythm and atrial fibrillation?
What is the clinical and cost effectiveness of pharmacological management of heart failure for adults with heart failure and severe aortic stenosis, severe aortic regurgitation or severe mitral regurgitation?
## Monitoring when there is no current need for intervention
What is the most clinically and cost‑effective monitoring strategy (type and frequency of test) for adults with asymptomatic severe heart valve disease (aortic regurgitation, mitral stenosis, mitral regurgitation or tricuspid regurgitation) and no current indication for intervention?
What is the most clinically and cost‑effective monitoring strategy (type and frequency of test) for adults with symptomatic moderate heart valve disease (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation and tricuspid regurgitation) and no current indication for intervention?
## Interventions
What is the most clinically and cost‑effective management strategy for adults with calcific mitral stenosis and an indication for intervention?
## Anticoagulation and antiplatelet therapy
What is the clinical and cost effectiveness of single or dual antiplatelet therapies or anticoagulants compared with placebo after transcatheter or surgical valve replacement (implantation) with biological prosthesis and after valve repair?
In adults with biological valve replacement, what effect does anticoagulation or antiplatelet therapy have on long-term valve function and outcomes?
## Repeat interventions
What is the clinical and cost effectiveness of transcatheter intervention compared with surgical redo intervention for adults with failing biological prosthetic aortic valves when either procedure is suitable?
What is the clinical and cost effectiveness of transcatheter intervention compared with surgical redo intervention for adults with failing biological prosthetic mitral valves when either procedure is suitable?# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Referral for echocardiography
Recommendations 1.1.1 and 1.1.2
## Why the committee made the recommendations
Limited evidence showed that murmur is an indicator of valve disease. But the evidence also showed that a substantial proportion of people with a murmur do not have valve disease confirmed by a reference test. The committee agreed that 'innocent' murmurs can occur, particularly during the teenage and young adult years and in pregnancy. These are difficult to differentiate from pathological murmurs by clinical examination alone. The evidence was not strong enough to recommend that everyone with a murmur should be referred for echocardiography. The committee agreed that this would be a change in practice, would increase pressure on echocardiography services and would offer uncertain benefit. However, when the nature of the murmur, family history, age or medical history suggest possible valve disease, echocardiography should be considered to establish a diagnosis.
Evidence suggested that the presence of a systolic heart murmur plus a reduced second heart sound had good specificity for aortic stenosis confirmed by echocardiography. The recommendation specifies ejection systolic murmur because this, combined with a reduced second heart sound, is a classic indicator of aortic stenosis and is most often present in severe aortic stenosis. Although this was based on only a few studies, the committee agreed that people with these features should be referred for echocardiography. Because of the limited evidence identified, this recommendation was limited to those in whom heart valve disease was considered a possible explanation of these signs based on the nature of the murmur, family history, age or medical history.
Studies showed that echocardiography detected valve disease in a higher proportion of people with murmur plus other signs and symptoms (abnormal ECG, angina, breathlessness, peripheral oedema) than in people with murmur alone. That is, murmur plus other signs or symptoms had a higher specificity for echocardiography confirmed valve disease. Again, this was based on a few studies only, so the committee agreed that the nature of the murmur, family history, age or medical history should also suggest valve disease as a possibility.
## How the recommendations might affect practice
The recommendations reflect current practice.
Return to recommendations
# Referral for urgent specialist assessment or urgent echocardiography
Recommendations 1.1.3 to 1.1.5
## Why the committee made the recommendations
Evidence showed that more cases of severe valve disease were picked up when a murmur plus other signs or symptoms were present. The committee agreed that mild and moderate valve disease does not usually present with these symptoms and using these criteria for referral would not result in unnecessary referral for urgent specialist assessment or echocardiography in most cases.
People with exertional syncope and a systolic murmur need an urgent diagnosis because exertional syncope caused by aortic stenosis has a high risk of a poor outcome. The diagnosis must be made quickly to allow appropriate management, which would likely include intervention if severe aortic stenosis is confirmed. Depending on local availability, an echocardiogram may be faster than direct specialist referral, which would include echocardiography, so the committee agreed to recommend either for this group. The committee agreed that the assessment or echocardiogram should be done within 2 weeks.
For people with severe symptoms (New York Heart Association classification III to IV or perceived by the person as severe) and a murmur, but without exertional syncope, the committee agreed that urgent specialist assessment within 2 weeks, which would include echocardiography, should be considered.
## How the recommendations might affect practice
The recommendations reflect current practice.
Return to recommendations
# Referral to a specialist after echocardiography
Recommendations 1.1.6 and 1.1.7
## Why the committee made the recommendations
Across the included studies, moderate and severe valve disease was consistently associated with more adverse outcomes than 'mild' or 'mild and moderate' valve disease. Despite limited evidence for each specific type of valve disease, the committee agreed that specialist referral should be offered to those with moderate or severe disease. This is consistent with current practice.
The evidence could not be used to recommend that people with mild valve disease should never be referred to a specialist, because outcomes were not compared with those without valve disease. However, the committee stressed that patients and healthcare professionals should be aware that mild valve disease is very common in people over 70, it seldom causes symptoms and does not progress in most cases. The committee recommended that people with bicuspid aortic valve disease of any severity (including mild disease) should be offered specialist referral because its progression is different to other types of valve disease, it can be associated with aortopathy and in practice is usually referred.
## How the recommendations might affect practice
The committee agreed that it is current practice for everyone with moderate or severe valve disease to be referred to a specialist, regardless of the type of disease and whether it is primary or secondary. The recommendation on moderate and severe valve disease would therefore not lead to a change in practice.
For mild valve disease, there is currently variation in specialist referral, with some unnecessary referrals being made. Although the recommendation does not preclude referral for this group, it may reassure individuals with mild valve disease, reduce the number of unnecessary referrals and be cost saving. The recommendations covering bicuspid aortic valve disease were considered to reflect current practice.
Return to recommendations
# Information, referral and specialist assessment for pregnant women and women considering pregnancy
Recommendations 1.1.8 to 1.1.13
## Why the committee made the recommendations
The committee recognised that the proportion of pregnant women with valve disease is small compared with the number of women with valve disease who may be considering pregnancy. These women need to carefully consider the impact of treatment on any future pregnancy and should be given advice before making a treatment decision. This should include advice on contraception and planned pregnancy for women with severe valve disease, and consideration of the type of valve they receive if surgery is performed. It may be appropriate for their clinician to seek specialist advice to inform this decision from a cardiologist with expertise in the care of pregnant women. The committee noted that healthcare professionals without specialist expertise may inappropriately advise women against becoming pregnant. They agreed that some women with valve disease who may wish to become pregnant or who are pregnant should be referred to a cardiologist with specialist expertise. The committee highlighted that only women with moderate or severe disease on echocardiography, bicuspid aortic valve disease with associated aortopathy or prosthetic valves need referral. Women with mild disease, for example, aortic regurgitation or mitral valve prolapse without regurgitation, do not need a referral. The committee acknowledged that an ejection systolic flow murmur is present in most pregnant women and is not a cause for concern. They also noted that there is no official subspecialty or national accreditation for cardiologists with a specialist interest in pregnancy.
## How the recommendations might affect practice
The committee acknowledged that it is not current practice to refer women who are considering pregnancy to a cardiologist with specialist expertise. Although moderate or severe heart valve disease is relatively rare in women of childbearing age, they still represent an important group of patients. Healthcare centres offering specialised support to women considering pregnancy are not widespread, so the committee expect a moderate change in practice in those centres.
Return to recommendations
# Pharmacological management to improve prognosis
## Why the committee made the recommendations
There was no evidence that pharmacological management can slow the progression of heart valve disease, only evidence that statins improve prognosis in aortic stenosis. The evidence showed that statins reduced cardiac mortality compared with placebo for adults with aortic stenosis. The committee agreed that this benefit is because of an improvement in overall cardiovascular health rather than a direct effect on the aortic stenosis. Therefore, no recommendation was made and statins should be used in line with the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.
There was not enough evidence for the committee to make recommendations on pharmacological management of other conditions (for example, systemic hypertension) in people who also have heart valve disease.
The committee decided to make recommendations for research to inform pharmacological management using common treatments (ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers, calcium channel blockers and diuretics) in adults with aortic stenosis, aortic regurgitation or mitral regurgitation. These are important areas of uncertainty in current UK clinical practice.
## How the recommendations might affect practice
The recommendation reflects current practice, so the committee agreed there is unlikely to be a significant resource impact.
# Pharmacological management of heart failure in heart valve disease
Recommendations 1.2.1 and 1.2.2
## Why the committee made the recommendation
Some evidence showed that beta‑blockers reduced hospital stay for heart failure and increased exercise tolerance compared with usual care in adults with mitral stenosis. As with all other indications for beta‑blockers, some adults with mitral stenosis stopped beta‑blockers because of adverse events (weakness, dizziness and shortness of breath). But the committee agreed that in their experience these medicines offer overall benefit for people with moderate to severe mitral stenosis and heart failure.
The studies included younger people than in UK clinical practice, with mitral stenosis often being because of rheumatic fever. Patients also had atrial fibrillation. The committee agreed to make a recommendation for research to inform future use of beta‑blockers for older adults with non‑rheumatic calcific mitral stenosis, which is currently more common in the UK than rheumatic mitral stenosis, in sinus rhythm or atrial fibrillation.
Although a recommendation to consider beta‑blockers in people with moderate to severe mitral stenosis and heart failure was made, there was not enough evidence for the committee to make recommendations on the use of beta‑blockers in other types of heart valve disease. Similarly, there was not enough evidence to make recommendations on other drugs for the management of heart failure in heart valve disease. They agreed to make a recommendation for research on the pharmacological management of heart failure in adults with severe aortic stenosis, aortic regurgitation, and mitral regurgitation.
## How the recommendation might affect practice
The recommendation reflects current practice, so the committee agreed there is unlikely to be a significant resource impact.
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# Indications for interventions
Recommendation 1.3.1
## Why the committee made the recommendation
Severe symptomatic heart valve disease has a poor prognosis and there is no treatment for the symptoms other than an intervention on the valve. Because of this, the committee recommended that an intervention should be offered to this group. The evidence to support this recommendation is discussed under the different types of valve disease in the section on intervention.
## How the recommendation might affect practice
The recommendation reflects current practice.
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# Indications for interventions for adults with aortic stenosis
Recommendations 1.3.2 to 1.3.5
## Why the committee made the recommendations
A peak aortic jet velocity more than 5 m/s was a risk factor for increased mortality (all‑cause and cardiac or cardiovascular) and sudden death in people with asymptomatic severe aortic stenosis who had not had a valve intervention. An aortic valve area less than 0.6 cm2 was also associated with increased all‑cause mortality, both before and after valve intervention in adults with asymptomatic severe aortic stenosis.
A left ventricular ejection fraction (LVEF) less than 55% was the best marker of early myocardial decompensation, being linked to increased mortality in adults with asymptomatic severe aortic stenosis.
Raised B-type natriuretic peptide (BNP), particularly when 2 to 3 times the normal level, was a risk factor for all‑cause mortality, before and after valve intervention, for people with asymptomatic severe aortic stenosis and a preserved ejection fraction. The committee agreed that this would also apply to N-terminal proBNP (NT-proBNP), which is more widely used currently in the UK than BNP.
Some of these indicators were broadly in line with current practice and the experience of the committee. In addition, the evidence for increased mortality was strong, including for BNP. Therefore, the committee agreed that these indicators of poorer prognosis should prompt a discussion about the possible need for referral for intervention in people with asymptomatic severe aortic stenosis. Recommendations were limited to considering referral because the evidence was low to very low quality.
There was some evidence of increased mortality in people with asymptomatic severe aortic stenosis and a global longitudinal strain less than 14.7% or 15%, even when ejection fraction was preserved. However, there is some concern about reproducibility of measurements. The committee agreed that further research in this area would help to inform future guidance, so they made a recommendation for research.
Despite limitations in the quality of the evidence, the committee agreed that there was enough to show that symptoms revealed during exercise testing predict a poor outcome in people with asymptomatic severe aortic stenosis. They noted that some people may not report symptoms because they have adapted, for example, by reducing their activity. Exercise testing may therefore reveal these symptoms, which is an indication for intervention.
There was evidence from 2 studies, but with limitations, that no increase in valve area on dobutamine stress testing was associated with worse outcome in symptomatic low-flow low-gradient aortic stenosis. Point estimates and confidence intervals from both studies were consistent with this being a risk factor for poor outcome. Severe aortic stenosis is suggested if a person with low-gradient aortic stenosis has an LVEF less than 50% and a valve area less than 1 cm2 at rest. Based on the evidence and the committee's experience, this can be confirmed on dobutamine stress testing if their valve area stays below 1 cm2 and their mean gradient rises above 40 mmHg. This would therefore be an indication for intervention.
The evidence showed that a higher aortic valve calcium score measured by cardiac CT indicates a worse prognosis for people with aortic stenosis. This could be because it is an index of the severity of aortic stenosis or because it is a marker of more widespread vascular disease. This was supported by the knowledge and experience of the committee, who noted that a more calcified aortic valve is associated with more severe aortic stenosis. However, the mechanism of aortic stenosis in bicuspid aortic valves or in rheumatic disease is different, and cardiac CT would not be as relevant for monitoring valve calcium.
Most of the evidence suggested that myocardial fibrosis was associated with increased risk of a poor outcome in severe aortic stenosis. This was in line with the committee's experience that myocardial fibrosis in general, not only in aortic stenosis, is associated with a worse prognosis. Furthermore, myocardial fibrosis in people with severe aortic stenosis indicates early decompensation and the possible need for early intervention to stop progression, because mid‑wall fibrosis cannot be reversed or improved by intervention. The committee agreed that follow up should be enhanced and further assessment should be offered in those with mid‑wall fibrosis to check for symptoms and enable earlier aortic valve intervention to improve prognosis.
## How the recommendations might affect practice
These recommendations largely reflect current best practice, although there is local variation and not all healthcare professionals will know that all of these thresholds should lead to referral for intervention.
However, the threshold of LVEF less than 55% does represent a change from current practice, because some centres use a threshold of less than 50%. However, for most adults this will mean earlier rather than additional intervention, with subsequent improvement in survival and quality of life.
Cardiac MRI is not currently used by all centres to assess aortic stenosis. The recommendation to consider enhanced follow up and further assessment if mid‑wall fibrosis is detected by cardiac MRI should not mean a change in practice because it will be implemented only when cardiac MRI data is available.
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# Indications for intervention for adults with aortic regurgitation
Recommendation 1.3.6
## Why the committee made the recommendation
The committee agreed that it is established practice to consider intervention for people with severe aortic regurgitation and reduced cardiac function. Severity is defined in line with British Society of Echocardiography guidelines. People with aortic regurgitation are often younger than people with other types of valve disease and benefit from timely intervention.
Evidence showed that when LVEF was less than 55%, the risk of cardiovascular mortality or heart failure after intervention was higher. End systolic diameter index (ESDI) is also a measure of systolic dysfunction. Evidence showed an increased risk of left ventricular systolic dysfunction or death when ESDI was more than 24 mm/m2. The committee agreed that either of these 2 indicators of early myocardial decompensation should prompt discussion of possible intervention for asymptomatic severe aortic regurgitation. Recommendations were limited because of the evidence included being low to very low quality.
There was not enough evidence to include BNP level as an indicator for referral for intervention for people with asymptomatic severe aortic regurgitation. The committee agreed to make a recommendation for research to inform future practice.
No evidence was identified for stress testing and stress echocardiography in adults with asymptomatic severe aortic regurgitation. The committee agreed that further research could answer questions about when to intervene in this population. Therefore, they made a recommendation for research to identify prognostic factors in this population on stress testing.
## How the recommendation might affect practice
The recommendation is in line with current practice.
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# Indications for intervention for adults with mitral regurgitation
Recommendation 1.3.7
## Why the committee made the recommendation
Evidence showed that an LVEF less than 60% was a risk factor for increased cardiac mortality after intervention for asymptomatic severe mitral regurgitation. An ESDI greater than 22 mm/m2 was associated with onset of symptoms, left ventricular dysfunction, or death without intervention. This is broadly equivalent to the non‑indexed ESD threshold of 45 mm used in current practice. The committee agreed that either of these indicators of early myocardial decompensation should prompt consideration of an intervention for people with asymptomatic severe mitral regurgitation. Recommendations were limited to considering an intervention because the evidence was low to very low quality. The evidence on valve morphology, atrial fibrillation and pulmonary hypertension was not robust enough to include these as independent indicators for referral for intervention. However, the evidence suggested that these were associated with increased mortality, so the committee agreed their presence should be considered when discussing the possibility of intervention.
There was not enough evidence to include BNP level as an indicator for referral for intervention for people with asymptomatic severe mitral regurgitation. The committee agreed to make a recommendation for research to inform future practice.
Evidence from 2 studies showed that an increase of systolic pulmonary artery pressure (SPAP) to more than 60 mmHg on exercise was associated with worse outcomes in people with mitral regurgitation (asymptomatic or asymptomatic/mildly symptomatic, moderate or severe). This agreed with the committee's experience. Although there is limited evidence that in severe mitral regurgitation, intervening before symptoms develop results in better outcomes, the committee agreed that this may be better. Evidence from 1 study showed that SPAP above 60 mmHg on exercise was associated with symptoms developing during follow up.
There was not enough evidence for the committee to make a recommendation about symptomatic non‑severe mitral regurgitation. The single small study identified suggested that an increase in effective regurgitant orifice area of 13 mm2 or more on exercise may indicate a worse outcome for this group. But the committee were not confident in this result and so made a recommendation for research to inform future practice.
## How the recommendation might affect practice
The recommendation largely reflects current best practice, although there is local variation and not all healthcare professionals will know that all of these thresholds should lead to referral for intervention.
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# Monitoring when there is no current need for intervention
Recommendations 1.4.1 and 1.4.2
## Why the committee made the recommendations
A single study from the US suggested that regular monitoring for people with severe asymptomatic aortic stenosis reduced all‑cause mortality and hospital admission for heart failure. However, the study had limitations, including lack of applicability to UK clinical practice.
The committee discussed that although frequency of monitoring currently varies in the UK, it is usually every 6 to 12 months. Some adults find 6‑monthly monitoring reassuring. For others this leads to anxiety and they would prefer less frequent monitoring (for example, every 12 months). The committee agreed that the exact frequency of monitoring within the 6-month to 12‑month timeframe should be determined by echocardiography results and shared decision making with the patient. Monitoring less often than every 12 months would be likely to lead to negative outcomes for the patient because valve changes in this group occur over months rather than years. However, monitoring less often than every 12 months may be suitable for a minority of patients who have demonstrated stability over several years. The recommendation covers all types of asymptomatic severe valve disease.
In line with current practice, echocardiographic assessment every 3 to 5 years should be considered for adults with mild aortic or mitral stenosis. This would help to identify people with asymptomatic disease that has become more severe and for whom intervention may be appropriate.
## How the recommendations might affect practice
The recommendations are in line with current practice.
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# Decisions about interventions
Recommendations 1.5.1 and 1.5.2
## Why the committee made the recommendations
The committee highlighted the importance of shared decision making when discussing interventions. This is to ensure that treatment options are fully explored, along with their risks and benefits. Specifically, the committee highlighted valve durability, the risks associated with the procedure, and the possible need for other cardiac procedures in the future.
The committee agreed that in their clinical experience there was no difference between minimally invasive and standard surgery replacement in terms of outcomes when done by those with expertise in minimally invasive surgery. The decision should be based on patient characteristics and preferences. A lack of expertise in minimally invasive surgery locally should not be used as a reason for not performing a minimally invasive procedure. Adults should be referred to a centre where this expertise is available if the procedure is agreed as most suitable. The evidence to support this recommendation is reported under the different types of valve disease.
## How the recommendations might affect practice
The recommendations are expected to have a very small impact on current practice. Minimally invasive surgery will not be suitable for many patients. Those for whom it is suitable may still decide to have standard surgery after considering the possible benefits and risks of both options.
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# Interventions for aortic valve disease
Recommendations 1.5.3 to 1.5.5
## Why the committee made the recommendations
Evidence from 8 randomised controlled trials (RCTs) showed no large or clear differences for most outcomes between transcatheter aortic valve implantation (TAVI) and surgery for adults with non‑bicuspid aortic stenosis, including mortality outcomes and quality of life. However, a benefit of TAVI was identified for major bleeding and atrial fibrillation at 30 days, and length of hospital stay after the intervention. Absolute effects for other outcomes also suggested a benefit, but there was more uncertainty based on the confidence intervals. A harm of TAVI was identified for pacemaker implantation at 30 days. Although absolute effects also suggested a possible harm of TAVI in terms of mortality and rehospitalisation, the direction and size of the effect was much more uncertain for these outcomes and no clear difference between the 2 groups could be identified.
Only 1 study reported data beyond 5 years, but only for all‑cause mortality. The health economic model developed as part of the guideline looked for cost effectiveness over a lifetime. Therefore, it included evidence about the impact of complications in the long term, beyond 5 years, given the longer life expectancy for younger people with lower surgical risk. The results of the health economic model showed that TAVI at current prices was cost effective for people at high risk of surgery but not for people at low or intermediate risk. The committee agreed that if surgery is an option, it should be offered to those with severe aortic stenosis who are low or intermediate risk. Although all of the evidence identified was for non‑bicuspid aortic stenosis, it was agreed that the recommendation should also apply to bicuspid aortic stenosis, because suitability of surgery does not depend on the type of aortic stenosis. TAVI is also considered to be more difficult in bicuspid aortic stenosis.
Evidence showed benefits for TAVI for people with inoperable non‑bicuspid severe aortic stenosis compared with pharmacological management at 1 to 5 years. These included benefits in all‑cause mortality, cardiac mortality, need for another intervention during follow up, and hospital admission. However, at 30 days TAVI was associated with increased mortality, stroke or transient ischaemic attack, major bleeding, and major vascular complications. The committee noted that TAVI is the only intervention available for some people with symptomatic severe aortic stenosis. They agreed that pharmacological management is not sufficient to help symptoms in severe aortic stenosis and for some aortic stenosis can be fatal without an intervention. TAVI can improve outcomes in many cases. Two UK‑based studies indicated that TAVI offers a good balance of benefits and costs in adults who cannot have surgery. The committee agreed to recommend TAVI, if suitable, for those with non‑bicuspid severe aortic stenosis if surgery is unsuitable. TAVI is the only option for this group and was deemed cost effective in this population.
All of the evidence identified was for non‑bicuspid aortic stenosis. TAVI is considered to be more difficult for bicuspid aortic stenosis and the committee could not extrapolate the evidence to cover this population.
Evidence was identified from 14 RCTs comparing minimally invasive surgery for aortic valve replacement with standard surgery by median sternotomy across different aortic valve disease populations. Some harms of minimally invasive surgery were observed, and 1 health economic study suggested that minimally invasive surgery was less cost effective than median sternotomy. However, the RCTs were small and a small number of events were observed for many outcomes. The health economic study was limited for the same reasons because it was based on 1 of the RCTs and was limited to a 12‑month time-horizon. Although the committee agreed it is likely there would not be a large difference in outcomes after 12 months, this may be too short to draw conclusions about cost effectiveness over a lifetime. The committee highlighted that in their experience there was no difference between minimally invasive surgery and median sternotomy when done by those with expertise. The committee were also aware of certain advantages of minimally invasive surgery, for example, smaller incisions. The committee agreed not to limit the use of minimally invasive surgery and to recommend a choice with the decision based on patient characteristics and preferences. A lack of expertise in minimally invasive surgery locally should not be used as a reason for not performing a minimally invasive procedure and adults should be referred to a centre where there is expertise if this procedure is agreed as most suitable.
Despite no direct evidence for bicuspid aortic stenosis, aortic regurgitation (bicuspid or non‑bicuspid) and mixed aortic valve disease (aortic stenosis and regurgitation in the same person), the committee agreed that the type of aortic valve disease would not affect decisions about the invasiveness of surgery and the evidence could be extrapolated to any aortic valve disease.
## How the recommendations might affect practice
The committee agreed that the use of TAVI is increasing, particularly when surgery is unsuitable and there are no other options for interventional procedures. It would be rare not to perform TAVI in these circumstances, but palliative care with pharmacological management is sometimes agreed. Therefore, the committee considered that the recommendation would represent a minimal change in practice and would not increase the number of TAVI procedures.
The committee agreed that TAVI is usually reserved for when surgery is unsuitable or carries high risks of mortality. But data from the UK TAVI registry suggests that in recent years the procedure has been expanded to groups of people with lower surgical risk. The recommendation to offer TAVI to those with high surgical risk should have a moderate impact, as only 1.9% of surgeries are currently done in this group.
The recommendation to offer surgery instead of TAVI to those with intermediate and low surgical risk should increase the number of surgeries and reduce TAVIs in this group. This will ultimately improve NHS efficiency.
Data suggests that between 5% and 10% of surgical isolated aortic valve replacements are done by minimally invasive surgery. If the recommendation leads to an increase in the number of aortic valve replacements being done by minimally invasive surgery, this could represent an important change in practice. There may be no increase in the short term, as more training in these procedures will be needed, but only in the long term when more centres will have the expertise and capacity of offering minimally invasive surgery.
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# Interventions for mitral stenosis
Recommendations 1.5.6 and 1.5.7
## Why the committee made the recommendations
Evidence from 7 RCTs comparing transcatheter valvotomy with surgical valvotomy (either by minimally invasive or standard surgery) in people with rheumatic severe mitral stenosis demonstrated very few differences in outcomes. The committee agreed that surgical valvotomy is no longer commonly used in practice because similar results can be achieved with the transcatheter procedure, with less trauma and scarring and at a lower cost to the NHS. The evidence was limited by small studies, often with only a small number of events, and most outcomes being graded as very low quality. The committee agreed that transcatheter valvotomy could be considered for adults with rheumatic severe mitral stenosis who need an intervention and for whom this procedure would be suitable.
No evidence was identified for mitral valve replacement in those with rheumatic mitral stenosis when transcatheter valvotomy is not suitable. The committee agreed this it was important to make a recommendation for these people. Although no evidence was included, the condition would likely deteriorate without an intervention.
It was not appropriate to extrapolate evidence from rheumatic mitral stenosis to calcific mitral stenosis because they are 2 very different pathologies. Because there was no evidence included for calcific mitral stenosis, the committee made a recommendation for research to inform future practice.
## How the recommendations might affect practice
The recommendations are in line with current practice.
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# Interventions for mitral regurgitation
Recommendations 1.5.8 to 1.5.14
## Why the committee made the recommendations
Evidence from 3 RCTs demonstrated few differences between surgical repair and surgical replacement in those with severe mitral regurgitation. (One study included both primary and secondary mitral regurgitation; the other 2 studies covered secondary mitral regurgitation only). The largest effect was for the need for reintervention for secondary mitral regurgitation, with fewer repeat interventions needed in the replacement group. Overall, the included evidence was limited; all studies were very small, with very few events reported for most outcomes and substantial uncertainty in the effects reported. Most outcomes were graded as very low quality. The lack of stronger evidence is likely to be because surgical repair has been preferred to replacement in mitral valve surgery for the past few decades. This was based on observational evidence and because randomising to repair or replacement in people for whom repair is suitable was thought to be unethical. Based on these limitations, the committee made recommendations reflecting current practice for those with severe mitral regurgitation requiring an intervention, with surgical repair recommended in those for whom it is suitable and replacement when repair is not suitable.
The committee noted that there are differences in the aetiology and treatment of primary and secondary mitral regurgitation. Although valve intervention is the next step for primary mitral regurgitation and an indication for intervention, for secondary mitral regurgitation the underlying heart failure is usually treated first. Therefore, the committee recommended that an intervention should be offered for severe primary mitral regurgitation and considered for secondary mitral regurgitation after optimisation of medical management.
Evidence from 5 RCTs comparing minimally invasive surgery with median sternotomy for mitral regurgitation or mixed/unclear mitral valve disease demonstrated few differences. The studies were limited by small participant numbers and a small number of events for many reported outcomes. There was substantial uncertainty for most reported outcomes, a lack of long-term data for many outcomes, and most outcomes were graded as low or very low quality. Overall, when any larger differences were observed (for example, length of stay), these were for a benefit of minimally invasive procedures. A single health economic study suggested the cost of minimally invasive surgery was less per person than median sternotomy. However, the committee did not consider the included evidence to be strong enough to support recommending 1 type of surgery over the other. They agreed that median sternotomy and minimally invasive surgery should be options for those with mitral regurgitation requiring mitral valve surgery, with the decision being based on patient characteristics and patient preferences. A lack of expertise in minimally invasive surgery locally should not be used as a reason for not performing a minimally invasive procedure and patients should be referred to a centre where there is expertise if this procedure is agreed as most suitable.
No clinical evidence was identified comparing transcatheter mitral valve repair with medical management for primary mitral regurgitation when surgery is not suitable. The committee noted that the lack of evidence may be because it is well established that medical management does not improve outcomes and transcatheter mitral valve repair is useful when surgery cannot be performed. One health economic study, based on a non‑randomised registry, reported that transcatheter repair was cost effective compared with medical management in those with severe mitral regurgitation when surgery was not suitable. This study had limitations because it included people with secondary mitral regurgitation and used data from a prospective, single‑arm registry with a control group obtained retrospectively. A second Japanese study on a mixed population with secondary and primary mitral regurgitation found transcatheter repair with the MitraClip device to be cost effective. This study had some limitations too as the relative treatment effects were informed from a propensity score matching study rather than an RCT.
A health economic model developed as part of this guideline did not find MitraClip to be cost effective for adults with secondary mitral regurgitation. However, the committee agreed that it was plausible that MitraClip would offer more benefits for people with primary mitral regurgitation because they are likely to have less residual disease affecting quality of life after the intervention. The committee agreed to recommend that transcatheter mitral valve repair should be considered for primary severe mitral regurgitation with symptoms when surgery is unsuitable.
Evidence was included from 3 RCTs comparing transcatheter mitral valve repair with medical management for secondary mitral regurgitation. Two of these were clearly in a population in which surgery was not suitable and covered the use of the MitraClip device; the third study covered a Carillon device rather than MitraClip and the population was unclear. Outcomes from all 3 studies were pooled if possible, in the clinical review, but the health economic modelling was limited to the population in which surgery was not suitable.
The clinical review highlighted uncertainty in the results for 3 outcomes (all‑cause mortality, cardiac mortality and onset/exacerbation of heart failure at 1 to 3 years or 2 to 3 years). Some studies demonstrated a benefit of transcatheter repair, some a harm (lack of benefit) and some no difference. One UK health economic study based on the results of the COAPT trial, which enrolled people with very severe secondary mitral regurgitation deemed inoperable, found that transcatheter edge-to-edge repair with MitraClip device had an incremental cost per quality-adjusted life year (QALY) of about £30,000.
A health economic model was developed as part of the guideline to investigate the cost effectiveness of using the MitraClip device when surgery is not suitable. The model demonstrated that transcatheter mitral valve repair had a low chance of being cost effective at £20,000 per QALY gained, with an incremental cost‑effectiveness ratio of £30,000 per QALY gained. These results are in line with the UK study identified in the literature review. The health economic model was largely based on results from the COAPT trial, which covered transcatheter mitral valve repair in severe secondary mitral regurgitation. This trial demonstrated substantial benefits over medical management alone when surgery was unsuitable. However, it was not considered to be cost effective at the current list price. For this reason, edge-to-edge mitral valve repair was not recommended over medical management.
## How the recommendations might affect practice
Edge-to-edge repair is not widely available in the NHS. Therefore, this recommendation may lead to a change in practice and increase the amount of percutaneous mitral intervention in those for whom it is suitable.
The recommendations are in line with current practice.
Transcatheter mitral valve repair is rarely done for primary mitral regurgitation when an intervention is needed and surgery is unsuitable, so the recommendation may lead to a change in practice. This procedure has only recently been commissioned by the NHS and its use is likely to increase now based on this commissioning. The recommendation is unlikely to increase use much beyond this.
Transcatheter mitral valve repair is not currently used for secondary mitral regurgitation because it has not been commissioned by the NHS for this. The recommendation is unlikely to lead to a change in practice.
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# Interventions for tricuspid regurgitation
Recommendations 1.5.15 and 1.5.16
## Why the committee made these recommendations
A single RCT was identified comparing transcatheter repair plus optimal medical management with optimal medical management alone in people with severe, symptomatic tricuspid regurgitation and a high surgical risk score. Patients with associated tricuspid regurgitation have worse prognosis after mitral valve intervention than those with mild or no tricuspid regurgitation. There is strong evidence that secondary functional tricuspid regurgitation that is severe does not improve after fixing the mitral lesion. Moderate tricuspid regurgitation does remain stable in a few patients after mitral correction. However, in a significant number, it does not improve and may get worse. Tricuspid annuloplasty by an experienced surgeon (at the time of mitral surgery) is a quick procedure that reduces the amount of tricuspid regurgitation and may improve prognosis.
Patients with associated tricuspid regurgitation have a worse prognosis after aortic valve intervention than those with mild or no tricuspid regurgitation. There is strong evidence (but not reviewed here) that secondary functional tricuspid regurgitation that is severe does not improve after fixing the left‑sided lesion. Tricuspid annuloplasty by an experienced surgeon is a quick procedure that does reduce the amount of tricuspid regurgitation and may improve prognosis of these patients.
The committee made a recommendation for research to inform future guidance.
## How the recommendations might affect practice
These recommendations are in line with current practice.
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# Repeat intervention
Recommendation 1.6.1
## Why the committee made the recommendation
No evidence was identified comparing surgery with medical management for people with failing biological prosthetic aortic valves. However, the committee agreed that surgery should be considered in this group because their condition may deteriorate if left without intervention on medical management.
Similarly, no evidence was identified comparing transcatheter repeat intervention with medical management when surgery is unsuitable for people with failing biological prosthetic aortic valves. However, the committee agreed that repeat transcatheter intervention should be considered in this group because their condition may deteriorate if left without intervention on medical management.
For people who can have surgery, there were no RCTs comparing transcatheter intervention with surgery for repeat intervention and the only included studies were non‑randomised. The committee were not able to base recommendations on this because of the limitations with non‑randomised evidence. Therefore, they recommended that a shared decision should be based on short- and longer-term benefits, the type of valve dysfunction and prosthesis, the risks associated with the procedure and the possible need for other cardiac procedures. The term 'degenerated' refers to progressive degeneration and does not include failure of the valve due to endocarditis or thrombosis. The recommendation was limited to those with symptoms because this was considered to be an indication for repeat intervention.
The committee also made recommendations for research for repeat intervention for failing biological prosthetic aortic, mitral and tricuspid valves because the only available evidence was non‑randomised.
## How the recommendation might affect practice
When both transcatheter and surgical procedures are options for repeat intervention, the choice of procedure is usually based on individual patient characteristics although surgery may be done more often. When surgery is not an option, transcatheter intervention is used as the only alternative to medical management. The recommendation will therefore not represent a change in practice.
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# Anticoagulation and antiplatelet therapy
Recommendations 1.7.1 to 1.7.3
## Why the committee made the recommendations
Evidence from a population without atrial fibrillation demonstrated an increased risk of major bleeding with vitamin K antagonist compared with single antiplatelet therapy (aspirin). No clear reduction in mortality or thromboembolic events was observed with vitamin K antagonist. Therefore, the committee agreed that anticoagulation should not be offered after surgical biological valve replacement unless there are other indications for anticoagulation. This covers both vitamin K antagonists and direct‑acting oral anticoagulants (DOACs) because there was no evidence to show that DOACs are safe. One small study in people with atrial fibrillation suggested there may be no clear differences in outcomes between DOACs and vitamin K antagonists, and it is not common practice to use DOACs for this group. The committee agreed that if there is already an indication for anticoagulation or antiplatelet therapy, for example, because of atrial fibrillation, the existing NICE guidelines for these indications should be followed.
Despite 1 study demonstrating a potential reduction in arterial thromboembolic events and vascular mortality with combined anticoagulant and antiplatelet therapy compared with anticoagulant therapy alone after surgical biological valve replacement, there was uncertainty around this result. This uncertainty, combined with further study limitations, including issues with the target international normalised ratio used and the selective population, meant that the study could not be used to inform general recommendations for surgical biological valve replacement.
There was a lack of evidence comparing anticoagulant or antiplatelet therapy with no treatment after surgical biological valve replacement, so the committee made a recommendation for research. They made another recommendation for research to investigate the long-term effect of anticoagulant or antithrombotic therapy on valve function and outcomes after biological valve replacement because no long-term data was available.
Evidence from 4 studies demonstrated a clinically important benefit of single antiplatelet therapy (aspirin) compared with dual antiplatelet therapy in reducing major and minor bleeding in the short-to-medium term. Based on this, the committee agreed that single rather than dual antiplatelet therapy should be considered after TAVI. As aspirin is used in practice, and this was used in all of the studies, aspirin was recommended, with clopidogrel specified as the alternative if aspirin was not tolerated.
The committee were also aware of observational evidence that antiplatelets reduced the risk of valve thrombosis and improved valve durability over the long term. There was also evidence from 1 study demonstrating harms of DOACs compared with single antiplatelet therapy for most reported outcomes, including mortality, bleeding and withdrawal because of adverse events. This further supported the recommendation for single antiplatelet therapy. Because of the lack of evidence comparing anticoagulant and antiplatelet therapy with no treatment after TAVI, the committee made a recommendation for research.
No evidence was identified comparing different anticoagulant and antiplatelet treatments in adults who have had valve repair. The committee made a recommendation for research comparing anticoagulant and antiplatelet treatments with placebo after valve repair.
## How the recommendations might affect practice
Practice is currently variable, with some centres offering vitamin K antagonists after surgical biological valve replacement. Therefore, the recommendation will lead to a change in practice in some centres.
It is unusual for people not to receive at least single antiplatelet therapy after TAVI and many people receive dual antiplatelet therapy. The recommendation was not thought to represent a change in practice in terms of the number of people who receive some form of antiplatelet therapy after a transcatheter procedure.
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# Monitoring after an intervention
Recommendation 1.8.1
## Why the committee made the recommendation
No evidence was found for the frequency of monitoring after an intervention for valve disease. Current practice is variable and depends on patient factors, such as comorbidities, other cardiac disease or previous heart surgery, as well as the type of procedure performed (repair or replacement). Follow up also depends on the type of valve used for a replacement. The committee agreed that mechanical valves have good durability with a low risk of failure. In contrast, biological valves have lower durability with deterioration possible within 10 years. The committee noted that, although practice varies, mechanical valves may be monitored over the first 12 months and then only checked if problems develop. Monitoring is usually more frequent for biological valves – with some centres offering annual follow up starting from the year of the operation and others starting annual follow up after 5 years. Any concerns about abnormal valve function may also affect the frequency of monitoring, with more frequent follow up if there are concerns.
The committee agreed that frequency of follow up should be discussed with the patient. Some people find more frequent monitoring reassuring whereas for others this leads to increased anxiety. People should be encouraged to seek advice if they feel that their condition has deteriorated. There is a higher risk of endocarditis in replacement valves and people should be encouraged to report symptoms.
## How the recommendation might affect practice
The recommendation reflects current practice, which is variable and depends on various factors, such as valve durability and patient comorbidities and preferences.
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# Information and advice
Recommendations 1.9.1 to 1.9.5
## Why the committee made the recommendations
Clear and consistent evidence outlined the negative impact of symptoms of valve disease and loss of control that led to feelings of despair and insecurity. In this context, a single point of contact for some people may increase the hope and security afforded between appointments.
The committee also agreed that it was useful to list areas of information and advice that are important to people with valve disease to ensure that their expectations accurately match the likely course of their condition. Having this information will be beneficial for planning, reducing anxiety and supporting shared decision making. This may include relevant information for patients and carers (when appropriate) about the possibility of delirium after valve surgery, in line with the NICE guideline on delirium.
From the evidence and their experience, the committee noted the psychological impact of valve disease on a person, whether or not the person currently has symptoms. They agreed that clinicians should be aware of the potential psychological impact of receiving a diagnosis of heart valve disease and consider providing additional advice and support.
The committee stressed the importance of individualised care and shared decision making and referenced the relevant NICE guidelines. Specific advice and support at the point of transition from paediatric to adult services was also agreed to be important to ensure young adults are given appropriate information on the likely progression of their valve disease and referrals to adult valve clinics.
The committee noted the limitations of the available evidence, which was mostly from those being considered for TAVI. These people typically have more complex comorbidities, and their older age means that their hopes and fears are different from those of younger adults. Therefore, the committee made a recommendation for research on the information and advice needs of all adult age groups with valve disease of all severities and stages. Studies should include patient‑reported outcomes and experiences of decision aids.
## How the recommendations might affect practice
Currently not all adults with valve disease have a point of contact between appointments or psychological support, and so these recommendations will need a change by some providers.
Return to recommendations# Context
The heart has 4 valves (aortic, mitral, tricuspid and pulmonary) that control blood flow.
In heart valve disease, valve function can be impaired by:
stenosis, a narrowing or stiffening of the valve, which restricts its opening and obstructs the forward flow of blood
regurgitation, failure of the valve to close completely, which allows blood to flow backward.
There can be stenosis and regurgitation of the same valve (mixed valve disease) or disease may affect more than one valve (multiple valve disease).
Mitral and tricuspid heart valve disease can be primary or secondary. Primary disease affects the valve structure, whereas secondary disease results from enlargement or dysfunction of the heart chambers (atria or ventricles) with otherwise normal mitral or tricuspid valve structure.
Heart valve disease can be congenital or acquired. Acquired valve degeneration is currently the main cause of heart valve disease, leading to the most common types of heart valve disease, as for example calcific aortic stenosis and myxomatous or calcific degeneration of the mitral valve.
Secondary heart valve disease can be classified as:
ventricular-secondary mitral or tricuspid regurgitation
atrial-secondary mitral or tricuspid regurgitation.
Among people aged 65 years or over the prevalence of asymptomatic heart valve disease may be more than 50%, whereas the prevalence of clinically significant heart valve disease is around 11%. It is predicted that for people over 65, the prevalence of heart valve disease will increase, from 1.5 million people currently to more than 3 million in 2046.
People with heart valve disease may have no symptoms or may have symptoms that can depend on the affected valve. Associated heart rhythm problems, such as atrial fibrillation or heart block, may cause palpitations and breathlessness, or dizziness and light‑headedness, respectively. Untreated severe disease can lead to valvular heart failure, with symptoms including breathlessness, reduced exercise capacity, tiredness and swollen ankles. Heart valves stiffen as part of the ageing process, making dysfunction more likely in older people. We hope that this guideline will raise awareness of heart valve disease and improve diagnosis and management.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Referral for echocardiography and specialist assessment\n\n## Referral for echocardiography\n\nConsider an echocardiogram for adults with a murmur and no other signs or symptoms if valve disease is suspected based on:\n\nthe nature of the murmur\n\nfamily history\n\nage (especially if over\xa075), or\n\nmedical history (for example, a history of atrial fibrillation).\n\nOffer an echocardiogram to adults with a murmur if valve disease is suspected (based on the nature of the murmur, family history, age or medical history) and they have:\n\nsigns (such as peripheral oedema) or symptoms (such as angina or breathlessness) or an abnormal ECG, or\n\nan ejection systolic murmur with a reduced second heart sound but no other signs or symptoms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for echocardiography\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: symptoms and signs indicating need for echocardiography or direct referral to a specialist.\n\nLoading. Please wait.\n\n## Referral for urgent specialist assessment or urgent echocardiography\n\nIf valve disease is suspected (based on the nature of the murmur, family history, age or medical history):\n\nOffer urgent (within 2\xa0weeks) specialist assessment that includes echocardiogram or if not available an urgent echocardiogram alone to adults with a systolic murmur and exertional syncope.\n\nConsider urgent (within 2\xa0weeks) specialist assessment that includes echocardiogram for adults with a murmur and severe symptoms (angina or breathlessness on minimal exertion or at rest) thought to be related to valvular heart disease.\n\nFor guidance on referral and assessment for adults with murmur and non-exertional syncope, follow the recommendations in the NICE guideline on transient loss of consciousness ('blackouts') in over 16s.\n\nFor guidance on referral and assessment for adults with breathlessness but no murmur, follow the recommendations in the NICE guideline on chronic heart failure in adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral for urgent specialist assessment or urgent echocardiography\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: symptoms and signs indicating need for echocardiography or direct referral to a specialist.\n\nLoading. Please wait.\n\n## Referral to a specialist after echocardiography\n\nBe aware that mild valve disease is common and rarely progresses to become clinically significant.\n\nOffer referral to a specialist to:\n\nadults with moderate or severe valve disease of any type\n\nadults with bicuspid aortic valve disease of any severity (including mild valve disease).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on referral to a specialist after echocardiography\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: indications for referral to a specialist following echocardiography.\n\nLoading. Please wait.\n\n## Information, referral and specialist assessment for pregnant women and women considering pregnancy\n\nBe aware that most women with valve disease can have a pregnancy without complications.\n\nOffer advice on the implications of treatment choices on any future pregnancy to women who need heart valve intervention.\n\nOffer advice on family planning to women with severe valve disease, particularly aortic and mitral stenosis.\n\nRefer pregnant women or women who are considering a pregnancy to a cardiologist with expertise in the care of pregnant women, if they have any of the following:\n\nmoderate or severe valve disease\n\nbicuspid aortic valve disease of any severity (including mild disease) and associated aortopathy\n\na prosthetic valve.Refer whether they have symptoms or not.\n\nConsider seeking specialist advice on the choice of replacement valve if heart valve replacement surgery is being considered for women of childbearing potential.\n\nFor guidance on intrapartum care, follow the recommendations on heart disease in the NICE guideline on intrapartum care for women with existing medical conditions or obstetric complications and their babies.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information, referral and specialist assessment for pregnant women and women considering a pregnancy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: symptoms and signs indicating need for echocardiography or direct referral to a specialist.\n\nLoading. Please wait.\n\n# Pharmacological management\n\n## Management of heart failure in people with valve disease\n\nConsider a beta-blocker for adults with moderate to severe mitral stenosis and heart failure.\n\nWhen adults with heart valve conditions and heart failure also have left ventricular dysfunction, refer to the NICE guideline on chronic heart failure in adults.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see rationale and impact section on pharmacological management of heart failure in heart valve disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: pharmacological management.\n\nLoading. Please wait.\n\n# Indications for interventions\n\nOffer an intervention to adults with symptomatic severe heart valve disease.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on indications for interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: transcatheter intervention, surgery or conservative management in heart valve disease.\n\nLoading. Please wait.\n\n## Aortic stenosis\n\nConsider referring adults with asymptomatic severe aortic stenosis for intervention, if suitable, if they have any of the following:\n\nVmax (peak aortic jet velocity) more than 5\xa0m/s on echocardiography\n\naortic valve area less than 0.6\xa0cm2 on echocardiography\n\nleft ventricular ejection fraction (LVEF) less than 55%\n\nB‑type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) level more than twice the upper limit of normal\n\nsymptoms unmasked on exercise testing.\n\nConsider referring adults with symptomatic low‑gradient aortic stenosis with LVEF less than 50% for intervention if during dobutamine stress echocardiography the aortic stenosis is shown to be severe by:\n\na mean gradient across the aortic valve that increases to more than 40\xa0mmHg and\n\nan aortic valve area that remains less than 1\xa0cm2.\n\nConsider measuring aortic valve calcium score on cardiac CT if the severity of symptomatic aortic stenosis is uncertain.\n\nOffer enhanced follow up (for example, more frequent reviews) and further assessment (for example, stress echocardiography) to monitor the need for intervention if mid‑wall fibrosis is detected on cardiac MRI in adults with severe aortic stenosis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on indications for interventions for adults with aortic stenosis\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review D: indications for intervention\n\nevidence review E: stress testing and stress echocardiography in determining need for intervention\n\nevidence review F: CT and MRI indications for intervention.\n\nLoading. Please wait.\n\n## Aortic regurgitation\n\nConsider referring adults with asymptomatic severe aortic regurgitation for intervention, if suitable, if they have either of the following:\n\nLVEF less than 55% or\n\nend systolic diameter (ESD) of more than 50\xa0mm or end systolic diameter index (ESDI) more than 24\xa0mm/m2 on echocardiography.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on indications for interventions for adults with aortic regurgitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: indications for intervention.\n\nLoading. Please wait.\n\n## Mitral regurgitation\n\nConsider referring adults with asymptomatic severe primary mitral regurgitation for intervention, if suitable, if they have any of the following:\n\nLVEF less than 60%\n\nESD more than 45\xa0mm or ESDI more than 22\xa0mm/m2 on echocardiography or\n\nan increase of systolic pulmonary artery pressure to more than 60\xa0mmHg on exercise testing.When making decisions about referral for surgery, take into account the suitability of the valve for repair and the presence of atrial fibrillation or systolic pulmonary artery pressure of more than 50\xa0mmHg on echocardiography at rest.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on indications for intervention for adults with mitral regurgitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: indications for intervention and evidence review\xa0E: stress testing and stress echocardiography in determining need for intervention.\n\nLoading. Please wait.\n\n# Monitoring when there is no current need for intervention\n\nOffer clinical review every 6 to 12\xa0months, with an echocardiogram, to adults with asymptomatic severe valve disease if an intervention is suitable but not currently needed. Base the frequency of the review on echocardiography findings and shared decision making with the patient.\n\nConsider echocardiographic assessment every 3 to 5\xa0years for adults with mild aortic or mitral stenosis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on monitoring where there is no current need for intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: monitoring of people with heart valve disease and no current indication for intervention.\n\nLoading. Please wait.\n\n# Interventions\n\nSee the recommendations on indications for interventions.\n\n## Decisions about interventions\n\nDiscuss the possible benefits and risks of interventions with adults who have an indication for valve intervention. Include in the discussion:\n\nthe benefits to quality of life (both in the short and long term)\n\nprosthetic valve durability\n\nthe risks associated with the procedures\n\nthe type of access for surgery (median sternotomy, minimally invasive surgery or, for people at high surgical risk, transcatheter)\n\nthe possible need for other cardiac procedures in the future.Follow the recommendations in the NICE guidelines on shared decision making and patient experience in adult NHS services and base decisions on the type of intervention on patient characteristics and preferences.\n\nWhen surgery is agreed, base the decision on the type of surgery (median sternotomy or minimally invasive surgery) on patient characteristics and preferences. If minimally invasive surgery is the agreed option and is not available locally, refer the person to another centre.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on decisions about interventions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: transcatheter intervention, surgery or conservative management in heart valve disease.\n\nLoading. Please wait.\n\n## Aortic valve disease\n\nFor NHS England and NHS Improvement's position on transcatheter aortic valve implantation for people at low or intermediate surgical risk, see the implementation strategy for transcatheter aortic valve implantation.\n\nOffer surgery, if suitable (by median sternotomy or minimally invasive surgery), as first-line intervention for adults with severe aortic stenosis, aortic regurgitation or mixed aortic valve disease and an indication for surgery who are at low or intermediate surgical risk. TAVI is not cost effective for people at low or intermediate surgical risk at the current list price.\n\nOffer TAVI, if suitable, to adults with non-bicuspid severe aortic stenosis who are at high surgical risk or if surgery is unsuitable.\n\nSee the recommendations on using TAVI in the NICE interventional procedures guidance on transcatheter aortic valve implantation for aortic stenosis, including entering the details of all people undergoing TAVI into the UK TAVI registry. See also the NICE interventional procedures guidance on sutureless aortic valve replacement in aortic stenosis and balloon valvuloplasty for aortic valve stenosis.\n\nSee NHS England's clinical commissioning policy on transcatheter aortic valve implantation for aortic stenosis.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for aortic valve disease\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: transcatheter intervention, surgery or conservative management in heart valve disease.\n\nLoading. Please wait.\n\n## Mitral stenosis\n\nConsider transcatheter valvotomy for adults with rheumatic severe mitral stenosis, if the valve is suitable for this procedure.\n\nOffer surgical mitral valve replacement to adults with rheumatic severe mitral stenosis if transcatheter valvotomy is unsuitable.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for mitral stenosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: transcatheter intervention, surgery or conservative management in heart valve disease.\n\nLoading. Please wait.\n\n## Mitral regurgitation\n\nOffer surgical mitral valve repair (by median sternotomy or minimally invasive surgery) to adults with severe primary mitral regurgitation and an indication for repair, if surgery is suitable.\n\nOffer surgical mitral valve replacement (by median sternotomy or minimally invasive surgery) to adults with severe primary mitral regurgitation and an indication for surgery, if the valve is not suitable for repair and surgery is suitable.\n\nConsider transcatheter edge-to-edge repair, if suitable, for adults with severe primary mitral regurgitation and symptoms, if surgery is unsuitable.\n\nSee NHS England's clinical commissioning policy on percutaneous mitral valve leaflet repair for primary degenerative mitral regurgitation in adults and the NICE interventional procedures guidance on percutaneous mitral valve leaflet repair for mitral regurgitation and thoracoscopically assisted mitral valve surgery.\n\nConsider surgical mitral valve repair (by median sternotomy or minimally invasive surgery) for adults with severe secondary mitral regurgitation who are having cardiac surgery for another indication, if surgery is suitable.\n\nConsider surgical mitral valve replacement (by median sternotomy or minimally invasive surgery) for adults with severe secondary mitral regurgitation who are having cardiac surgery for another indication, if the valve is not suitable for repair and surgery is suitable.\n\nOffer medical management to adults with heart failure and severe secondary mitral regurgitation, if surgery is unsuitable.\n\nConsider transcatheter mitral edge-to-edge repair for adults with heart failure and severe secondary mitral regurgitation, if surgery is unsuitable and they remain symptomatic on medical management.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for mitral regurgitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: transcatheter intervention, surgery or conservative management in heart valve disease.\n\nLoading. Please wait.\n\nConsider surgical tricuspid valve repair at the time of mitral valve surgery when tricuspid regurgitation is moderate or severe.\n\nConsider surgical tricuspid valve repair at the time of aortic valve surgery when tricuspid regurgitation is severe.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on interventions for tricuspid regurgitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: transcatheter intervention, surgery or conservative management in heart valve disease.\n\nLoading. Please wait.\n\n# Repeat intervention\n\nConsider transcatheter or redo surgical intervention for adults with severe aortic degeneration of a biological prosthetic valve and symptoms. Take into account the following factors to inform a shared decision about the choice of intervention:\n\nthe short- and long-term benefits\n\ntype of valve dysfunction and prosthesis\n\nthe risks associated with the procedure\n\nthe possible need for other cardiac procedures in the future.See the NICE interventional procedures guidance on using transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis, transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair and valve-in-valve TAVI for aortic bioprosthetic dysfunction.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see rationale and impact section on repeat intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: repeat intervention for failure of biological or repaired valves.\n\nLoading. Please wait.\n\n# Anticoagulation and antiplatelet therapy\n\nDo not offer anticoagulation after surgical biological valve replacement unless there are other indications for anticoagulation.\n\nConsider aspirin, or clopidogrel if aspirin is not tolerated, after TAVI.\n\nIf people have other indications for anticoagulation or antiplatelet therapy, follow the recommendations in the NICE guidelines on atrial fibrillation and acute coronary syndromes.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on anticoagulation and antiplatelet therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: anticoagulant and/or antiplatelet therapy for biological prosthetic valves and after valve repair.\n\nLoading. Please wait.\n\n# Monitoring after an intervention\n\nBase decisions on the frequency and type of monitoring for adults who have had an intervention (valve repair or replacement) for valve disease on:\n\ndurability of the prosthetic valve or durability of the repair\n\nthe presence of another condition, including other heart disease\n\nresidual valve abnormality or consequences of the procedure, for example, paravalvular leak\n\nconcerns about abnormal function of the prosthetic valve\n\nthe patient's wishes.Advise people and their family members or carers (as appropriate) to seek advice if the heart condition deteriorates.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on monitoring after an intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: monitoring in people with repaired or replaced heart valves.\n\nLoading. Please wait.\n\n# Information and advice\n\nFollow the NICE guideline on shared decision making and the recommendations in the NICE guideline on patient experience in adult NHS services on:\n\ninvolvement of family members and carers\n\ncommunication\n\ninformation\n\ntailoring healthcare services.\n\nConsider providing a point of contact for accessing specialist advice between appointments.\n\nBe aware of the psychological impact on the person receiving a diagnosis of valve disease, whether or not they have symptoms. Consider the person's needs for additional information and support.\n\nProvide information and advice to adults with valve disease about:\n\nthe expected progression and prognosis of their condition, including the likely length of an asymptomatic stage\n\nany need for intervention, including the type of intervention\n\npregnancy, if appropriate\n\nthe possible effects of other conditions on long-term outcomes\n\nrehabilitation and long‑term outcomes\n\npalliative care, if appropriate, including how to access this.\n\nProvide information and support to young adults about transition from paediatric to adult services, in line with the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and advice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: information and advice.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline.\n\n## Degenerated\n\nDegenerated covers progressive degeneration and does not include failure of the valve due to endocarditis or thrombosis.\n\n## Risk of surgery\n\nThis is calculated using EuroSCORE\xa0II. People have low surgical risk if they score less than 4%, intermediate risk if they score between 4% and 8% and high risk if they score more than 8%.\n\n## Severe valve disease\n\nSeverity of valve disease is defined in line with the British Society of Echocardiography guidelines on the assessment of aortic stenosis, the tricuspid and pulmonary valves, and mitral valve disease.\n\n## Specialist assessment and advice\n\nThis could include assessment and advice from a cardiologist with expertise in heart valve disease, a multidisciplinary team or a heart valve clinic.\n\n## Suitability for transcatheter aortic valve implantation\n\nSuitability for transcatheter aortic valve implantation (TAVI) depends on:\n\nan appropriate access for inserting the TAVI catheter\n\nthe morphology of the valve, aortic root and ascending aorta\n\nthe degree and distribution of calcium in the aortic valve.\n\nIt is an option for:\n\nAll people expected to have an unacceptably high risk of mortality or morbidity as a result of surgery (for example, because of a risk of infection in people who are immunosuppressed). See also the definition of high risk of surgery according to EuroSCORE\xa0II.\n\nAll people expected to have unacceptably strenuous and prolonged recovery from surgery and an extended need for rehabilitation because of frailty, reduced mobility, or musculoskeletal conditions.\n\nAll people with low life expectancy, either because of their age or because they have life-limiting comorbidities.\n\n## Suitability for transcatheter edge-to-edge repair\n\nSuitability for transcatheter edge-to-edge repair depends on:\n\nthe morphology of the person's valve\n\nthe feasibility of using transoesophageal echocardiography to guide the procedure\n\nthe person's fitness for general anaesthesia.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Monitoring when there is no current need for intervention\n\nWhat is the most clinically and cost-effective monitoring (type and frequency of test) for adults with asymptomatic mild or moderate heart valve disease (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation and tricuspid regurgitation) and no current need for intervention?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on monitoring where there is no current need for intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: monitoring of people with heart valve disease and no current indication for intervention.\n\nLoading. Please wait.\n\n## Interventions for tricuspid regurgitation\n\nWhat is the most clinically and cost-effective management strategy for adults with tricuspid regurgitation?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on interventions for tricuspid regurgitation\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: transcatheter intervention, surgery or conservative management in heart valve disease.\n\nLoading. Please wait.\n\n## Interventions for a failed valve\n\nWhat is the clinical and cost effectiveness of transcatheter intervention compared with surgical redo intervention for adults with failing biological prosthetic tricuspid valves or failing repaired native tricuspid valves when either procedure is suitable?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on repeat intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: repeat intervention for failure of biological or repaired valves.\n\nLoading. Please wait.\n\n## Monitoring after an intervention\n\nWhat is the most clinically and cost‑effective timing, nature and frequency of follow up for different types of valve interventions, including repair and replacement with tissue or mechanical valves?\n\nFor a short explanation of why the committee made the recommendation for research, see rationale on monitoring after an intervention\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: monitoring in people with repaired or replaced heart valves.\n\nLoading. Please wait.\n\n## Information and advice\n\nWhat are the information and advice needs of all adult age groups with heart valve disease of all severities and stages?\n\nFor a short explanation of why the committee made the recommendation for research, see the rationale on information and advice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: information and advice.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Indications for interventions – stress testing or echocardiography\n\nWhat is the prognostic value of severe mitral regurgitation unmasked on exercise echocardiography in adults with symptomatic non‑severe mitral regurgitation at rest?\n\nWhat is the prognostic value of parameters observed on exercise stress testing and exercise stress echocardiography in asymptomatic severe aortic regurgitation?\n\n## Indications for interventions – CT or MRI\n\nIn adults with aortic or primary mitral regurgitation in whom the need for intervention is unclear after echocardiography, what is the prognostic value and cost effectiveness of cardiac MRI to assess the severity of valvular regurgitation?\n\nIn adults with aortic or mitral regurgitation in whom the need for intervention is unclear after echocardiography, what is the prognostic value and cost effectiveness of left ventricular ejection fraction (LVEF) measured on cardiac MRI to assess the need for intervention?\n\nIn adults with asymptomatic severe aortic stenosis what is the prognostic value and cost effectiveness of LVEF measured on cardiac MRI to assess the need for intervention?\n\nIn adults with asymptomatic severe tricuspid regurgitation what is the prognostic value and cost effectiveness of cardiac MRI for assessment of the right ventricle to assess the need for intervention?\n\n## Indications for interventions – global longitudinal strain\n\nIn adults with severe heart valve disease what is the prognostic value and cost effectiveness of global longitudinal strain to assess the need for intervention?\n\nIn adults with asymptomatic, severe aortic regurgitation or mitral regurgitation what is the prognostic value and cost effectiveness of B‑type natriuretic peptide (BNP) to assess the need for intervention?\n\n## Pharmacological management for adults with heart valve disease\n\nWhat is the clinical and cost effectiveness of ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers and diuretics for adults with severe aortic stenosis?\n\nWhat is the clinical and cost effectiveness of ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers and calcium channel blockers, including compared with placebo, for adults with aortic regurgitation?\n\nWhat is the clinical and cost effectiveness of ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers and diuretics for adults with primary severe mitral regurgitation?\n\nWhat is the clinical and cost effectiveness of beta‑blockers for adults over 75\xa0years with non‑rheumatic/calcific mitral stenosis, in both sinus rhythm and atrial fibrillation?\n\nWhat is the clinical and cost effectiveness of pharmacological management of heart failure for adults with heart failure and severe aortic stenosis, severe aortic regurgitation or severe mitral regurgitation?\n\n## Monitoring when there is no current need for intervention\n\nWhat is the most clinically and cost‑effective monitoring strategy (type and frequency of test) for adults with asymptomatic severe heart valve disease (aortic regurgitation, mitral stenosis, mitral regurgitation or tricuspid regurgitation) and no current indication for intervention?\n\nWhat is the most clinically and cost‑effective monitoring strategy (type and frequency of test) for adults with symptomatic moderate heart valve disease (aortic stenosis, aortic regurgitation, mitral stenosis, mitral regurgitation and tricuspid regurgitation) and no current indication for intervention?\n\n## Interventions\n\nWhat is the most clinically and cost‑effective management strategy for adults with calcific mitral stenosis and an indication for intervention?\n\n## Anticoagulation and antiplatelet therapy\n\nWhat is the clinical and cost effectiveness of single or dual antiplatelet therapies or anticoagulants compared with placebo after transcatheter or surgical valve replacement (implantation) with biological prosthesis and after valve repair?\n\nIn adults with biological valve replacement, what effect does anticoagulation or antiplatelet therapy have on long-term valve function and outcomes?\n\n## Repeat interventions\n\nWhat is the clinical and cost effectiveness of transcatheter intervention compared with surgical redo intervention for adults with failing biological prosthetic aortic valves when either procedure is suitable?\n\nWhat is the clinical and cost effectiveness of transcatheter intervention compared with surgical redo intervention for adults with failing biological prosthetic mitral valves when either procedure is suitable?", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Referral for echocardiography\n\nRecommendations 1.1.1 and 1.1.2\n\n## Why the committee made the recommendations\n\nLimited evidence showed that murmur is an indicator of valve disease. But the evidence also showed that a substantial proportion of people with a murmur do not have valve disease confirmed by a reference test. The committee agreed that 'innocent' murmurs can occur, particularly during the teenage and young adult years and in pregnancy. These are difficult to differentiate from pathological murmurs by clinical examination alone. The evidence was not strong enough to recommend that everyone with a murmur should be referred for echocardiography. The committee agreed that this would be a change in practice, would increase pressure on echocardiography services and would offer uncertain benefit. However, when the nature of the murmur, family history, age or medical history suggest possible valve disease, echocardiography should be considered to establish a diagnosis.\n\nEvidence suggested that the presence of a systolic heart murmur plus a reduced second heart sound had good specificity for aortic stenosis confirmed by echocardiography. The recommendation specifies ejection systolic murmur because this, combined with a reduced second heart sound, is a classic indicator of aortic stenosis and is most often present in severe aortic stenosis. Although this was based on only a few studies, the committee agreed that people with these features should be referred for echocardiography. Because of the limited evidence identified, this recommendation was limited to those in whom heart valve disease was considered a possible explanation of these signs based on the nature of the murmur, family history, age or medical history.\n\nStudies showed that echocardiography detected valve disease in a higher proportion of people with murmur plus other signs and symptoms (abnormal ECG, angina, breathlessness, peripheral oedema) than in people with murmur alone. That is, murmur plus other signs or symptoms had a higher specificity for echocardiography confirmed valve disease. Again, this was based on a few studies only, so the committee agreed that the nature of the murmur, family history, age or medical history should also suggest valve disease as a possibility.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nReturn to recommendations\n\n# Referral for urgent specialist assessment or urgent echocardiography\n\nRecommendations 1.1.3 to 1.1.5\n\n## Why the committee made the recommendations\n\nEvidence showed that more cases of severe valve disease were picked up when a murmur plus other signs or symptoms were present. The committee agreed that mild and moderate valve disease does not usually present with these symptoms and using these criteria for referral would not result in unnecessary referral for urgent specialist assessment or echocardiography in most cases.\n\nPeople with exertional syncope and a systolic murmur need an urgent diagnosis because exertional syncope caused by aortic stenosis has a high risk of a poor outcome. The diagnosis must be made quickly to allow appropriate management, which would likely include intervention if severe aortic stenosis is confirmed. Depending on local availability, an echocardiogram may be faster than direct specialist referral, which would include echocardiography, so the committee agreed to recommend either for this group. The committee agreed that the assessment or echocardiogram should be done within 2\xa0weeks.\n\nFor people with severe symptoms (New York Heart Association classification III to IV or perceived by the person as severe) and a murmur, but without exertional syncope, the committee agreed that urgent specialist assessment within 2\xa0weeks, which would include echocardiography, should be considered.\n\n## How the recommendations might affect practice\n\nThe recommendations reflect current practice.\n\nReturn to recommendations\n\n# Referral to a specialist after echocardiography\n\nRecommendations 1.1.6 and 1.1.7\n\n## Why the committee made the recommendations\n\nAcross the included studies, moderate and severe valve disease was consistently associated with more adverse outcomes than 'mild' or 'mild and moderate' valve disease. Despite limited evidence for each specific type of valve disease, the committee agreed that specialist referral should be offered to those with moderate or severe disease. This is consistent with current practice.\n\nThe evidence could not be used to recommend that people with mild valve disease should never be referred to a specialist, because outcomes were not compared with those without valve disease. However, the committee stressed that patients and healthcare professionals should be aware that mild valve disease is very common in people over\xa070, it seldom causes symptoms and does not progress in most cases. The committee recommended that people with bicuspid aortic valve disease of any severity (including mild disease) should be offered specialist referral because its progression is different to other types of valve disease, it can be associated with aortopathy and in practice is usually referred.\n\n## How the recommendations might affect practice\n\nThe committee agreed that it is current practice for everyone with moderate or severe valve disease to be referred to a specialist, regardless of the type of disease and whether it is primary or secondary. The recommendation on moderate and severe valve disease would therefore not lead to a change in practice.\n\nFor mild valve disease, there is currently variation in specialist referral, with some unnecessary referrals being made. Although the recommendation does not preclude referral for this group, it may reassure individuals with mild valve disease, reduce the number of unnecessary referrals and be cost saving. The recommendations covering bicuspid aortic valve disease were considered to reflect current practice.\n\nReturn to recommendations\n\n# Information, referral and specialist assessment for pregnant women and women considering pregnancy\n\nRecommendations 1.1.8 to 1.1.13\n\n## Why the committee made the recommendations\n\nThe committee recognised that the proportion of pregnant women with valve disease is small compared with the number of women with valve disease who may be considering pregnancy. These women need to carefully consider the impact of treatment on any future pregnancy and should be given advice before making a treatment decision. This should include advice on contraception and planned pregnancy for women with severe valve disease, and consideration of the type of valve they receive if surgery is performed. It may be appropriate for their clinician to seek specialist advice to inform this decision from a cardiologist with expertise in the care of pregnant women. The committee noted that healthcare professionals without specialist expertise may inappropriately advise women against becoming pregnant. They agreed that some women with valve disease who may wish to become pregnant or who are pregnant should be referred to a cardiologist with specialist expertise. The committee highlighted that only women with moderate or severe disease on echocardiography, bicuspid aortic valve disease with associated aortopathy or prosthetic valves need referral. Women with mild disease, for example, aortic regurgitation or mitral valve prolapse without regurgitation, do not need a referral. The committee acknowledged that an ejection systolic flow murmur is present in most pregnant women and is not a cause for concern. They also noted that there is no official subspecialty or national accreditation for cardiologists with a specialist interest in pregnancy.\n\n## How the recommendations might affect practice\n\nThe committee acknowledged that it is not current practice to refer women who are considering pregnancy to a cardiologist with specialist expertise. Although moderate or severe heart valve disease is relatively rare in women of childbearing age, they still represent an important group of patients. Healthcare centres offering specialised support to women considering pregnancy are not widespread, so the committee expect a moderate change in practice in those centres.\n\nReturn to recommendations\n\n# Pharmacological management to improve prognosis\n\n## Why the committee made the recommendations\n\nThere was no evidence that pharmacological management can slow the progression of heart valve disease, only evidence that statins improve prognosis in aortic stenosis. The evidence showed that statins reduced cardiac mortality compared with placebo for adults with aortic stenosis. The committee agreed that this benefit is because of an improvement in overall cardiovascular health rather than a direct effect on the aortic stenosis. Therefore, no recommendation was made and statins should be used in line with the NICE guideline on cardiovascular disease: risk assessment and reduction, including lipid modification.\n\nThere was not enough evidence for the committee to make recommendations on pharmacological management of other conditions (for example, systemic hypertension) in people who also have heart valve disease.\n\nThe committee decided to make recommendations for research to inform pharmacological management using common treatments (ACE inhibitors, angiotensin II receptor antagonists, beta‑blockers, calcium channel blockers and diuretics) in adults with aortic stenosis, aortic regurgitation or mitral regurgitation. These are important areas of uncertainty in current UK clinical practice.\n\n## How the recommendations might affect practice\n\nThe recommendation reflects current practice, so the committee agreed there is unlikely to be a significant resource impact.\n\n# Pharmacological management of heart failure in heart valve disease\n\nRecommendations 1.2.1 and 1.2.2\n\n## Why the committee made the recommendation\n\nSome evidence showed that beta‑blockers reduced hospital stay for heart failure and increased exercise tolerance compared with usual care in adults with mitral stenosis. As with all other indications for beta‑blockers, some adults with mitral stenosis stopped beta‑blockers because of adverse events (weakness, dizziness and shortness of breath). But the committee agreed that in their experience these medicines offer overall benefit for people with moderate to severe mitral stenosis and heart failure.\n\nThe studies included younger people than in UK clinical practice, with mitral stenosis often being because of rheumatic fever. Patients also had atrial fibrillation. The committee agreed to make a recommendation for research to inform future use of beta‑blockers for older adults with non‑rheumatic calcific mitral stenosis, which is currently more common in the UK than rheumatic mitral stenosis, in sinus rhythm or atrial fibrillation.\n\nAlthough a recommendation to consider beta‑blockers in people with moderate to severe mitral stenosis and heart failure was made, there was not enough evidence for the committee to make recommendations on the use of beta‑blockers in other types of heart valve disease. Similarly, there was not enough evidence to make recommendations on other drugs for the management of heart failure in heart valve disease. They agreed to make a recommendation for research on the pharmacological management of heart failure in adults with severe aortic stenosis, aortic regurgitation, and mitral regurgitation.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice, so the committee agreed there is unlikely to be a significant resource impact.\n\nReturn to recommendations\n\n# Indications for interventions\n\nRecommendation 1.3.1\n\n## Why the committee made the recommendation\n\nSevere symptomatic heart valve disease has a poor prognosis and there is no treatment for the symptoms other than an intervention on the valve. Because of this, the committee recommended that an intervention should be offered to this group. The evidence to support this recommendation is discussed under the different types of valve disease in the section on intervention.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice.\n\nReturn to the recommendation\n\n# Indications for interventions for adults with aortic stenosis\n\nRecommendations 1.3.2 to 1.3.5\n\n## Why the committee made the recommendations\n\nA peak aortic jet velocity more than 5\xa0m/s was a risk factor for increased mortality (all‑cause and cardiac or cardiovascular) and sudden death in people with asymptomatic severe aortic stenosis who had not had a valve intervention. An aortic valve area less than 0.6\xa0cm2 was also associated with increased all‑cause mortality, both before and after valve intervention in adults with asymptomatic severe aortic stenosis.\n\nA left ventricular ejection fraction (LVEF) less than 55% was the best marker of early myocardial decompensation, being linked to increased mortality in adults with asymptomatic severe aortic stenosis.\n\nRaised B-type natriuretic peptide (BNP), particularly when 2 to 3\xa0times the normal level, was a risk factor for all‑cause mortality, before and after valve intervention, for people with asymptomatic severe aortic stenosis and a preserved ejection fraction. The committee agreed that this would also apply to N-terminal proBNP (NT-proBNP), which is more widely used currently in the UK than BNP.\n\nSome of these indicators were broadly in line with current practice and the experience of the committee. In addition, the evidence for increased mortality was strong, including for BNP. Therefore, the committee agreed that these indicators of poorer prognosis should prompt a discussion about the possible need for referral for intervention in people with asymptomatic severe aortic stenosis. Recommendations were limited to considering referral because the evidence was low to very low quality.\n\nThere was some evidence of increased mortality in people with asymptomatic severe aortic stenosis and a global longitudinal strain less than 14.7% or 15%, even when ejection fraction was preserved. However, there is some concern about reproducibility of measurements. The committee agreed that further research in this area would help to inform future guidance, so they made a recommendation for research.\n\nDespite limitations in the quality of the evidence, the committee agreed that there was enough to show that symptoms revealed during exercise testing predict a poor outcome in people with asymptomatic severe aortic stenosis. They noted that some people may not report symptoms because they have adapted, for example, by reducing their activity. Exercise testing may therefore reveal these symptoms, which is an indication for intervention.\n\nThere was evidence from 2\xa0studies, but with limitations, that no increase in valve area on dobutamine stress testing was associated with worse outcome in symptomatic low-flow low-gradient aortic stenosis. Point estimates and confidence intervals from both studies were consistent with this being a risk factor for poor outcome. Severe aortic stenosis is suggested if a person with low-gradient aortic stenosis has an LVEF less than 50% and a valve area less than 1\xa0cm2 at rest. Based on the evidence and the committee's experience, this can be confirmed on dobutamine stress testing if their valve area stays below 1\xa0cm2 and their mean gradient rises above 40\xa0mmHg. This would therefore be an indication for intervention.\n\nThe evidence showed that a higher aortic valve calcium score measured by cardiac CT indicates a worse prognosis for people with aortic stenosis. This could be because it is an index of the severity of aortic stenosis or because it is a marker of more widespread vascular disease. This was supported by the knowledge and experience of the committee, who noted that a more calcified aortic valve is associated with more severe aortic stenosis. However, the mechanism of aortic stenosis in bicuspid aortic valves or in rheumatic disease is different, and cardiac CT would not be as relevant for monitoring valve calcium.\n\nMost of the evidence suggested that myocardial fibrosis was associated with increased risk of a poor outcome in severe aortic stenosis. This was in line with the committee's experience that myocardial fibrosis in general, not only in aortic stenosis, is associated with a worse prognosis. Furthermore, myocardial fibrosis in people with severe aortic stenosis indicates early decompensation and the possible need for early intervention to stop progression, because mid‑wall fibrosis cannot be reversed or improved by intervention. The committee agreed that follow up should be enhanced and further assessment should be offered in those with mid‑wall fibrosis to check for symptoms and enable earlier aortic valve intervention to improve prognosis.\n\n## How the recommendations might affect practice\n\nThese recommendations largely reflect current best practice, although there is local variation and not all healthcare professionals will know that all of these thresholds should lead to referral for intervention.\n\nHowever, the threshold of LVEF less than 55% does represent a change from current practice, because some centres use a threshold of less than 50%. However, for most adults this will mean earlier rather than additional intervention, with subsequent improvement in survival and quality of life.\n\nCardiac MRI is not currently used by all centres to assess aortic stenosis. The recommendation to consider enhanced follow up and further assessment if mid‑wall fibrosis is detected by cardiac MRI should not mean a change in practice because it will be implemented only when cardiac MRI data is available.\n\nReturn to recommendations\n\n# Indications for intervention for adults with aortic regurgitation\n\nRecommendation 1.3.6\n\n## Why the committee made the recommendation\n\nThe committee agreed that it is established practice to consider intervention for people with severe aortic regurgitation and reduced cardiac function. Severity is defined in line with British Society of Echocardiography guidelines. People with aortic regurgitation are often younger than people with other types of valve disease and benefit from timely intervention.\n\nEvidence showed that when LVEF was less than 55%, the risk of cardiovascular mortality or heart failure after intervention was higher. End systolic diameter index (ESDI) is also a measure of systolic dysfunction. Evidence showed an increased risk of left ventricular systolic dysfunction or death when ESDI was more than 24\xa0mm/m2. The committee agreed that either of these 2\xa0indicators of early myocardial decompensation should prompt discussion of possible intervention for asymptomatic severe aortic regurgitation. Recommendations were limited because of the evidence included being low to very low quality.\n\nThere was not enough evidence to include BNP level as an indicator for referral for intervention for people with asymptomatic severe aortic regurgitation. The committee agreed to make a recommendation for research to inform future practice.\n\nNo evidence was identified for stress testing and stress echocardiography in adults with asymptomatic severe aortic regurgitation. The committee agreed that further research could answer questions about when to intervene in this population. Therefore, they made a recommendation for research to identify prognostic factors in this population on stress testing.\n\n## How the recommendation might affect practice\n\nThe recommendation is in line with current practice.\n\nReturn to recommendation\n\n# Indications for intervention for adults with mitral regurgitation\n\nRecommendation 1.3.7\n\n## Why the committee made the recommendation\n\nEvidence showed that an LVEF less than 60% was a risk factor for increased cardiac mortality after intervention for asymptomatic severe mitral regurgitation. An ESDI greater than 22\xa0mm/m2 was associated with onset of symptoms, left ventricular dysfunction, or death without intervention. This is broadly equivalent to the non‑indexed ESD threshold of 45\xa0mm used in current practice. The committee agreed that either of these indicators of early myocardial decompensation should prompt consideration of an intervention for people with asymptomatic severe mitral regurgitation. Recommendations were limited to considering an intervention because the evidence was low to very low quality. The evidence on valve morphology, atrial fibrillation and pulmonary hypertension was not robust enough to include these as independent indicators for referral for intervention. However, the evidence suggested that these were associated with increased mortality, so the committee agreed their presence should be considered when discussing the possibility of intervention.\n\nThere was not enough evidence to include BNP level as an indicator for referral for intervention for people with asymptomatic severe mitral regurgitation. The committee agreed to make a recommendation for research to inform future practice.\n\nEvidence from 2\xa0studies showed that an increase of systolic pulmonary artery pressure (SPAP) to more than 60\xa0mmHg on exercise was associated with worse outcomes in people with mitral regurgitation (asymptomatic or asymptomatic/mildly symptomatic, moderate or severe). This agreed with the committee's experience. Although there is limited evidence that in severe mitral regurgitation, intervening before symptoms develop results in better outcomes, the committee agreed that this may be better. Evidence from 1\xa0study showed that SPAP above 60\xa0mmHg on exercise was associated with symptoms developing during follow up.\n\nThere was not enough evidence for the committee to make a recommendation about symptomatic non‑severe mitral regurgitation. The single small study identified suggested that an increase in effective regurgitant orifice area of 13\xa0mm2 or more on exercise may indicate a worse outcome for this group. But the committee were not confident in this result and so made a recommendation for research to inform future practice.\n\n## How the recommendation might affect practice\n\nThe recommendation largely reflects current best practice, although there is local variation and not all healthcare professionals will know that all of these thresholds should lead to referral for intervention.\n\nReturn to recommendation\n\n# Monitoring when there is no current need for intervention\n\nRecommendations 1.4.1 and 1.4.2\n\n## Why the committee made the recommendations\n\nA single study from the US suggested that regular monitoring for people with severe asymptomatic aortic stenosis reduced all‑cause mortality and hospital admission for heart failure. However, the study had limitations, including lack of applicability to UK clinical practice.\n\nThe committee discussed that although frequency of monitoring currently varies in the UK, it is usually every 6 to 12\xa0months. Some adults find 6‑monthly monitoring reassuring. For others this leads to anxiety and they would prefer less frequent monitoring (for example, every 12\xa0months). The committee agreed that the exact frequency of monitoring within the 6-month to 12‑month timeframe should be determined by echocardiography results and shared decision making with the patient. Monitoring less often than every 12\xa0months would be likely to lead to negative outcomes for the patient because valve changes in this group occur over months rather than years. However, monitoring less often than every 12\xa0months may be suitable for a minority of patients who have demonstrated stability over several years. The recommendation covers all types of asymptomatic severe valve disease.\n\nIn line with current practice, echocardiographic assessment every 3 to 5\xa0years should be considered for adults with mild aortic or mitral stenosis. This would help to identify people with asymptomatic disease that has become more severe and for whom intervention may be appropriate.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice.\n\nReturn to recommendations\n\n# Decisions about interventions\n\nRecommendations 1.5.1 and 1.5.2\n\n## Why the committee made the recommendations\n\nThe committee highlighted the importance of shared decision making when discussing interventions. This is to ensure that treatment options are fully explored, along with their risks and benefits. Specifically, the committee highlighted valve durability, the risks associated with the procedure, and the possible need for other cardiac procedures in the future.\n\nThe committee agreed that in their clinical experience there was no difference between minimally invasive and standard surgery replacement in terms of outcomes when done by those with expertise in minimally invasive surgery. The decision should be based on patient characteristics and preferences. A lack of expertise in minimally invasive surgery locally should not be used as a reason for not performing a minimally invasive procedure. Adults should be referred to a centre where this expertise is available if the procedure is agreed as most suitable. The evidence to support this recommendation is reported under the different types of valve disease.\n\n## How the recommendations might affect practice\n\nThe recommendations are expected to have a very small impact on current practice. Minimally invasive surgery will not be suitable for many patients. Those for whom it is suitable may still decide to have standard surgery after considering the possible benefits and risks of both options.\n\nReturn to recommendations\n\n# Interventions for aortic valve disease\n\nRecommendations 1.5.3 to 1.5.5\n\n## Why the committee made the recommendations\n\nEvidence from 8\xa0randomised controlled trials (RCTs) showed no large or clear differences for most outcomes between transcatheter aortic valve implantation (TAVI) and surgery for adults with non‑bicuspid aortic stenosis, including mortality outcomes and quality of life. However, a benefit of TAVI was identified for major bleeding and atrial fibrillation at 30\xa0days, and length of hospital stay after the intervention. Absolute effects for other outcomes also suggested a benefit, but there was more uncertainty based on the confidence intervals. A harm of TAVI was identified for pacemaker implantation at 30\xa0days. Although absolute effects also suggested a possible harm of TAVI in terms of mortality and rehospitalisation, the direction and size of the effect was much more uncertain for these outcomes and no clear difference between the 2\xa0groups could be identified.\n\nOnly 1\xa0study reported data beyond 5\xa0years, but only for all‑cause mortality. The health economic model developed as part of the guideline looked for cost effectiveness over a lifetime. Therefore, it included evidence about the impact of complications in the long term, beyond 5\xa0years, given the longer life expectancy for younger people with lower surgical risk. The results of the health economic model showed that TAVI at current prices was cost effective for people at high risk of surgery but not for people at low or intermediate risk. The committee agreed that if surgery is an option, it should be offered to those with severe aortic stenosis who are low or intermediate risk. Although all of the evidence identified was for non‑bicuspid aortic stenosis, it was agreed that the recommendation should also apply to bicuspid aortic stenosis, because suitability of surgery does not depend on the type of aortic stenosis. TAVI is also considered to be more difficult in bicuspid aortic stenosis.\n\nEvidence showed benefits for TAVI for people with inoperable non‑bicuspid severe aortic stenosis compared with pharmacological management at 1 to 5\xa0years. These included benefits in all‑cause mortality, cardiac mortality, need for another intervention during follow up, and hospital admission. However, at 30\xa0days TAVI was associated with increased mortality, stroke or transient ischaemic attack, major bleeding, and major vascular complications. The committee noted that TAVI is the only intervention available for some people with symptomatic severe aortic stenosis. They agreed that pharmacological management is not sufficient to help symptoms in severe aortic stenosis and for some aortic stenosis can be fatal without an intervention. TAVI can improve outcomes in many cases. Two UK‑based studies indicated that TAVI offers a good balance of benefits and costs in adults who cannot have surgery. The committee agreed to recommend TAVI, if suitable, for those with non‑bicuspid severe aortic stenosis if surgery is unsuitable. TAVI is the only option for this group and was deemed cost effective in this population.\n\nAll of the evidence identified was for non‑bicuspid aortic stenosis. TAVI is considered to be more difficult for bicuspid aortic stenosis and the committee could not extrapolate the evidence to cover this population.\n\nEvidence was identified from 14\xa0RCTs comparing minimally invasive surgery for aortic valve replacement with standard surgery by median sternotomy across different aortic valve disease populations. Some harms of minimally invasive surgery were observed, and 1\xa0health economic study suggested that minimally invasive surgery was less cost effective than median sternotomy. However, the RCTs were small and a small number of events were observed for many outcomes. The health economic study was limited for the same reasons because it was based on 1 of the RCTs and was limited to a 12‑month time-horizon. Although the committee agreed it is likely there would not be a large difference in outcomes after 12\xa0months, this may be too short to draw conclusions about cost effectiveness over a lifetime. The committee highlighted that in their experience there was no difference between minimally invasive surgery and median sternotomy when done by those with expertise. The committee were also aware of certain advantages of minimally invasive surgery, for example, smaller incisions. The committee agreed not to limit the use of minimally invasive surgery and to recommend a choice with the decision based on patient characteristics and preferences. A lack of expertise in minimally invasive surgery locally should not be used as a reason for not performing a minimally invasive procedure and adults should be referred to a centre where there is expertise if this procedure is agreed as most suitable.\n\nDespite no direct evidence for bicuspid aortic stenosis, aortic regurgitation (bicuspid or non‑bicuspid) and mixed aortic valve disease (aortic stenosis and regurgitation in the same person), the committee agreed that the type of aortic valve disease would not affect decisions about the invasiveness of surgery and the evidence could be extrapolated to any aortic valve disease.\n\n## How the recommendations might affect practice\n\nThe committee agreed that the use of TAVI is increasing, particularly when surgery is unsuitable and there are no other options for interventional procedures. It would be rare not to perform TAVI in these circumstances, but palliative care with pharmacological management is sometimes agreed. Therefore, the committee considered that the recommendation would represent a minimal change in practice and would not increase the number of TAVI procedures.\n\nThe committee agreed that TAVI is usually reserved for when surgery is unsuitable or carries high risks of mortality. But data from the UK TAVI registry suggests that in recent years the procedure has been expanded to groups of people with lower surgical risk. The recommendation to offer TAVI to those with high surgical risk should have a moderate impact, as only 1.9% of surgeries are currently done in this group.\n\nThe recommendation to offer surgery instead of TAVI to those with intermediate and low surgical risk should increase the number of surgeries and reduce TAVIs in this group. This will ultimately improve NHS efficiency.\n\nData suggests that between 5% and 10% of surgical isolated aortic valve replacements are done by minimally invasive surgery. If the recommendation leads to an increase in the number of aortic valve replacements being done by minimally invasive surgery, this could represent an important change in practice. There may be no increase in the short term, as more training in these procedures will be needed, but only in the long term when more centres will have the expertise and capacity of offering minimally invasive surgery.\n\nReturn to recommendations\n\n# Interventions for mitral stenosis\n\nRecommendations 1.5.6 and 1.5.7\n\n## Why the committee made the recommendations\n\nEvidence from 7\xa0RCTs comparing transcatheter valvotomy with surgical valvotomy (either by minimally invasive or standard surgery) in people with rheumatic severe mitral stenosis demonstrated very few differences in outcomes. The committee agreed that surgical valvotomy is no longer commonly used in practice because similar results can be achieved with the transcatheter procedure, with less trauma and scarring and at a lower cost to the NHS. The evidence was limited by small studies, often with only a small number of events, and most outcomes being graded as very low quality. The committee agreed that transcatheter valvotomy could be considered for adults with rheumatic severe mitral stenosis who need an intervention and for whom this procedure would be suitable.\n\nNo evidence was identified for mitral valve replacement in those with rheumatic mitral stenosis when transcatheter valvotomy is not suitable. The committee agreed this it was important to make a recommendation for these people. Although no evidence was included, the condition would likely deteriorate without an intervention.\n\nIt was not appropriate to extrapolate evidence from rheumatic mitral stenosis to calcific mitral stenosis because they are 2\xa0very different pathologies. Because there was no evidence included for calcific mitral stenosis, the committee made a recommendation for research to inform future practice.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with current practice.\n\nReturn to the recommendations\n\n# Interventions for mitral regurgitation\n\nRecommendations 1.5.8 to 1.5.14\n\n## Why the committee made the recommendations\n\nEvidence from 3\xa0RCTs demonstrated few differences between surgical repair and surgical replacement in those with severe mitral regurgitation. (One study included both primary and secondary mitral regurgitation; the other 2\xa0studies covered secondary mitral regurgitation only). The largest effect was for the need for reintervention for secondary mitral regurgitation, with fewer repeat interventions needed in the replacement group. Overall, the included evidence was limited; all studies were very small, with very few events reported for most outcomes and substantial uncertainty in the effects reported. Most outcomes were graded as very low quality. The lack of stronger evidence is likely to be because surgical repair has been preferred to replacement in mitral valve surgery for the past few decades. This was based on observational evidence and because randomising to repair or replacement in people for whom repair is suitable was thought to be unethical. Based on these limitations, the committee made recommendations reflecting current practice for those with severe mitral regurgitation requiring an intervention, with surgical repair recommended in those for whom it is suitable and replacement when repair is not suitable.\n\nThe committee noted that there are differences in the aetiology and treatment of primary and secondary mitral regurgitation. Although valve intervention is the next step for primary mitral regurgitation and an indication for intervention, for secondary mitral regurgitation the underlying heart failure is usually treated first. Therefore, the committee recommended that an intervention should be offered for severe primary mitral regurgitation and considered for secondary mitral regurgitation after optimisation of medical management.\n\nEvidence from 5\xa0RCTs comparing minimally invasive surgery with median sternotomy for mitral regurgitation or mixed/unclear mitral valve disease demonstrated few differences. The studies were limited by small participant numbers and a small number of events for many reported outcomes. There was substantial uncertainty for most reported outcomes, a lack of long-term data for many outcomes, and most outcomes were graded as low or very low quality. Overall, when any larger differences were observed (for example, length of stay), these were for a benefit of minimally invasive procedures. A single health economic study suggested the cost of minimally invasive surgery was less per person than median sternotomy. However, the committee did not consider the included evidence to be strong enough to support recommending 1\xa0type of surgery over the other. They agreed that median sternotomy and minimally invasive surgery should be options for those with mitral regurgitation requiring mitral valve surgery, with the decision being based on patient characteristics and patient preferences. A lack of expertise in minimally invasive surgery locally should not be used as a reason for not performing a minimally invasive procedure and patients should be referred to a centre where there is expertise if this procedure is agreed as most suitable.\n\nNo clinical evidence was identified comparing transcatheter mitral valve repair with medical management for primary mitral regurgitation when surgery is not suitable. The committee noted that the lack of evidence may be because it is well established that medical management does not improve outcomes and transcatheter mitral valve repair is useful when surgery cannot be performed. One health economic study, based on a non‑randomised registry, reported that transcatheter repair was cost effective compared with medical management in those with severe mitral regurgitation when surgery was not suitable. This study had limitations because it included people with secondary mitral regurgitation and used data from a prospective, single‑arm registry with a control group obtained retrospectively. A second Japanese study on a mixed population with secondary and primary mitral regurgitation found transcatheter repair with the MitraClip device to be cost effective. This study had some limitations too as the relative treatment effects were informed from a propensity score matching study rather than an RCT.\n\nA health economic model developed as part of this guideline did not find MitraClip to be cost effective for adults with secondary mitral regurgitation. However, the committee agreed that it was plausible that MitraClip would offer more benefits for people with primary mitral regurgitation because they are likely to have less residual disease affecting quality of life after the intervention. The committee agreed to recommend that transcatheter mitral valve repair should be considered for primary severe mitral regurgitation with symptoms when surgery is unsuitable.\n\nEvidence was included from 3\xa0RCTs comparing transcatheter mitral valve repair with medical management for secondary mitral regurgitation. Two of these were clearly in a population in which surgery was not suitable and covered the use of the MitraClip device; the third study covered a Carillon device rather than MitraClip and the population was unclear. Outcomes from all 3\xa0studies were pooled if possible, in the clinical review, but the health economic modelling was limited to the population in which surgery was not suitable.\n\nThe clinical review highlighted uncertainty in the results for 3\xa0outcomes (all‑cause mortality, cardiac mortality and onset/exacerbation of heart failure at 1 to 3\xa0years or 2 to 3\xa0years). Some studies demonstrated a benefit of transcatheter repair, some a harm (lack of benefit) and some no difference. One UK health economic study based on the results of the COAPT trial, which enrolled people with very severe secondary mitral regurgitation deemed inoperable, found that transcatheter edge-to-edge repair with MitraClip device had an incremental cost per quality-adjusted life year (QALY) of about £30,000.\n\nA health economic model was developed as part of the guideline to investigate the cost effectiveness of using the MitraClip device when surgery is not suitable. The model demonstrated that transcatheter mitral valve repair had a low chance of being cost effective at £20,000 per QALY gained, with an incremental cost‑effectiveness ratio of £30,000 per QALY gained. These results are in line with the UK study identified in the literature review. The health economic model was largely based on results from the COAPT trial, which covered transcatheter mitral valve repair in severe secondary mitral regurgitation. This trial demonstrated substantial benefits over medical management alone when surgery was unsuitable. However, it was not considered to be cost effective at the current list price. For this reason, edge-to-edge mitral valve repair was not recommended over medical management.\n\n## How the recommendations might affect practice\n\nEdge-to-edge repair is not widely available in the NHS. Therefore, this recommendation may lead to a change in practice and increase the amount of percutaneous mitral intervention in those for whom it is suitable.\n\nThe recommendations are in line with current practice.\n\nTranscatheter mitral valve repair is rarely done for primary mitral regurgitation when an intervention is needed and surgery is unsuitable, so the recommendation may lead to a change in practice. This procedure has only recently been commissioned by the NHS and its use is likely to increase now based on this commissioning. The recommendation is unlikely to increase use much beyond this.\n\nTranscatheter mitral valve repair is not currently used for secondary mitral regurgitation because it has not been commissioned by the NHS for this. The recommendation is unlikely to lead to a change in practice.\n\nReturn to recommendations\n\n# Interventions for tricuspid regurgitation\n\nRecommendations 1.5.15 and 1.5.16\n\n## Why the committee made these recommendations\n\nA single RCT was identified comparing transcatheter repair plus optimal medical management with optimal medical management alone in people with severe, symptomatic tricuspid regurgitation and a high surgical risk score. Patients with associated tricuspid regurgitation have worse prognosis after mitral valve intervention than those with mild or no tricuspid regurgitation. There is strong evidence that secondary functional tricuspid regurgitation that is severe does not improve after fixing the mitral lesion. Moderate tricuspid regurgitation does remain stable in a few patients after mitral correction. However, in a significant number, it does not improve and may get worse. Tricuspid annuloplasty by an experienced surgeon (at the time of mitral surgery) is a quick procedure that reduces the amount of tricuspid regurgitation and may improve prognosis.\n\nPatients with associated tricuspid regurgitation have a worse prognosis after aortic valve intervention than those with mild or no tricuspid regurgitation. There is strong evidence (but not reviewed here) that secondary functional tricuspid regurgitation that is severe does not improve after fixing the left‑sided lesion. Tricuspid annuloplasty by an experienced surgeon is a quick procedure that does reduce the amount of tricuspid regurgitation and may improve prognosis of these patients.\n\nThe committee made a recommendation for research to inform future guidance.\n\n## How the recommendations might affect practice\n\nThese recommendations are in line with current practice.\n\nReturn to recommendations\n\n# Repeat intervention\n\nRecommendation 1.6.1\n\n## Why the committee made the recommendation\n\nNo evidence was identified comparing surgery with medical management for people with failing biological prosthetic aortic valves. However, the committee agreed that surgery should be considered in this group because their condition may deteriorate if left without intervention on medical management.\n\nSimilarly, no evidence was identified comparing transcatheter repeat intervention with medical management when surgery is unsuitable for people with failing biological prosthetic aortic valves. However, the committee agreed that repeat transcatheter intervention should be considered in this group because their condition may deteriorate if left without intervention on medical management.\n\nFor people who can have surgery, there were no RCTs comparing transcatheter intervention with surgery for repeat intervention and the only included studies were non‑randomised. The committee were not able to base recommendations on this because of the limitations with non‑randomised evidence. Therefore, they recommended that a shared decision should be based on short- and longer-term benefits, the type of valve dysfunction and prosthesis, the risks associated with the procedure and the possible need for other cardiac procedures. The term 'degenerated' refers to progressive degeneration and does not include failure of the valve due to endocarditis or thrombosis. The recommendation was limited to those with symptoms because this was considered to be an indication for repeat intervention.\n\nThe committee also made recommendations for research for repeat intervention for failing biological prosthetic aortic, mitral and tricuspid valves because the only available evidence was non‑randomised.\n\n## How the recommendation might affect practice\n\nWhen both transcatheter and surgical procedures are options for repeat intervention, the choice of procedure is usually based on individual patient characteristics although surgery may be done more often. When surgery is not an option, transcatheter intervention is used as the only alternative to medical management. The recommendation will therefore not represent a change in practice.\n\nReturn to recommendation\n\n# Anticoagulation and antiplatelet therapy\n\nRecommendations 1.7.1 to 1.7.3\n\n## Why the committee made the recommendations\n\nEvidence from a population without atrial fibrillation demonstrated an increased risk of major bleeding with vitamin K antagonist compared with single antiplatelet therapy (aspirin). No clear reduction in mortality or thromboembolic events was observed with vitamin K antagonist. Therefore, the committee agreed that anticoagulation should not be offered after surgical biological valve replacement unless there are other indications for anticoagulation. This covers both vitamin K antagonists and direct‑acting oral anticoagulants (DOACs) because there was no evidence to show that DOACs are safe. One small study in people with atrial fibrillation suggested there may be no clear differences in outcomes between DOACs and vitamin K antagonists, and it is not common practice to use DOACs for this group. The committee agreed that if there is already an indication for anticoagulation or antiplatelet therapy, for example, because of atrial fibrillation, the existing NICE guidelines for these indications should be followed.\n\nDespite 1\xa0study demonstrating a potential reduction in arterial thromboembolic events and vascular mortality with combined anticoagulant and antiplatelet therapy compared with anticoagulant therapy alone after surgical biological valve replacement, there was uncertainty around this result. This uncertainty, combined with further study limitations, including issues with the target international normalised ratio used and the selective population, meant that the study could not be used to inform general recommendations for surgical biological valve replacement.\n\nThere was a lack of evidence comparing anticoagulant or antiplatelet therapy with no treatment after surgical biological valve replacement, so the committee made a recommendation for research. They made another recommendation for research to investigate the long-term effect of anticoagulant or antithrombotic therapy on valve function and outcomes after biological valve replacement because no long-term data was available.\n\nEvidence from 4\xa0studies demonstrated a clinically important benefit of single antiplatelet therapy (aspirin) compared with dual antiplatelet therapy in reducing major and minor bleeding in the short-to-medium term. Based on this, the committee agreed that single rather than dual antiplatelet therapy should be considered after TAVI. As aspirin is used in practice, and this was used in all of the studies, aspirin was recommended, with clopidogrel specified as the alternative if aspirin was not tolerated.\n\nThe committee were also aware of observational evidence that antiplatelets reduced the risk of valve thrombosis and improved valve durability over the long term. There was also evidence from 1\xa0study demonstrating harms of DOACs compared with single antiplatelet therapy for most reported outcomes, including mortality, bleeding and withdrawal because of adverse events. This further supported the recommendation for single antiplatelet therapy. Because of the lack of evidence comparing anticoagulant and antiplatelet therapy with no treatment after TAVI, the committee made a recommendation for research.\n\nNo evidence was identified comparing different anticoagulant and antiplatelet treatments in adults who have had valve repair. The committee made a recommendation for research comparing anticoagulant and antiplatelet treatments with placebo after valve repair.\n\n## How the recommendations might affect practice\n\nPractice is currently variable, with some centres offering vitamin K antagonists after surgical biological valve replacement. Therefore, the recommendation will lead to a change in practice in some centres.\n\nIt is unusual for people not to receive at least single antiplatelet therapy after TAVI and many people receive dual antiplatelet therapy. The recommendation was not thought to represent a change in practice in terms of the number of people who receive some form of antiplatelet therapy after a transcatheter procedure.\n\nReturn to recommendations\n\n# Monitoring after an intervention\n\nRecommendation 1.8.1\n\n## Why the committee made the recommendation\n\nNo evidence was found for the frequency of monitoring after an intervention for valve disease. Current practice is variable and depends on patient factors, such as comorbidities, other cardiac disease or previous heart surgery, as well as the type of procedure performed (repair or replacement). Follow up also depends on the type of valve used for a replacement. The committee agreed that mechanical valves have good durability with a low risk of failure. In contrast, biological valves have lower durability with deterioration possible within 10\xa0years. The committee noted that, although practice varies, mechanical valves may be monitored over the first 12\xa0months and then only checked if problems develop. Monitoring is usually more frequent for biological valves – with some centres offering annual follow up starting from the year of the operation and others starting annual follow up after 5\xa0years. Any concerns about abnormal valve function may also affect the frequency of monitoring, with more frequent follow up if there are concerns.\n\nThe committee agreed that frequency of follow up should be discussed with the patient. Some people find more frequent monitoring reassuring whereas for others this leads to increased anxiety. People should be encouraged to seek advice if they feel that their condition has deteriorated. There is a higher risk of endocarditis in replacement valves and people should be encouraged to report symptoms.\n\n## How the recommendation might affect practice\n\nThe recommendation reflects current practice, which is variable and depends on various factors, such as valve durability and patient comorbidities and preferences.\n\nReturn to recommendation\n\n# Information and advice\n\nRecommendations 1.9.1 to 1.9.5\n\n## Why the committee made the recommendations\n\nClear and consistent evidence outlined the negative impact of symptoms of valve disease and loss of control that led to feelings of despair and insecurity. In this context, a single point of contact for some people may increase the hope and security afforded between appointments.\n\nThe committee also agreed that it was useful to list areas of information and advice that are important to people with valve disease to ensure that their expectations accurately match the likely course of their condition. Having this information will be beneficial for planning, reducing anxiety and supporting shared decision making. This may include relevant information for patients and carers (when appropriate) about the possibility of delirium after valve surgery, in line with the NICE guideline on delirium.\n\nFrom the evidence and their experience, the committee noted the psychological impact of valve disease on a person, whether or not the person currently has symptoms. They agreed that clinicians should be aware of the potential psychological impact of receiving a diagnosis of heart valve disease and consider providing additional advice and support.\n\nThe committee stressed the importance of individualised care and shared decision making and referenced the relevant NICE guidelines. Specific advice and support at the point of transition from paediatric to adult services was also agreed to be important to ensure young adults are given appropriate information on the likely progression of their valve disease and referrals to adult valve clinics.\n\nThe committee noted the limitations of the available evidence, which was mostly from those being considered for TAVI. These people typically have more complex comorbidities, and their older age means that their hopes and fears are different from those of younger adults. Therefore, the committee made a recommendation for research on the information and advice needs of all adult age groups with valve disease of all severities and stages. Studies should include patient‑reported outcomes and experiences of decision aids.\n\n## How the recommendations might affect practice\n\nCurrently not all adults with valve disease have a point of contact between appointments or psychological support, and so these recommendations will need a change by some providers.\n\nReturn to recommendations", 'Context': 'The heart has 4\xa0valves (aortic, mitral, tricuspid and pulmonary) that control blood flow.\n\nIn heart valve disease, valve function can be impaired by:\n\nstenosis, a narrowing or stiffening of the valve, which restricts its opening and obstructs the forward flow of blood\n\nregurgitation, failure of the valve to close completely, which allows blood to flow backward.\n\nThere can be stenosis and regurgitation of the same valve (mixed valve disease) or disease may affect more than one valve (multiple valve disease).\n\nMitral and tricuspid heart valve disease can be primary or secondary. Primary disease affects the valve structure, whereas secondary disease results from enlargement or dysfunction of the heart chambers (atria or ventricles) with otherwise normal mitral or tricuspid valve structure.\n\nHeart valve disease can be congenital or acquired. Acquired valve degeneration is currently the main cause of heart valve disease, leading to the most common types of heart valve disease, as for example calcific aortic stenosis and myxomatous or calcific degeneration of the mitral valve.\n\nSecondary heart valve disease can be classified as:\n\nventricular-secondary mitral or tricuspid regurgitation\n\natrial-secondary mitral or tricuspid regurgitation.\n\nAmong people aged 65\xa0years or over the prevalence of asymptomatic heart valve disease may be more than 50%, whereas the prevalence of clinically significant heart valve disease is around 11%. It is predicted that for people over\xa065, the prevalence of heart valve disease will increase, from 1.5\xa0million people currently to more than 3\xa0million in 2046.\n\nPeople with heart valve disease may have no symptoms or may have symptoms that can depend on the affected valve. Associated heart rhythm problems, such as atrial fibrillation or heart block, may cause palpitations and breathlessness, or dizziness and light‑headedness, respectively. Untreated severe disease can lead to valvular heart failure, with symptoms including breathlessness, reduced exercise capacity, tiredness and swollen ankles. Heart valves stiffen as part of the ageing process, making dysfunction more likely in older people. We hope that this guideline will raise awareness of heart valve disease and improve diagnosis and management.'}
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https://www.nice.org.uk/guidance/ng208
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This guideline covers investigation and management of heart valve disease presenting in adults. It aims to improve quality of life and survival for people with heart valve disease through timely diagnosis and appropriate intervention.
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e5de8404b6555e7457e0a3cf77b9fbd6584ab817
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nice
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Nivolumab for adjuvant treatment of resected oesophageal or gastro-oesophageal junction cancer
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Nivolumab for adjuvant treatment of resected oesophageal or gastro-oesophageal junction cancer
Evidence-based recommendations on nivolumab (Opdivo) as a possible treatment for completely resected oesophageal or gastro‑oesophageal junction cancer in adults.
# Recommendations
Nivolumab is recommended, within its marketing authorisation, for adjuvant treatment of completely resected oesophageal or gastro‑oesophageal junction cancer in adults who have residual disease after previous neoadjuvant chemoradiotherapy. It is recommended only if the company provides nivolumab according to the commercial arrangement.
Why the committee made these recommendations
The most common treatment for oesophageal or gastro‑oesophageal junction cancer is neoadjuvant chemoradiotherapy then surgery. Treatment choice depends on various factors including histology, tumour size and location, patient preference and treatment suitability.
Clinical trial evidence shows that after trimodal therapy (chemoradiotherapy and surgery), nivolumab increases how long people live without the cancer returning compared with standard care, which is surveillance alone. Nivolumab is also likely to be more effective at extending how long people live, but clinical trial evidence is not yet available.
The cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources, so nivolumab is recommended.# Information about nivolumab
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol Myers Squibb) as monotherapy is indicated for 'the adjuvant treatment of adult patients with completely resected oesophageal or gastro‑oesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
Nivolumab is available in 3 different sizes as a concentrate for solution for infusion vials. The cost varies according to vial size: £439 (40 mg per 4 ml), £1,097 (100 mg per 10 ml) and £2,633 (240 mg per 24 ml; excluding VAT; BNF online, accessed August 2021). The cost for 1 dose of treatment is £2,633 (240 mg per 24 ml).
The company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that 3 issues were resolved during the technical engagement stage, and agreed that:
The generalised F‑distribution should be used to model disease-free survival in the nivolumab and routine surveillance arms.
The average age of people included in the economic model should be 62.66 years. The company provided adjusted CheckMate‑577 data that reflected the age distribution of people with oesophageal cancer who had chemoradiotherapy and surgical resection in the NHS.
General population utility and post-recurrence utility should be adjusted for age using the Ara and Brazier adjustment factor. The company provided updated inputs for the economic model that amended an error causing utilities for the disease-free and recurred-disease health states to be equal after 75 years.
The committee recognised that there were 2 remaining areas of uncertainty associated with the 'cure' point and costs of treatment. It took these into account in its decision making.
# The condition
## There is high unmet need for adjuvant treatments in this area
Oesophageal cancer is a malignant tumour of cells lining the oesophagus. The 2 main types are squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma usually affects the upper and middle oesophagus. Adenocarcinoma is more common in the UK and usually affects the lower oesophagus, including the gastro‑oesophageal junction. Early symptoms may be vague, subtle and similar to benign conditions, which can result in late diagnosis and a poor prognosis. Clinical experts highlighted that the aim of treatment is to cure disease, but recurrence occurs for around 50% to 60% of people who have residual disease after chemoradiotherapy. The patient expert explained that people have ongoing fear because of a lack of available active treatments after surgery, which affects mental wellbeing and quality of life. The committee concluded that there is an unmet need for active treatments for this condition, and that these would have physical and psychological benefits.
# Treatment pathway
## There is variation in current practice but the nivolumab marketing authorisation includes a specific population
Current standard care for oesophageal or gastro‑oesophageal junction cancer depends on clinical evidence, histology and the patient's informed preferences. Clinical experts explained that most people who have squamous cell carcinoma have chemoradiotherapy then surgery. But a proportion of people have definitive chemoradiotherapy alone with no surgery, which is considered to be broadly equivalent. People who have adenocarcinoma may have either neoadjuvant chemoradiotherapy then surgery or perioperative FLOT (fluorouracil, folinic acid, oxaliplatin, docetaxel) chemotherapy. The clinical trial inclusion criteria included adults with oesophageal or gastro‑oesophageal junction cancer who had neoadjuvant chemoradiotherapy and complete surgical resection with clear margins, but residual pathologic disease was present in the removed surgical specimen. The company indicated that the marketing authorisation corresponds with these criteria and people who have treatment with FLOT are not included. The clinical experts explained that this was a specific population who were identifiable in clinical practice in the NHS. They noted that over 80% of people have complete resection after chemoradiotherapy. Also, in the CROSS trial comparing neoadjuvant chemoradiotherapy plus surgery with surgery alone for oesophageal or gastro‑oesophageal junction cancer, 92% of people who had chemoradiotherapy plus surgery had a complete resection. However, they explained that the presence of detectable residual disease in the surgical specimen depended on histology, with residual disease more likely in those with adenocarcinoma than squamous cancer. The committee can only appraise a technology within its licensed indication and the evidence supporting this appraisal was from a single clinical trial with a specific population, in line with the marketing authorisation. This means people who have had other treatments such as chemotherapy alone, or definitive chemoradiotherapy (with no surgery) are outside the scope of this appraisal. The committee concluded that people with completely resected oesophageal or gastro‑oesophageal junction cancer who have residual pathologic disease after neoadjuvant chemoradiotherapy would be the population considered in this appraisal, based on the clinical evidence available.
## Evidence is only available for people who had surgical treatment in line with the CheckMate-577 trial protocol
The committee was aware that a proportion of people have definitive chemoradiotherapy with no pre-planned surgery, but could later have salvage resection. The clinical experts explained that there are 2 populations who might have delayed surgery in clinical practice. One population includes people in whom there is no intention to operate as part of the primary treatment, but resection is done if the cancer recurs. The committee noted that this population was different to the population included in the marketing authorisation and agreed it could not be considered for adjuvant nivolumab treatment. The second population are those in whom there is thought to be a high surgical risk. In those cases, definitive chemoradiotherapy may be used first to avoid surgery, followed by an early assessment after 2 or 3 months. Primary salvage resection is then done if residual disease is found. The clinical lead for the Cancer Drugs Fund explained that primary salvage resection may have been allowed in the clinical trial if the window of time between chemoradiotherapy and resection covered the 2- to 3‑month assessment point. The committee agreed that only people who had salvage resection within the window included in the trial protocol could be considered equivalent and would be eligible for treatment with adjuvant nivolumab.
# Clinical evidence
## CheckMate-577 is generalisable to current clinical practice in the NHS
Clinical evidence was based on CheckMate‑577, a phase 3, multicentre, randomised, double-blind, placebo-controlled trial that included a very small number of people from the UK. It compared nivolumab monotherapy with placebo. The committee noted that baseline characteristics were well balanced between arms. But the ERG advised that there were several differences between the population in CheckMate‑577 and the population in the NHS:
The average age in the full population was 62, which is younger than in the NHS.
The proportion of men was higher in the trial than in the NHS.
The proportion of different ethnicities in the trial was likely to be different to those seen in the NHS.The patient expert explained that younger people and more women are now being seen in clinical practice. The clinical experts agreed but noted that these demographic changes were unlikely to be reflected in current clinical trials and that differences in age, sex and ethnicity were unlikely to affect the clinical efficacy of nivolumab. On balance they considered the trial to be generalisable to the NHS and also agreed that the distribution of histology in the trial reflected the population seen in the NHS. The committee concluded that data from the CheckMate‑577 trial was generalisable to the NHS and could be used for the clinical-effectiveness analyses.
## Nivolumab is clinically effective and extends disease-free survival compared with placebo
The primary outcome in the CheckMate‑577 trial is disease-free survival. The February 2021 data cut showed that nivolumab increased disease-free survival compared with placebo (hazard ratio 0.67, 96% confidence interval 0.55 to 0.81). The median disease-free survival in people who had nivolumab was 22.4 months and 10.4 months with placebo. Results for overall survival are not yet available. The clinical lead for the Cancer Drugs Fund and clinical experts agreed that the disease-free survival Kaplan–Meier data showed a clear separation between the curves. This shows that more people were disease-free who had nivolumab than those who had placebo. The clinical expert also noted that this data showed that some people are likely to never have disease recurrence, and that this proportion is higher for those who had nivolumab. The committee concluded that, based on the CheckMate‑577 results, adjuvant nivolumab is clinically effective and extends disease-free survival compared with placebo.
## Disease-free survival is a reasonable outcome to consider for modelling because of the extended follow up
The committee was aware that the company used disease-free survival results in the economic model because no overall survival data was available. The company explained that overall survival was a secondary end point in the clinical trial, which was event driven. The data remained immature and so the company did not yet have access to the overall survival data and remained blinded to the results. The company assumed a benefit for overall survival (assuming that if the disease recurred there would be equal mortality for those who had placebo or nivolumab). Both the clinical experts and clinical lead for the Cancer Drugs Fund had agreed that the disease-free survival benefit shown for nivolumab was compelling. Assuming an overall survival benefit based on a surrogate end point, in this case disease-free survival, is uncertain. The committee was aware this has been subject to much debate in previous appraisals, in some of which surrogate outcomes had proven unreliable. However, the ERG noted that the evidence in these cases came from highly heterogeneous populations and had short follow ups. So, it did not reflect the data available for CheckMate‑577, where at least 44 months of follow up was available for disease-free survival, which is close to the time point the ERG considered reasonable to assume a 'cure'. The committee agreed that given the extended follow up this was a suitable outcome to use for modelling survival and that the assumption of overall survival benefit was reasonable.
## Nivolumab may be more effective for people who have squamous cell carcinoma, but it is beneficial regardless of histology
The committee considered the subgroup results from CheckMate‑577. The latest results are considered confidential and cannot be reported here. The committee was aware that the trial was not powered to test for statistical significance of an interaction between treatment and subgroups. But the results showed that nivolumab appeared more effective in squamous cell carcinoma than adenocarcinoma. The clinical experts advised that survival curves from the CROSS trial suggested that people who have squamous cell carcinoma have better outcomes than those who have adenocarcinoma, based on current standard care, and that squamous cell carcinoma may respond better to treatment. However, both histological types appeared to benefit from adjuvant nivolumab. The company and ERG highlighted that, despite not being powered for subgroups, the results showed hazard ratios less than 1 for almost all pre‑specified subgroups. The committee concluded that nivolumab may be more effective for people who have squamous cell carcinoma, but it is beneficial regardless of histology.
## Nivolumab is generally well tolerated and adverse events are included in the economic modelling
In CheckMate‑577 a similar number of people experienced adverse events in the nivolumab and placebo arms. The clinical experts highlighted in their written submissions that serious adverse events can happen after treatment with nivolumab that need additional management and monitoring. The clinical lead for the Cancer Drugs Fund explained that as there are now improved clinical systems to detect and treat immune-mediated toxicities of nivolumab, serious side effects are rarer than previously seen. The ERG and the company confirmed that all serious adverse events were considered in the economic modelling. The committee concluded that adverse events are adequately included in the economic modelling.
# Cost effectiveness
## The company's model is appropriate for decision making
The company presented a 3‑state semi‑Markov model to estimate the cost effectiveness of nivolumab compared with standard care. The 3 health states were disease-free, recurrent disease and death. The company explained that a partitioned survival model was not possible because of unavailable overall survival data, but the semi‑Markov model allows dependency between events rather than using priori assumptions in traditional Markov models. The ERG agreed with this approach. The model cycle length was 1 week, and the time horizon was 40 years. No half-cycle correction was included in the model. The ERG noted that this was not a limitation because of the weekly time cycles used in the model. The committee had already concluded that disease-free survival was a suitable outcome given the extended follow up in CheckMate‑577. It recalled that the company assumed an overall survival benefit and equal deaths after recurrence. The ERG explained that the company used external data from Lou et al. to apply a mortality rate to both arms. The company had explored alternative assumptions and sensitivity analyses on this parameter that showed broadly similar results when applied to both arms. The committee concluded that the company's semi‑Markov model was suitable for decision making.
# Survival extrapolations
## The generalised F-distribution gives the most appropriate long-term estimate of disease-free survival
In its original submission the company modelled disease-free survival using a 1‑knot spline log-normal distribution. The ERG noted that the generalised F‑distribution had a better statistical fit to the trial data. More recent disease-free survival data became available from the CheckMate‑577 trial after the original submission data. Therefore, after technical engagement, the company updated its analysis to use the recent cut-off data (February 2021). In addition, the company updated the distribution used to model disease-free survival to a generalised F‑distribution because it provided the lowest AIC (Akaike's Information Criteria) and BIC (Bayesian Information Criteria) values. The company noted that the 1‑knot spline distribution remained plausible and provided results in scenario analyses. The committee agreed that the generalised F‑distribution was suitable and gave the most appropriate estimate of long-term disease-free survival.
## People who are free from cancer at 5 years are unlikely to have recurrence and can be considered 'cured'
In its base case, the company assumed that all patients who were alive and disease free at 3 years were 'cured' of cancer, that is, it would not recur. After 3 years, people in the disease-free health state were modelled with the same mortality risk as the general population. The 3‑year cure assumption was based on results from CheckMate‑577, which showed a low risk of recurrence after 2 years, and clinical advice given to the company. The clinical experts explained that the Kaplan–Meier curves from CheckMate‑577 showed a plateau at around 36 months, suggesting that few relapses happened after 3 years. So, this was a reasonable cure point assumption. The ERG preferred a 'cure' point at 5 years disease-free survival, noting that some disease recurrence happened after 3 years and that a longer duration before assuming cure was more plausible. The company highlighted the low frequency of events after 3 years. However, the committee considered that although a precise 'cure' point was uncertain, it had concerns about applying a 3‑year cure point and preferred the ERG's 5‑year assumption. It concluded that a cure point at 5 years was plausible.
## The mortality rate of people who are 'cured' of cancer is likely to be higher than that of the general population
In both the company and ERG base case the cure point assumes that all patients who are alive and disease free at that time have 'cured' cancer and have the same mortality rate as the general population. This indicated not just no recurrence, but also that the quality of life and life expectancy would then be the same as a person who had not had the disease. The committee recalled that nivolumab treatment would involve chemoradiotherapy, major surgery and immunotherapy. In addition, there were risk factors that can pre‑dispose people to oesophageal cancer, which may increase background mortality rates. The patient expert explained that there are health consequences associated with a trimodal treatment pathway (chemoradiotherapy and surgery) followed by nivolumab. For example, fatigue and nutritional issues are potential lasting effects from surgery and chemoradiotherapy. The patient expert highlighted that people define themselves as disease-free survivors rather than 'cured' because of these lasting effects. The company explained it had clinical advice that people can be considered disease free after resection, but the risk of death may not become the same as the general population for 3 to 5 years. The committee therefore considered a scenario analysis where the mortality rate of people who are 'cured' of cancer is higher than that of the general population. This was done by modelling survival using an uplifted general population mortality rate (standardised mortality ratio of 1.1). This meant the probability of death was increased by an arbitrary 10% for all patients aged 68 and over. The clinical experts explained that an increase in mortality was likely to be because of treatment effects experienced by patients. For instance, there may be an increased risk of heart disease and lung damage for people who have had chemoradiotherapy. The clinical experts agreed that there are background environmental and genetic factors and a 10% increase in mortality was reasonable and unlikely to be higher. However, implementing this increased mortality risk had a minimal effect on the incremental cost-effectiveness ratio (ICER). The committee agreed that the mortality rate of people who are 'cured' of cancer is likely to be higher than that of the general population. It concluded that that a standardised mortality ratio of 1.1 was arbitrary and may not capture all the long-term effects, but this did not have a significant effect on the cost-effectiveness results.
# Costs in the economic model
## It is appropriate to apply a dose modifier to reflect the 1-year stopping rule for nivolumab
In the economic model, the company originally assumed that clinicians would stop treatment with nivolumab after 1 year. This was in line with the CheckMate‑577 protocol and the summary of product characteristics. However, the ERG noted that the average time people had treatment in the clinical trial was 63 weeks so costs could have been underestimated in the model. Clinical experts confirmed that in clinical practice, they would stop treatment with nivolumab after 1 year or a maximum number of cycles in people whose disease had not recurred. The company and clinical experts explained that the additional time on treatment in the clinical trial was a result of dose delays and not people having additional treatment cycles. The clinical experts explained that allowing treatment up to 63 weeks in the model could overestimate costs. To align the benefit and time on treatment the company provided updated data from CheckMate‑577 after technical engagement and applied a dose modifier to the time on treatment in the model. This meant that the number of cycles were effectively capped to 1 year. The clinical lead for the Cancer Drugs Fund confirmed that a stopping rule would be implemented so that people would have 52 weeks' worth of treatment. An equivalent of 13, 4‑weekly treatment cycles could be implemented, and they explained that there is a lot of experience implementing this in clinical practice. The committee concluded that it was appropriate to apply a dose modifier to reflect the 1‑year stopping rule for nivolumab and align costs and benefits in the economic model.
# Cost-effectiveness estimates
## Nivolumab is cost effective compared with routine surveillance
The committee agreed that its preferred assumptions to compare nivolumab with routine surveillance included:
The generalised F‑distribution to model disease-free survival in the nivolumab and routine surveillance arms.
An average age of 62.66 years for people included in the economic model.
General population utility and post-recurrence utility adjusted for age using the Ara and Brazier adjustment factor.
A dose modifier to represent the 1‑year stopping rule.
People in the disease-free state have no further risk of disease recurrence after 5 years.
A standardised mortality ratio of 1.1 to reflect the mortality rate of people who are 'cured' of cancer as higher than that of the general population after 5 years.The committee considered the ICER for both the ERG and company's base cases for nivolumab compared with routine surveillance, which differed only in the application of the 'cure' point. The committee noted that all estimates of cost effectiveness were less than £20,000 per quality-adjusted life year gained. It concluded that nivolumab is a cost-effective use of resources in the NHS compared with routine surveillance.
# Other factors
## Nivolumab is a step change for people with oesophageal or gastro-oesophageal junction cancer, but the model captures all benefits
The company, clinical experts and patient experts stated that adjuvant nivolumab represents a step change in treatment for people with oesophageal or gastro‑oesophageal junction cancer and that there is high unmet need for this population. The committee recalled that there are currently no active treatments available for this population. The company and clinical experts explained that treatment with nivolumab was well tolerated, would be beneficial to wellbeing, and would improve clinical outcomes. The committee noted that the treatment could be curative in some people, which would transform their quality of life. It concluded that nivolumab is a step change for people with oesophageal or gastro‑oesophageal junction cancer, but all the benefits are captured in the cost-effectiveness estimates.
# Conclusion
## Nivolumab is recommended for routine commissioning
The committee agreed that the most plausible ICERs for nivolumab compared with current standard care were within what NICE normally considers to be an acceptable use of NHS resources. It therefore concluded that it could recommend nivolumab for the adjuvant treatment of completely resected oesophageal or gastro‑oesophageal junction cancer in adults who have residual disease after neoadjuvant chemoradiotherapy.
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{'Recommendations': 'Nivolumab is recommended, within its marketing authorisation, for adjuvant treatment of completely resected oesophageal or gastro‑oesophageal junction cancer in adults who have residual disease after previous neoadjuvant chemoradiotherapy. It is recommended only if the company provides nivolumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThe most common treatment for oesophageal or gastro‑oesophageal junction cancer is neoadjuvant chemoradiotherapy then surgery. Treatment choice depends on various factors including histology, tumour size and location, patient preference and treatment suitability.\n\nClinical trial evidence shows that after trimodal therapy (chemoradiotherapy and surgery), nivolumab increases how long people live without the cancer returning compared with standard care, which is surveillance alone. Nivolumab is also likely to be more effective at extending how long people live, but clinical trial evidence is not yet available.\n\nThe cost-effectiveness estimates are within what NICE normally considers an acceptable use of NHS resources, so nivolumab is recommended.', 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol Myers Squibb) as monotherapy is indicated for 'the adjuvant treatment of adult patients with completely resected oesophageal or gastro‑oesophageal junction cancer who have residual pathologic disease following prior neoadjuvant chemoradiotherapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nNivolumab is available in 3\xa0different sizes as a concentrate for solution for infusion vials. The cost varies according to vial size: £439 (40\xa0mg per 4\xa0ml), £1,097 (100\xa0mg per 10\xa0ml) and £2,633 (240\xa0mg per 24\xa0ml; excluding VAT; BNF online, accessed August\xa02021). The cost for 1\xa0dose of treatment is £2,633 (240\xa0mg per 24\xa0ml).\n\nThe company has a commercial arrangement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that 3\xa0issues were resolved during the technical engagement stage, and agreed that:\n\nThe generalised F‑distribution should be used to model disease-free survival in the nivolumab and routine surveillance arms.\n\nThe average age of people included in the economic model should be 62.66\xa0years. The company provided adjusted CheckMate‑577 data that reflected the age distribution of people with oesophageal cancer who had chemoradiotherapy and surgical resection in the NHS.\n\nGeneral population utility and post-recurrence utility should be adjusted for age using the Ara and Brazier adjustment factor. The company provided updated inputs for the economic model that amended an error causing utilities for the disease-free and recurred-disease health states to be equal after 75\xa0years.\n\nThe committee recognised that there were 2\xa0remaining areas of uncertainty associated with the 'cure' point and costs of treatment. It took these into account in its decision making.\n\n# The condition\n\n## There is high unmet need for adjuvant treatments in this area\n\nOesophageal cancer is a malignant tumour of cells lining the oesophagus. The 2\xa0main types are squamous cell carcinoma and adenocarcinoma. Squamous cell carcinoma usually affects the upper and middle oesophagus. Adenocarcinoma is more common in the UK and usually affects the lower oesophagus, including the gastro‑oesophageal junction. Early symptoms may be vague, subtle and similar to benign conditions, which can result in late diagnosis and a poor prognosis. Clinical experts highlighted that the aim of treatment is to cure disease, but recurrence occurs for around 50% to 60% of people who have residual disease after chemoradiotherapy. The patient expert explained that people have ongoing fear because of a lack of available active treatments after surgery, which affects mental wellbeing and quality of life. The committee concluded that there is an unmet need for active treatments for this condition, and that these would have physical and psychological benefits.\n\n# Treatment pathway\n\n## There is variation in current practice but the nivolumab marketing authorisation includes a specific population\n\nCurrent standard care for oesophageal or gastro‑oesophageal junction cancer depends on clinical evidence, histology and the patient's informed preferences. Clinical experts explained that most people who have squamous cell carcinoma have chemoradiotherapy then surgery. But a proportion of people have definitive chemoradiotherapy alone with no surgery, which is considered to be broadly equivalent. People who have adenocarcinoma may have either neoadjuvant chemoradiotherapy then surgery or perioperative FLOT (fluorouracil, folinic acid, oxaliplatin, docetaxel) chemotherapy. The clinical trial inclusion criteria included adults with oesophageal or gastro‑oesophageal junction cancer who had neoadjuvant chemoradiotherapy and complete surgical resection with clear margins, but residual pathologic disease was present in the removed surgical specimen. The company indicated that the marketing authorisation corresponds with these criteria and people who have treatment with FLOT are not included. The clinical experts explained that this was a specific population who were identifiable in clinical practice in the NHS. They noted that over 80% of people have complete resection after chemoradiotherapy. Also, in the CROSS trial comparing neoadjuvant chemoradiotherapy plus surgery with surgery alone for oesophageal or gastro‑oesophageal junction cancer, 92% of people who had chemoradiotherapy plus surgery had a complete resection. However, they explained that the presence of detectable residual disease in the surgical specimen depended on histology, with residual disease more likely in those with adenocarcinoma than squamous cancer. The committee can only appraise a technology within its licensed indication and the evidence supporting this appraisal was from a single clinical trial with a specific population, in line with the marketing authorisation. This means people who have had other treatments such as chemotherapy alone, or definitive chemoradiotherapy (with no surgery) are outside the scope of this appraisal. The committee concluded that people with completely resected oesophageal or gastro‑oesophageal junction cancer who have residual pathologic disease after neoadjuvant chemoradiotherapy would be the population considered in this appraisal, based on the clinical evidence available.\n\n## Evidence is only available for people who had surgical treatment in line with the CheckMate-577 trial protocol\n\nThe committee was aware that a proportion of people have definitive chemoradiotherapy with no pre-planned surgery, but could later have salvage resection. The clinical experts explained that there are 2\xa0populations who might have delayed surgery in clinical practice. One population includes people in whom there is no intention to operate as part of the primary treatment, but resection is done if the cancer recurs. The committee noted that this population was different to the population included in the marketing authorisation and agreed it could not be considered for adjuvant nivolumab treatment. The second population are those in whom there is thought to be a high surgical risk. In those cases, definitive chemoradiotherapy may be used first to avoid surgery, followed by an early assessment after 2\xa0or 3\xa0months. Primary salvage resection is then done if residual disease is found. The clinical lead for the Cancer Drugs Fund explained that primary salvage resection may have been allowed in the clinical trial if the window of time between chemoradiotherapy and resection covered the 2- to 3‑month assessment point. The committee agreed that only people who had salvage resection within the window included in the trial protocol could be considered equivalent and would be eligible for treatment with adjuvant nivolumab.\n\n# Clinical evidence\n\n## CheckMate-577 is generalisable to current clinical practice in the NHS\n\nClinical evidence was based on CheckMate‑577, a phase\xa03, multicentre, randomised, double-blind, placebo-controlled trial that included a very small number of people from the UK. It compared nivolumab monotherapy with placebo. The committee noted that baseline characteristics were well balanced between arms. But the ERG advised that there were several differences between the population in CheckMate‑577 and the population in the NHS:\n\nThe average age in the full population was 62, which is younger than in the NHS.\n\nThe proportion of men was higher in the trial than in the NHS.\n\nThe proportion of different ethnicities in the trial was likely to be different to those seen in the NHS.The patient expert explained that younger people and more women are now being seen in clinical practice. The clinical experts agreed but noted that these demographic changes were unlikely to be reflected in current clinical trials and that differences in age, sex and ethnicity were unlikely to affect the clinical efficacy of nivolumab. On balance they considered the trial to be generalisable to the NHS and also agreed that the distribution of histology in the trial reflected the population seen in the NHS. The committee concluded that data from the CheckMate‑577 trial was generalisable to the NHS and could be used for the clinical-effectiveness analyses.\n\n## Nivolumab is clinically effective and extends disease-free survival compared with placebo\n\nThe primary outcome in the CheckMate‑577 trial is disease-free survival. The February\xa02021 data cut showed that nivolumab increased disease-free survival compared with placebo (hazard ratio 0.67, 96% confidence interval 0.55\xa0to 0.81). The median disease-free survival in people who had nivolumab was 22.4\xa0months and 10.4\xa0months with placebo. Results for overall survival are not yet available. The clinical lead for the Cancer Drugs Fund and clinical experts agreed that the disease-free survival Kaplan–Meier data showed a clear separation between the curves. This shows that more people were disease-free who had nivolumab than those who had placebo. The clinical expert also noted that this data showed that some people are likely to never have disease recurrence, and that this proportion is higher for those who had nivolumab. The committee concluded that, based on the CheckMate‑577 results, adjuvant nivolumab is clinically effective and extends disease-free survival compared with placebo.\n\n## Disease-free survival is a reasonable outcome to consider for modelling because of the extended follow up\n\nThe committee was aware that the company used disease-free survival results in the economic model because no overall survival data was available. The company explained that overall survival was a secondary end point in the clinical trial, which was event driven. The data remained immature and so the company did not yet have access to the overall survival data and remained blinded to the results. The company assumed a benefit for overall survival (assuming that if the disease recurred there would be equal mortality for those who had placebo or nivolumab). Both the clinical experts and clinical lead for the Cancer Drugs Fund had agreed that the disease-free survival benefit shown for nivolumab was compelling. Assuming an overall survival benefit based on a surrogate end point, in this case disease-free survival, is uncertain. The committee was aware this has been subject to much debate in previous appraisals, in some of which surrogate outcomes had proven unreliable. However, the ERG noted that the evidence in these cases came from highly heterogeneous populations and had short follow ups. So, it did not reflect the data available for CheckMate‑577, where at least 44\xa0months of follow up was available for disease-free survival, which is close to the time point the ERG considered reasonable to assume a 'cure'. The committee agreed that given the extended follow up this was a suitable outcome to use for modelling survival and that the assumption of overall survival benefit was reasonable.\n\n## Nivolumab may be more effective for people who have squamous cell carcinoma, but it is beneficial regardless of histology\n\nThe committee considered the subgroup results from CheckMate‑577. The latest results are considered confidential and cannot be reported here. The committee was aware that the trial was not powered to test for statistical significance of an interaction between treatment and subgroups. But the results showed that nivolumab appeared more effective in squamous cell carcinoma than adenocarcinoma. The clinical experts advised that survival curves from the CROSS trial suggested that people who have squamous cell carcinoma have better outcomes than those who have adenocarcinoma, based on current standard care, and that squamous cell carcinoma may respond better to treatment. However, both histological types appeared to benefit from adjuvant nivolumab. The company and ERG highlighted that, despite not being powered for subgroups, the results showed hazard ratios less than\xa01 for almost all pre‑specified subgroups. The committee concluded that nivolumab may be more effective for people who have squamous cell carcinoma, but it is beneficial regardless of histology.\n\n## Nivolumab is generally well tolerated and adverse events are included in the economic modelling\n\nIn CheckMate‑577 a similar number of people experienced adverse events in the nivolumab and placebo arms. The clinical experts highlighted in their written submissions that serious adverse events can happen after treatment with nivolumab that need additional management and monitoring. The clinical lead for the Cancer Drugs Fund explained that as there are now improved clinical systems to detect and treat immune-mediated toxicities of nivolumab, serious side effects are rarer than previously seen. The ERG and the company confirmed that all serious adverse events were considered in the economic modelling. The committee concluded that adverse events are adequately included in the economic modelling.\n\n# Cost effectiveness\n\n## The company's model is appropriate for decision making\n\nThe company presented a 3‑state semi‑Markov model to estimate the cost effectiveness of nivolumab compared with standard care. The 3\xa0health states were disease-free, recurrent disease and death. The company explained that a partitioned survival model was not possible because of unavailable overall survival data, but the semi‑Markov model allows dependency between events rather than using priori assumptions in traditional Markov models. The ERG agreed with this approach. The model cycle length was 1\xa0week, and the time horizon was 40\xa0years. No half-cycle correction was included in the model. The ERG noted that this was not a limitation because of the weekly time cycles used in the model. The committee had already concluded that disease-free survival was a suitable outcome given the extended follow up in CheckMate‑577. It recalled that the company assumed an overall survival benefit and equal deaths after recurrence. The ERG explained that the company used external data from Lou et al. to apply a mortality rate to both arms. The company had explored alternative assumptions and sensitivity analyses on this parameter that showed broadly similar results when applied to both arms. The committee concluded that the company's semi‑Markov model was suitable for decision making.\n\n# Survival extrapolations\n\n## The generalised F-distribution gives the most appropriate long-term estimate of disease-free survival\n\nIn its original submission the company modelled disease-free survival using a 1‑knot spline log-normal distribution. The ERG noted that the generalised F‑distribution had a better statistical fit to the trial data. More recent disease-free survival data became available from the CheckMate‑577 trial after the original submission data. Therefore, after technical engagement, the company updated its analysis to use the recent cut-off data (February\xa02021). In addition, the company updated the distribution used to model disease-free survival to a generalised F‑distribution because it provided the lowest AIC (Akaike's Information Criteria) and BIC (Bayesian Information Criteria) values. The company noted that the 1‑knot spline distribution remained plausible and provided results in scenario analyses. The committee agreed that the generalised F‑distribution was suitable and gave the most appropriate estimate of long-term disease-free survival.\n\n## People who are free from cancer at 5\xa0years are unlikely to have recurrence and can be considered 'cured'\n\nIn its base case, the company assumed that all patients who were alive and disease free at 3\xa0years were 'cured' of cancer, that is, it would not recur. After 3\xa0years, people in the disease-free health state were modelled with the same mortality risk as the general population. The 3‑year cure assumption was based on results from CheckMate‑577, which showed a low risk of recurrence after 2\xa0years, and clinical advice given to the company. The clinical experts explained that the Kaplan–Meier curves from CheckMate‑577 showed a plateau at around 36\xa0months, suggesting that few relapses happened after 3\xa0years. So, this was a reasonable cure point assumption. The ERG preferred a 'cure' point at 5\xa0years disease-free survival, noting that some disease recurrence happened after 3\xa0years and that a longer duration before assuming cure was more plausible. The company highlighted the low frequency of events after 3\xa0years. However, the committee considered that although a precise 'cure' point was uncertain, it had concerns about applying a 3‑year cure point and preferred the ERG's 5‑year assumption. It concluded that a cure point at 5\xa0years was plausible.\n\n## The mortality rate of people who are 'cured' of cancer is likely to be higher than that of the general population\n\nIn both the company and ERG base case the cure point assumes that all patients who are alive and disease free at that time have 'cured' cancer and have the same mortality rate as the general population. This indicated not just no recurrence, but also that the quality of life and life expectancy would then be the same as a person who had not had the disease. The committee recalled that nivolumab treatment would involve chemoradiotherapy, major surgery and immunotherapy. In addition, there were risk factors that can pre‑dispose people to oesophageal cancer, which may increase background mortality rates. The patient expert explained that there are health consequences associated with a trimodal treatment pathway (chemoradiotherapy and surgery) followed by nivolumab. For example, fatigue and nutritional issues are potential lasting effects from surgery and chemoradiotherapy. The patient expert highlighted that people define themselves as disease-free survivors rather than 'cured' because of these lasting effects. The company explained it had clinical advice that people can be considered disease free after resection, but the risk of death may not become the same as the general population for 3\xa0to 5\xa0years. The committee therefore considered a scenario analysis where the mortality rate of people who are 'cured' of cancer is higher than that of the general population. This was done by modelling survival using an uplifted general population mortality rate (standardised mortality ratio of 1.1). This meant the probability of death was increased by an arbitrary 10% for all patients aged\xa068 and over. The clinical experts explained that an increase in mortality was likely to be because of treatment effects experienced by patients. For instance, there may be an increased risk of heart disease and lung damage for people who have had chemoradiotherapy. The clinical experts agreed that there are background environmental and genetic factors and a 10% increase in mortality was reasonable and unlikely to be higher. However, implementing this increased mortality risk had a minimal effect on the incremental cost-effectiveness ratio (ICER). The committee agreed that the mortality rate of people who are 'cured' of cancer is likely to be higher than that of the general population. It concluded that that a standardised mortality ratio of 1.1 was arbitrary and may not capture all the long-term effects, but this did not have a significant effect on the cost-effectiveness results.\n\n# Costs in the economic model\n\n## It is appropriate to apply a dose modifier to reflect the 1-year stopping rule for nivolumab\n\nIn the economic model, the company originally assumed that clinicians would stop treatment with nivolumab after 1\xa0year. This was in line with the CheckMate‑577 protocol and the summary of product characteristics. However, the ERG noted that the average time people had treatment in the clinical trial was 63\xa0weeks so costs could have been underestimated in the model. Clinical experts confirmed that in clinical practice, they would stop treatment with nivolumab after 1\xa0year or a maximum number of cycles in people whose disease had not recurred. The company and clinical experts explained that the additional time on treatment in the clinical trial was a result of dose delays and not people having additional treatment cycles. The clinical experts explained that allowing treatment up to 63\xa0weeks in the model could overestimate costs. To align the benefit and time on treatment the company provided updated data from CheckMate‑577 after technical engagement and applied a dose modifier to the time on treatment in the model. This meant that the number of cycles were effectively capped to 1\xa0year. The clinical lead for the Cancer Drugs Fund confirmed that a stopping rule would be implemented so that people would have 52\xa0weeks' worth of treatment. An equivalent of 13, 4‑weekly treatment cycles could be implemented, and they explained that there is a lot of experience implementing this in clinical practice. The committee concluded that it was appropriate to apply a dose modifier to reflect the 1‑year stopping rule for nivolumab and align costs and benefits in the economic model.\n\n# Cost-effectiveness estimates\n\n## Nivolumab is cost effective compared with routine surveillance\n\nThe committee agreed that its preferred assumptions to compare nivolumab with routine surveillance included:\n\nThe generalised F‑distribution to model disease-free survival in the nivolumab and routine surveillance arms.\n\nAn average age of 62.66\xa0years for people included in the economic model.\n\nGeneral population utility and post-recurrence utility adjusted for age using the Ara and Brazier adjustment factor.\n\nA dose modifier to represent the 1‑year stopping rule.\n\nPeople in the disease-free state have no further risk of disease recurrence after 5\xa0years.\n\nA standardised mortality ratio of 1.1 to reflect the mortality rate of people who are 'cured' of cancer as higher than that of the general population after 5\xa0years.The committee considered the ICER for both the ERG and company's base cases for nivolumab compared with routine surveillance, which differed only in the application of the 'cure' point. The committee noted that all estimates of cost effectiveness were less than £20,000 per quality-adjusted life year gained. It concluded that nivolumab is a cost-effective use of resources in the NHS compared with routine surveillance.\n\n# Other factors\n\n## Nivolumab is a step change for people with oesophageal or gastro-oesophageal junction cancer, but the model captures all benefits\n\nThe company, clinical experts and patient experts stated that adjuvant nivolumab represents a step change in treatment for people with oesophageal or gastro‑oesophageal junction cancer and that there is high unmet need for this population. The committee recalled that there are currently no active treatments available for this population. The company and clinical experts explained that treatment with nivolumab was well tolerated, would be beneficial to wellbeing, and would improve clinical outcomes. The committee noted that the treatment could be curative in some people, which would transform their quality of life. It concluded that nivolumab is a step change for people with oesophageal or gastro‑oesophageal junction cancer, but all the benefits are captured in the cost-effectiveness estimates.\n\n# Conclusion\n\n## Nivolumab is recommended for routine commissioning\n\nThe committee agreed that the most plausible ICERs for nivolumab compared with current standard care were within what NICE normally considers to be an acceptable use of NHS resources. It therefore concluded that it could recommend nivolumab for the adjuvant treatment of completely resected oesophageal or gastro‑oesophageal junction cancer in adults who have residual disease after neoadjuvant chemoradiotherapy."}
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https://www.nice.org.uk/guidance/ta746
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Evidence-based recommendations on nivolumab (Opdivo) as a possible treatment for completely resected oesophageal or gastro‑oesophageal junction cancer in adults.
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f94e8a4a4726a48be0a0738b794de0753a34dc4a
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nice
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Nintedanib for treating progressive fibrosing interstitial lung diseases
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Nintedanib for treating progressive fibrosing interstitial lung diseases
Evidence-based recommendations on nintedanib for treating progressive fibrosing interstitial lung diseases in adults.
# Recommendations
Nintedanib is recommended, within its marketing authorisation, as an option for treating chronic progressive fibrosing interstitial lung diseases (PF‑ILD) in adults.
Why the committee made these recommendations
Current treatment for PF‑ILD often starts with immunosuppressants, which may or may not be continued when nintedanib is offered.
The clinical trial evidence suggests that nintedanib slows the decline of lung function compared with placebo. But, there are uncertainties in the evidence: it is unclear if nintedanib helps people to live longer, and the trial reflects how nintedanib would be used in the NHS in some but not all people with PF‑ILD.
Because follow up was short in the trial for nintedanib in PF‑ILD, the economic model uses longer follow-up data from nintedanib trials in idiopathic pulmonary fibrosis, a related condition that progresses in a similar way. This allows better modelling of nintedanib's long-term effect on life expectancy. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. So, nintedanib is recommended.# Information about nintedanib
# Marketing authorisation indication
Nintedanib (Ofev, Boehringer Ingelheim) is indicated in adults for the treatment of chronic fibrosing interstitial lung diseases with a progressive phenotype.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price of nintedanib is £2,151.10 per pack of 60 capsules, each containing 150 mg (excluding VAT; BNF online accessed July 2021). The company has a commercial arrangement. This makes nintedanib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Boehringer Ingelheim, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Nature of the condition
## Progressive fibrosing interstitial lung disease is a debilitating condition that increases the risk of dying
Interstitial lung disease (ILD) encompasses a large and varied group of lung disorders characterised by inflammation and fibrosis of the lung parenchyma. Idiopathic pulmonary fibrosis is one of the most common types of ILD and NICE has recommended nintedanib (see NICE's technology appraisal guidance on nintedanib for treating idiopathic pulmonary fibrosis, from now on referred to as TA379) and pirfenidone for its treatment (see NICE's technology appraisal guidance on pirfenidone for treating idiopathic pulmonary fibrosis, from now on referred to as TA504). Some ILDs progress and become fibrotic and are referred to as progressive fibrosing ILD (PF‑ILD). This appraisal addresses PF‑ILD excluding idiopathic pulmonary fibrosis. It also covers systemic sclerosis associated ILD (SSc-ILD) with the progressive fibrosing phenotype. Nintedanib has a separate marketing authorisation for SSc-ILD, which is outside the scope of this appraisal. Other types of PF‑ILD include, but are not limited to, idiopathic interstitial pneumonias, autoimmune ILDs, and hypersensitivity pneumonitis. People with PF‑ILD often have underlying systemic conditions such as rheumatoid arthritis or sarcoidosis. PF‑ILD is characterised by a gradual decline in lung function, breathlessness, worsening physical performance and quality of life, poor response to immunomodulatory therapies and mortality (Cottin et al. 2019). One patient expert explained that he understood that most people with cancer live longer than people with PF‑ILD and although the committee was not presented with these data, it appreciated that PF‑ILD increased the risk of dying. The patient expert explained that symptoms can evolve quickly and, within a short time, breathlessness limits physical activity. Ultimately, some people become housebound and depend on supplementary oxygen. The committee concluded that PF‑ILD is a debilitating condition that increases the risk of dying relative to the general population.
# Diagnosis and progression of PF‑ILD
## The key trial uses multiple criteria to diagnose PF‑ILD, which reflects NHS practice
Clinical experts explained that in the NHS, people with PF‑ILD are seen by different medical specialities, notably respiratory and rheumatology. Clinicians identify disease progression and fibrosis using multiple criteria. These include a relative decline of at least 10% on spirometry in forced vital capacity percentage (FVC%) predicted compared with pre-screening, based on algorithms adjusting for age, sex and height; worsening of fibrosis on CT scan; and respiratory symptoms. Clinical experts explained that these criteria are comparable to the diagnostic criteria of PF‑ILD in INBUILD, the company's main trial (see section 3.5). This trial included people who met 1 or more criteria despite treatment, including:
A relative decline in FVC% predicted of at least 10% predicted compared with pre-screening in the past 24 months.
A relative decline in FVC% predicted of at least 5% predicted, but less than 10% predicted, with worsening respiratory symptoms or increasing fibrotic changes on high-resolution chest imaging compared with pre-screening in the past 24 months.
Worsening respiratory symptoms and increasing fibrotic changes on high-resolution chest imaging in the past 24 months.The company estimates that there are nearly 900 people living with PF‑ILD in the UK. The committee understood that clinicians use multiple criteria to diagnose PF‑ILD in practice which are comparable to the key trial.
## A decline in FVC of at least 10% predicted defines progression and is associated with worsening disease and mortality
The committee was aware that a relative (Cottin et al. 2019) or absolute (Goos et al. 2021; Wong et al. 2020) decline in FVC of at least 10% predicted from baseline is one of the criteria that defines disease progression in PF‑ILD. The committee recognised that the company reported the trial results in difference between treatment groups in absolute FVC adjusted for baseline FVC and imaging pattern, whereas in its economic model, the company used a 10% absolute decline in FVC% predicted to categorise disease progression and health states (see section 3.12). In its first meeting, the committee requested details of this transformation. At consultation, the company presented the equation it used to estimate FVC% predicted from absolute FVC in millilitres accounting for ethnicity, age, and height (Quanjer et al. 2012). Evidence suggests that a decline in FVC% predicted is associated with worsening disease and mortality in idiopathic pulmonary fibrosis (Cottin et al. 2019) and, according to the clinical experts, also in PF‑ILD. The committee concluded that a relative or absolute decline of at least 10% predicted in FVC is an acceptable criterion for disease progression and is associated with higher risk of death in PF‑ILD.
# The company's positioning of nintedanib
## The company's positioning of nintedanib as an add-on treatment that will be stopped if disease progression is not slowed is appropriate
Current treatment of PF‑ILD in the NHS includes treatments for the underlying disease (see section 3.1) including, but not limited to, systemic corticosteroids, mycophenolate mofetil, azathioprine, cyclophosphamide, methotrexate, rituximab, infliximab and best supportive care. The company explained that these treatments do not have marketing authorisations for PF‑ILD. However, the committee was aware that NICE's guide to the methods of technology appraisal, permits it to consider unlicensed treatments as part of standard care and if relevant, as comparators if their use in clinical practice is established. The clinical and patient experts noted that treatments for PF‑ILD treat the inflammation rather than the fibrosis, and that immunosuppressants are used for the underlying autoimmune diseases. They explained that there are no trials that suggest that these treatments delay progression of chronic fibrosis in PF‑ILD. Clinical experts explained that while they stop treatments that have not slowed the decline of pulmonary function, they would not stop drugs that treat the underlying condition. The committee understood that clinical experts would stop nintedanib if disease progression was not sufficiently slowed. The committee concluded that, if recommended, nintedanib would be an add-on treatment rather than a direct comparator to conventional treatments that may or may not be continued when adding nintedanib. The committee appreciated that the company did not model a formal stopping rule because clinicians would stop treatment with nintedanib if they deemed that it was not effective. The committee concluded that the company's positioning of nintedanib, as an add-on treatment to standard care when ILD has progressed despite conventional treatments, is appropriate. The committee also agreed that nintedanib would be stopped if disease progression was not markedly slowed.
## The baseline characteristics of the INBUILD population are generalisable to the NHS
INBUILD was a phase 3, randomised, multicentre trial comparing nintedanib (n=332) with placebo (n=331) in people with PF‑ILD. Clinical experts noted that the criteria for disease progression for entry into INBUILD (see section 3.2) are in line with NHS practice. INBUILD included 22 participants from the UK. The trial consisted of 2 parts: Part A, the main part of the trial, had a follow up of 52 weeks; and Part B, in which patients continued blinded, randomised treatment beyond week 52. The trial continued until all patients reached their week-52 visit or withdrew. Patients had different durations of treatment in Part B. Those who stopped study treatments were asked to attend all visits as originally planned. The company performed 2 database locks: database lock 1 occurred after the last participant had completed the week-52 visit, and database lock 2 (median follow up about 19 months; Brown et al. 2020) after all patients had completed the follow-up visit, about 3 months after finishing Part A. The company chose database lock 2 to inform the economic model. An extension study, INBUILD-ON (n=434, completed), offered open-label nintedanib to participants who the investigator deemed would benefit. The clinical experts noted that age, sex, and decline in lung function of INBUILD participants reflected NHS patients. The committee concluded that these baseline characteristics of the INBUILD population were representative of NHS patients.
## Concurrent treatments in INBUILD reflect current NHS care for some, but not all, patients
The committee was aware that people in the INBUILD trial could not have immunosuppressants other than up to 20 mg per day of oral corticosteroids (see section 3.4) at randomisation and for the first 6 months or unless they underwent a wash-out period 4 weeks to 8 weeks before randomisation. After the first 6 months and for the rest of the 52-week period, patients with worsening ILD or connective tissue disease could have immunosuppressants. During this time, approximately 16% of patients started immunosuppressants (21% in the placebo arm and 11% in the nintedanib arm). The committee interpreted this as showing that some participants needed treatments that the protocol restricted earlier in the trial. The committee was aware that the NICE scope listed established clinical management of PF‑ILD as azathioprine, cyclophosphamide, mycophenalate, corticosteroids, infliximab, rituximab, and best supportive care. The ERG noted that immunosuppressants are not restricted in clinical practice and that the trial population therefore does not reflect NHS clinical practice. The committee concluded that the INBUILD trial, which restricted concurrent medications, reflects NHS clinical practice in some, but not all people, with PF‑ILD.
## Placebo is an appropriate comparator for NHS clinical practice
The committee appreciated that the INBUILD trial was a placebo-controlled trial. The committee was aware that the NICE scope listed the comparators as established clinical management without nintedanib. The committee considered nintedanib to be an add-on treatment (see section 3.4) and concluded that placebo was the appropriate comparator for the decision problem and NHS clinical practice.
# Clinical effectiveness
## Nintedanib is associated with a slower decline of lung function compared with placebo, but its long-term treatment effect is uncertain
The primary endpoint of INBUILD (see section 3.5) was annual rate of decline in FVC (in millilitres per year) over 52 weeks analysed as the change in absolute FVC in millilitres using a random coefficient regression model, with baseline FVC and imaging pattern as covariates. The analysis included people who had discontinued treatment (see section 3.5). Results from adjusted annual rate of decline in FVC showed that:
Over 52 weeks, the decline in lung function differed between the nintedanib (-80.8 ml/year) and placebo (-187.8 ml/year) arms (alpha level=0.05 ) by 107.0 ml/year (95% confidence interval 65.4 to 148.5; p<0.001). The corresponding results on decline in FVC% predicted showed that nintedanib was associated with a slower decline in FVC% predicted from baseline (-2.6%) compared with placebo (-5.9%) at week 52 (mean difference: 3.2%; 95% CI 2.09 to 4.40). At consultation, the company reported that the minimum clinically meaningful difference for decline in FVC% predicted could be 2% to 6% in people with idiopathic pulmonary fibrosis according to Bois et al. (2011). Also at consultation, stakeholders explained that a difference of 107 ml in decline of FVC is significant in clinical practice.
After 52 weeks, the difference in adjusted annual rate of decline in FVC between nintedanib and placebo narrowed. The committee noted that the data suggests a waning effect of nintedanib in the long term, or effect modification by concurrent medications added after the first 6 months of the trial (see section 3.6). The company disputed this and explained that the results reflected different durations of treatment that patients had in Part B of the trial and missing FVC values. The company considered that the analysis that incorporated data from Part B that it used in its model, should be 'interpreted with caution' and had 'methodological limitations'. In the company's view, this included the possibility of 'healthy survivor bias' because patients in the nintedanib arm stopped treatment because of adverse events while those in the placebo arm stopped treatment because of lack of effect. However, the ERG and committee appreciated that the company did not present data to support this. The committee also appreciated the limitations of INBUILD in measuring the effect of long-term treatment but recalled that the company chose the timepoint of database lock 2 to inform its economic model (see section 3.5). The committee concluded that there was uncertainty in nintedanib's long-term treatment effect and that it would account for this in its decision making.
## Effect modification by concurrent treatment remains uncertain
The committee questioned whether the treatment effect of nintedanib without concurrent conventional treatments, as in INBUILD, would be the same as with them. During the committee's second meeting, the company presented a post-hoc analysis of the treatment effect of nintedanib on adjusted annual rate of decline in FVC in the whole INBUILD population compared with the subgroup of patients who did not receive concurrent conventional treatments . The committee concluded that comparing a subgroup with the whole population (including the subgroup) was not a statistically meaningful comparison and that the subgroup used did not reflect NHS practice. The company presented another post-hoc analysis from INBUILD suggesting that there was no difference in the treatment effect of nintedanib between patients receiving or not receiving glucocorticoids at baseline (interaction p=0.18). The committee was aware that 70.1% in the placebo arm and 67.2% in the nintedanib arm used prednisolone over the 52-week period in INBUIILD. The committee concluded that it did not see evidence of an interaction, but could not discount the possibility that effect modification exists.
## Nintedanib's treatment effect on mortality is uncertain
Secondary endpoints assessed in INBUILD included overall survival, change from baseline in the score for the King's Brief Interstitial Lung Disease (K-BILD) questionnaire (a health-related quality-of-life measure) and time until first acute exacerbation of ILD or death. Other endpoints included the EQ-5D questionnaire and safety. Endpoints were collected at 52 weeks and at database lock 2 (see section3.5). Results showed that:
The hazard ratio (HR) for death for people randomised to nintedanib (4.8%; n=16 of 332) compared with people randomised to placebo (5.1%; 17 of 331) at 52 weeks was 0.94 (95% CI 0.47 to 1.86; p=0.85). The HR for death for nintedanib (10.8%; 36 of 332) compared with placebo (13.6%; 45 of 331) at database lock 2 was 0.78 (95% CI 0.50 to 1.21; p value not reported). Median overall survival was not reached because of a low number of events. The committee noted the wide confidence intervals.
Absolute change from baseline in total score on K-BILD showed no statistically significant difference at a 5% alpha between nintedanib (adjusted mean: 0.55) and placebo (adjusted mean: -0.79) arms at 52 weeks; adjusted mean difference: 1.34; 95% CI -0.31 to 2.98; p=0.1115.
Results for time to first acute ILD exacerbation or death for nintedanib (7.8%, 26 of 332) and placebo (9.7%, 32 of 331) arms up to 52 weeks were HR 0.80; 95% CI 0.48 to 1.34; p=0.3948. At database lock 2, 13.9% (46 of 332) and 19.6% (65 of 331) of patients in nintedanib and placebo arms experienced an event (HR 0.67; 95% CI 0.46 to 0.98). The committee noted that this composite endpoint did not specifically inform the risk of exacerbation associated with nintedanib, which the company included in its model. It was aware that occurrence of exacerbation can increase the risk of death in PF‑ILD (see section 3.13) and agreed that it would have been helpful to have data on this.The committee was aware that the trial was not powered to detect a difference in mortality. It concluded that the data from INBUILD did not show conclusively that nintedanib prolongs life.
# Adverse events
## The adverse event profile of nintedanib is acceptable
In INBUILD at 52 weeks, the nintedanib and placebo arms showed similar frequencies of any adverse event and of serious adverse events based on on-treatment analyses. Gastrointestinal discomfort, especially diarrhoea, was the most common adverse event (66.9% in the nintedanib arm compared with 23.9% in the placebo arm). People taking nintedanib were more likely to have raised biochemical serum markers of hepatic injury and were more likely to reduce the dose of nintedanib because of gastrointestinal symptoms. Based on their observations, the clinical experts explained that 25% to 30% of people may not tolerate nintedanib. They noted that nintedanib is not associated with an increased risk of infection unlike immunosuppressants. The committee concluded that the safety profile of nintedanib was acceptable.
# Economic model
## The model structure is acceptable for decision making, but there are important uncertainties in its assumptions
To model the natural history of PF‑ILD beyond the end of the trial, the company assumed that idiopathic pulmonary fibrosis and PF‑ILD have a similar natural history of disease. The company adopted the same Markov model structure it had used in TA379. In the model, patients accrue quality-adjusted life years (QALYs) by improving both quality and length of life. The company assumed in its model that nintedanib improves the quality of life because patients experience fewer exacerbations, and their lung function declines more slowly. The company defined health states using lung function (10%-point categorisations of FVC% predicted) and rates of exacerbation over a cycle length of 3 months in the model. Patients enter the model at different lung-function health states assuming they have not yet had an exacerbation. They can then remain in the same health state, have an exacerbation and transition to a health state with the same lung function or move to health state with a lower lung function, or not have an exacerbation and transition to health states characterised by a lower FVC% predicted, or die. The company defined the health states to reflect a clinically meaningful decline in FVC% predicted (see section 3.7). The health state in which a patient starts reflects the distribution of patients at randomisation in INBUILD.
The company used the data from database lock 2 of INBUILD to inform the model parameters including overall survival, time to first acute exacerbation, loss of lung function, stopping treatment, utility values and costs. The company estimated transition probabilities of mortality on parametric extrapolations (Bayesian approach) of overall survival data from INBUILD and applied irrespective of health states or model events with the exception of a FVC% predicted below 40% (see section 3.15 and section 3.16). The company fitted standard parametric models to extrapolate the risk of time to first exacerbation (see section 3.24), and calculated the probabilities of losing lung function in the 2 treatment arms using 2 different methods (see section 3.25). The committee was aware that the modelled FVC% predicted was transformed from the absolute decline in FVC controlled for baseline FVC and imaging, the primary endpoint of INBUILD (see section 3.3). The company assumed that patients could not transition to a health state with better lung function. After an exacerbation, patients could not transition to a health state without exacerbation for the rest of the time horizon. Transition to death can either happen from any health state, but does not differ by health state; it is based on a survival analysis using the INBUILD data, or by reaching a level of FVC% predicted below 40%, at which the company assumed that lung function is unsustainable. Although there were 2 routes to death in the model, the ERG noted that the company modelled mortality based only on overall survival data from INBUILD. This means that mortality is independently modelled from lung function and that the same risk of death is applied to all health states. The committee recalled that a lower level of lung function was strongly associated with a higher mortality rate (see section 3.3) and questioned the company on why it did not model a change in risk of death as a function of FVC percent predicted. The company explained that this was to avoid double counting as the overall survival data includes all deaths. The company also modelled mortality independently from acute exacerbations, despite it stating that acute exacerbations may be fatal and a cause of mortality in PF‑ILD.
The ERG did not change any of the company's modelling assumptions. It noted that modelling mortality independently from lung-function decline and acute exacerbations can produce implausible results in relation to stopping treatment in the model. The committee understood that the way the company modelled mortality meant that modifying assumptions around the rate at which people stop treatment with nintedanib or placebo (see section 3.28), exacerbation rates (see section 3.24), and decline in lung function (see section 3.25) have minimal impact on cost effectiveness. At consultation, the company considered changing the structure of the model to include a link between mortality and exacerbations and decline in lung function. However, the company stated that the adapted model produced increased and unrealistic life years for both placebo and nintedanib compared with the current model. It considered this was because of the uncertainty with separate risks of death for each modelled health state. The committee was aware that mortality data from INBUILD showed no clear difference in mortality between treatments (see section 3.10). The committee concluded that there are important uncertainties in the model structure and limitations when implementing it.
## The company used frequentist and Bayesian approaches to extrapolate overall survival
The company used 2 approaches to extrapolate overall survival for people with PF‑ILD beyond the trial duration: a frequentist method and a Bayesian analysis.
The frequentist approach involved fitting standard parametric distributions independently to each arm of INBUILD. The study included people with PF‑ILD only. The company considered that the best fitting curves for the observed data had the best statistical fits (lower Akaike information criterion /Bayesian information criterion scores). These were log-logistic, Gompertz and Weibull curves. The committee appreciated that considerable uncertainty exists given the immaturity of the survival data with some 90% of the population alive after database lock 2 (see section 3.10).
The company extrapolated overall survival using a Bayesian approach by combining short-term data on PF‑ILD from INBUILD (median 19 months) with longer-term data from clinical trials of idiopathic pulmonary fibrosis (up to median 56.3 months for nintedanib arm, but a median of only up to 13.1 months for placebo). The company assumed PF‑ILD and idiopathic pulmonary fibrosis have similar disease trajectories including death, based on evidence from Brown et al. (2020) and Simpson et al. (2020). In general, the company used data from trials of idiopathic pulmonary fibrosis and matched participants from these trials to participants with PF‑ILD in INBUILD based on characteristics that might be associated with survival. The company then fitted survival curves to matched patients with idiopathic pulmonary fibrosis to inform the shape parameter of the survival curves for PF‑ILD in the model. This specifically involved:
Obtaining data on idiopathic pulmonary fibrosis by combining several trials of idiopathic pulmonary fibrosis, including: TOMORROW, a phase 2 trial; INPULSIS I and II, 2 phase 3 randomised control trials (RCTs); and INPULSIS ON, a combined long-term extension of the 2 RCTs.
Matching patients with idiopathic pulmonary fibrosis (from the combined idiopathic pulmonary fibrosis trials) to PF‑ILD patients (from INBUILD) on chosen baseline characteristics using a propensity score weighting method. They included age, sex, ethnicity, duration of disease, FVC% predicted at baseline and smoking.
Generating survival curves for the matched idiopathic pulmonary fibrosis patients. The company then fitted parametric survival curves to the matched idiopathic pulmonary fibrosis data for both nintedanib and placebo arms and selected models with the lowest AIC and BIC.
Generating an informative prior from parametric survival curves for idiopathic pulmonary fibrosis and generating survival curves for PF‑ILD. For the selected parametric survival curves for idiopathic pulmonary fibrosis, the company retained the shape parameters as the informative prior for nintedanib and placebo. Using these informative priors, the company fitted parametric models to the INBUILD trial data. The company considered the 3 best fitting curves to be Weibull, log-logistic and gamma distributions.
Validating the 3 best fitting curves by seeking clinicians' advice and comparing survival curves with external registry data on idiopathic pulmonary fibrosis. Based on this, the company considered that the Bayesian approach, by using data from clinical trials of idiopathic pulmonary fibrosis and a Weibull model, better estimated long-term survival than the frequentist approach. The company adopted Weibull Bayesian curves for both nintedanib and placebo arms in its base case. The committee appreciated the company's approach using longer-term trial data from a related disease, but noted it was not without uncertainty. Given the absence of long-term data in PF‑ILD, the committee concluded that the Bayesian approach itself was reasonable to model overall survival, but that uncertainties exist.
## It is reasonable to consider that idiopathic pulmonary fibrosis and PF‑ILD share similar disease trajectories
In using a Bayesian approach, the company assumed that PF‑ILD and idiopathic pulmonary fibrosis have similar disease trajectories for death (see section 3.16). The committee was aware that PF‑ILD and idiopathic pulmonary fibrosis may share features and natural history but questioned how valid it was to assume similar survival. The company explained that it based this assumption on 2 sources. The first, Brown et al. (2020), an observational study assessing the clinical course of PF‑ILD and idiopathic pulmonary fibrosis, includes people randomised to placebo in the INBUILD trial (PF‑ILD,) and INPULSIS trials (idiopathic pulmonary fibrosis). The study, sponsored by the manufacturer, reported death rates at 52 weeks for PF‑ILD (5.1%, 17 of 331) and idiopathic pulmonary fibrosis (7.8%, 33 of 423). The committee was aware that the HR of 0.63 (95% CI 0.35 to 1.13) suggested the possibility of a lower rate of death for PF‑ILD than for idiopathic pulmonary fibrosis. The committee was aware that deaths were sparse, and that Brown et al. did not report what confounding factors were considered, and the possibility of residual confounding. Simpson et al. (2020), an observational study of PF‑ILD across the UK, included 2,368 people with a new referral for ILD and diagnosed with the same criteria for PF‑ILD as used in the INBUILD trial (see section 3.2). The study reports that people with PF‑ILD and people with idiopathic pulmonary fibrosis have similar survival at 900 days (HR 1.06; 95% CI 0.84 to 1.35). Additionally, it showed that the shapes of the survival curves between PF‑ILD and idiopathic pulmonary fibrosis were similar. The committee considered that the shape of the survival curve was more important than the reported crude HR when assuming similar disease trajectories. The committee concluded it was reasonable to assume a similar shape parameter for survival between PF‑ILD and idiopathic pulmonary fibrosis.
## Using registries of idiopathic pulmonary fibrosis to validate the survival extrapolations is a reasonable approach
The committee discussed the company's attempt to validate its choice of the Weibull overall survival curves based on Bayesian analyses for both nintedanib and placebo using clinical input and registry data for idiopathic pulmonary fibrosis. Clinicians consulted by the company noted that they had limited knowledge on long-term survival for people with PF‑ILD on nintedanib, but, for placebo, Weibull curves (based either on the frequentist or Bayesian approaches) were plausible. The company validated its choice using the following studies and registries for idiopathic pulmonary fibrosis:
Nintedanib: registry data from the EMPIRE study (Vasakova et al. 2013) and a Greek registry (Antoniou et al. 2020) that provided longer-term data on the effect of nintedanib. The EMPIRE study (n=637) provides approximately 10 years of follow up in people across Europe (excluding the UK) with idiopathic pulmonary fibrosis. The Greek registry (n=244) reports 5-year survival data in 244 people in Greece with idiopathic pulmonary fibrosis taking nintedanib (see section 3.19).
Standard care (placebo): Kaplan–Meier data from the treatment arms without anti-fibrotic drugs (nintedanib or pirfenidone) in the EMPIRE study, an Australian registry (Helen et al. 2016), a European registry (eurIPFreg, Guenther et al. 2018) including British patients, and a Finnish registry (Kaunisto et al. 2018, see section 3.20) were compared with the extrapolations fitted for people with idiopathic pulmonary fibrosis not treated with nintedanib. The Australian registry provides up to 4.5 years of follow up (median 2 years) for 647 people with idiopathic pulmonary fibrosis (mean age 70.9 years, 71.7% were smokers or had history of smoking). The European registry provides data on 525 people with idiopathic pulmonary fibrosis across Europe (no follow-up duration reported, mean age 65.2 years, 69.4% were smoker or had history of smoking). The Finnish registry provides data on up to 4.6 years of follow up on 453 people with idiopathic pulmonary fibrosis across Finland (mean age 73 years, 54% were smokers or had history of smoking). The company explained that nintedanib and pirfenidone had similar treatment effect, as suggested by the network meta-analysis carried out in TA379. During the first committee meeting, the committee noted that extrapolating overall survival posed uncertainties, especially for the placebo arm; and survival for people not treated with an antifibrotic varied across registries (see section 3.20). However, given the scarcity in long-term PF‑ILD data, the committee concluded that using registries for idiopathic pulmonary fibrosis to validate potential extrapolation curves generated by the Bayesian approach is reasonable.
## For the nintedanib arm, it is appropriate to use the Weibull distribution based on Bayesian analyses to model overall survival
The committee discussed validating the extrapolations fitted for nintedanib for overall survival. It understood that the company used EMPIRE and Greek registries of idiopathic pulmonary fibrosis to select and validate the Weibull curves based on Bayesian analyses it chose in its base case (see section 3.16). The company considered that its model overpredicts survival compared with the Greek registry and the EMPIRE study after the first 2 years. The committee appreciated that the Greek registry and EMPIRE study are from countries where nintedanib may be offered to people with more severe idiopathic pulmonary fibrosis than in the UK, whereas NICE recommends treatment only to people with an FVC between 50% and 80% predicted. The committee was also aware that neither registry matched the Weibull curves well. The committee understood that these registries, although imperfect, were the only observational data available for nintedanib (see section 3.18). The committee concluded that, despite uncertainties, it was reasonable to use Weibull curves based on Bayesian analyses to model overall survival in the nintedanib arm.
## For the placebo arm, it is appropriate to use the log-logistic distribution based on the Bayesian analyses to model overall survival
The committee discussed validating extrapolations fitted for the placebo arm based on a Bayesian approach. During its first meeting, the committee noted that placebo arms had shorter follow up than nintedanib arms (up to median 13.1 months compared with up to median 56.3 months) in the trials of idiopathic pulmonary fibrosis that the company used to inform the shape of survival curves for PF‑ILD (see section 3.16). The committee appreciated that mortality data for patients randomised to placebo in the trials on idiopathic pulmonary fibrosis was not meaningfully more mature than data from INBUILD. Therefore, the committee concluded that there is more uncertainty when extrapolating survival for the placebo arm compared with the nintedanib arm. The committee noted that the Weibull curve from Bayesian analyses fitted to the placebo arm of the model had a higher death rate than the registries of idiopathic pulmonary fibrosis. The committee interpreted this to mean that by using Weibull curves (based on Bayesian analyses) the company may underestimate the survival of patients who do not take nintedanib, despite patients in registries being generally sicker than patients in trials. When comparing the registries, the company noted the survival of people not treated with antifibrotic drugs varied considerably. It considered that the Weibull curve from Bayesian analyses aligned closely with the Australian idiopathic pulmonary fibrosis registry for people not treated with antifibrotics. The committee noted that the European registry, which had a baseline mean FVC% predicted comparable to INBUILD, showed the lowest death rate among all the registries. The committee considered at its first meeting that the European registry which included patients from the UK may be the appropriate source to validate placebo arm survival estimates. But they also noted that people in the European registry had worse baseline characteristics and prognostic factors (a higher proportion of people who smoke) than people in INBUILD. This suggested that the company's modelling of survival for people with PF‑ILD on who do not take antifibrotics appears pessimistic even when using the European registry. Therefore, the committee was concerned that the modelling of survival in the placebo arm may overpredict deaths in the placebo arm.
At consultation in response to the committee's considerations on modelling and validating survival of people not treated with antifibrotics, the company presented survival curves other than a Weibull based on Bayesian analyses. Because survival in the European registry for patients treated and not treated with antifibrotics was higher than other registries or trials in idiopathic pulmonary fibrosis, the company fitted other curves for placebo and nintedanib arms aligning to the European registry. The company explained that the European registry might have included patients "without true idiopathic pulmonary fibrosis", which could explain the high survival. The company considered that the lognormal and exponential curves based on frequentist analyses matched the INBUILD placebo arm when using the European registry to validate. In addition, the company presented alternative survival curves for placebo to match the people not treated with antifibrotics from the Australian registry. This was the registry the company considered most appropriate for validation based on reports from clinical experts of the similarities in Australian and UK clinical practice noted during the first committee meeting. The company considered that both the Bayesian gamma and Bayesian log-logistic curves matched the Australian registry data for placebo. When validating against the Australian data, the company considered it most appropriate to continue to use the Bayesian Weibull curve for nintedanib.
The ERG reproduced the company's model, fitting alternative curves for placebo to match the European and Australian registries. Using Weibull (based on Bayesian analyses) for the nintedanib arm (as considered reasonable by the committee, see section 3.18) and alternative curves for the placebo arm, the ERG calculated HRs for overall survival for nintedanib compared with placebo over time. The committee noted that, when using Weibull (Bayesian) analyses for nintedanib and the log-logistic (Bayesian) for placebo, the extrapolated HR initially declines to about 0.45 (increasing treatment effect) at about 2.5 years. The committee understood that this drop in the HR was driven by INBUILD trial data; the committee recalled that the HR for overall survival reported by INBUILD was 0.78 at database lock 2 (see section 3.10). However, it considered the 0.78 figure not meaningful because it relied on short-term data and non-proportional hazards (see section 3.23) and agreed that the decline of HR was representative of what happens in INBUILD in the short term. The committee noted that, after the initial decline of the HRs in the plots produced by the ERG, the model then predicts a slowing of that decline before the HR increases (treatment effect reduces) after about 3 years. For these reasons, and because the Australian registry was deemed to represent NHS practice, the committee agreed that the log-logistic curve (Bayesian) seemed reasonable to extrapolate overall survival in the placebo arm. The committee noted biases that may be introduced when using data from registries for idiopathic pulmonary fibrosis to validate extrapolations fitted for PF‑ILD, but it considered the uncertainty acceptable. The committee concluded that the log-logistic curve based on Bayesian analyses was appropriate to model overall survival in the placebo arm.
## Fitting independent parametric survival distributions to both arms is reasonable although uncertainties remain
The company fitted parametric distributions to the nintedanib and placebo arms independently to extrapolate overall survival beyond the trial data in its frequentist and Bayesian approaches (see section 3.18, section 3.19, and sections 3.20 to 3.22). The committee understood that when fitting parametric distributions individually to each treatment arm, there is no need to assume proportionality of treatment effects over time. During its first meeting, the committee noted that the company's chosen fits resulted in ever-increasing survival benefits for nintedanib compared with placebo in the extrapolated portion of the survival curves and that the mortality data from INBUILD did not support this (see section 3.10). The committee recommended that the company explore the proportionality of hazards in the data. At consultation, the company confirmed that the proportional hazards assumption was not met for the time to discontinuation outcome. The company explained during the second committee meeting that it had not calculated HR over time assuming non-proportional hazards. Instead, the ERG calculated the HRs (see section 3.22). The committee was aware that there were uncertainties in fitting parametric distributions independently to each arm, but, because of INBUILD's short follow up, there would also be uncertainties around whether the proportional hazards assumption held, and how long it would hold for, if using a joint model to extrapolate overall survival. Considering the evidence, the committee concluded that fitting independent parametric survival curves to the 2 arms was reasonable although uncertainties remain, and it would take this into account in its decision making.
## The modelling of exacerbations is acceptable
The company fitted standard parametric models to extrapolate time to exacerbation (see section 3.13). It selected the exponential curve that generated risks per 3-month cycle and fixed risk of exacerbation of 1.76% and 1.12% for people receiving placebo and nintedanib, respectively. The ERG noted that the exponential model overpredicts the risk of exacerbation after approximately 8 months for both arms and sharply drops towards the end of follow up. The ERG considered this likely to increase the difference observed between nintedanib and placebo. The committee was aware that in both the company and the ERG's scenario analyses, varying the risk of exacerbation had little impact on cost effectiveness because the model does not link exacerbation to mortality (see section 3.13). During the committee's second meeting it heard from the company that exacerbations, a safety endpoint, were rare in INBUILD. The committee concluded that the extrapolation curve used to model exacerbations was acceptable although the lack of a link between exacerbations and mortality was an uncertainty of the model.
## The modelling of loss in lung function is acceptable but the lack of link to mortality is a limitation
Simulated patients start the model in different categories of FVC% predicted, with the distribution informed by patients' baseline values in INBUILD (see section 3.13). The company used different methods to calculate transition probabilities in the placebo and nintedanib arms. For the placebo arm, the company modelled the baseline risk of decline in lung function per cycle using data from INBUILD and a multivariate mixed effects logistic regression model. Predictors of decline in lung function assessed in the model for the placebo arm included age, sex, ethnicity, underlying ILD diagnosis, FVC% predicted, and exacerbation during the analysed 3-month cycle. The company then applied an odds ratio reflecting a treatment effect to this baseline placebo risk, which it assumed was constant over time, to estimate the risk of loss of lung function in the nintedanib arm. The company estimated this treatment effect odds ratio using data from INBUILD using logistic regression, in which nintedanib treatment was the only predictor. Before the committee's first meeting, the ERG suggested that the company use a full regression model to estimate the probability of progression in the placebo arm instead of a separate model. The ERG noted that the 2 different methods produced different probabilities of loss in lung function but minimally changed cost effectiveness. This is probably because, while the absolute values differ substantially, the relative differences in probability of lung-function decline between pre- and post-exacerbation and between nintedanib and placebo do not differ substantially between the 2 methods. The ERG noted that both methods assumed a lifetime treatment effect for nintedanib. The committee was aware that decline of lung function is not linked to mortality (see section 3.13) in the model, and that data from the INBUILD trial suggested that the treatment effect of nintedanib may decrease over time. The committee concluded that the method used to model the loss of lung function over time was acceptable, but the lack of link between loss of lung function and mortality was an important limitation that it would consider.
## The ERG's adjustment of utility values is appropriate
EQ-5D was collected in INBUILD and the company used the data to estimate the utility values in the model for each FVC% predicted health state (see section 3.12). The regression analysis to estimate the utility values resulted in a higher value in people in the 80% to 89% FVC% predicted category than in the 90% to 99% predicted category (0.7333 compared with 0.7287). Because the ERG considered this implausible, it applied a linear decline in utility from the 90% to 99% predicted and 70% to 79% predicted health states resulting in a utility value of 0.7265 for the 80% to 89% FVC% predicted health state in its base case cost-effectiveness analyses. The committee concluded it was satisfied with the ERG's adjustment to utility.
## The company's choice of utility decrement for recurrent exacerbations and gastrointestinal events is appropriate
The company modelled utility decrements for recurrent exacerbations and adverse events. When people have an exacerbation, utility drops by 0.167, which the company estimated from regression analysis using EQ-5D data collected in INBUILD. The company estimated that when people experience gastrointestinal adverse events, utility drops by 0.034. In TA379 (idiopathic pulmonary fibrosis) the company used a decrement of 0.068. But for this appraisal, the company assumed that 0.034 (half of 0.068) was plausible for PF‑ILD. The company based this on a phase 3 trial in recurrent non-small-cell lung cancer using nintedanib, which estimated a decrement for grade 3/4 diarrhoea of 0.042 (Boehringer Ingelheim: data on file, 2014). The ERG was unclear on the company's rationale behind using 0.034 rather than 0.068. However, it noted that adverse events had limited impact on the model results. The ERG identified 2 other estimates for gastrointestinal events and explored the impact of those in scenario analyses. The committee was broadly satisfied with the company's choice of utility decrements for recurrent exacerbations and gastrointestinal events, noting these had minimal impact on the cost effectiveness.
## The way the company modelled time to stopping treatment is uncertain and may underestimate the cost of nintedanib
The cost of treatment reflects the price of nintedanib (which the company offered to the NHS at a confidential discount), the dose, and the duration of treatment. The company modelled time to stopping treatment with nintedanib using an exponential curve, consistent with TA379. This resulted in a rate for stopping nintedanib of 5.97% per month. The company considered that the exponential model did not fit the INBUILD data because the model underestimated stopping nintedanib in the first year, while from about 15 months onwards, the model appeared to overestimate stopping nintedanib. After validating the model with long-term data on the safety and efficacy of nintedanib in people with idiopathic pulmonary fibrosis (Lancaster et al. 2019), the company considered that the exponential model may underestimate the true rate of stopping nintedanib and overestimate its costs. Yet the committee noted that the exponential curve dropped quickly and seemed to overestimate stopping of nintedanib compared with the INBUILD trial, and therefore underestimate its costs. In response to the technical engagement, the company provided alternative models to extrapolate time to stopping treatment with nintedanib beyond the trial period. The company considered that the Gompertz curve was closest to the Kaplan–Meier data on time to stopping treatment from INBUILD over 3 years, but it underestimated the rate of stopping nintedanib treatment over the long term. The ERG noted that, given the mean age of 65 years at baseline in the INBUILD trial, the Weibull model gave a more realistic extrapolation of time on nintedanib than other curves. The committee noted that the choice of distribution does not impact on the QALYs. During the second committee meeting, the committee discussed whether applying a stopping rule could help resolve the uncertainty and reflect TA379. It appreciated that stopping rules generally improve cost effectiveness by minimising continued treatment and costs in people for whom a medicine is not effective. However, it had heard from clinicians that they would stop nintedanib in people whose disease did not respond to treatment (see section 3.4). The committee concluded that the way the company has modelled time to stopping treatment with nintedanib was uncertain and may have underestimated the cost of nintedanib in the model, and it would account for this in its decision making.
# End of life
## The company does not make a case for end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company did not make a case for end of life criteria in its submission. The committee noted that people in INBUILD randomised to placebo would normally live longer than 24 months. Further evidence suggested that the median overall survival is 2 to 5 years in people with PF‑ILD not receiving antifibrotic therapy (Meltzer et al. 2008; Raghu et al. 2011). The committee concluded that the criteria were not met for nintedanib for PF‑ILD.
## Nintedanib is not innovative
The committee discussed innovation defined by NICE as a step-change in treatment and benefits not captured in the company's model. In discussing whether nintedanib reflects a 'step-change' in treatment for PF‑ILD, the committee noted that the company considered nintedanib to be innovative because it is the only treatment licensed for people with PF‑ILD. Stakeholders stated that nintedanib is the first treatment to show evidence of slowing disease progression in PF‑ILD. However, the committee did not hear that there were any additional gains in health-related quality of life not already captured in the modelling. The committee deemed that nintedanib was not 'innovative'.
## There are no equality issues
Patient experts considered that inequalities exist because people with idiopathic pulmonary fibrosis can access nintedanib, while people with PF‑ILD cannot. They noted that compared with people with idiopathic pulmonary fibrosis, people with PF‑ILD are generally younger and more likely to be of South Asian or African-Caribbean family origin. The committee concluded that these did not constitute equality issues.
# Cost-effectiveness estimates
## Nintedanib is likely to be cost effective for PF‑ILD
Because of confidential commercial arrangements for nintedanib, the cost-effectiveness estimates cannot be reported. For its second meeting, the company provided the committee with an alternative overall survival curve (log-logistic based on Bayesian analyses) for people who do not take nintedanib. That curve provided a reasonable match to the Australian registry and addressed other uncertainties including the impact of the trial not reflecting NHS treatments. The committee recognised that the company chose not to explore several uncertainties during consultation. These included incorporating a decrease in nintedanib's treatment effect in the cost-effectiveness analyses, addressing limitations in the model structure, and addressing uncertainties in modelling stopping nintedanib. Considering the evidence and uncertainties, and recognising the absence of any licensed treatment for PF‑ILD, the committee noted that the incremental cost-effectiveness ratio that most likely reflected its preferred assumptions was within £20,000 to £30,000 per QALY gained. It concluded that nintedanib is a cost-effective use of NHS resources for treating PF‑ILD.
|
{'Recommendations': "Nintedanib is recommended, within its marketing authorisation, as an option for treating chronic progressive fibrosing interstitial lung diseases (PF‑ILD) in adults.\n\nWhy the committee made these recommendations\n\nCurrent treatment for PF‑ILD often starts with immunosuppressants, which may or may not be continued when nintedanib is offered.\n\nThe clinical trial evidence suggests that nintedanib slows the decline of lung function compared with placebo. But, there are uncertainties in the evidence: it is unclear if nintedanib helps people to live longer, and the trial reflects how nintedanib would be used in the NHS in some but not all people with PF‑ILD.\n\nBecause follow up was short in the trial for nintedanib in PF‑ILD, the economic model uses longer follow-up data from nintedanib trials in idiopathic pulmonary fibrosis, a related condition that progresses in a similar way. This allows better modelling of nintedanib's long-term effect on life expectancy. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. So, nintedanib is recommended.", 'Information about nintedanib': "# Marketing authorisation indication\n\nNintedanib (Ofev, Boehringer Ingelheim) is indicated in adults for the treatment of chronic fibrosing interstitial lung diseases with a progressive phenotype.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price of nintedanib is £2,151.10 per pack of 60\xa0capsules, each containing 150\xa0mg (excluding VAT; BNF online accessed July\xa02021). The company has a commercial arrangement. This makes nintedanib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': 'The appraisal committee considered evidence submitted by Boehringer Ingelheim, a review of this submission by the evidence review group (ERG), NICE\'s technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Nature of the condition\n\n## Progressive fibrosing interstitial lung disease is a debilitating condition that increases the risk of dying\n\nInterstitial lung disease (ILD) encompasses a large and varied group of lung disorders characterised by inflammation and fibrosis of the lung parenchyma. Idiopathic pulmonary fibrosis is one of the most common types of ILD and NICE has recommended nintedanib (see NICE\'s technology appraisal guidance on nintedanib for treating idiopathic pulmonary fibrosis, from now on referred to as TA379) and pirfenidone for its treatment (see NICE\'s technology appraisal guidance on pirfenidone for treating idiopathic pulmonary fibrosis, from now on referred to as TA504). Some ILDs progress and become fibrotic and are referred to as progressive fibrosing ILD (PF‑ILD). This appraisal addresses PF‑ILD excluding idiopathic pulmonary fibrosis. It also covers systemic sclerosis associated ILD (SSc-ILD) with the progressive fibrosing phenotype. Nintedanib has a separate marketing authorisation for SSc-ILD, which is outside the scope of this appraisal. Other types of PF‑ILD include, but are not limited to, idiopathic interstitial pneumonias, autoimmune ILDs, and hypersensitivity pneumonitis. People with PF‑ILD often have underlying systemic conditions such as rheumatoid arthritis or sarcoidosis. PF‑ILD is characterised by a gradual decline in lung function, breathlessness, worsening physical performance and quality of life, poor response to immunomodulatory therapies and mortality (Cottin et\xa0al. 2019). One patient expert explained that he understood that most people with cancer live longer than people with PF‑ILD and although the committee was not presented with these data, it appreciated that PF‑ILD increased the risk of dying. The patient expert explained that symptoms can evolve quickly and, within a short time, breathlessness limits physical activity. Ultimately, some people become housebound and depend on supplementary oxygen. The committee concluded that PF‑ILD is a debilitating condition that increases the risk of dying relative to the general population.\n\n# Diagnosis and progression of PF‑ILD\n\n## The key trial uses multiple criteria to diagnose PF‑ILD, which reflects NHS practice\n\nClinical experts explained that in the NHS, people with PF‑ILD are seen by different medical specialities, notably respiratory and rheumatology. Clinicians identify disease progression and fibrosis using multiple criteria. These include a relative decline of at least 10% on spirometry in forced vital capacity percentage (FVC%) predicted compared with pre-screening, based on algorithms adjusting for age, sex and height; worsening of fibrosis on CT scan; and respiratory symptoms. Clinical experts explained that these criteria are comparable to the diagnostic criteria of PF‑ILD in INBUILD, the company\'s main trial (see section\xa03.5). This trial included people who met 1 or more criteria despite treatment, including:\n\nA relative decline in FVC% predicted of at least 10% predicted compared with pre-screening in the past 24\xa0months.\n\nA relative decline in FVC% predicted of at least 5% predicted, but less than 10% predicted, with worsening respiratory symptoms or increasing fibrotic changes on high-resolution chest imaging compared with pre-screening in the past 24\xa0months.\n\nWorsening respiratory symptoms and increasing fibrotic changes on high-resolution chest imaging in the past 24\xa0months.The company estimates that there are nearly 900\xa0people living with PF‑ILD in the UK. The committee understood that clinicians use multiple criteria to diagnose PF‑ILD in practice which are comparable to the key trial.\n\n## A decline in FVC of at least 10% predicted defines progression and is associated with worsening disease and mortality\n\nThe committee was aware that a relative (Cottin et\xa0al. 2019) or absolute (Goos et\xa0al. 2021; Wong et\xa0al. 2020) decline in FVC of at least 10% predicted from baseline is one of the criteria that defines disease progression in PF‑ILD. The committee recognised that the company reported the trial results in difference between treatment groups in absolute FVC adjusted for baseline FVC and imaging pattern, whereas in its economic model, the company used a 10% absolute decline in FVC% predicted to categorise disease progression and health states (see section\xa03.12). In its first meeting, the committee requested details of this transformation. At consultation, the company presented the equation it used to estimate FVC% predicted from absolute FVC in millilitres accounting for ethnicity, age, and height (Quanjer et\xa0al. 2012). Evidence suggests that a decline in FVC% predicted is associated with worsening disease and mortality in idiopathic pulmonary fibrosis (Cottin et\xa0al. 2019) and, according to the clinical experts, also in PF‑ILD. The committee concluded that a relative or absolute decline of at least 10% predicted in FVC is an acceptable criterion for disease progression and is associated with higher risk of death in PF‑ILD.\n\n# The company\'s positioning of nintedanib\n\n## The company\'s positioning of nintedanib as an add-on treatment that will be stopped if disease progression is not slowed is appropriate\n\nCurrent treatment of PF‑ILD in the NHS includes treatments for the underlying disease (see section\xa03.1) including, but not limited to, systemic corticosteroids, mycophenolate mofetil, azathioprine, cyclophosphamide, methotrexate, rituximab, infliximab and best supportive care. The company explained that these treatments do not have marketing authorisations for PF‑ILD. However, the committee was aware that NICE\'s guide to the methods of technology appraisal, permits it to consider unlicensed treatments as part of standard care and if relevant, as comparators if their use in clinical practice is established. The clinical and patient experts noted that treatments for PF‑ILD treat the inflammation rather than the fibrosis, and that immunosuppressants are used for the underlying autoimmune diseases. They explained that there are no trials that suggest that these treatments delay progression of chronic fibrosis in PF‑ILD. Clinical experts explained that while they stop treatments that have not slowed the decline of pulmonary function, they would not stop drugs that treat the underlying condition. The committee understood that clinical experts would stop nintedanib if disease progression was not sufficiently slowed. The committee concluded that, if recommended, nintedanib would be an add-on treatment rather than a direct comparator to conventional treatments that may or may not be continued when adding nintedanib. The committee appreciated that the company did not model a formal stopping rule because clinicians would stop treatment with nintedanib if they deemed that it was not effective. The committee concluded that the company\'s positioning of nintedanib, as an add-on treatment to standard care when ILD has progressed despite conventional treatments, is appropriate. The committee also agreed that nintedanib would be stopped if disease progression was not markedly slowed.\n\n## The baseline characteristics of the INBUILD population are generalisable to the NHS\n\nINBUILD was a phase\xa03, randomised, multicentre trial comparing nintedanib (n=332) with placebo (n=331) in people with PF‑ILD. Clinical experts noted that the criteria for disease progression for entry into INBUILD (see section\xa03.2) are in line with NHS practice. INBUILD included 22\xa0participants from the UK. The trial consisted of 2\xa0parts: Part A, the main part of the trial, had a follow up of 52\xa0weeks; and Part B, in which patients continued blinded, randomised treatment beyond week 52. The trial continued until all patients reached their week-52 visit or withdrew. Patients had different durations of treatment in Part B. Those who stopped study treatments were asked to attend all visits as originally planned. The company performed 2 database locks: database lock\xa01 occurred after the last participant had completed the week-52 visit, and database lock\xa02 (median follow up about 19\xa0months; Brown et\xa0al. 2020) after all patients had completed the follow-up visit, about 3\xa0months after finishing Part A. The company chose database lock\xa02 to inform the economic model. An extension study, INBUILD-ON (n=434, completed), offered open-label nintedanib to participants who the investigator deemed would benefit. The clinical experts noted that age, sex, and decline in lung function of INBUILD participants reflected NHS patients. The committee concluded that these baseline characteristics of the INBUILD population were representative of NHS patients.\n\n## Concurrent treatments in INBUILD reflect current NHS care for some, but not all, patients\n\nThe committee was aware that people in the INBUILD trial could not have immunosuppressants other than up to 20\xa0mg per day of oral corticosteroids (see section\xa03.4) at randomisation and for the first 6\xa0months or unless they underwent a wash-out period 4\xa0weeks to 8\xa0weeks before randomisation. After the first 6\xa0months and for the rest of the 52-week period, patients with worsening ILD or connective tissue disease could have immunosuppressants. During this time, approximately 16% of patients started immunosuppressants (21% in the placebo arm and 11% in the nintedanib arm). The committee interpreted this as showing that some participants needed treatments that the protocol restricted earlier in the trial. The committee was aware that the NICE scope listed established clinical management of PF‑ILD as azathioprine, cyclophosphamide, mycophenalate, corticosteroids, infliximab, rituximab, and best supportive care. The ERG noted that immunosuppressants are not restricted in clinical practice and that the trial population therefore does not reflect NHS clinical practice. The committee concluded that the INBUILD trial, which restricted concurrent medications, reflects NHS clinical practice in some, but not all people, with PF‑ILD.\n\n## Placebo is an appropriate comparator for NHS clinical practice\n\nThe committee appreciated that the INBUILD trial was a placebo-controlled trial. The committee was aware that the NICE scope listed the comparators as established clinical management without nintedanib. The committee considered nintedanib to be an add-on treatment (see section\xa03.4) and concluded that placebo was the appropriate comparator for the decision problem and NHS clinical practice.\n\n# Clinical effectiveness\n\n## Nintedanib is associated with a slower decline of lung function compared with placebo, but its long-term treatment effect is uncertain\n\nThe primary endpoint of INBUILD (see section\xa03.5) was annual rate of decline in FVC (in millilitres per year) over 52\xa0weeks analysed as the change in absolute FVC in millilitres using a random coefficient regression model, with baseline FVC and imaging pattern as covariates. The analysis included people who had discontinued treatment (see section\xa03.5). Results from adjusted annual rate of decline in FVC showed that:\n\nOver 52\xa0weeks, the decline in lung function differed between the nintedanib (-80.8\xa0ml/year) and placebo (-187.8\xa0ml/year) arms (alpha level=0.05 [2-sided]) by 107.0\xa0ml/year (95% confidence interval [CI] 65.4 to 148.5; p<0.001). The corresponding results on decline in FVC% predicted showed that nintedanib was associated with a slower decline in FVC% predicted from baseline (-2.6%) compared with placebo (-5.9%) at week 52 (mean difference: 3.2%; 95% CI 2.09 to 4.40). At consultation, the company reported that the minimum clinically meaningful difference for decline in FVC% predicted could be 2% to 6% in people with idiopathic pulmonary fibrosis according to Bois et\xa0al. (2011). Also at consultation, stakeholders explained that a difference of 107\xa0ml in decline of FVC is significant in clinical practice.\n\nAfter 52\xa0weeks, the difference in adjusted annual rate of decline in FVC between nintedanib and placebo narrowed. The committee noted that the data suggests a waning effect of nintedanib in the long term, or effect modification by concurrent medications added after the first 6\xa0months of the trial (see section\xa03.6). The company disputed this and explained that the results reflected different durations of treatment that patients had in Part B of the trial and missing FVC values. The company considered that the analysis that incorporated data from Part B that it used in its model, should be \'interpreted with caution\' and had \'methodological limitations\'. In the company\'s view, this included the possibility of \'healthy survivor bias\' because patients in the nintedanib arm stopped treatment because of adverse events while those in the placebo arm stopped treatment because of lack of effect. However, the ERG and committee appreciated that the company did not present data to support this. The committee also appreciated the limitations of INBUILD in measuring the effect of long-term treatment but recalled that the company chose the timepoint of database lock\xa02 to inform its economic model (see section\xa03.5). The committee concluded that there was uncertainty in nintedanib\'s long-term treatment effect and that it would account for this in its decision making.\n\n## Effect modification by concurrent treatment remains uncertain\n\nThe committee questioned whether the treatment effect of nintedanib without concurrent conventional treatments, as in INBUILD, would be the same as with them. During the committee\'s second meeting, the company presented a post-hoc analysis of the treatment effect of nintedanib on adjusted annual rate of decline in FVC in the whole INBUILD population compared with the subgroup of patients who did not receive concurrent conventional treatments . The committee concluded that comparing a subgroup with the whole population (including the subgroup) was not a statistically meaningful comparison and that the subgroup used did not reflect NHS practice. The company presented another post-hoc analysis from INBUILD suggesting that there was no difference in the treatment effect of nintedanib between patients receiving or not receiving glucocorticoids at baseline (interaction p=0.18). The committee was aware that 70.1% in the placebo arm and 67.2% in the nintedanib arm used prednisolone over the 52-week period in INBUIILD. The committee concluded that it did not see evidence of an interaction, but could not discount the possibility that effect modification exists.\n\n## Nintedanib\'s treatment effect on mortality is uncertain\n\nSecondary endpoints assessed in INBUILD included overall survival, change from baseline in the score for the King\'s Brief Interstitial Lung Disease (K-BILD) questionnaire (a health-related quality-of-life measure) and time until first acute exacerbation of ILD or death. Other endpoints included the EQ-5D questionnaire and safety. Endpoints were collected at 52\xa0weeks and at database lock\xa02 (see section3.5). Results showed that:\n\nThe hazard ratio (HR) for death for people randomised to nintedanib (4.8%; n=16 of 332) compared with people randomised to placebo (5.1%; 17 of 331) at 52\xa0weeks was 0.94 (95% CI 0.47 to 1.86; p=0.85). The HR for death for nintedanib (10.8%; 36 of 332) compared with placebo (13.6%; 45 of 331) at database lock\xa02 was 0.78 (95% CI 0.50 to 1.21; p value not reported). Median overall survival was not reached because of a low number of events. The committee noted the wide confidence intervals.\n\nAbsolute change from baseline in total score on K-BILD showed no statistically significant difference at a 5% alpha between nintedanib (adjusted mean: 0.55) and placebo (adjusted mean: -0.79) arms at 52\xa0weeks; adjusted mean difference: 1.34; 95% CI -0.31 to 2.98; p=0.1115.\n\nResults for time to first acute ILD exacerbation or death for nintedanib (7.8%, 26 of 332) and placebo (9.7%, 32 of 331) arms up to 52\xa0weeks were HR 0.80; 95% CI 0.48 to 1.34; p=0.3948. At database lock\xa02, 13.9% (46 of 332) and 19.6% (65 of 331) of patients in nintedanib and placebo arms experienced an event (HR 0.67; 95% CI 0.46 to 0.98). The committee noted that this composite endpoint did not specifically inform the risk of exacerbation associated with nintedanib, which the company included in its model. It was aware that occurrence of exacerbation can increase the risk of death in PF‑ILD (see section\xa03.13) and agreed that it would have been helpful to have data on this.The committee was aware that the trial was not powered to detect a difference in mortality. It concluded that the data from INBUILD did not show conclusively that nintedanib prolongs life.\n\n# Adverse events\n\n## The adverse event profile of nintedanib is acceptable\n\nIn INBUILD at 52\xa0weeks, the nintedanib and placebo arms showed similar frequencies of any adverse event and of serious adverse events based on on-treatment analyses. Gastrointestinal discomfort, especially diarrhoea, was the most common adverse event (66.9% in the nintedanib arm compared with 23.9% in the placebo arm). People taking nintedanib were more likely to have raised biochemical serum markers of hepatic injury and were more likely to reduce the dose of nintedanib because of gastrointestinal symptoms. Based on their observations, the clinical experts explained that 25% to 30% of people may not tolerate nintedanib. They noted that nintedanib is not associated with an increased risk of infection unlike immunosuppressants. The committee concluded that the safety profile of nintedanib was acceptable.\n\n# Economic model\n\n## The model structure is acceptable for decision making, but there are important uncertainties in its assumptions\n\nTo model the natural history of PF‑ILD beyond the end of the trial, the company assumed that idiopathic pulmonary fibrosis and PF‑ILD have a similar natural history of disease. The company adopted the same Markov model structure it had used in TA379. In the model, patients accrue quality-adjusted life years (QALYs) by improving both quality and length of life. The company assumed in its model that nintedanib improves the quality of life because patients experience fewer exacerbations, and their lung function declines more slowly. The company defined health states using lung function (10%-point categorisations of FVC% predicted) and rates of exacerbation over a cycle length of 3\xa0months in the model. Patients enter the model at different lung-function health states assuming they have not yet had an exacerbation. They can then remain in the same health state, have an exacerbation and transition to a health state with the same lung function or move to health state with a lower lung function, or not have an exacerbation and transition to health states characterised by a lower FVC% predicted, or die. The company defined the health states to reflect a clinically meaningful decline in FVC% predicted (see section\xa03.7). The health state in which a patient starts reflects the distribution of patients at randomisation in INBUILD.\n\nThe company used the data from database lock\xa02 of INBUILD to inform the model parameters including overall survival, time to first acute exacerbation, loss of lung function, stopping treatment, utility values and costs. The company estimated transition probabilities of mortality on parametric extrapolations (Bayesian approach) of overall survival data from INBUILD and applied irrespective of health states or model events with the exception of a FVC% predicted below 40% (see section 3.15 and section\xa03.16). The company fitted standard parametric models to extrapolate the risk of time to first exacerbation (see section\xa03.24), and calculated the probabilities of losing lung function in the 2\xa0treatment arms using 2\xa0different methods (see section\xa03.25). The committee was aware that the modelled FVC% predicted was transformed from the absolute decline in FVC controlled for baseline FVC and imaging, the primary endpoint of INBUILD (see section\xa03.3). The company assumed that patients could not transition to a health state with better lung function. After an exacerbation, patients could not transition to a health state without exacerbation for the rest of the time horizon. Transition to death can either happen from any health state, but does not differ by health state; it is based on a survival analysis using the INBUILD data, or by reaching a level of FVC% predicted below 40%, at which the company assumed that lung function is unsustainable. Although there were 2\xa0routes to death in the model, the ERG noted that the company modelled mortality based only on overall survival data from INBUILD. This means that mortality is independently modelled from lung function and that the same risk of death is applied to all health states. The committee recalled that a lower level of lung function was strongly associated with a higher mortality rate (see section\xa03.3) and questioned the company on why it did not model a change in risk of death as a function of FVC percent predicted. The company explained that this was to avoid double counting as the overall survival data includes all deaths. The company also modelled mortality independently from acute exacerbations, despite it stating that acute exacerbations may be fatal and a cause of mortality in PF‑ILD.\n\nThe ERG did not change any of the company\'s modelling assumptions. It noted that modelling mortality independently from lung-function decline and acute exacerbations can produce implausible results in relation to stopping treatment in the model. The committee understood that the way the company modelled mortality meant that modifying assumptions around the rate at which people stop treatment with nintedanib or placebo (see section\xa03.28), exacerbation rates (see section\xa03.24), and decline in lung function (see section\xa03.25) have minimal impact on cost effectiveness. At consultation, the company considered changing the structure of the model to include a link between mortality and exacerbations and decline in lung function. However, the company stated that the adapted model produced increased and unrealistic life years for both placebo and nintedanib compared with the current model. It considered this was because of the uncertainty with separate risks of death for each modelled health state. The committee was aware that mortality data from INBUILD showed no clear difference in mortality between treatments (see section\xa03.10). The committee concluded that there are important uncertainties in the model structure and limitations when implementing it.\n\n## The company used frequentist and Bayesian approaches to extrapolate overall survival\n\nThe company used 2 approaches to extrapolate overall survival for people with PF‑ILD beyond the trial duration: a frequentist method and a Bayesian analysis.\n\nThe frequentist approach involved fitting standard parametric distributions independently to each arm of INBUILD. The study included people with PF‑ILD only. The company considered that the best fitting curves for the observed data had the best statistical fits (lower Akaike information criterion [AIC]/Bayesian information criterion [BIC] scores). These were log-logistic, Gompertz and Weibull curves. The committee appreciated that considerable uncertainty exists given the immaturity of the survival data with some 90% of the population alive after database lock\xa02 (see section\xa03.10).\n\nThe company extrapolated overall survival using a Bayesian approach by combining short-term data on PF‑ILD from INBUILD (median 19\xa0months) with longer-term data from clinical trials of idiopathic pulmonary fibrosis (up to median 56.3\xa0months for nintedanib arm, but a median of only up to 13.1\xa0months for placebo). The company assumed PF‑ILD and idiopathic pulmonary fibrosis have similar disease trajectories including death, based on evidence from Brown et\xa0al. (2020) and Simpson et\xa0al. (2020). In general, the company used data from trials of idiopathic pulmonary fibrosis and matched participants from these trials to participants with PF‑ILD in INBUILD based on characteristics that might be associated with survival. The company then fitted survival curves to matched patients with idiopathic pulmonary fibrosis to inform the shape parameter of the survival curves for PF‑ILD in the model. This specifically involved:\n\nObtaining data on idiopathic pulmonary fibrosis by combining several trials of idiopathic pulmonary fibrosis, including: TOMORROW, a phase\xa02 trial; INPULSIS I and II, 2\xa0phase\xa03 randomised control trials (RCTs); and INPULSIS ON, a combined long-term extension of the 2\xa0RCTs.\n\nMatching patients with idiopathic pulmonary fibrosis (from the combined idiopathic pulmonary fibrosis trials) to PF‑ILD patients (from INBUILD) on chosen baseline characteristics using a propensity score weighting method. They included age, sex, ethnicity, duration of disease, FVC% predicted at baseline and smoking.\n\nGenerating survival curves for the matched idiopathic pulmonary fibrosis patients. The company then fitted parametric survival curves to the matched idiopathic pulmonary fibrosis data for both nintedanib and placebo arms and selected models with the lowest AIC and BIC.\n\nGenerating an informative prior from parametric survival curves for idiopathic pulmonary fibrosis and generating survival curves for PF‑ILD. For the selected parametric survival curves for idiopathic pulmonary fibrosis, the company retained the shape parameters as the informative prior for nintedanib and placebo. Using these informative priors, the company fitted parametric models to the INBUILD trial data. The company considered the 3\xa0best fitting curves to be Weibull, log-logistic and gamma distributions.\n\nValidating the 3\xa0best fitting curves by seeking clinicians\' advice and comparing survival curves with external registry data on idiopathic pulmonary fibrosis. Based on this, the company considered that the Bayesian approach, by using data from clinical trials of idiopathic pulmonary fibrosis and a Weibull model, better estimated long-term survival than the frequentist approach. The company adopted Weibull Bayesian curves for both nintedanib and placebo arms in its base case. The committee appreciated the company\'s approach using longer-term trial data from a related disease, but noted it was not without uncertainty. Given the absence of long-term data in PF‑ILD, the committee concluded that the Bayesian approach itself was reasonable to model overall survival, but that uncertainties exist.\n\n## It is reasonable to consider that idiopathic pulmonary fibrosis and PF‑ILD share similar disease trajectories\n\nIn using a Bayesian approach, the company assumed that PF‑ILD and idiopathic pulmonary fibrosis have similar disease trajectories for death (see section\xa03.16). The committee was aware that PF‑ILD and idiopathic pulmonary fibrosis may share features and natural history but questioned how valid it was to assume similar survival. The company explained that it based this assumption on 2\xa0sources. The first, Brown et\xa0al. (2020), an observational study assessing the clinical course of PF‑ILD and idiopathic pulmonary fibrosis, includes people randomised to placebo in the INBUILD trial (PF‑ILD,) and INPULSIS trials (idiopathic pulmonary fibrosis). The study, sponsored by the manufacturer, reported death rates at 52\xa0weeks for PF‑ILD (5.1%, 17 of 331) and idiopathic pulmonary fibrosis (7.8%, 33 of 423). The committee was aware that the HR of 0.63 (95% CI 0.35 to 1.13) suggested the possibility of a lower rate of death for PF‑ILD than for idiopathic pulmonary fibrosis. The committee was aware that deaths were sparse, and that Brown et al. did not report what confounding factors were considered, and the possibility of residual confounding. Simpson et\xa0al. (2020), an observational study of PF‑ILD across the UK, included 2,368\xa0people with a new referral for ILD and diagnosed with the same criteria for PF‑ILD as used in the INBUILD trial (see section\xa03.2). The study reports that people with PF‑ILD and people with idiopathic pulmonary fibrosis have similar survival at 900\xa0days (HR 1.06; 95% CI 0.84 to 1.35). Additionally, it showed that the shapes of the survival curves between PF‑ILD and idiopathic pulmonary fibrosis were similar. The committee considered that the shape of the survival curve was more important than the reported crude HR when assuming similar disease trajectories. The committee concluded it was reasonable to assume a similar shape parameter for survival between PF‑ILD and idiopathic pulmonary fibrosis.\n\n## Using registries of idiopathic pulmonary fibrosis to validate the survival extrapolations is a reasonable approach\n\nThe committee discussed the company\'s attempt to validate its choice of the Weibull overall survival curves based on Bayesian analyses for both nintedanib and placebo using clinical input and registry data for idiopathic pulmonary fibrosis. Clinicians consulted by the company noted that they had limited knowledge on long-term survival for people with PF‑ILD on nintedanib, but, for placebo, Weibull curves (based either on the frequentist or Bayesian approaches) were plausible. The company validated its choice using the following studies and registries for idiopathic pulmonary fibrosis:\n\nNintedanib: registry data from the EMPIRE study (Vasakova et\xa0al. 2013) and a Greek registry (Antoniou et\xa0al. 2020) that provided longer-term data on the effect of nintedanib. The EMPIRE study (n=637) provides approximately 10\xa0years of follow up in\xa0people across Europe (excluding the UK) with idiopathic pulmonary fibrosis. The Greek registry (n=244) reports 5-year survival data in 244\xa0people in Greece with idiopathic pulmonary fibrosis taking nintedanib (see section\xa03.19).\n\nStandard care (placebo): Kaplan–Meier data from the treatment arms without anti-fibrotic drugs (nintedanib or pirfenidone) in the EMPIRE study, an Australian registry (Helen et al. 2016), a European registry (eurIPFreg, Guenther et al. 2018) including British patients, and a Finnish registry (Kaunisto et al. 2018, see section\xa03.20) were compared with the extrapolations fitted for people with idiopathic pulmonary fibrosis not treated with nintedanib. The Australian registry provides up to 4.5\xa0years of follow up (median 2\xa0years) for 647\xa0people with idiopathic pulmonary fibrosis (mean age 70.9\xa0years, 71.7% were smokers or had history of smoking). The European registry provides data on 525\xa0people with idiopathic pulmonary fibrosis across Europe (no follow-up duration reported, mean age 65.2\xa0years, 69.4% were smoker or had history of smoking). The Finnish registry provides data on up to 4.6\xa0years of follow up on 453\xa0people with idiopathic pulmonary fibrosis across Finland (mean age 73\xa0years, 54% were smokers or had history of smoking). The company explained that nintedanib and pirfenidone had similar treatment effect, as suggested by the network meta-analysis carried out in TA379. During the first committee meeting, the committee noted that extrapolating overall survival posed uncertainties, especially for the placebo arm; and survival for people not treated with an antifibrotic varied across registries (see section\xa03.20). However, given the scarcity in long-term PF‑ILD data, the committee concluded that using registries for idiopathic pulmonary fibrosis to validate potential extrapolation curves generated by the Bayesian approach is reasonable.\n\n## For the nintedanib arm, it is appropriate to use the Weibull distribution based on Bayesian analyses to model overall survival\n\nThe committee discussed validating the extrapolations fitted for nintedanib for overall survival. It understood that the company used EMPIRE and Greek registries of idiopathic pulmonary fibrosis to select and validate the Weibull curves based on Bayesian analyses it chose in its base case (see section\xa03.16). The company considered that its model overpredicts survival compared with the Greek registry and the EMPIRE study after the first 2\xa0years. The committee appreciated that the Greek registry and EMPIRE study are from countries where nintedanib may be offered to people with more severe idiopathic pulmonary fibrosis than in the UK, whereas NICE recommends treatment only to people with an FVC between 50% and 80% predicted. The committee was also aware that neither registry matched the Weibull curves well. The committee understood that these registries, although imperfect, were the only observational data available for nintedanib (see section\xa03.18). The committee concluded that, despite uncertainties, it was reasonable to use Weibull curves based on Bayesian analyses to model overall survival in the nintedanib arm.\n\n## For the placebo arm, it is appropriate to use the log-logistic distribution based on the Bayesian analyses to model overall survival\n\nThe committee discussed validating extrapolations fitted for the placebo arm based on a Bayesian approach. During its first meeting, the committee noted that placebo arms had shorter follow up than nintedanib arms (up to median 13.1\xa0months compared with up to median 56.3\xa0months) in the trials of idiopathic pulmonary fibrosis that the company used to inform the shape of survival curves for PF‑ILD (see section\xa03.16). The committee appreciated that mortality data for patients randomised to placebo in the trials on idiopathic pulmonary fibrosis was not meaningfully more mature than data from INBUILD. Therefore, the committee concluded that there is more uncertainty when extrapolating survival for the placebo arm compared with the nintedanib arm. The committee noted that the Weibull curve from Bayesian analyses fitted to the placebo arm of the model had a higher death rate than the registries of idiopathic pulmonary fibrosis. The committee interpreted this to mean that by using Weibull curves (based on Bayesian analyses) the company may underestimate the survival of patients who do not take nintedanib, despite patients in registries being generally sicker than patients in trials. When comparing the registries, the company noted the survival of people not treated with antifibrotic drugs varied considerably. It considered that the Weibull curve from Bayesian analyses aligned closely with the Australian idiopathic pulmonary fibrosis registry for people not treated with antifibrotics. The committee noted that the European registry, which had a baseline mean FVC% predicted comparable to INBUILD, showed the lowest death rate among all the registries. The committee considered at its first meeting that the European registry which included patients from the UK may be the appropriate source to validate placebo arm survival estimates. But they also noted that people in the European registry had worse baseline characteristics and prognostic factors (a higher proportion of people who smoke) than people in INBUILD. This suggested that the company\'s modelling of survival for people with PF‑ILD on who do not take antifibrotics appears pessimistic even when using the European registry. Therefore, the committee was concerned that the modelling of survival in the placebo arm may overpredict deaths in the placebo arm.\n\nAt consultation in response to the committee\'s considerations on modelling and validating survival of people not treated with antifibrotics, the company presented survival curves other than a Weibull based on Bayesian analyses. Because survival in the European registry for patients treated and not treated with antifibrotics was higher than other registries or trials in idiopathic pulmonary fibrosis, the company fitted other curves for placebo and nintedanib arms aligning to the European registry. The company explained that the European registry might have included patients "without true idiopathic pulmonary fibrosis", which could explain the high survival. The company considered that the lognormal and exponential curves based on frequentist analyses matched the INBUILD placebo arm when using the European registry to validate. In addition, the company presented alternative survival curves for placebo to match the people not treated with antifibrotics from the Australian registry. This was the registry the company considered most appropriate for validation based on reports from clinical experts of the similarities in Australian and UK clinical practice noted during the first committee meeting. The company considered that both the Bayesian gamma and Bayesian log-logistic curves matched the Australian registry data for placebo. When validating against the Australian data, the company considered it most appropriate to continue to use the Bayesian Weibull curve for nintedanib.\n\nThe ERG reproduced the company\'s model, fitting alternative curves for placebo to match the European and Australian registries. Using Weibull (based on Bayesian analyses) for the nintedanib arm (as considered reasonable by the committee, see section\xa03.18) and alternative curves for the placebo arm, the ERG calculated HRs for overall survival for nintedanib compared with placebo over time. The committee noted that, when using Weibull (Bayesian) analyses for nintedanib and the log-logistic (Bayesian) for placebo, the extrapolated HR initially declines to about 0.45 (increasing treatment effect) at about 2.5\xa0years. The committee understood that this drop in the HR was driven by INBUILD trial data; the committee recalled that the HR for overall survival reported by INBUILD was 0.78 at database lock\xa02 (see section\xa03.10). However, it considered the 0.78 figure not meaningful because it relied on short-term data and non-proportional hazards (see section\xa03.23) and agreed that the decline of HR was representative of what happens in INBUILD in the short term. The committee noted that, after the initial decline of the HRs in the plots produced by the ERG, the model then predicts a slowing of that decline before the HR increases (treatment effect reduces) after about 3\xa0years. For these reasons, and because the Australian registry was deemed to represent NHS practice, the committee agreed that the log-logistic curve (Bayesian) seemed reasonable to extrapolate overall survival in the placebo arm. The committee noted biases that may be introduced when using data from registries for idiopathic pulmonary fibrosis to validate extrapolations fitted for PF‑ILD, but it considered the uncertainty acceptable. The committee concluded that the log-logistic curve based on Bayesian analyses was appropriate to model overall survival in the placebo arm.\n\n## Fitting independent parametric survival distributions to both arms is reasonable although uncertainties remain\n\nThe company fitted parametric distributions to the nintedanib and placebo arms independently to extrapolate overall survival beyond the trial data in its frequentist and Bayesian approaches (see section 3.18, section 3.19, and sections 3.20 to 3.22). The committee understood that when fitting parametric distributions individually to each treatment arm, there is no need to assume proportionality of treatment effects over time. During its first meeting, the committee noted that the company\'s chosen fits resulted in ever-increasing survival benefits for nintedanib compared with placebo in the extrapolated portion of the survival curves and that the mortality data from INBUILD did not support this (see section\xa03.10). The committee recommended that the company explore the proportionality of hazards in the data. At consultation, the company confirmed that the proportional hazards assumption was not met for the time to discontinuation outcome. The company explained during the second committee meeting that it had not calculated HR over time assuming non-proportional hazards. Instead, the ERG calculated the HRs (see section\xa03.22). The committee was aware that there were uncertainties in fitting parametric distributions independently to each arm, but, because of INBUILD\'s short follow up, there would also be uncertainties around whether the proportional hazards assumption held, and how long it would hold for, if using a joint model to extrapolate overall survival. Considering the evidence, the committee concluded that fitting independent parametric survival curves to the 2\xa0arms was reasonable although uncertainties remain, and it would take this into account in its decision making.\n\n## The modelling of exacerbations is acceptable\n\nThe company fitted standard parametric models to extrapolate time to exacerbation (see section\xa03.13). It selected the exponential curve that generated risks per 3-month cycle and fixed risk of exacerbation of 1.76% and 1.12% for people receiving placebo and nintedanib, respectively. The ERG noted that the exponential model overpredicts the risk of exacerbation after approximately 8\xa0months for both arms and sharply drops towards the end of follow up. The ERG considered this likely to increase the difference observed between nintedanib and placebo. The committee was aware that in both the company and the ERG\'s scenario analyses, varying the risk of exacerbation had little impact on cost effectiveness because the model does not link exacerbation to mortality (see section\xa03.13). During the committee\'s second meeting it heard from the company that exacerbations, a safety endpoint, were rare in INBUILD. The committee concluded that the extrapolation curve used to model exacerbations was acceptable although the lack of a link between exacerbations and mortality was an uncertainty of the model.\n\n## The modelling of loss in lung function is acceptable but the lack of link to mortality is a limitation\n\nSimulated patients start the model in different categories of FVC% predicted, with the distribution informed by patients\' baseline values in INBUILD (see section\xa03.13). The company used different methods to calculate transition probabilities in the placebo and nintedanib arms. For the placebo arm, the company modelled the baseline risk of decline in lung function per cycle using data from INBUILD and a multivariate mixed effects logistic regression model. Predictors of decline in lung function assessed in the model for the placebo arm included age, sex, ethnicity, underlying ILD diagnosis, FVC% predicted, and exacerbation during the analysed 3-month cycle. The company then applied an odds ratio reflecting a treatment effect to this baseline placebo risk, which it assumed was constant over time, to estimate the risk of loss of lung function in the nintedanib arm. The company estimated this treatment effect odds ratio using data from INBUILD using logistic regression, in which nintedanib treatment was the only predictor. Before the committee\'s first meeting, the ERG suggested that the company use a full regression model to estimate the probability of progression in the placebo arm instead of a separate model. The ERG noted that the 2\xa0different methods produced different probabilities of loss in lung function but minimally changed cost effectiveness. This is probably because, while the absolute values differ substantially, the relative differences in probability of lung-function decline between pre- and post-exacerbation and between nintedanib and placebo do not differ substantially between the 2\xa0methods. The ERG noted that both methods assumed a lifetime treatment effect for nintedanib. The committee was aware that decline of lung function is not linked to mortality (see section\xa03.13) in the model, and that data from the INBUILD trial suggested that the treatment effect of nintedanib may decrease over time. The committee concluded that the method used to model the loss of lung function over time was acceptable, but the lack of link between loss of lung function and mortality was an important limitation that it would consider.\n\n## The ERG\'s adjustment of utility values is appropriate\n\nEQ-5D was collected in INBUILD and the company used the data to estimate the utility values in the model for each FVC% predicted health state (see section\xa03.12). The regression analysis to estimate the utility values resulted in a higher value in people in the 80% to 89% FVC% predicted category than in the 90% to 99% predicted category (0.7333 compared with 0.7287). Because the ERG considered this implausible, it applied a linear decline in utility from the 90% to 99% predicted and 70% to 79% predicted health states resulting in a utility value of 0.7265 for the 80% to 89% FVC% predicted health state in its base case cost-effectiveness analyses. The committee concluded it was satisfied with the ERG\'s adjustment to utility.\n\n## The company\'s choice of utility decrement for recurrent exacerbations and gastrointestinal events is appropriate\n\nThe company modelled utility decrements for recurrent exacerbations and adverse events. When people have an exacerbation, utility drops by 0.167, which the company estimated from regression analysis using EQ-5D data collected in INBUILD. The company estimated that when people experience gastrointestinal adverse events, utility drops by 0.034. In TA379 (idiopathic pulmonary fibrosis) the company used a decrement of 0.068. But for this appraisal, the company assumed that 0.034 (half of 0.068) was plausible for PF‑ILD. The company based this on a phase\xa03 trial in recurrent non-small-cell lung cancer using nintedanib, which estimated a decrement for grade 3/4 diarrhoea of 0.042 (Boehringer Ingelheim: data on file, 2014). The ERG was unclear on the company\'s rationale behind using 0.034 rather than 0.068. However, it noted that adverse events had limited impact on the model results. The ERG identified 2\xa0other estimates for gastrointestinal events and explored the impact of those in scenario analyses. The committee was broadly satisfied with the company\'s choice of utility decrements for recurrent exacerbations and gastrointestinal events, noting these had minimal impact on the cost effectiveness.\n\n## The way the company modelled time to stopping treatment is uncertain and may underestimate the cost of nintedanib\n\nThe cost of treatment reflects the price of nintedanib (which the company offered to the NHS at a confidential discount), the dose, and the duration of treatment. The company modelled time to stopping treatment with nintedanib using an exponential curve, consistent with TA379. This resulted in a rate for stopping nintedanib of 5.97% per month. The company considered that the exponential model did not fit the INBUILD data because the model underestimated stopping nintedanib in the first year, while from about 15\xa0months onwards, the model appeared to overestimate stopping nintedanib. After validating the model with long-term data on the safety and efficacy of nintedanib in people with idiopathic pulmonary fibrosis (Lancaster et\xa0al. 2019), the company considered that the exponential model may underestimate the true rate of stopping nintedanib and overestimate its costs. Yet the committee noted that the exponential curve dropped quickly and seemed to overestimate stopping of nintedanib compared with the INBUILD trial, and therefore underestimate its costs. In response to the technical engagement, the company provided alternative models to extrapolate time to stopping treatment with nintedanib beyond the trial period. The company considered that the Gompertz curve was closest to the Kaplan–Meier data on time to stopping treatment from INBUILD over 3\xa0years, but it underestimated the rate of stopping nintedanib treatment over the long term. The ERG noted that, given the mean age of 65\xa0years at baseline in the INBUILD trial, the Weibull model gave a more realistic extrapolation of time on nintedanib than other curves. The committee noted that the choice of distribution does not impact on the QALYs. During the second committee meeting, the committee discussed whether applying a stopping rule could help resolve the uncertainty and reflect TA379. It appreciated that stopping rules generally improve cost effectiveness by minimising continued treatment and costs in people for whom a medicine is not effective. However, it had heard from clinicians that they would stop nintedanib in people whose disease did not respond to treatment (see section\xa03.4). The committee concluded that the way the company has modelled time to stopping treatment with nintedanib was uncertain and may have underestimated the cost of nintedanib in the model, and it would account for this in its decision making.\n\n# End of life\n\n## The company does not make a case for end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE\'s guide to the methods of technology appraisal. The company did not make a case for end of life criteria in its submission. The committee noted that people in INBUILD randomised to placebo would normally live longer than 24\xa0months. Further evidence suggested that the median overall survival is 2 to 5\xa0years in people with PF‑ILD not receiving antifibrotic therapy (Meltzer et\xa0al. 2008; Raghu et\xa0al. 2011). The committee concluded that the criteria were not met for nintedanib for PF‑ILD.\n\n## Nintedanib is not innovative\n\nThe committee discussed innovation defined by NICE as a step-change in treatment and benefits not captured in the company\'s model. In discussing whether nintedanib reflects a \'step-change\' in treatment for PF‑ILD, the committee noted that the company considered nintedanib to be innovative because it is the only treatment licensed for people with PF‑ILD. Stakeholders stated that nintedanib is the first treatment to show evidence of slowing disease progression in PF‑ILD. However, the committee did not hear that there were any additional gains in health-related quality of life not already captured in the modelling. The committee deemed that nintedanib was not \'innovative\'.\n\n## There are no equality issues\n\nPatient experts considered that inequalities exist because people with idiopathic pulmonary fibrosis can access nintedanib, while people with PF‑ILD cannot. They noted that compared with people with idiopathic pulmonary fibrosis, people with PF‑ILD are generally younger and more likely to be of South Asian or African-Caribbean family origin. The committee concluded that these did not constitute equality issues.\n\n# Cost-effectiveness estimates\n\n## Nintedanib is likely to be cost effective for PF‑ILD\n\nBecause of confidential commercial arrangements for nintedanib, the cost-effectiveness estimates cannot be reported. For its second meeting, the company provided the committee with an alternative overall survival curve (log-logistic based on Bayesian analyses) for people who do not take nintedanib. That curve provided a reasonable match to the Australian registry and addressed other uncertainties including the impact of the trial not reflecting NHS treatments. The committee recognised that the company chose not to explore several uncertainties during consultation. These included incorporating a decrease in nintedanib\'s treatment effect in the cost-effectiveness analyses, addressing limitations in the model structure, and addressing uncertainties in modelling stopping nintedanib. Considering the evidence and uncertainties, and recognising the absence of any licensed treatment for PF‑ILD, the committee noted that the incremental cost-effectiveness ratio that most likely reflected its preferred assumptions was within £20,000 to £30,000 per QALY gained. It concluded that nintedanib is a cost-effective use of NHS resources for treating PF‑ILD.'}
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https://www.nice.org.uk/guidance/ta747
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Evidence-based recommendations on nintedanib for treating progressive fibrosing interstitial lung diseases in adults.
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72402635e5cb422301293b9fb4508969e9ec973e
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nice
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COVID-19 rapid guideline: managing the long-term effects of COVID-19
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COVID-19 rapid guideline: managing the long-term effects of COVID-19
This guideline covers identifying, assessing and managing the long-term effects of COVID-19, often described as ‘long COVID’. It makes recommendations about care in all healthcare settings for adults, children and young people who have new or ongoing symptoms 4 weeks or more after the start of acute COVID-19. It also includes advice on organising services for long COVID.
# Recommendations
How to use this guideline
Identification
Assessment
Investigations and referral
Planning care
Management
Self-management and supported self-management
Multidisciplinary rehabilitation
Additional support
Follow up, monitoring and discharge
Sharing information and continuity of care
Service organisation
Common symptoms
Recommendations for research
Equality considerations
Equalities impact assessment during scope development
Equalities impact assessment during scoping - final scope
Equalities impact assessment during guideline development
Equalities impact assessment final guideline
Methods and evidence reviews
Methods and processes
Evidence reviews
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{'Recommendations': 'How to use this guideline\n\nIdentification\n\nAssessment\n\nInvestigations and referral\n\nPlanning care\n\nManagement\n\n\n\nSelf-management and supported self-management\n\nMultidisciplinary rehabilitation\n\nAdditional support\n\n\n\nFollow up, monitoring and discharge\n\nSharing information and continuity of care\n\nService organisation\n\nCommon symptoms\n\nRecommendations for research\n\nEquality considerations\n\n\n\nEqualities impact assessment during scope development\n\nEqualities impact assessment during scoping - final scope\n\nEqualities impact assessment during guideline development\n\nEqualities impact assessment final guideline\n\n\n\nMethods and evidence reviews\n\n\n\nMethods and processes\n\nEvidence reviews\n\n'}
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https://www.nice.org.uk/guidance/ng188
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This guideline covers identifying, assessing and managing the long-term effects of COVID-19, often described as ‘long COVID’. It makes recommendations about care in all healthcare settings for adults, children and young people who have new or ongoing symptoms 4 weeks or more after the start of acute COVID-19. It also includes advice on organising services for long COVID.
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00ab5602c0206e6569e965ad938f0529e005c059
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nice
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Upadacitinib for treating moderate rheumatoid arthritis
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Upadacitinib for treating moderate rheumatoid arthritis
Evidence-based recommendations on upadacitinib (Rinvoq) for treating moderate active rheumatoid arthritis in adults.
# Recommendations
This guidance only includes recommendations for treating moderate rheumatoid arthritis.
The scope for this technology appraisal also included severe rheumatoid arthritis. This is covered by NICE technology appraisal guidance on upadacitinib for treating severe rheumatoid arthritis.
Upadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with 2 or more conventional disease‑modifying antirheumatic drugs (DMARDs), only if:
disease is moderate (a disease activity score of 3.2 to 5.1) and
the company provides upadacitinib according to the commercial arrangement.
Upadacitinib can be used as monotherapy when methotrexate is contraindicated or if people cannot tolerate it, when the criteria in section 1.1 are met.
If more than 1 treatment is suitable, start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary because of differences in how the drugs are used and treatment schedules.
Continue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6 months after starting therapy. If this initial response is not maintained, stop treatment.
Take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.
These recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Clinical trial evidence suggests that upadacitinib plus conventional DMARDs (including methotrexate) is more effective than placebo plus conventional DMARDs for treating moderate disease that has not responded well enough to conventional DMARDs. Evidence also suggests that upadacitinib alone is more effective than methotrexate for the same population.
Using methods accepted in NICE technology appraisal guidance 375 and NICE technology appraisal guidance 715, the cost-effectiveness estimate was within what NICE normally considers an acceptable use of NHS resources, although these methods may have to be reconsidered in future appraisals. So upadacitinib, alone or with methotrexate, is recommended for people with moderate rheumatoid arthritis whose disease has responded inadequately to intensive therapy with 2 or more conventional DMARDs.# Information about upadacitinib
# Marketing authorisation indication
Upadacitinib (Rinvoq, AbbVie) is indicated 'for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to 1 or more disease-modifying antirheumatic drugs (DMARDs)'. Upadacitinib may be used as monotherapy or in combination with methotrexate.
# Dosage in the marketing authorisation
The dosage schedule is available in upadacitinib's summary of product characteristics.
# Price
The list price for upadacitinib is £805.56 per 28‑day pack (company submission). The average cost for each patient per year is estimated at £10,508, based on the list price. The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage.
After technical engagement, there were a number of outstanding uncertainties in the analyses (see technical report, pages 13 to 14). The committee took these into account in its decision making.
# Treatments for rheumatoid arthritis
## A range of treatment options is important in rheumatoid arthritis and upadacitinib is an additional option
The patient expert explained that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are inadequate for many people with active rheumatoid arthritis. A range of biological and targeted synthetic DMARDs are available for moderate rheumatoid arthritis (see NICE technology appraisal guidance on filgotinib , and NICE's technology appraisal guidance on adalimumab, etanercept, infliximab and abatacept ). But these were not recommended at the time of the committee's discussion, so these treatments were not considered comparators. At the first committee meeting, patient experts explained that people with moderate disease that has not responded adequately to conventional DMARDs had few effective treatment options. The committee concluded that it is important for people with moderate rheumatoid arthritis to have a range of treatment options.
## There are 2 different points in the moderate disease treatment pathway when upadacitinib might be used
Disease severity is assessed using the disease activity score (DAS28). A DAS28 above 5.1 indicates severe disease and a DAS28 between 3.2 to 5.1 indicates moderate disease. Upadacitinib's marketing authorisation and the company's evidence submission covers its use at 2 points in the treatment pathway, specifically in adults with:
Moderate disease that has not responded adequately to 1 conventional DMARD. The comparator at this position was conventional DMARDs.
Moderate disease that has not responded adequately to 2 or more conventional DMARDs. At this position there were 2 potential comparators, conventional DMARDs or best supportive care (see section 3.3 and section 3.4).The committee noted that the marketing authorisation includes the use of upadacitinib alone or with methotrexate.
## The preferred position for upadacitinib is after 2 or more conventional DMARDs
The company presented results for upadacitinib at 2 positions in the moderate rheumatoid arthritis treatment pathway (see section 3.2). A clinical expert stated that it was more likely that upadacitinib would be used after 2 conventional DMARDs. Also, the European League Against Rheumatism (EULAR) guidelines state that 2 conventional DMARDs should be tried before considering a biological DMARD. But the guidelines recommend considering a biological DMARD after 1 conventional DMARD when poor prognostic factors are present. These include the presence of rheumatoid factor, antibodies against cyclic citrullinated peptide, high disease activity and early joint damage. The ERG explained that the company's network meta-analysis did not give separate results for people with a poor prognosis. Analyses done by the ERG showed that positioning upadacitinib after 1 conventional DMARD was more likely to lead to a cost-effectiveness estimate much higher than £30,000 per quality‑adjusted life year (QALY) gained than positioning it after 2 or more conventional DMARDs. The committee concluded that the most appropriate position for upadacitinib was after treatment with 2 or more conventional DMARDs. It also concluded that, if methotrexate was tolerated, upadacitinib plus methotrexate was preferred to upadacitinib alone. The committee noted that these conclusions were in line with previous NICE technology appraisals for rheumatoid arthritis.
## The appropriate comparator after 2 conventional DMARDs is best supportive care, which is unlikely to give a EULAR response
In the company and ERG analysis, after 2 conventional DMARDs, there were 2 potential comparators: further conventional DMARD treatment or best supportive care. The clinical expert explained that at this position, further treatment with conventional DMARDs was not expected to give a EULAR response. Despite this, patients are usually offered continued treatment with a combination of conventional DMARDs that have not been used previously, and corticosteroids are also a treatment option. The clinical expert also highlighted that after disease progression with methotrexate, it is unlikely to be used again except as part of combination therapy. The company explained that best supportive care after 2 conventional DMARDs included some continued conventional DMARDs, particularly methotrexate. The committee concluded that after 2 conventional DMARDs, best supportive care is the conventional DMARDs that had been used before, with optional corticosteroids. This was the most appropriate comparator in this group because it reflects clinical practice. The committee also concluded that best supportive care is unlikely to give a response measured using EULAR criteria but noted this was difficult to account for (see section 3.8).
# Clinical effectiveness
## Subgroup analyses of the moderate population in SELECT-NEXT and SELECT-MONOTHERAPY trials are most relevant for decision making, but may not reflect clinical practice
The company's clinical evidence came from 4 phase 3 randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis (defined in section 3.2). The trials were:
SELECT-COMPARE, which included people whose disease responded inadequately to methotrexate. Upadacitinib was taken with methotrexate and the comparator was adalimumab with methotrexate or placebo with methotrexate.
SELECT-NEXT, which included people whose disease responded inadequately to at least 1 conventional DMARD. Upadacitinib was taken with conventional DMARDs and the comparator was placebo with conventional DMARDs.
SELECT-MONOTHERAPY, which included people whose disease responded inadequately to methotrexate. Upadacitinib was taken as a monotherapy and the comparator was methotrexate.
SELECT-BEYOND, which included people whose disease responded inadequately to biological DMARDs. Upadacitinib was taken with conventional DMARDs and the comparator was conventional DMARDs and placebo.The committee considered the subgroup analyses of people with moderate disease. It noted that SELECT-NEXT was most relevant for the population who could tolerate methotrexate, because it included people who had an inadequate response to at least 1 conventional DMARD. It also included a higher proportion of people who were taking 2 conventional DMARDs at baseline than SELECT-COMPARE (the exact data is confidential and cannot be reported here). The only trial that included a treatment effect for upadacitinib alone was SELECT‑MONOTHERAPY. But it only included people who had had an inadequate response to methotrexate. The committee considered that it was reasonable to use the clinical‑effectiveness data from this trial, even though it did not reflect the population of people who could not tolerate methotrexate. The committee concluded that SELECT-NEXT and SELECT-MONOTHERAPY were acceptable for decision making but may not reflect clinical practice.
## Upadacitinib is more effective than conventional DMARDs for moderate disease
In the full population of SELECT-NEXT, upadacitinib with conventional DMARDs showed a statistically significant improvement in American College of Rheumatology response (ACR20) at 12 weeks, compared with placebo plus conventional DMARDs (upadacitinib 64%, placebo 36%, p˂0.001). In SELECT-MONOTHERAPY, upadacitinib alone showed a statistically significant improvement in ACR20 at 12 weeks compared with methotrexate alone (upadacitinib 68%, methotrexate 41%, p˂0.001). Similar results were seen for the moderate subgroups in both trials (exact data is confidential and cannot be reported here). The ERG and company considered that upadacitinib's safety profile is similar to that of other biological DMARDs. The committee concluded that upadacitinib plus conventional DMARDs (including methotrexate) is more clinically effective than placebo plus conventional DMARDs (including methotrexate) for moderate disease. Also, it concluded that upadacitinib alone was more clinically effective than methotrexate alone for moderate rheumatoid arthritis that has responded inadequately to conventional DMARDs.
## Direct head-to-head trial data is most appropriate to model efficacy of upadacitinib
A network meta-analysis was used for decision making for people with severe disease in NICE's technology appraisal guidance of upadacitinib for treating severe rheumatoid arthritis. However, the ERG explained that for moderate disease, it may be more appropriate to use the SELECT trials because:
the trials measured EULAR responses for all relevant comparators for moderate disease (with placebo plus conventional DMARDs used as a proxy for best supportive care, see section 3.8 and section 3.9)
the company's method for estimating the placebo effect in the network meta-analysis was uncertain and the ERG could not fully assess its reliability
using direct head-to-head evidence is in line with NICE's guide to the methods of technology appraisal. The committee concluded that direct head-to-head trial data was more appropriate to model efficacy of upadacitinib than the network meta-analysis results for moderate disease.
## Using the placebo arms of the SELECT trials to model the efficacy of best supportive care has limitations but is acceptable
The ERG modelled the efficacy of best supportive care based on the response rates seen in the placebo plus conventional DMARDs arm of the SELECT-NEXT trial (the SELECT-MONOTHERAPY trial was used to model cost effectiveness for people who could not tolerate methotrexate; see section 3.5). Best supportive care was the committee's preferred comparator and was not expected to give a EULAR response in clinical practice. However, the committee noted that a considerable response rate was seen in the placebo arms of the SELECT trials, as well as in other clinical trials in rheumatoid arthritis. It noted that this response could have been caused by several factors, including a placebo effect, disease resolving naturally over time, regression to the mean, response bias and variation in symptoms. Some of these factors might have also contributed to the response to upadacitinib in the SELECT trials. Therefore, the committee agreed it would not be appropriate to assume full clinical efficacy for upadacitinib while assuming no response to best supportive care. The ERG provided analyses that used SELECT-NEXT response rates for upadacitinib plus methotrexate and for placebo plus conventional DMARDs (a proxy for best supportive care) because it retained the relative treatment effect seen in the clinical evidence. In line with clinical expert opinion, the committee stated that it preferred to compare upadacitinib (with or without methotrexate) with methotrexate plus placebo (best supportive care) using data from the SELECT trials. After this, patients in both treatment arms would have conventional DMARDs with or without corticosteroids and no EULAR response would be expected in clinical practice. The committee concluded that the ERG's analyses had limitations because the trials did not fully reflect what is expected to happen in clinical practice, but were acceptable.
## Using estimates from the TA375 network meta-analysis to model the efficacy of best supportive care also has limitations but is acceptable
The committee was aware that since this appraisal began, TA715 had published. This was a partial review of NICE technology appraisal guidance 375 (TA375). In TA375, the efficacy of methotrexate from a network meta‑analysis was used to estimate the efficacy of best supportive care in the comparator arm of the model. In TA715, the committee agreed that because no new evidence was being considered in that appraisal, there was no strong reason to deviate from the assumptions in TA375. In its response to the second consultation, the company considered that applying the efficacy estimate from TA375 was the most consistent and transparent approach and there was no robust justification to change it. The committee noted that the treatment sequence in TA375 included methotrexate monotherapy before best supportive care. This was not consistent with clinical expert advice that methotrexate would only be used as part of combination therapy. It also noted that the network meta‑analysis in TA375 showed a moderate or good EULAR response in a significant number of patients on methotrexate, but clinical advice was that a EULAR response would not be expected at this point in the treatment pathway. The committee concluded that using estimates from the TA375 network meta‑analysis had limitations but may be acceptable. It agreed to consider this analysis as well as the analysis using the placebo arm of the SELECT trials (see section 3.8) in its decision making.
# Modelling progression from moderate to severe rheumatoid arthritis
## Assuming 19% of people have disease progression after 2 years is appropriate
The company's model included treatment for moderate disease that had progressed to severe disease. This was consistent with recent NICE technology appraisals on treating rheumatoid arthritis. The company modelled progression by estimating the relationship between the DAS28 and health assessment questionnaire (HAQ) results from the clinical evidence. HAQ is 1 component of the ACR20 response criteria. It scores physical disability and pain from 0 (least disability) to 3 (most severe disability). The ERG noted that the company's original model did not apply this estimated relationship. After the first consultation, the company submitted 2 scenario analyses assuming that 11% and 19% of people with moderate disease have disease progression to severe disease after 2 years. The ERG explained that this was in line with the figure predicted by the UK Early Rheumatoid Arthritis Network database (19%). The committee noted that in the company's scenario analyses, most people's disease progressed to severe after 12 years, which produced lower cost-effectiveness estimates for upadacitinib. The clinical expert estimated that in clinical practice around 30% of people with moderate disease were likely to have disease progression to severe disease by 12 years. However, at the second consultation, consultees explained that rheumatoid arthritis disease activity tends to be fairly stable over time and that analysis of the Early Rheumatoid Arthritis Study did not provide any evidence that a larger number of patients (than 19%) would have an increased DAS28 score over a longer period of time. The committee was aware that this estimate may no longer be correct because of the introduction of biologic DMARDs recommended in TA715 and TA676 but noted that in this analysis varying the rate of progression did not have a large impact on the cost-effectiveness results. It concluded that it was appropriate to assume that 19% of people with moderate disease have disease progression to severe disease after 2 years.
## Including an effect of methotrexate after upadacitinib for moderate rheumatoid arthritis is debatable
The committee considered the treatment sequences for the populations with moderate disease and whether it was appropriate to include a clinical effect for methotrexate after upadacitinib, and before best supportive care (which had no efficacy). The committee was aware that the original ERG report criticised this approach for allowing the upadacitinib arm of the model to count the placebo effect twice, while the comparator arm only counted it once. In the second consultation, the company noted that for moderate disease, TA375 assumed that methotrexate would be given after biological treatment and that this was associated with a response. The same assumption was used in TA715, and a similar assumption was made in NICE's technology appraisal guidance on baricitinib, tofacitinib and sarilumab, which did not make positive recommendations for moderate rheumatoid arthritis. A clinical expert considered that methotrexate would not be used as monotherapy again when it had already been used earlier in the pathway. They explained that methotrexate would be continued only as part of combination treatment. The committee considered it debatable whether methotrexate monotherapy would be used at this point in the treatment pathway or what size of response would be expected, if any. On balance, the committee agreed that although it was debatable, it would consider analyses that included an effect of methotrexate after upadacitinib in its decision making.
## Alternative treatment sequences after progression from moderate to severe disease are plausible
The committee understood that using upadacitinib to treat moderate disease could change the treatment pathway for severe disease. The ERG explored 3 alternative treatment sequences for severe disease: scenario 1, scenario 2 and a preferred scenario. These included people who could and could not tolerate methotrexate. For people who could tolerate methotrexate, all treatments were taken in combination with methotrexate. Table 1 describes the treatment options in each scenario at first, second and third line for severe disease. The ERG's clinical expert explained that for people whose disease progresses to severe, adalimumab would generally be used first because it is the cheapest biological DMARD. If there was an inadequate response, rituximab is likely to be used next, even for people who cannot tolerate methotrexate. The ERG's clinical expert explained that in the first scenario analysis, people who have had upadacitinib could have abatacept instead of sarilumab because it works in a different way to upadacitinib. The ERG's second scenario explored using upadacitinib instead of sarilumab because people tend to prefer oral treatments to subcutaneous injections. The clinical expert agreed that abatacept, sarilumab and upadacitinib could be used as third‑line treatment options. Fourth‑line treatment was best supportive care in all the scenarios. The clinical expert clarified that the decision to use a particular treatment would depend on several factors including infection risk, liver function and cost of treatment. Given the multiple factors used to decide the appropriate treatment, the committee agreed that it was difficult to know with certainty if upadacitinib should be included in the treatment sequences for severe disease in the comparator arm before it had been used in routine clinical practice. It agreed that sequences in both arms should reflect clinical practice. Sequences for both arms may include different treatment options depending on what patients have previously received at an earlier disease stage. The committee understood that TA375 and the summary of product characteristics for rituximab recommend it only in combination with methotrexate. It was concerned that the ERG's analyses may not reflect treatment sequences for people who cannot tolerate methotrexate, because rituximab is not licensed as a monotherapy. It understood that this was a small population and may reflect clinical practice but noted that treatment sequences may vary in the NHS in England. The committee concluded that the ERG's alternative treatment sequences for severe disease were plausible.
Scenario
Treatment arm
First‑line treatment for severe disease
Second‑line treatment for severe disease
Third‑line treatment for severe disease
Preferred
Upadacitinib
Adalimumab
Rituximab
Sarilumab
Preferred
Best supportive care
Adalimumab
Rituximab
Sarilumab
Scenario 1
Upadacitinib
Adalimumab
Rituximab
Abatacept (subcutaneous)
Scenario 1
Best supportive care
Adalimumab
Rituximab
Sarilumab
Scenario 2
Upadacitinib
Adalimumab
Rituximab
Sarilumab
Scenario 2
Best supportive care
Adalimumab
Rituximab
Upadacitinib
# Utility values
## The company's and the ERG's mapping algorithms are plausible methods for estimating utility values
In the company's base-case analysis, health-related quality of life data was calculated using a mapping function to work out a person's pain score from their HAQ score. The mapping algorithm used data from the SELECT trials to estimate EQ‑5D values. The ERG noted that TA375 used data from the National Databank for Rheumatic Diseases dataset to map pain scores from HAQ scores. It explained that the company's approach may be acceptable, but it preferred mapping based on the National Databank for Rheumatic Diseases dataset. This was because the dataset contained over 100,000 observations. After the first consultation, the company suggested that mapping based on the National Databank for Rheumatic Diseases dataset produced some counterintuitive results. Some of the lowest functionality was associated with a reduction in pain. The company noted that this did not happen using its preferred method of mapping using data from the clinical trials. The committee noted that the choice of mapping did not have a large effect on the cost‑effectiveness estimates for severe disease, because health‑related quality of life was similar across the different comparators. But it noted that for moderate disease, the company's method gave lower cost‑effectiveness estimates for upadacitinib compared with best supportive care. The committee concluded that both mapping approaches were plausible, but noted that the ERG's approach was used in TA375 and was based on a much larger dataset.
## The company's approach to modelling long-term health assessment questionnaire results is acceptable
In the ERG's preferred base-case analysis, people whose disease responded to best supportive care were assumed to have the same long‑term HAQ results as those whose disease responded to biological DMARDs. The ERG explained that a large amount of the upadacitinib response was likely to have been caused by a placebo effect. This was also present in the trial control arms, so it may be inappropriate to make different assumptions about long-term HAQ results in the model. The clinical and patient experts advised that natural recovery from symptoms is rare, and it would not be sustained for a long time. The committee agreed that applying the long‑term HAQ results associated with biological DMARDs to best supportive care was likely to be an overly optimistic assumption. In response to technical engagement, the company provided an alternative scenario analysis. In this, people whose disease responded to best supportive care were assumed to have the same long‑term HAQ results as those whose disease responded to conventional DMARDs. The committee concluded that it was appropriate to assume that people whose disease responded to best supportive care had the same decreasing long‑term HAQ results as people whose disease responded to conventional DMARDs. This was consistent with previous NICE technology appraisals in rheumatoid arthritis.
# Economic model validation
## The company's model is reasonably consistent with the model used in TA375
The company based its model on the model developed by the assessment group for TA375. The company provided a validation analysis comparing the outputs of its model with those from the model used in TA375, for several treatment sequences. The ERG suggested that the results of this analysis appeared to show that the company's model overestimated QALY gains for biological DMARDs compared with conventional DMARDs. It explained that this mostly affects the cost‑effectiveness analysis for moderate disease, when upadacitinib is compared with conventional DMARDs. At the committee meeting, the company advised that it had found errors in the ERG's validation analysis and that its own model produced similar results to the TA375 model. After the first consultation, the company submitted further validation results that included corrections of 4 errors. The ERG noted that after consultation the company's results were reasonably aligned with TA375. The committee concluded that the company's model is reasonably consistent with the model used in TA375, which was considered acceptable for decision making.
# Cost-effectiveness results
## Upadacitinib with methotrexate is cost effective after 2 conventional DMARDs
The committee evaluated the cost effectiveness of upadacitinib for moderate disease considering the following conclusions:
The most appropriate position for upadacitinib in the moderate rheumatoid arthritis treatment pathway is after 2 or more conventional DMARDs (see section 3.3).
Best supportive care is the relevant comparator at this point in the treatment pathway (see section 3.4).
Subgroup analyses including only the moderate population from SELECT-NEXT and SELECT‑MONOTHERAPY are appropriate to model the efficacy of upadacitinib (see section 3.5). Using the placebo arm of the SELECT trials or the methotrexate estimate from the TA375 network meta‑analysis is acceptable to model the efficacy of best supportive care (see section 3.8 and section 3.9). After this, all people had further best supportive care with no efficacy until their disease had progressed to severe.
Although debatable, analyses that include a treatment effect for methotrexate or best supportive care after upadacitinib should be considered (see section 3.11).
It is appropriate to assume that 19% of people with moderate disease have disease progression to severe disease after 2 years (see section 3.10).
The ERG's alternative treatment sequences for severe disease were plausible but uncertain, particularly for the population who cannot tolerate methotrexate (see section 3.12).
The company's and the ERG's mapping algorithms that link HAQ and pain scores are plausible methods for estimating utility values (see section 3.13).
It is appropriate to assume that long-term HAQ results after response to best supportive care are different than after response to biological DMARDs (see section 3.14).The ERG included the confidential discounts for the comparators and subsequent treatments in its analyses. Because of these confidential discounts, the exact incremental cost‑effectiveness ratios (ICERs) cannot be reported here. When including methotrexate after upadacitinib in the treatment sequence and the TA375 network meta-analysis estimate, the ICER was between £20,000 and £30,000 per QALY gained, compared with best supportive care. The committee also considered scenarios using alternative treatments and using the SELECT trials placebo results. These gave ICERs above £30,000 per QALY gained compared with best supportive care. The committee considered the benefits and risks of routinely commissioning upadacitinib for the NHS. It acknowledged that although several treatment options (such as filgotinib, adalimumab, etanercept and infliximab) were now available, it was important for people with moderate rheumatoid arthritis to have a range of treatment options (see section 3.1). It agreed that patients, carers and healthcare professionals would need to consider the advantages and disadvantages of each technology. If more than 1 treatment is suitable, the committee considered that choosing the least expensive treatment would be important, especially for technologies with reasonably similar mechanisms of action. It agreed that choosing the least expensive option would be an appropriate way to manage financial risk to the NHS. The committee considered that using methods accepted in TA375 and TA715, the cost‑effectiveness estimate was in the range that NICE normally considers an acceptable use of NHS resources. However, it noted that these methods may have to be reconsidered in future appraisals (see section 3.18). The committee concluded that it could recommend upadacitinib with methotrexate as a cost‑effective use of NHS resources for people with moderate rheumatoid arthritis whose disease has responded inadequately to intensive therapy with 2 or more conventional DMARDs. In line with previous NICE guidance for rheumatoid arthritis, the committee also concluded that treatment should continue only if there is a moderate response measured using the EULAR criteria at 6 months after starting therapy.
## Upadacitinib monotherapy's cost effectiveness is more uncertain but it is likely to be a reasonable use of NHS resources if methotrexate is unsuitable
The committee noted that the cost-effectiveness estimates for upadacitinib monotherapy would be higher than for upadacitinib plus methotrexate, because methotrexate could not be included in the treatment sequence. This would have the most impact when removing methotrexate from the treatment sequence from its position after upadacitinib in moderate disease (see section 3.11). However, the committee noted that this population is much smaller than the population who can have methotrexate. In line with previous appraisals for rheumatoid arthritis, it agreed that the small number of people who could not tolerate methotrexate should not be disadvantaged compared with other people with moderate disease, as far as possible. Therefore, the committee recommended upadacitinib monotherapy when methotrexate is contraindicated or if people cannot tolerate it.
## Cost-effectiveness modelling assumptions for future rheumatoid arthritis technologies may need to be reconsidered
The committee noted that the treatment pathway for moderate rheumatoid arthritis was now substantially different from the assumptions used in TA715 and TA676. Committees considering technologies for rheumatoid arthritis in the future may need to reconsider cost-effectiveness modelling assumptions in the following areas:
The sequence of treatments available for moderate and severe disease in both the intervention and comparator arms so that it truly reflects current NHS practice.
The treatment effect for methotrexate or best supportive care for moderate disease.
Estimates of the proportion of people with moderate disease who have disease progression to severe disease.
# Other factors
## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure
During the scoping process a potential equality issue was raised about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.
## The benefits of upadacitinib were captured in the cost-effectiveness analysis
Upadacitinib, like several other biological DMARDs, is taken orally. This is valued by patients. The committee noted that there are other oral treatments with a similar mechanism of action available for rheumatoid arthritis. It concluded that all the benefits of upadacitinib were captured in the model.
|
{'Recommendations': 'This guidance only includes recommendations for treating moderate rheumatoid arthritis.\n\nThe scope for this technology appraisal also included severe rheumatoid arthritis. This is covered by NICE technology appraisal guidance on upadacitinib for treating severe rheumatoid arthritis.\n\nUpadacitinib, with methotrexate, is recommended as an option for treating active rheumatoid arthritis in adults whose disease has responded inadequately to intensive therapy with 2 or more conventional disease‑modifying antirheumatic drugs (DMARDs), only if:\n\ndisease is moderate (a disease activity score [DAS28] of 3.2 to 5.1) and\n\nthe company provides upadacitinib according to the commercial arrangement.\n\nUpadacitinib can be used as monotherapy when methotrexate is contraindicated or if people cannot tolerate it, when the criteria in section\xa01.1 are met.\n\nIf more than 1 treatment is suitable, start treatment with the least expensive drug (taking into account administration costs, dose needed and product price per dose). This may vary because of differences in how the drugs are used and treatment schedules.\n\nContinue treatment only if there is a moderate response measured using European League Against Rheumatism (EULAR) criteria at 6\xa0months after starting therapy. If this initial response is not maintained, stop treatment.\n\nTake into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.\n\nThese recommendations are not intended to affect treatment with upadacitinib that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nClinical trial evidence suggests that upadacitinib plus conventional DMARDs (including methotrexate) is more effective than placebo plus conventional DMARDs for treating moderate disease that has not responded well enough to conventional DMARDs. Evidence also suggests that upadacitinib alone is more effective than methotrexate for the same population.\n\nUsing methods accepted in NICE technology appraisal guidance 375 and NICE technology appraisal guidance 715, the cost-effectiveness estimate was within what NICE normally considers an acceptable use of NHS resources, although these methods may have to be reconsidered in future appraisals. So upadacitinib, alone or with methotrexate, is recommended for people with moderate rheumatoid arthritis whose disease has responded inadequately to intensive therapy with 2 or more conventional DMARDs.', 'Information about upadacitinib': "# Marketing authorisation indication\n\nUpadacitinib (Rinvoq, AbbVie) is indicated 'for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to 1 or more disease-modifying antirheumatic drugs (DMARDs)'. Upadacitinib may be used as monotherapy or in combination with methotrexate.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in upadacitinib's summary of product characteristics.\n\n# Price\n\nThe list price for upadacitinib is £805.56 per 28‑day pack (company submission). The average cost for each patient per year is estimated at £10,508, based on the list price. The company has a commercial arrangement. This makes upadacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by AbbVie, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage.\n\nAfter technical engagement, there were a number of outstanding uncertainties in the analyses (see technical report, pages\xa013 to\xa014). The committee took these into account in its decision making.\n\n# Treatments for rheumatoid arthritis\n\n## A range of treatment options is important in rheumatoid arthritis and upadacitinib is an additional option\n\nThe patient expert explained that rheumatoid arthritis is a lifetime condition that can severely reduce quality of life. The clinical experts stated that conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate are inadequate for many people with active rheumatoid arthritis. A range of biological and targeted synthetic DMARDs are available for moderate rheumatoid arthritis (see NICE technology appraisal guidance on filgotinib [TA676], and NICE's technology appraisal guidance on adalimumab, etanercept, infliximab and abatacept [TA715]). But these were not recommended at the time of the committee's discussion, so these treatments were not considered comparators. At the first committee meeting, patient experts explained that people with moderate disease that has not responded adequately to conventional DMARDs had few effective treatment options. The committee concluded that it is important for people with moderate rheumatoid arthritis to have a range of treatment options.\n\n## There are 2 different points in the moderate disease treatment pathway when upadacitinib might be used\n\nDisease severity is assessed using the disease activity score (DAS28). A DAS28 above 5.1 indicates severe disease and a DAS28 between 3.2 to 5.1 indicates moderate disease. Upadacitinib's marketing authorisation and the company's evidence submission covers its use at 2\xa0points in the treatment pathway, specifically in adults with:\n\nModerate disease that has not responded adequately to 1\xa0conventional DMARD. The comparator at this position was conventional DMARDs.\n\nModerate disease that has not responded adequately to 2 or more conventional DMARDs. At this position there were 2 potential comparators, conventional DMARDs or best supportive care (see section\xa03.3 and section\xa03.4).The committee noted that the marketing authorisation includes the use of upadacitinib alone or with methotrexate.\n\n## The preferred position for upadacitinib is after 2 or more conventional DMARDs\n\nThe company presented results for upadacitinib at 2\xa0positions in the moderate rheumatoid arthritis treatment pathway (see section\xa03.2). A clinical expert stated that it was more likely that upadacitinib would be used after 2\xa0conventional DMARDs. Also, the European League Against Rheumatism (EULAR) guidelines state that 2\xa0conventional DMARDs should be tried before considering a biological DMARD. But the guidelines recommend considering a biological DMARD after 1\xa0conventional DMARD when poor prognostic factors are present. These include the presence of rheumatoid factor, antibodies against cyclic citrullinated peptide, high disease activity and early joint damage. The ERG explained that the company's network meta-analysis did not give separate results for people with a poor prognosis. Analyses done by the ERG showed that positioning upadacitinib after 1\xa0conventional DMARD was more likely to lead to a cost-effectiveness estimate much higher than £30,000 per quality‑adjusted life year (QALY) gained than positioning it after 2 or more conventional DMARDs. The committee concluded that the most appropriate position for upadacitinib was after treatment with 2 or more conventional DMARDs. It also concluded that, if methotrexate was tolerated, upadacitinib plus methotrexate was preferred to upadacitinib alone. The committee noted that these conclusions were in line with previous NICE technology appraisals for rheumatoid arthritis.\n\n## The appropriate comparator after 2 conventional DMARDs is best supportive care, which is unlikely to give a EULAR response\n\nIn the company and ERG analysis, after 2\xa0conventional DMARDs, there were 2\xa0potential comparators: further conventional DMARD treatment or best supportive care. The clinical expert explained that at this position, further treatment with conventional DMARDs was not expected to give a EULAR response. Despite this, patients are usually offered continued treatment with a combination of conventional DMARDs that have not been used previously, and corticosteroids are also a treatment option. The clinical expert also highlighted that after disease progression with methotrexate, it is unlikely to be used again except as part of combination therapy. The company explained that best supportive care after 2\xa0conventional DMARDs included some continued conventional DMARDs, particularly methotrexate. The committee concluded that after 2\xa0conventional DMARDs, best supportive care is the conventional DMARDs that had been used before, with optional corticosteroids. This was the most appropriate comparator in this group because it reflects clinical practice. The committee also concluded that best supportive care is unlikely to give a response measured using EULAR criteria but noted this was difficult to account for (see section\xa03.8).\n\n# Clinical effectiveness\n\n## Subgroup analyses of the moderate population in SELECT-NEXT and SELECT-MONOTHERAPY trials are most relevant for decision making, but may not reflect clinical practice\n\nThe company's clinical evidence came from 4\xa0phase\xa03 randomised controlled trials. The trials included people with moderate to severe rheumatoid arthritis (defined in section\xa03.2). The trials were:\n\nSELECT-COMPARE, which included people whose disease responded inadequately to methotrexate. Upadacitinib was taken with methotrexate and the comparator was adalimumab with methotrexate or placebo with methotrexate.\n\nSELECT-NEXT, which included people whose disease responded inadequately to at least 1\xa0conventional DMARD. Upadacitinib was taken with conventional DMARDs and the comparator was placebo with conventional DMARDs.\n\nSELECT-MONOTHERAPY, which included people whose disease responded inadequately to methotrexate. Upadacitinib was taken as a monotherapy and the comparator was methotrexate.\n\nSELECT-BEYOND, which included people whose disease responded inadequately to biological DMARDs. Upadacitinib was taken with conventional DMARDs and the comparator was conventional DMARDs and placebo.The committee considered the subgroup analyses of people with moderate disease. It noted that SELECT-NEXT was most relevant for the population who could tolerate methotrexate, because it included people who had an inadequate response to at least 1\xa0conventional DMARD. It also included a higher proportion of people who were taking 2\xa0conventional DMARDs at baseline than SELECT-COMPARE (the exact data is confidential and cannot be reported here). The only trial that included a treatment effect for upadacitinib alone was SELECT‑MONOTHERAPY. But it only included people who had had an inadequate response to methotrexate. The committee considered that it was reasonable to use the clinical‑effectiveness data from this trial, even though it did not reflect the population of people who could not tolerate methotrexate. The committee concluded that SELECT-NEXT and SELECT-MONOTHERAPY were acceptable for decision making but may not reflect clinical practice.\n\n## Upadacitinib is more effective than conventional DMARDs for moderate disease\n\nIn the full population of SELECT-NEXT, upadacitinib with conventional DMARDs showed a statistically significant improvement in American College of Rheumatology response (ACR20) at 12\xa0weeks, compared with placebo plus conventional DMARDs (upadacitinib 64%, placebo 36%, p˂0.001). In SELECT-MONOTHERAPY, upadacitinib alone showed a statistically significant improvement in ACR20 at 12\xa0weeks compared with methotrexate alone (upadacitinib 68%, methotrexate 41%, p˂0.001). Similar results were seen for the moderate subgroups in both trials (exact data is confidential and cannot be reported here). The ERG and company considered that upadacitinib's safety profile is similar to that of other biological DMARDs. The committee concluded that upadacitinib plus conventional DMARDs (including methotrexate) is more clinically effective than placebo plus conventional DMARDs (including methotrexate) for moderate disease. Also, it concluded that upadacitinib alone was more clinically effective than methotrexate alone for moderate rheumatoid arthritis that has responded inadequately to conventional DMARDs.\n\n## Direct head-to-head trial data is most appropriate to model efficacy of upadacitinib\n\nA network meta-analysis was used for decision making for people with severe disease in NICE's technology appraisal guidance of upadacitinib for treating severe rheumatoid arthritis. However, the ERG explained that for moderate disease, it may be more appropriate to use the SELECT trials because:\n\nthe trials measured EULAR responses for all relevant comparators for moderate disease (with placebo plus conventional DMARDs used as a proxy for best supportive care, see section\xa03.8 and section\xa03.9)\n\nthe company's method for estimating the placebo effect in the network meta-analysis was uncertain and the ERG could not fully assess its reliability\n\nusing direct head-to-head evidence is in line with NICE's guide to the methods of technology appraisal. The committee concluded that direct head-to-head trial data was more appropriate to model efficacy of upadacitinib than the network meta-analysis results for moderate disease.\n\n## Using the placebo arms of the SELECT trials to model the efficacy of best supportive care has limitations but is acceptable\n\nThe ERG modelled the efficacy of best supportive care based on the response rates seen in the placebo plus conventional DMARDs arm of the SELECT-NEXT trial (the SELECT-MONOTHERAPY trial was used to model cost effectiveness for people who could not tolerate methotrexate; see section\xa03.5). Best supportive care was the committee's preferred comparator and was not expected to give a EULAR response in clinical practice. However, the committee noted that a considerable response rate was seen in the placebo arms of the SELECT trials, as well as in other clinical trials in rheumatoid arthritis. It noted that this response could have been caused by several factors, including a placebo effect, disease resolving naturally over time, regression to the mean, response bias and variation in symptoms. Some of these factors might have also contributed to the response to upadacitinib in the SELECT trials. Therefore, the committee agreed it would not be appropriate to assume full clinical efficacy for upadacitinib while assuming no response to best supportive care. The ERG provided analyses that used SELECT-NEXT response rates for upadacitinib plus methotrexate and for placebo plus conventional DMARDs (a proxy for best supportive care) because it retained the relative treatment effect seen in the clinical evidence. In line with clinical expert opinion, the committee stated that it preferred to compare upadacitinib (with or without methotrexate) with methotrexate plus placebo (best supportive care) using data from the SELECT trials. After this, patients in both treatment arms would have conventional DMARDs with or without corticosteroids and no EULAR response would be expected in clinical practice. The committee concluded that the ERG's analyses had limitations because the trials did not fully reflect what is expected to happen in clinical practice, but were acceptable.\n\n## Using estimates from the TA375 network meta-analysis to model the efficacy of best supportive care also has limitations but is acceptable\n\nThe committee was aware that since this appraisal began, TA715 had published. This was a partial review of NICE technology appraisal guidance 375 (TA375). In TA375, the efficacy of methotrexate from a network meta‑analysis was used to estimate the efficacy of best supportive care in the comparator arm of the model. In TA715, the committee agreed that because no new evidence was being considered in that appraisal, there was no strong reason to deviate from the assumptions in TA375. In its response to the second consultation, the company considered that applying the efficacy estimate from TA375 was the most consistent and transparent approach and there was no robust justification to change it. The committee noted that the treatment sequence in TA375 included methotrexate monotherapy before best supportive care. This was not consistent with clinical expert advice that methotrexate would only be used as part of combination therapy. It also noted that the network meta‑analysis in TA375 showed a moderate or good EULAR response in a significant number of patients on methotrexate, but clinical advice was that a EULAR response would not be expected at this point in the treatment pathway. The committee concluded that using estimates from the TA375 network meta‑analysis had limitations but may be acceptable. It agreed to consider this analysis as well as the analysis using the placebo arm of the SELECT trials (see section\xa03.8) in its decision making.\n\n# Modelling progression from moderate to severe rheumatoid arthritis\n\n## Assuming 19% of people have disease progression after 2 years is appropriate\n\nThe company's model included treatment for moderate disease that had progressed to severe disease. This was consistent with recent NICE technology appraisals on treating rheumatoid arthritis. The company modelled progression by estimating the relationship between the DAS28 and health assessment questionnaire (HAQ) results from the clinical evidence. HAQ is 1\xa0component of the ACR20 response criteria. It scores physical disability and pain from 0 (least disability) to 3 (most severe disability). The ERG noted that the company's original model did not apply this estimated relationship. After the first consultation, the company submitted 2\xa0scenario analyses assuming that 11% and 19% of people with moderate disease have disease progression to severe disease after 2\xa0years. The ERG explained that this was in line with the figure predicted by the UK Early Rheumatoid Arthritis Network database (19%). The committee noted that in the company's scenario analyses, most people's disease progressed to severe after 12\xa0years, which produced lower cost-effectiveness estimates for upadacitinib. The clinical expert estimated that in clinical practice around 30% of people with moderate disease were likely to have disease progression to severe disease by 12\xa0years. However, at the second consultation, consultees explained that rheumatoid arthritis disease activity tends to be fairly stable over time and that analysis of the Early Rheumatoid Arthritis Study did not provide any evidence that a larger number of patients (than 19%) would have an increased DAS28 score over a longer period of time. The committee was aware that this estimate may no longer be correct because of the introduction of biologic DMARDs recommended in TA715 and TA676 but noted that in this analysis varying the rate of progression did not have a large impact on the cost-effectiveness results. It concluded that it was appropriate to assume that 19% of people with moderate disease have disease progression to severe disease after 2\xa0years.\n\n## Including an effect of methotrexate after upadacitinib for moderate rheumatoid arthritis is debatable\n\nThe committee considered the treatment sequences for the populations with moderate disease and whether it was appropriate to include a clinical effect for methotrexate after upadacitinib, and before best supportive care (which had no efficacy). The committee was aware that the original ERG report criticised this approach for allowing the upadacitinib arm of the model to count the placebo effect twice, while the comparator arm only counted it once. In the second consultation, the company noted that for moderate disease, TA375 assumed that methotrexate would be given after biological treatment and that this was associated with a response. The same assumption was used in TA715, and a similar assumption was made in NICE's technology appraisal guidance on baricitinib, tofacitinib and sarilumab, which did not make positive recommendations for moderate rheumatoid arthritis. A clinical expert considered that methotrexate would not be used as monotherapy again when it had already been used earlier in the pathway. They explained that methotrexate would be continued only as part of combination treatment. The committee considered it debatable whether methotrexate monotherapy would be used at this point in the treatment pathway or what size of response would be expected, if any. On balance, the committee agreed that although it was debatable, it would consider analyses that included an effect of methotrexate after upadacitinib in its decision making.\n\n## Alternative treatment sequences after progression from moderate to severe disease are plausible\n\nThe committee understood that using upadacitinib to treat moderate disease could change the treatment pathway for severe disease. The ERG explored 3\xa0alternative treatment sequences for severe disease: scenario\xa01, scenario\xa02 and a preferred scenario. These included people who could and could not tolerate methotrexate. For people who could tolerate methotrexate, all treatments were taken in combination with methotrexate. Table\xa01 describes the treatment options in each scenario at first, second and third line for severe disease. The ERG's clinical expert explained that for people whose disease progresses to severe, adalimumab would generally be used first because it is the cheapest biological DMARD. If there was an inadequate response, rituximab is likely to be used next, even for people who cannot tolerate methotrexate. The ERG's clinical expert explained that in the first scenario analysis, people who have had upadacitinib could have abatacept instead of sarilumab because it works in a different way to upadacitinib. The ERG's second scenario explored using upadacitinib instead of sarilumab because people tend to prefer oral treatments to subcutaneous injections. The clinical expert agreed that abatacept, sarilumab and upadacitinib could be used as third‑line treatment options. Fourth‑line treatment was best supportive care in all the scenarios. The clinical expert clarified that the decision to use a particular treatment would depend on several factors including infection risk, liver function and cost of treatment. Given the multiple factors used to decide the appropriate treatment, the committee agreed that it was difficult to know with certainty if upadacitinib should be included in the treatment sequences for severe disease in the comparator arm before it had been used in routine clinical practice. It agreed that sequences in both arms should reflect clinical practice. Sequences for both arms may include different treatment options depending on what patients have previously received at an earlier disease stage. The committee understood that TA375 and the summary of product characteristics for rituximab recommend it only in combination with methotrexate. It was concerned that the ERG's analyses may not reflect treatment sequences for people who cannot tolerate methotrexate, because rituximab is not licensed as a monotherapy. It understood that this was a small population and may reflect clinical practice but noted that treatment sequences may vary in the NHS in England. The committee concluded that the ERG's alternative treatment sequences for severe disease were plausible.\n\nScenario\n\nTreatment arm\n\nFirst‑line treatment for severe disease\n\nSecond‑line treatment for severe disease\n\nThird‑line treatment for severe disease\n\nPreferred\n\nUpadacitinib\n\nAdalimumab\n\nRituximab\n\nSarilumab\n\nPreferred\n\nBest supportive care\n\nAdalimumab\n\nRituximab\n\nSarilumab\n\nScenario 1\n\nUpadacitinib\n\nAdalimumab\n\nRituximab\n\nAbatacept (subcutaneous)\n\nScenario 1\n\nBest supportive care\n\nAdalimumab\n\nRituximab\n\nSarilumab\n\nScenario 2\n\nUpadacitinib\n\nAdalimumab\n\nRituximab\n\nSarilumab\n\nScenario 2\n\nBest supportive care\n\nAdalimumab\n\nRituximab\n\nUpadacitinib\n\n# Utility values\n\n## The company's and the ERG's mapping algorithms are plausible methods for estimating utility values\n\nIn the company's base-case analysis, health-related quality of life data was calculated using a mapping function to work out a person's pain score from their HAQ score. The mapping algorithm used data from the SELECT trials to estimate EQ‑5D values. The ERG noted that TA375 used data from the National Databank for Rheumatic Diseases dataset to map pain scores from HAQ scores. It explained that the company's approach may be acceptable, but it preferred mapping based on the National Databank for Rheumatic Diseases dataset. This was because the dataset contained over 100,000\xa0observations. After the first consultation, the company suggested that mapping based on the National Databank for Rheumatic Diseases dataset produced some counterintuitive results. Some of the lowest functionality was associated with a reduction in pain. The company noted that this did not happen using its preferred method of mapping using data from the clinical trials. The committee noted that the choice of mapping did not have a large effect on the cost‑effectiveness estimates for severe disease, because health‑related quality of life was similar across the different comparators. But it noted that for moderate disease, the company's method gave lower cost‑effectiveness estimates for upadacitinib compared with best supportive care. The committee concluded that both mapping approaches were plausible, but noted that the ERG's approach was used in TA375 and was based on a much larger dataset.\n\n## The company's approach to modelling long-term health assessment questionnaire results is acceptable\n\nIn the ERG's preferred base-case analysis, people whose disease responded to best supportive care were assumed to have the same long‑term HAQ results as those whose disease responded to biological DMARDs. The ERG explained that a large amount of the upadacitinib response was likely to have been caused by a placebo effect. This was also present in the trial control arms, so it may be inappropriate to make different assumptions about long-term HAQ results in the model. The clinical and patient experts advised that natural recovery from symptoms is rare, and it would not be sustained for a long time. The committee agreed that applying the long‑term HAQ results associated with biological DMARDs to best supportive care was likely to be an overly optimistic assumption. In response to technical engagement, the company provided an alternative scenario analysis. In this, people whose disease responded to best supportive care were assumed to have the same long‑term HAQ results as those whose disease responded to conventional DMARDs. The committee concluded that it was appropriate to assume that people whose disease responded to best supportive care had the same decreasing long‑term HAQ results as people whose disease responded to conventional DMARDs. This was consistent with previous NICE technology appraisals in rheumatoid arthritis.\n\n# Economic model validation\n\n## The company's model is reasonably consistent with the model used in TA375\n\nThe company based its model on the model developed by the assessment group for TA375. The company provided a validation analysis comparing the outputs of its model with those from the model used in TA375, for several treatment sequences. The ERG suggested that the results of this analysis appeared to show that the company's model overestimated QALY gains for biological DMARDs compared with conventional DMARDs. It explained that this mostly affects the cost‑effectiveness analysis for moderate disease, when upadacitinib is compared with conventional DMARDs. At the committee meeting, the company advised that it had found errors in the ERG's validation analysis and that its own model produced similar results to the TA375 model. After the first consultation, the company submitted further validation results that included corrections of 4\xa0errors. The ERG noted that after consultation the company's results were reasonably aligned with TA375. The committee concluded that the company's model is reasonably consistent with the model used in TA375, which was considered acceptable for decision making.\n\n# Cost-effectiveness results\n\n## Upadacitinib with methotrexate is cost effective after 2\xa0conventional DMARDs\n\nThe committee evaluated the cost effectiveness of upadacitinib for moderate disease considering the following conclusions:\n\nThe most appropriate position for upadacitinib in the moderate rheumatoid arthritis treatment pathway is after 2 or more conventional DMARDs (see section\xa03.3).\n\nBest supportive care is the relevant comparator at this point in the treatment pathway (see section\xa03.4).\n\nSubgroup analyses including only the moderate population from SELECT-NEXT and SELECT‑MONOTHERAPY are appropriate to model the efficacy of upadacitinib (see section\xa03.5). Using the placebo arm of the SELECT trials or the methotrexate estimate from the TA375 network meta‑analysis is acceptable to model the efficacy of best supportive care (see section\xa03.8 and section\xa03.9). After this, all people had further best supportive care with no efficacy until their disease had progressed to severe.\n\nAlthough debatable, analyses that include a treatment effect for methotrexate or best supportive care after upadacitinib should be considered (see section\xa03.11).\n\nIt is appropriate to assume that 19% of people with moderate disease have disease progression to severe disease after 2\xa0years (see section\xa03.10).\n\nThe ERG's alternative treatment sequences for severe disease were plausible but uncertain, particularly for the population who cannot tolerate methotrexate (see section\xa03.12).\n\nThe company's and the ERG's mapping algorithms that link HAQ and pain scores are plausible methods for estimating utility values (see section\xa03.13).\n\nIt is appropriate to assume that long-term HAQ results after response to best supportive care are different than after response to biological DMARDs (see section\xa03.14).The ERG included the confidential discounts for the comparators and subsequent treatments in its analyses. Because of these confidential discounts, the exact incremental cost‑effectiveness ratios (ICERs) cannot be reported here. When including methotrexate after upadacitinib in the treatment sequence and the TA375 network meta-analysis estimate, the ICER was between £20,000 and £30,000 per QALY gained, compared with best supportive care. The committee also considered scenarios using alternative treatments and using the SELECT trials placebo results. These gave ICERs above £30,000 per QALY gained compared with best supportive care. The committee considered the benefits and risks of routinely commissioning upadacitinib for the NHS. It acknowledged that although several treatment options (such as filgotinib, adalimumab, etanercept and infliximab) were now available, it was important for people with moderate rheumatoid arthritis to have a range of treatment options (see section\xa03.1). It agreed that patients, carers and healthcare professionals would need to consider the advantages and disadvantages of each technology. If more than 1\xa0treatment is suitable, the committee considered that choosing the least expensive treatment would be important, especially for technologies with reasonably similar mechanisms of action. It agreed that choosing the least expensive option would be an appropriate way to manage financial risk to the NHS. The committee considered that using methods accepted in TA375 and TA715, the cost‑effectiveness estimate was in the range that NICE normally considers an acceptable use of NHS resources. However, it noted that these methods may have to be reconsidered in future appraisals (see section\xa03.18). The committee concluded that it could recommend upadacitinib with methotrexate as a cost‑effective use of NHS resources for people with moderate rheumatoid arthritis whose disease has responded inadequately to intensive therapy with 2 or more conventional DMARDs. In line with previous NICE guidance for rheumatoid arthritis, the committee also concluded that treatment should continue only if there is a moderate response measured using the EULAR criteria at 6\xa0months after starting therapy.\n\n## Upadacitinib monotherapy's cost effectiveness is more uncertain but it is likely to be a reasonable use of NHS resources if methotrexate is unsuitable\n\nThe committee noted that the cost-effectiveness estimates for upadacitinib monotherapy would be higher than for upadacitinib plus methotrexate, because methotrexate could not be included in the treatment sequence. This would have the most impact when removing methotrexate from the treatment sequence from its position after upadacitinib in moderate disease (see section\xa03.11). However, the committee noted that this population is much smaller than the population who can have methotrexate. In line with previous appraisals for rheumatoid arthritis, it agreed that the small number of people who could not tolerate methotrexate should not be disadvantaged compared with other people with moderate disease, as far as possible. Therefore, the committee recommended upadacitinib monotherapy when methotrexate is contraindicated or if people cannot tolerate it.\n\n## Cost-effectiveness modelling assumptions for future rheumatoid arthritis technologies may need to be reconsidered\n\nThe committee noted that the treatment pathway for moderate rheumatoid arthritis was now substantially different from the assumptions used in TA715 and TA676. Committees considering technologies for rheumatoid arthritis in the future may need to reconsider cost-effectiveness modelling assumptions in the following areas:\n\nThe sequence of treatments available for moderate and severe disease in both the intervention and comparator arms so that it truly reflects current NHS practice.\n\nThe treatment effect for methotrexate or best supportive care for moderate disease.\n\nEstimates of the proportion of people with moderate disease who have disease progression to severe disease.\n\n# Other factors\n\n## Healthcare professionals should consider any disabilities or communication difficulties when using the DAS28 measure\n\nDuring the scoping process a potential equality issue was raised about people with rheumatoid arthritis who have difficulty communicating. For these people, it may be more difficult to assess outcomes when using the DAS28 measure. The committee concluded that healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DAS28 and make any appropriate adjustments.\n\n## The benefits of upadacitinib were captured in the cost-effectiveness analysis\n\nUpadacitinib, like several other biological DMARDs, is taken orally. This is valued by patients. The committee noted that there are other oral treatments with a similar mechanism of action available for rheumatoid arthritis. It concluded that all the benefits of upadacitinib were captured in the model."}
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https://www.nice.org.uk/guidance/ta744
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Evidence-based recommendations on upadacitinib (Rinvoq) for treating moderate active rheumatoid arthritis in adults.
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779f5b530bf054465ae704c8c0847c5e0eaa159f
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nice
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Inducing labour
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Inducing labour
This guideline covers the circumstances for inducing labour, methods of induction, assessment, monitoring, pain relief and managing complications. It aims to improve advice and care for pregnant women who are thinking about or having induction of labour.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Information and decision making
This section should be read in conjunction with the NICE guidelines on antenatal care, caesarean birth and intrapartum care for healthy women and babies.
Discuss preferences about mode of birth with women early on in their pregnancy. Take into account their individual circumstances, and discuss that options for birth can include:
expectant management, or
induction of labour, or
planned caesarean birth (see the NICE guideline on caesarean birth).Record these discussions and the woman's preferences in her notes.
Confirm a woman's preferences for birth at antenatal visits towards the end of pregnancy, as these may have changed since earlier discussions.
Explain to women that induction of labour is a medical intervention that will affect their birth options and their experience of the birth process. This could include that:
vaginal examinations to assess the cervix are needed before and during induction, to determine the best method of induction and to monitor progress
their choice of place of birth will be limited, as they may be recommended interventions (for example, oxytocin infusion, continuous fetal heart rate monitoring and epidurals) that are not available for home birth or in midwife-led birth units
there may be limitations on the use of a birthing pool
there may be a need for an assisted vaginal birth (using forceps or ventouse), with the associated increased risk of obstetric anal sphincter injury (for example, third- or fourth-degree perineal tears)
pharmacological methods of induction can cause hyperstimulation – this is when the uterus contracts too frequently or contractions last too long, which can lead to changes in fetal heart rate and result in fetal compromise
an induced labour may be more painful than a spontaneous labour
their hospital stay may be longer than with a spontaneous labour.
Discuss with women being offered induction of labour:
the reasons for induction being offered
when, where and how induction could be carried out
the arrangements for support and pain relief (see also recommendations on pain relief)
the alternative options if the woman chooses not to have induction of labour, or decides at a later stage that she no longer wishes to proceed with the induction process
the risks and benefits of induction of labour in specific circumstances, and the proposed induction methods
that induction may not be successful, and how this would affect the woman's options (see the recommendations on unsuccessful induction).
When offering induction of labour:
give women time to discuss this information with others (for example, their partners, birthing companion or family) if they wish to do so before making a decision
encourage women to look at other information (for example, by providing written information leaflets or encouraging them to look at information on the NHS website)
ensure women have the opportunity to ask questions, and time to think about their options
recognise that women can decide to proceed with, delay, decline or stop an induction. Respect the woman's decision, even if healthcare professionals disagree with it, and do not allow personal views to influence the care they are given. Record the woman's decision in her notes.
Provide information on induction of labour in line with the NICE guideline on patient experience in adult NHS services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for pregnancy lasting longer than 41 weeks .
Full details of the evidence and the committee's discussion are in evidence review C: induction of labour for prevention of prolonged pregnancy.
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# Induction of labour in specific circumstances
## Pregnancy lasting longer than 41 weeks
Give women with uncomplicated pregnancies every opportunity to go into spontaneous labour.
Explain to women that labour usually starts naturally before 42+0 weeks, based on the gestational age estimated by their dating scan (see table 1).
Gestational age (weeks)
Proportion of spontaneous labours that started at this gestational age
Cumulative proportion of spontaneous labours that started by this gestational age
weeks and under
+0 to 36+6 weeks
+0 to 37+6 weeks
+0 to 38+6 weeks
+0 to 39+6 weeks
+0 to 40+6 weeks
+0 to 41+6 weeks
+0 weeks and over
Data from NHS Hospital Episode Statistics/Maternity Services Data set 2019-20.
Using the information in appendix A, explain to women that some risks associated with a pregnancy continuing beyond 41+0 weeks may increase over time and these include:
increased likelihood of caesarean birth
increased likelihood of the baby needing admission to a neonatal intensive care unit
increased likelihood of stillbirth and neonatal death.
Discuss with women that induction of labour from 41+0 weeks may reduce these risks, but that they will also need to consider the impact of induction on their birth experience (see recommendations on information and decision making) when making their decision.
Be aware that, according to the 2020 MBRRACE-UK report on perinatal mortality, women from some minority ethnic backgrounds or who live in deprived areas have an increased risk of stillbirth and may benefit from closer monitoring and additional support. The report showed that across all births (not just those induced):
compared with white babies (34/10,000), the stillbirth rate is
more than twice as high in black babies (74/10,000)
around 50% higher in Asian babies (53/10,000)
the stillbirth rate increases according to the level of deprivation in the area the mother lives in, with almost twice as many stillbirths for women living in the most deprived areas (47/10,000) compared with the least deprived areas (26/10,000).
If a woman chooses not to have induction of labour, discuss the woman's options from this point on with her (for example, expectant management or caesarean birth) and record the woman's decision in her notes.
Discuss with women who choose not to have their labour induced if they wish to have additional fetal monitoring from 42 weeks. Advise women that:
monitoring only gives a snapshot of the current situation, and cannot predict reliably any changes after monitoring ends, but provides information on how their baby is at the moment and so may help them make a decision on options for birth
adverse effects on the baby (including stillbirth), and when these events might happen, cannot be predicted reliably or prevented even with monitoring
fetal monitoring might consist of twice-weekly cardiotocography and ultrasound estimation of maximum amniotic pool depth.
Offer women who choose to await the spontaneous onset of labour the opportunity to discuss their decision again at all subsequent reviews, if they wish to do so.
Advise women to contact their midwife or maternity unit if they change their mind before their next appointment, or as soon as possible if they have concerns about their baby (for example reduced or altered fetal movements).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for pregnancy lasting longer than 41 weeks .
Full details of the evidence and the committee's discussion are in evidence review C: induction of labour for prevention of prolonged pregnancy.
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## Preterm prelabour rupture of membranes
If a woman has preterm prelabour rupture of membranes, do not carry out induction of labour before 34+0 weeks unless there are additional obstetric indications (for example, infection or fetal compromise). Offer expectant management until 37+0 weeks.
If a woman has preterm prelabour rupture of membranes after 34+0 weeks, but before 37+0 weeks, discuss the options of expectant management until 37+0 weeks or induction of labour with her. When making a shared decision, take into consideration the following factors:
risks to the woman (for example, sepsis, possible need for caesarean birth)
risks to the baby (for example, sepsis, problems relating to preterm birth)
local availability of neonatal intensive care facilities
the woman's individual circumstances and her preferences
If a woman has preterm prelabour rupture of membranes after 34+0 weeks (but before 37+0 weeks), and has had a positive group B streptococcus test at any time in their current pregnancy, offer immediate induction of labour or caesarean birth. See the NICE guidelines on neonatal infection and preterm labour and birth.
## Prelabour rupture of membrane at term
Offer women with prelabour rupture of membranes at term (at or after 37+0 weeks) a choice of:
expectant management for up to 24 hours, or
induction of labour as soon as possible.Discuss the benefits and risks of these options with the woman, and take into account her individual circumstances and preferences.
For women who choose expectant management after prelabour rupture of the membranes at term (at or after 37+0 weeks), offer induction of labour if labour has not started naturally after approximately 24 hours. See the NICE guideline on intrapartum care.
Respect the woman's decision if she chooses to wait for spontaneous onset of labour for over 24 hours after prelabour rupture of membranes at term. Discuss the woman's options for birth from this point onwards with her.
If a woman has prelabour rupture of membranes at term (at or after 37+0 weeks) and has had a positive group B streptococcus test at any time in their current pregnancy, offer immediate induction of labour or caesarean birth. See the NICE guideline on neonatal infection for advice on intrapartum antibiotics.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for prelabour rupture of membranes .
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## Previous caesarean birth
Discuss methods of induction with a woman who has had a previous caesarean birth, so that she can make an informed decision about the most appropriate choice. This should cover the following:
induction of labour can lead to an increased risk of emergency caesarean birth
induction of labour can lead to a risk of uterine rupture
the suitability of mechanical methods of induction, including the risk of infection
the marketing authorisations for dinoprostone and misoprostol contraindicate their use for inducing labour in women with a uterine scar, because they increase the risk of uterine rupture
the risks and consequences of caesarean birth, including both short- and long-term morbidity.
If birth needs to be expedited, offer women who have had a previous caesarean birth a choice of:
induction of labour, or
planned caesarean birth.Take into account the woman's circumstances and preferences and record the discussions and plan in the woman's notes.
Advise women that they can choose not to have induction of labour or caesarean birth, even when it may benefit their or their baby's health
## Maternal request
Consider requests for induction of labour only after discussing the benefits and risks with the woman, taking into account the woman's circumstances and preferences.
## Breech position
Induction of labour is not generally recommended if a woman's baby is in the breech position.
Consider induction of labour for babies in the breech position if:
birth needs to be expedited, and
external cephalic version is unsuccessful, declined or contraindicated, and
the woman chooses not to have a planned caesarean birth.Discuss the benefits and risks associated with induction of labour with the woman.
## Fetal growth restriction
Do not induce labour if there is fetal growth restriction with confirmed fetal compromise. Offer caesarean birth instead.
## Suspected fetal macrosomia
Using the information in appendix B, discuss with women without diabetes and with suspected fetal macrosomia that:
the options for birth are expectant management, induction of labour or caesarean birth (see the NICE guideline on caesarean birth)
there is uncertainty about the benefits and risks of induction of labour compared to expectant management, but:
with induction of labour the risk of shoulder dystocia reduced compared with expectant management
with induction of labour the risk of third- or fourth-degree perineal tears is increased compared with expectant management
there is evidence that the risk of perinatal death, brachial plexus injuries in the baby, or the need for emergency caesarean birth is the same between the 2 options
they will also need to consider the impact of induction on their birth experience and on their baby (see recommendation 1.1.3).Discuss the options for birth with the woman, taking into account her individual circumstances and her preferences, and respect her decision. Support recruitment into clinical trials, if available.
For guidance on suspected fetal macrosomia in women with pre-existing or gestational diabetes see the NICE guideline on diabetes in pregnancy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for suspected fetal macrosomia .
Full details of the evidence and the committee's discussion are in evidence review A: induction of labour for suspected fetal macrosomia.
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## History of precipitate labour
Do not routinely offer induction of labour to women with a history of precipitate labour to avoid a birth unattended by healthcare professionals.
## Intrauterine fetal death – all women
In the event of an intrauterine fetal death, offer support to help women and their partners and family cope with the emotional and physical consequences of the death. Offer them information about specialist support.
In the event of an intrauterine fetal death, if the woman appears to be physically well, her membranes are intact and there is no evidence of infection or bleeding, discuss the options for birth (expectant management, induction of labour or caesarean birth) and respect the woman's decision.
In the event of an intrauterine fetal death, if there is evidence of ruptured membranes, infection or bleeding, offer immediate induction of labour or caesarean birth.
If a woman with an intrauterine fetal death chooses an induced labour, follow the recommendations on monitoring of uterine contractions (preferably using manual assessment) and provide one-to-one midwifery care of the woman during labour and birth.
If a woman with an intrauterine fetal death chooses an induced labour, offer:
-ral mifepristone 200 mg followed by vaginal dinoprostone or oral or vaginal misoprostol. Base the choice and dosage of drug used on clinical circumstances and national protocols, or
a mechanical method of induction. In November 2021, some uses of mifepristone, dinoprostone and misoprostol were off label. See NICE's information on prescribing medicines.
Discuss methods of induction with a woman who has had intrauterine fetal death and a previous caesarean birth, so that she can make an informed decision about the most appropriate choice. This should cover the following:
induction of labour can lead to a risk of uterine rupture
the suitability of mechanical methods of induction, including the risk of infection
the marketing authorisations for dinoprostone and misoprostol contraindicate their use for inducing labour in women with a uterine scar, because they increase the risk of uterine rupture
the risks and consequences of caesarean birth, including both short- and long-term morbidity.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for intrauterine fetal death after previous caesarean birth .
Full details of the evidence and the committee's discussion are in evidence review D: induction of labour for intrauterine fetal death after previous caesarean birth.
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# Methods for induction of labour
## Membrane sweeping
Explain to women:
what a membrane sweep is
that membrane sweeping might make it more likely that labour will start without the need for additional pharmacological or mechanical methods of induction
that pain, discomfort and vaginal bleeding are possible from the procedure.
At antenatal visits after 39+0 weeks, discuss with women if they would like a vaginal examination for membrane sweeping, and if so obtain verbal consent from them before carrying out the membrane sweep.
Discuss with women whether they would like to have additional membrane sweeping if labour does not start spontaneously following the first sweep.
## Pharmacological and mechanical methods for inducing labour
Explain to women that a vaginal examination to assess the readiness of the cervix (recorded as the Bishop score) will help to decide which method of induction they will be offered first, and obtain consent to carry this out.
Discuss with women the risks and benefits of different methods to induce labour. Include that:
both dinoprostone and misoprostol can cause hyperstimulation (see information on hyperstimulation rates in appendix C)
when using pharmacological methods of induction, uterine activity and fetal condition must be monitored regularly
if hyperstimulation does occur, the induction treatment will be stopped by giving no further medication, or by removal of vaginally administered products when possible
there are differences in the ease with which different vaginal products can be removed (for example, dinoprostone controlled-release vaginal delivery systems can be more easily removed than gel or vaginal tablets)
hyperstimulation can be treated with tocolysis, but hyperstimulation caused by misoprostol may be more difficult to reverse
mechanical methods are less likely to cause hyperstimulation than pharmacological methods.
Follow the manufacturers' guidance on the use of dinoprostone and misoprostol preparations for the induction of labour, including when to remove dinoprostone controlled-release vaginal delivery systems.
For women with a Bishop score of 6 or less, offer induction of labour with dinoprostone as vaginal tablet, vaginal gel or controlled-release vaginal delivery system or with low dose (25 microgram) oral misoprostol tablets.
For women with a Bishop score of 6 or less, consider a mechanical method to induce labour (for example, a balloon catheter or osmotic cervical dilator) if:
pharmacological methods are not suitable (for example, in women with a higher risk of, or from, hyperstimulation, or those who have had a previous caesarean birth), or
the woman chooses to use a mechanical method.See the NICE interventional procedures guidance on double balloon catheters for induction.
For women with a Bishop score of more than 6, offer induction of labour with amniotomy and an intravenous oxytocin infusion.
Advise women that they can have an amniotomy and can choose whether or not to have an oxytocin infusion, or can delay starting this, but that this may mean labour takes longer and there may be an increased risk of neonatal infection.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on methods for induction of labour .
Full details of the evidence and the committee's discussion are in evidence review B: methods for induction of labour.
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# Methods that are not recommended for induction of labour
## Pharmacological methods
Be aware that the available evidence does not support the use of the following methods for induction of labour:
-ral dinoprostone
intravenous dinoprostone
extra-amniotic dinoprostone or PGF2
intracervical dinoprostone
vaginal PGF2
intravenous oxytocin alone
hyaluronidase
corticosteroids
-estrogen
relaxin
mifepristone (except in combination for intrauterine fetal death, see recommendation 1.2.31)
vaginal nitric oxide donors.
## Non-pharmacological methods
Be aware that the available evidence does not support the following methods for induction of labour:
herbal supplements
acupuncture
homeopathy
castor oil
hot baths
enemas
sexual intercourse.
# Assessment before induction, monitoring and pain relief
## Assessment before induction
Ensure the position of the baby and the woman's condition are suitable for induction by:
abdominally assessing the level and stability of the fetal head in the lower part of the uterus at or near the pelvic brim
carrying out an ultrasound scan if there are any concerns about the position of the baby (for example, if it might be in the breech position)
assessing and recording the Bishop score
confirming a normal fetal heart rate pattern using antenatal cardiotocography interpretation
confirming the absence of significant uterine contractions (not Braxton-Hicks) using cardiotocography.
Ensure facilities are available for cardiotocography wherever induction of labour is started.
## Monitoring
Note that the summaries of product characteristics for different preparations of dinoprostone contain different monitoring requirements. Always use the NICE guidance on dinoprostone in conjunction with the relevant summary of product characteristics.
When uterine contractions begin after administering dinoprostone or misoprostol, assess fetal wellbeing and uterine contractions with intrapartum cardiotocography interpretation and:
if the cardiotocogram is confirmed as normal, review the individual circumstances and, if considered low risk, use intermittent auscultation unless there are clear indications for further cardiotocography
if the fetal heart rate is abnormal or there are excessive uterine contractions:
continue or restart continuous cardiotocography
do not administer any more doses, and
remove any vaginal pessaries or delivery systems if possible.Follow the advice on monitoring during labour in the NICE guideline on fetal monitoring in labour.
Offer to reassess the wellbeing of the woman and baby and the Bishop score at appropriate intervals to monitor progress, depending on the method of induction being used, and the clinical condition of the woman.
Once active labour is established, carry out maternal and fetal monitoring as described in the NICE guideline on fetal monitoring in labour.
## Pain relief
Explain to women that induced labour may be more painful than spontaneous labour.
Discuss the available pain relief options in different settings with women.
During induction of labour, provide women with the pain relief appropriate for them and their pain as described in the NICE guideline on intrapartum care. This can include simple analgesia, labour in water and epidural analgesia.
# Outpatient induction
Note that the summaries of product characteristics for different preparations of dinoprostone contain different monitoring requirements. Always use the NICE guidance on dinoprostone in conjunction with the relevant summary of product characteristics.
Consider outpatient induction of labour with vaginal dinoprostone preparations or mechanical methods in women who wish to return home, and who have no co-existing medical conditions or obstetric complications. Discuss with the woman the benefits and risks of returning home, and respect her decision.
Carry out a full clinical assessment of the woman and baby (see recommendations 1.5.1 and 1.5.2) and ensure safety and support procedures are in place.
For induction being undertaken on an outpatient basis, agree a review plan with the woman before she returns home.
Ask women to contact their midwife, maternity unit or obstetrician:
when contractions begin, or
if there are no contractions (in an agreed timeframe, depending on the method used), or
if her membranes rupture, or
if she develops bleeding, or
if she has any other concerns, such as reduced or altered fetal movements, excessive pain or uterine contractions, side-effects or loss of the pessary.
# Prevention and management of complications
## Uterine hyperstimulation
If uterine hyperstimulation occurs during induction of labour:
carry out a fetal assessment
do not administer any more doses of medicines to induce labour and remove any vaginal pessaries or delivery systems if possible
consider tocolysis.
## Unsuccessful induction
If induction is unsuccessful, discuss this with the woman and provide support. Fully reassess the woman's condition and the pregnancy in general, and assess fetal wellbeing using antenatal cardiotocography interpretation.
If induction is unsuccessful, discuss and agree a plan for further management with the woman, including whether she would like further attempts at induction, taking into account the clinical circumstances and her preferences.
If induction is unsuccessful, the subsequent management options include:
-ffering a rest period if clinically appropriate and then re-assessing the woman
expectant management
further attempts to induce labour
caesarean birth. See the NICE guideline on caesarean birth.
## Cord prolapse
Take the following precautions to avoid the adverse effects of cord prolapse, which may occur if labour is induced:
before induction, abdominally assess the level and stability of the fetal head in the lower part of the uterus at or near the pelvic brim (see the recommendations on assessment before induction)
during the preliminary vaginal examination, obstetricians and midwives should palpate for umbilical cord presentation and avoid dislodging the baby's head
carry out continuous cardiotocography during induction after the membranes have ruptured, if the presenting part is not stable and not well-applied to the cervix. In this situation, discuss the risks and benefits of induction of labour with the woman, and if necessary consider caesarean birth. If the presenting part stabilises and the cardiotocogram is normal, use intermittent auscultation unless there are clear indications for further cardiotocography.
## Placenta praevia, low-lying placenta or a previous history of antepartum haemorrhage
Check that there is no evidence of a low-lying placenta on previous scans before membrane sweeping and before induction of labour.
## Uterine rupture
If uterine rupture is suspected during induced labour, carry out an immediate category 1 caesarean birth. See the NICE guideline on caesarean birth.
# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.
## Bishop score
The Bishop score is a numerical value obtained by doing a vaginal examination, and is based on the dilation, effacement (or length), position and consistency of the cervix and the station of the head with respect to the ischial spines of the pelvis. A score of 8 or more generally indicates that the cervix is ready to dilate, (previously the terms 'ripe' or 'favourable' were widely used) and when there is a high chance of spontaneous labour, or response to interventions made to induce labour. For the purposes of this guideline, a Bishop score of less than or equal to 6, or a score greater than 6, was used to help determine choice of pharmacological or mechanical methods to induce labour.
## Dinoprostone
Dinoprostone is the international non-proprietary name for prostaglandin E2. Previous versions of this guideline referred to prostaglandin E2, or PGE2, but in order to ensure uniformity with the naming conventions in the BNF, this version refers to this medication as dinoprostone.
## Expectant management
A management approach, also called 'watch and wait', when no medical or surgical treatment is given. The aim is to allow labour to begin naturally.
## Hyperstimulation
This is overactivity of the uterus as a result of induction of labour. It is variously defined as uterine tachysystole (more than 5 contractions per 10 minutes for at least 20 minutes) and uterine hypersystole/hypertonicity (a contraction lasting at least 2 minutes). These may or may not be associated with changes in the fetal heart rate pattern (persistent decelerations, tachycardia or increased/decreased short term variability).
## Membrane sweeping
Membrane sweeping involves the examining finger passing through the cervix to rotate against the wall of the uterus, to separate the chorionic membrane from the decidua of the uterus. If the cervix will not admit a finger, massaging around the cervix in the vaginal fornices may achieve a similar effect.
## MBRRACE-UK
Mothers and babies: reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK) is a series of audits carried out with the aim of identifying causes of maternal and perinatal death and morbidity and making recommendations to inform maternity care and so reduce these poor outcomes.
## Osmotic cervical dilator
A medical device used to dilate the uterine cervix by swelling as it absorbs fluid from surrounding tissue.
## Precipitate labour
A labour that is very quick and short, and the baby is born less than 3 hours after the start of uterine contractions.
## Suspected fetal macrosomia
A baby that is believed to be large for its gestational age, defined for the purposes of this guideline as an estimated fetal weight above the 95th percentile, at or after 36 weeks of pregnancy.
## Unsuccessful induction
Unsuccessful induction is defined as labour not starting after one cycle of treatment.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Prevention of prolonged pregnancy
At what gestational age should induction of labour be offered in the subgroups of women who may be more likely to experience adverse outcomes if pregnancy continues?
For a short explanation of why the committee made the recommendation for research, see the rationale section on induction of labour for pregnancy lasting longer than 41 weeks .
Full details of the evidence and the committee's discussion are in evidence review C: induction of labour for prevention of prolonged pregnancy.
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## Prevention of prolonged pregnancy
Based on individual patient data meta-analysis, what is the optimal timing of induction of labour?
For a short explanation of why the committee made the recommendation for research, see the rationale section on induction of labour for pregnancy lasting longer than 41 weeks .
Full details of the evidence and the committee's discussion are in evidence review C: induction of labour for prevention of prolonged pregnancy.
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## Preterm prelabour rupture of membranes
What are the relative risks and benefits of induced labour versus expectant management in women whose membranes have ruptured spontaneously between 34 and 37 weeks?
## Why this is important
Intrauterine sepsis is more likely to develop in pregnancies that continue after the membranes have ruptured, putting both the woman and the baby at risk. In some such pregnancies, labour begins spontaneously at a variable interval after the membranes have ruptured, avoiding the need for induction. The value of antibiotic therapy and the administration of corticosteroids to the woman is unclear in this situation. A randomised study of active versus expectant management, taking account of time since membrane rupture, gestational age and maternal therapy, would be valuable.
## Intrauterine fetal death after previous caesarean birth
How should labour be induced in women with intrauterine fetal death who have had a previous caesarean birth, and who choose to be induced?
For a short explanation of why the committee made the recommendation for research, see the rationale section on induction of labour for intrauterine fetal death after previous caesarean birth .
Full details of the evidence and the committee's discussion are in evidence review D: induction of labour for intrauterine fetal death after previous caesarean birth.
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## Membrane sweeping
What are the effectiveness and acceptability of, and maternal satisfaction with, the following:
multiple versus once-only membrane sweeping, at varying gestational ages, depending on parity
membrane sweeping versus cervical massage?
## Why this is important
Membrane sweeping is considered to be a relatively simple intervention that may positively influence the transition from maintenance of pregnancy to the onset of labour, reducing the need for formal induction of labour. However, there are disadvantages, such as possible vaginal bleeding and discomfort. Research into when and how frequently membrane sweeping should be carried out to maximise its effectiveness and acceptability would be of value.
## Vaginal dinoprostone
What are the effectiveness, safety and maternal acceptability of:
different regimens of vaginal dinoprostone, stratified by: clinical indications; cervical and membrane status; parity; and previous caesarean birth
different management policies for unsuccessful induction of labour with vaginal dinoprostone (additional dinoprostone, oxytocin, elective caesarean birth or delay of induction, if appropriate).
## Why this is important
Despite extensive studies carried out over the past 30 years to determine the most effective ways of inducing labour with vaginal dinoprostone, uncertainties remain about how best to apply these agents in terms of their dosage and timing. It would be particularly useful to understand more clearly why vaginal dinoprostone is unsuccessful in inducing labour in some women.
## Setting for induction of labour
Is it safe, effective and cost effective to carry out induction of labour in an outpatient setting? What are the advantages and disadvantages of such an approach, taking into account women's views?
## Why this is important
In line with the way healthcare has developed in many areas of acute care, there is an increasing desire to reduce the time women spend in hospital. Several units are already exploring outpatient induction of labour policies and there is a need to study this approach in order to determine relative risks and benefits, as well as acceptability to women.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Induction of labour for pregnancy lasting longer than 41 weeks
Recommendations 1.1.3 and 1.1.6, and recommendations 1.2.3 to 1.2.5, 1.2.8 and 1.2.9
## Why the committee made the recommendations
Based on their knowledge and experience the committee made recommendations on the advice that should be provided to all women in early pregnancy about mode of birth, the process of inducing labour, and the impact this may have on their place of birth, mode of birth and on their experience of birth. The committee also made recommendations about how these discussions may need to be revisited in later pregnancy, or if women decline induction.
There was evidence that caesarean birth, perinatal mortality and neonatal intensive care unit admission are reduced by earlier induction of labour (at 41+0 weeks) compared to later induction (at 42+0 weeks or after). However, there was not enough evidence, so the committee made a recommendation for research to identify the optimal timing of induction more precisely.
The committee were aware that data from the 2020 MBRRACE-UK report on perinatal mortality had shown that babies born to certain groups of women may be at higher risk of stillbirth and chose to highlight this in the guideline. As there was no evidence, the committee made a recommendation for research to identify the optimal timing of induction in groups of women who may be at higher risk of stillbirth.
## How the recommendations might affect practice
The recommendations decrease the gestational age at which induction of labour is discussed to prevent prolonged pregnancy, and may increase the number of women who undergo induction. The recommendations on monitoring may also increase the number of women who decline induction and then choose to have additional monitoring. Both these factors may increase resource use in the NHS.
Return to recommendations 1.1.3 and 1.1.6
Return to recommendations 1.2.3 to 1.2.5, 1.2.8 and 1.2.9
# Induction of labour for prelabour rupture of the membranes
Recommendations 1.2.12, 1.2.15 and 1.2.16
## Why the committee made the recommendations
The committee were aware of the recommendations in the NICE guideline on neonatal infection that advised immediate induction of labour or caesarean birth after preterm prelabour rupture of the membranes between 34+0 weeks and 37+0 weeks in women with a positive group B streptococcus test, and so added this recommendation to this section of the guideline.
Based on their knowledge and experience of the risks of group B streptococcal infection to the baby after rupture of the membranes, the committee agreed that with prelabour rupture of the membranes after 37+0 weeks in women with a positive group B streptococcus test, immediate induction of labour or caesarean birth would also be recommended.
In women who did not have a positive group B streptococcus test, but who had prelabour rupture of the membranes after 37+0 weeks, the committee were aware that expectant management for 24 hours was an option as the risk of infection to the baby was low. However, after that period, induction should be advised as the committee were aware that prolonged pregnancy at term after rupture of the membranes can increase risks to the baby, and they therefore advised that birth options should be discussed with women who choose not to have induction of labour after 24 hours.
## How the recommendations might affect practice
The recommendations will reinforce current practice.
Return to recommendations
# Induction of labour for suspected fetal macrosomia
Recommendations 1.2.24 and 1.2.25
## Why the committee made the recommendations
There was some evidence of both benefits and harms for induction of labour and for expectant management in women without diabetes with suspected fetal macrosomia, but there was uncertainty around this evidence, particularly relating to the risk of perineal tears. As there was not enough evidence to recommend one method over another, the committee recommended that women should be provided with information about different modes of birth so they can make an informed decision, and that recruitment into relevant clinical trials should be supported.
## How the recommendations might affect practice
Currently, there is variation in clinical practice and so the recommendations may mean an increase in consultation time to counsel women appropriately in some areas. This is not expected to lead to a substantial resource impact at national level.
Return to recommendations
# Induction of labour for intrauterine fetal death after previous caesarean birth
Recommendations 1.2.30 and 1.2.32
## Why the committee made the recommendations
In the absence of evidence, the committee made recommendations based on their knowledge and experience and also made a recommendation for research on intrauterine fetal death after previous caesarean birth. The committee agreed that the different options for birth should be discussed with women after intrauterine fetal death if they have had a previous caesarean birth, and their choice should be respected. They also agreed that women with IUFD should be cared for on a one-to-one basis and monitored.
The committee explained that, after intrauterine fetal death, women with a scarred uterus are at increased risk of uterine rupture. This should be taken into account when considering options for birth and if induction is carried out, uterine contractions should be carefully monitored.
The committee discussed that mifepristone 600 mg daily for 2 days is approved for the induction of labour following intrauterine fetal death when prostaglandin or oxytocin cannot be used, but that no evidence for its safety or efficacy in women with a previous caesarean birth had been identified and so they were unable to recommend it. The committee discussed that in women with intrauterine fetal death and no previous caesarean birth a lower dose of mifepristone was used to sensitise the myometrium to prostaglandin-induced contractions, followed by a prostaglandin (dinoprostone or misoprostol). However, the committee were aware that both dinoprostone and misoprostol are contraindicated after previous caesarean birth and so made a recommendation to state this.
The committee recognised that mechanical methods of induction may be safe to use in women with a previous caesarean birth, and so they advised that these could be considered. This also brought the recommendations for induction after a previous caesarean birth for women with live babies or after intrauterine fetal death, in line with each other.
## How the recommendations might affect practice
Currently, there is variation in the management of women after an intrauterine fetal death who have had previous caesarean birth, so the recommendations may mean an increase in consultation time to counsel women appropriately in some areas, and an increase in monitoring to reduce the risk of uterine rupture. This is not expected to lead to a substantial resource impact at national level.
Return to recommendations
# Methods for induction of labour
Recommendations 1.3.4 to 1.3.10
## Why the committee made the recommendations
The committee agreed that, in their experience, women value being informed about the reason why certain treatments are offered, and that it should be made clear to women that the possible methods for induction of labour will depend primarily on the readiness of their cervix, which is assessed with a vaginal examination and recorded as the Bishop score.
There was good evidence that vaginal dinoprostone was effective at promoting vaginal birth within 24 hours for women with a Bishop score of 6 or less, without significantly increasing the risk of adverse outcomes for the woman or her baby. When the different preparations of vaginal dinoprostone were compared, there was little evidence to demonstrate that one preparation was superior to another. Therefore, the committee agreed that it was appropriate to offer a choice of preparation, depending on availability and the woman's preference. There was some evidence that dinoprostone preparations could lead to hyperstimulation with fetal heart rate changes.
Misoprostol was as effective as dinoprostone at promoting vaginal birth within 24 hours. There was evidence showing a risk of hyperstimulation with misoprostol, although this was predominantly with higher doses and vaginal preparations, and the committee took into consideration previous MHRA warnings relating to the misoprostol vaginal insert about this risk. The committee noted that, for the low dose oral preparations of misoprostol, the risk of hyperstimulation appeared to be the same or lower than with the dinoprostone vaginal preparations. Therefore, the committee agreed that misoprostol could be an alternative to dinoprostone for induction of labour, particularly for women who would prefer an oral preparation.
There was evidence that there was no increased risk of hyperstimulation when using mechanical methods for induction of labour (including osmotic cervical dilators and balloon catheters). Balloon catheters were also effective at promoting vaginal birth within 24 hours and did not appear to markedly increase the risk of other adverse outcomes. There was no evidence for the effectiveness of osmotic cervical dilators at promoting vaginal birth within 24 hours, but they too did not appear to markedly increase the risk of other adverse outcomes. Therefore, the committee agreed that these mechanical methods could be considered for induction of labour for women, particularly when there is a concern about hyperstimulation.
There was very little evidence for women with a Bishop score of more than 6. However, the committee noted that amniotomy and intravenous oxytocin was the most effective method to promote vaginal birth within 24 hours across the whole population. This was in keeping with their clinical experience, so they agreed that this should be the first choice for induction of labour for women in this group.
## How the recommendations might affect practice
Most hospitals use the recommended methods for induction of labour already, so these recommendations will not result in a significant change of practice. The advice specific to women with a Bishop score of more than 6 should provide more individualised care and standardise practice for this subgroup of women.
Return to recommendations# Context
Induced labour may be recommended in circumstances when it appears that the benefits outweigh the risks for the mother and baby of continuing with the pregnancy, but with the aim of still enabling a vaginal birth. However, induction has an impact on the birth experience of women as it:
removes the satisfaction of achieving the more natural birth that many woman hope for
is generally more painful than spontaneous labour
is more likely to lead to additional interventions such as assisted or operative birth, including caesarean birth, and
is more likely to need epidural analgesia.
Induction of labour is a common procedure, with approximately a third of all women in the UK undergoing induction, and there are a variety of methods available using both pharmacological treatments and mechanical methods. The choice of method depends on the readiness of the woman's cervix (assessed using a vaginal examination, and categorised using the Bishop score), whether the membranes have ruptured, and the woman's preferences. The options available should be discussed and this discussion should include:
an awareness of the efficacy and possible adverse effects for the woman and her baby associated with each method, and
the likelihood that additional interventions (such as emergency caesarean birth) might be needed if the induction is not successful.
Women can choose not to have induction of labour, and appropriate care should then be offered to optimise the outcome of the pregnancy while respecting the woman's wishes.
The aim of this guideline is to give advice to healthcare professionals providing obstetric services, and to pregnant women, on the information and support women and their families and birth partners should be offered when making decisions about induction of labour. It also aims to define the circumstances when induction of labour may be appropriate, and identify the most effective way to induce labour, including choice of method, setting, timing, monitoring and pain relief.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Information and decision making\n\nThis section should be read in conjunction with the NICE guidelines on antenatal care, caesarean birth and intrapartum care for healthy women and babies.\n\nDiscuss preferences about mode of birth with women early on in their pregnancy. Take into account their individual circumstances, and discuss that options for birth can include:\n\nexpectant management, or\n\ninduction of labour, or\n\nplanned caesarean birth (see the NICE guideline on caesarean birth).Record these discussions and the woman's preferences in her notes. [2008, amended 2021]\n\nConfirm a woman's preferences for birth at antenatal visits towards the end of pregnancy, as these may have changed since earlier discussions. [2008, amended 2021]\n\nExplain to women that induction of labour is a medical intervention that will affect their birth options and their experience of the birth process. This could include that:\n\nvaginal examinations to assess the cervix are needed before and during induction, to determine the best method of induction and to monitor progress\n\ntheir choice of place of birth will be limited, as they may be recommended interventions (for example, oxytocin infusion, continuous fetal heart rate monitoring and epidurals) that are not available for home birth or in midwife-led birth units\n\nthere may be limitations on the use of a birthing pool\n\nthere may be a need for an assisted vaginal birth (using forceps or ventouse), with the associated increased risk of obstetric anal sphincter injury (for example, third- or fourth-degree perineal tears)\n\npharmacological methods of induction can cause hyperstimulation – this is when the uterus contracts too frequently or contractions last too long, which can lead to changes in fetal heart rate and result in fetal compromise\n\nan induced labour may be more painful than a spontaneous labour\n\ntheir hospital stay may be longer than with a spontaneous labour. \n\nDiscuss with women being offered induction of labour:\n\nthe reasons for induction being offered\n\nwhen, where and how induction could be carried out\n\nthe arrangements for support and pain relief (see also recommendations on pain relief)\n\nthe alternative options if the woman chooses not to have induction of labour, or decides at a later stage that she no longer wishes to proceed with the induction process\n\nthe risks and benefits of induction of labour in specific circumstances, and the proposed induction methods\n\nthat induction may not be successful, and how this would affect the woman's options (see the recommendations on unsuccessful induction). [2008, amended 2021]\n\nWhen offering induction of labour:\n\ngive women time to discuss this information with others (for example, their partners, birthing companion or family) if they wish to do so before making a decision\n\nencourage women to look at other information (for example, by providing written information leaflets or encouraging them to look at information on the NHS website)\n\nensure women have the opportunity to ask questions, and time to think about their options\n\nrecognise that women can decide to proceed with, delay, decline or stop an induction. Respect the woman's decision, even if healthcare professionals disagree with it, and do not allow personal views to influence the care they are given. Record the woman's decision in her notes. [2008, amended 2021]\n\nProvide information on induction of labour in line with the NICE guideline on patient experience in adult NHS services. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for pregnancy lasting longer than 41 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: induction of labour for prevention of prolonged pregnancy.\n\nLoading. Please wait.\n\n# Induction of labour in specific circumstances\n\n## Pregnancy lasting longer than 41 weeks\n\nGive women with uncomplicated pregnancies every opportunity to go into spontaneous labour. \n\nExplain to women that labour usually starts naturally before 42+0\xa0weeks, based on the gestational age estimated by their dating scan (see table 1). [2008, amended 2021]\n\nGestational age (weeks)\n\nProportion of spontaneous labours that started at this gestational age\n\nCumulative proportion of spontaneous labours that started by this gestational age\n\nweeks and under\n\n%\n\n%\n\n+0 to 36+6 weeks\n\n%\n\n%\n\n+0 to 37+6 weeks\n\n%\n\n%\n\n+0 to 38+6 weeks\n\n%\n\n%\n\n+0 to 39+6 weeks\n\n%\n\n%\n\n+0 to 40+6 weeks\n\n%\n\n%\n\n+0 to 41+6 weeks\n\n%\n\n%\n\n+0 weeks and over\n\n%\n\n%\n\nData from NHS Hospital Episode Statistics/Maternity Services Data set 2019-20.\n\nUsing the information in appendix A, explain to women that some risks associated with a pregnancy continuing beyond 41+0\xa0weeks may increase over time and these include:\n\nincreased likelihood of caesarean birth\n\nincreased likelihood of the baby needing admission to a neonatal intensive care unit\n\nincreased likelihood of stillbirth and neonatal death. \n\nDiscuss with women that induction of labour from 41+0\xa0weeks may reduce these risks, but that they will also need to consider the impact of induction on their birth experience (see recommendations on information and decision making) when making their decision. \n\nBe aware that, according to the 2020 MBRRACE-UK report on perinatal mortality, women from some minority ethnic backgrounds or who live in deprived areas have an increased risk of stillbirth and may benefit from closer monitoring and additional support. The report showed that across all births (not just those induced):\n\ncompared with white babies (34/10,000), the stillbirth rate is\n\n\n\nmore than twice as high in black babies (74/10,000)\n\naround 50% higher in Asian babies (53/10,000)\n\n\n\nthe stillbirth rate increases according to the level of deprivation in the area the mother lives in, with almost twice as many stillbirths for women living in the most deprived areas (47/10,000) compared with the least deprived areas (26/10,000). \n\nIf a woman chooses not to have induction of labour, discuss the woman's options from this point on with her (for example, expectant management or caesarean birth) and record the woman's decision in her notes. [2008, amended 2021]\n\nDiscuss with women who choose not to have their labour induced if they wish to have additional fetal monitoring from 42\xa0weeks. Advise women that:\n\nmonitoring only gives a snapshot of the current situation, and cannot predict reliably any changes after monitoring ends, but provides information on how their baby is at the moment and so may help them make a decision on options for birth\n\nadverse effects on the baby (including stillbirth), and when these events might happen, cannot be predicted reliably or prevented even with monitoring\n\nfetal monitoring might consist of twice-weekly cardiotocography and ultrasound estimation of maximum amniotic pool depth. [2008, amended 2021]\n\nOffer women who choose to await the spontaneous onset of labour the opportunity to discuss their decision again at all subsequent reviews, if they wish to do so. \n\nAdvise women to contact their midwife or maternity unit if they change their mind before their next appointment, or as soon as possible if they have concerns about their baby (for example reduced or altered fetal movements). \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for pregnancy lasting longer than 41 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: induction of labour for prevention of prolonged pregnancy.\n\nLoading. Please wait.\n\n## Preterm prelabour rupture of membranes\n\nIf a woman has preterm prelabour rupture of membranes, do not carry out induction of labour before 34+0 weeks unless there are additional obstetric indications (for example, infection or fetal compromise). Offer expectant management until 37+0 weeks. [2008, amended 2021]\n\nIf a woman has preterm prelabour rupture of membranes after 34+0 weeks, but before 37+0 weeks, discuss the options of expectant management until 37+0 weeks or induction of labour with her. When making a shared decision, take into consideration the following factors:\n\nrisks to the woman (for example, sepsis, possible need for caesarean birth)\n\nrisks to the baby (for example, sepsis, problems relating to preterm birth)\n\nlocal availability of neonatal intensive care facilities\n\nthe woman's individual circumstances and her preferences [2008, amended 2021]\n\nIf a woman has preterm prelabour rupture of membranes after 34+0 weeks (but before 37+0 weeks), and has had a positive group B streptococcus test at any time in their current pregnancy, offer immediate induction of labour or caesarean birth. See the NICE guidelines on neonatal infection and preterm labour and birth. \n\n## Prelabour rupture of membrane at term\n\nOffer women with prelabour rupture of membranes at term (at or after 37+0 weeks) a choice of:\n\nexpectant management for up to 24\xa0hours, or\n\ninduction of labour as soon as possible.Discuss the benefits and risks of these options with the woman, and take into account her individual circumstances and preferences. [2008, amended 2021]\n\nFor women who choose expectant management after prelabour rupture of the membranes at term (at or after 37+0 weeks), offer induction of labour if labour has not started naturally after approximately 24\xa0hours. See the NICE guideline on intrapartum care. [2008, amended 2021]\n\nRespect the woman's decision if she chooses to wait for spontaneous onset of labour for over 24\xa0hours after prelabour rupture of membranes at term. Discuss the woman's options for birth from this point onwards with her. \n\nIf a woman has prelabour rupture of membranes at term (at or after 37+0 weeks) and has had a positive group B streptococcus test at any time in their current pregnancy, offer immediate induction of labour or caesarean birth. See the NICE guideline on neonatal infection for advice on intrapartum antibiotics. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for prelabour rupture of membranes\xa0.\n\nLoading. Please wait.\n\n## Previous caesarean birth\n\nDiscuss methods of induction with a woman who has had a previous caesarean birth, so that she can make an informed decision about the most appropriate choice. This should cover the following:\n\ninduction of labour can lead to an increased risk of emergency caesarean birth\n\ninduction of labour can lead to a risk of uterine rupture\n\nthe suitability of mechanical methods of induction, including the risk of infection\n\nthe marketing authorisations for dinoprostone and misoprostol contraindicate their use for inducing labour in women with a uterine scar, because they increase the risk of uterine rupture\n\nthe risks and consequences of caesarean birth, including both short- and long-term morbidity. [2008, amended 2021]\n\nIf birth needs to be expedited, offer women who have had a previous caesarean birth a choice of:\n\ninduction of labour, or\n\nplanned caesarean birth.Take into account the woman's circumstances and preferences and record the discussions and plan in the woman's notes. [2008, amended 2021]\n\nAdvise women that they can choose not to have induction of labour or caesarean birth, even when it may benefit their or their baby's health [2008, amended 2021]\n\n## Maternal request\n\nConsider requests for induction of labour only after discussing the benefits and risks with the woman, taking into account the woman's circumstances and preferences. [2008, amended 2021]\n\n## Breech position\n\nInduction of labour is not generally recommended if a woman's baby is in the breech position. [2008, amended 2021]\n\nConsider induction of labour for babies in the breech position if:\n\nbirth needs to be expedited, and\n\nexternal cephalic version is unsuccessful, declined or contraindicated, and\n\nthe woman chooses not to have a planned caesarean birth.Discuss the benefits and risks associated with induction of labour with the woman. [2008, amended 2021]\n\n## Fetal growth restriction\n\nDo not induce labour if there is fetal growth restriction with confirmed fetal compromise. Offer caesarean birth instead. [2008, amended 2021]\n\n## Suspected fetal macrosomia\n\nUsing the information in appendix B, discuss with women without diabetes and with suspected fetal macrosomia that:\n\nthe options for birth are expectant management, induction of labour or caesarean birth (see the NICE guideline on caesarean birth)\n\nthere is uncertainty about the benefits and risks of induction of labour compared to expectant management, but:\n\n\n\nwith induction of labour the risk of shoulder dystocia reduced compared with expectant management\n\nwith induction of labour the risk of third- or fourth-degree perineal tears is increased compared with expectant management\n\nthere is evidence that the risk of perinatal death, brachial plexus injuries in the baby, or the need for emergency caesarean birth is the same between the 2 options\n\n\n\nthey will also need to consider the impact of induction on their birth experience and on their baby (see recommendation 1.1.3).Discuss the options for birth with the woman, taking into account her individual circumstances and her preferences, and respect her decision. Support recruitment into clinical trials, if available. \n\nFor guidance on suspected fetal macrosomia in women with pre-existing or gestational diabetes see the NICE guideline on diabetes in pregnancy. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for suspected fetal macrosomia\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: induction of labour for suspected fetal macrosomia.\n\nLoading. Please wait.\n\n## History of precipitate labour\n\nDo not routinely offer induction of labour to women with a history of precipitate labour to avoid a birth unattended by healthcare professionals. \n\n## Intrauterine fetal death – all women\n\nIn the event of an intrauterine fetal death, offer support to help women and their partners and family cope with the emotional and physical consequences of the death. Offer them information about specialist support. \n\nIn the event of an intrauterine fetal death, if the woman appears to be physically well, her membranes are intact and there is no evidence of infection or bleeding, discuss the options for birth (expectant management, induction of labour or caesarean birth) and respect the woman's decision. [2008, amended 2021]\n\nIn the event of an intrauterine fetal death, if there is evidence of ruptured membranes, infection or bleeding, offer immediate induction of labour or caesarean birth. [2008, amended 2021]\n\nIf a woman with an intrauterine fetal death chooses an induced labour, follow the recommendations on monitoring of uterine contractions (preferably using manual assessment) and provide one-to-one midwifery care of the woman during labour and birth. \n\nIf a woman with an intrauterine fetal death chooses an induced labour, offer:\n\noral mifepristone 200\xa0mg followed by vaginal dinoprostone or oral or vaginal misoprostol. Base the choice and dosage of drug used on clinical circumstances and national protocols, or\n\na mechanical method of induction. [2008, amended 2021]In November 2021, some uses of mifepristone, dinoprostone and misoprostol were off label. See NICE's information on prescribing medicines.\n\nDiscuss methods of induction with a woman who has had intrauterine fetal death and a previous caesarean birth, so that she can make an informed decision about the most appropriate choice. This should cover the following:\n\ninduction of labour can lead to a risk of uterine rupture\n\nthe suitability of mechanical methods of induction, including the risk of infection\n\nthe marketing authorisations for dinoprostone and misoprostol contraindicate their use for inducing labour in women with a uterine scar, because they increase the risk of uterine rupture\n\nthe risks and consequences of caesarean birth, including both short- and long-term morbidity. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on induction of labour for intrauterine fetal death after previous caesarean birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: induction of labour for intrauterine fetal death after previous caesarean birth.\n\nLoading. Please wait.\n\n# Methods for induction of labour\n\n## Membrane sweeping\n\nExplain to women:\n\nwhat a membrane sweep is\n\nthat membrane sweeping might make it more likely that labour will start without the need for additional pharmacological or mechanical methods of induction\n\nthat pain, discomfort and vaginal bleeding are possible from the procedure. [2008, amended 2021]\n\nAt antenatal visits after 39+0 weeks, discuss with women if they would like a vaginal examination for membrane sweeping, and if so obtain verbal consent from them before carrying out the membrane sweep. [2008, amended 2021]\n\nDiscuss with women whether they would like to have additional membrane sweeping if labour does not start spontaneously following the first sweep. [2008, amended 2021]\n\n## Pharmacological and mechanical methods for inducing labour\n\nExplain to women that a vaginal examination to assess the readiness of the cervix (recorded as the Bishop score) will help to decide which method of induction they will be offered first, and obtain consent to carry this out. \n\nDiscuss with women the risks and benefits of different methods to induce labour. Include that:\n\nboth dinoprostone and misoprostol can cause hyperstimulation (see information on hyperstimulation rates in appendix C)\n\nwhen using pharmacological methods of induction, uterine activity and fetal condition must be monitored regularly\n\nif hyperstimulation does occur, the induction treatment will be stopped by giving no further medication, or by removal of vaginally administered products when possible\n\nthere are differences in the ease with which different vaginal products can be removed (for example, dinoprostone controlled-release vaginal delivery systems can be more easily removed than gel or vaginal tablets)\n\nhyperstimulation can be treated with tocolysis, but hyperstimulation caused by misoprostol may be more difficult to reverse\n\nmechanical methods are less likely to cause hyperstimulation than pharmacological methods. \n\nFollow the manufacturers' guidance on the use of dinoprostone and misoprostol preparations for the induction of labour, including when to remove dinoprostone controlled-release vaginal delivery systems. \n\nFor women with a Bishop score of 6 or less, offer induction of labour with dinoprostone as vaginal tablet, vaginal gel or controlled-release vaginal delivery system or with low dose (25\xa0microgram) oral misoprostol tablets. \n\nFor women with a Bishop score of 6 or less, consider a mechanical method to induce labour (for example, a balloon catheter or osmotic cervical dilator) if:\n\npharmacological methods are not suitable (for example, in women with a higher risk of, or from, hyperstimulation, or those who have had a previous caesarean birth), or\n\nthe woman chooses to use a mechanical method.See the NICE interventional procedures guidance on double balloon catheters for induction. \n\nFor women with a Bishop score of more than 6, offer induction of labour with amniotomy and an intravenous oxytocin infusion. \n\nAdvise women that they can have an amniotomy and can choose whether or not to have an oxytocin infusion, or can delay starting this, but that this may mean labour takes longer and there may be an increased risk of neonatal infection. \n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on methods for induction of labour\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: methods for induction of labour.\n\nLoading. Please wait.\n\n# Methods that are not recommended for induction of labour\n\n## Pharmacological methods\n\nBe aware that the available evidence does not support the use of the following methods for induction of labour:\n\noral dinoprostone\n\nintravenous dinoprostone\n\nextra-amniotic dinoprostone or PGF2\n\nintracervical dinoprostone\n\nvaginal PGF2\n\nintravenous oxytocin alone\n\nhyaluronidase\n\ncorticosteroids\n\noestrogen\n\nrelaxin\n\nmifepristone (except in combination for intrauterine fetal death, see recommendation 1.2.31)\n\nvaginal nitric oxide donors. [2008, amended 2021]\n\n## Non-pharmacological methods\n\nBe aware that the available evidence does not support the following methods for induction of labour:\n\nherbal supplements\n\nacupuncture\n\nhomeopathy\n\ncastor oil\n\nhot baths\n\nenemas\n\nsexual intercourse. \n\n# Assessment before induction, monitoring and pain relief\n\n## Assessment before induction\n\nEnsure the position of the baby and the woman's condition are suitable for induction by:\n\nabdominally assessing the level and stability of the fetal head in the lower part of the uterus at or near the pelvic brim\n\ncarrying out an ultrasound scan if there are any concerns about the position of the baby (for example, if it might be in the breech position)\n\nassessing and recording the Bishop score\n\nconfirming a normal fetal heart rate pattern using antenatal cardiotocography interpretation\n\nconfirming the absence of significant uterine contractions (not Braxton-Hicks) using cardiotocography. [2008, amended 2021]\n\nEnsure facilities are available for cardiotocography wherever induction of labour is started. [2008, amended 2021]\n\n## Monitoring\n\nNote that the summaries of product characteristics for different preparations of dinoprostone contain different monitoring requirements. Always use the NICE guidance on dinoprostone in conjunction with the relevant summary of product characteristics.\n\nWhen uterine contractions begin after administering dinoprostone or misoprostol, assess fetal wellbeing and uterine contractions with intrapartum cardiotocography interpretation and:\n\nif the cardiotocogram is confirmed as normal, review the individual circumstances and, if considered low risk, use intermittent auscultation unless there are clear indications for further cardiotocography\n\nif the fetal heart rate is abnormal or there are excessive uterine contractions:\n\n\n\ncontinue or restart continuous cardiotocography\n\ndo not administer any more doses, and\n\nremove any vaginal pessaries or delivery systems if possible.Follow the advice on monitoring during labour in the NICE guideline on fetal monitoring in labour. [2008, amended 2021]\n\n\n\nOffer to reassess the wellbeing of the woman and baby and the Bishop score at appropriate intervals to monitor progress, depending on the method of induction being used, and the clinical condition of the woman. [2008, amended 2021]\n\nOnce active labour is established, carry out maternal and fetal monitoring as described in the NICE guideline on fetal monitoring in labour. \n\n## Pain relief\n\nExplain to women that induced labour may be more painful than spontaneous labour. \n\nDiscuss the available pain relief options in different settings with women. \n\nDuring induction of labour, provide women with the pain relief appropriate for them and their pain as described in the NICE guideline on intrapartum care. This can include simple analgesia, labour in water and epidural analgesia. [2008, amended 2021]\n\n# Outpatient induction\n\nNote that the summaries of product characteristics for different preparations of dinoprostone contain different monitoring requirements. Always use the NICE guidance on dinoprostone in conjunction with the relevant summary of product characteristics.\n\nConsider outpatient induction of labour with vaginal dinoprostone preparations or mechanical methods in women who wish to return home, and who have no co-existing medical conditions or obstetric complications. Discuss with the woman the benefits and risks of returning home, and respect her decision. [2008, amended 2021]\n\nCarry out a full clinical assessment of the woman and baby (see recommendations 1.5.1 and 1.5.2) and ensure safety and support procedures are in place. [2008, amended 2021]\n\nFor induction being undertaken on an outpatient basis, agree a review plan with the woman before she returns home. [2008, amended 2021]\n\nAsk women to contact their midwife, maternity unit or obstetrician:\n\nwhen contractions begin, or\n\nif there are no contractions (in an agreed timeframe, depending on the method used), or\n\nif her membranes rupture, or\n\nif she develops bleeding, or\n\nif she has any other concerns, such as reduced or altered fetal movements, excessive pain or uterine contractions, side-effects or loss of the pessary. [2008, amended 2021]\n\n# Prevention and management of complications\n\n## Uterine hyperstimulation\n\nIf uterine hyperstimulation occurs during induction of labour:\n\ncarry out a fetal assessment\n\ndo not administer any more doses of medicines to induce labour and remove any vaginal pessaries or delivery systems if possible\n\nconsider tocolysis. [2008, amended 2021]\n\n## Unsuccessful induction\n\nIf induction is unsuccessful, discuss this with the woman and provide support. Fully reassess the woman's condition and the pregnancy in general, and assess fetal wellbeing using antenatal cardiotocography interpretation. [2008, amended 2021]\n\nIf induction is unsuccessful, discuss and agree a plan for further management with the woman, including whether she would like further attempts at induction, taking into account the clinical circumstances and her preferences. [2008, amended 2021]\n\nIf induction is unsuccessful, the subsequent management options include:\n\noffering a rest period if clinically appropriate and then re-assessing the woman\n\nexpectant management\n\nfurther attempts to induce labour\n\ncaesarean birth. See the NICE guideline on caesarean birth. [2008, amended 2021]\n\n## Cord prolapse\n\nTake the following precautions to avoid the adverse effects of cord prolapse, which may occur if labour is induced:\n\nbefore induction, abdominally assess the level and stability of the fetal head in the lower part of the uterus at or near the pelvic brim (see the recommendations on assessment before induction)\n\nduring the preliminary vaginal examination, obstetricians and midwives should palpate for umbilical cord presentation and avoid dislodging the baby's head\n\ncarry out continuous cardiotocography during induction after the membranes have ruptured, if the presenting part is not stable and not well-applied to the cervix. In this situation, discuss the risks and benefits of induction of labour with the woman, and if necessary consider caesarean birth. If the presenting part stabilises and the cardiotocogram is normal, use intermittent auscultation unless there are clear indications for further cardiotocography. [2008, amended 2021]\n\n## Placenta praevia, low-lying placenta or a previous history of antepartum haemorrhage\n\nCheck that there is no evidence of a low-lying placenta on previous scans before membrane sweeping and before induction of labour. [2008, amended 2021]\n\n## Uterine rupture\n\nIf uterine rupture is suspected during induced labour, carry out an immediate category 1 caesarean birth. See the NICE guideline on caesarean birth. [2008, amended 2021]\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Bishop score\n\nThe Bishop score is a numerical value obtained by doing a vaginal examination, and is based on the dilation, effacement (or length), position and consistency of the cervix and the station of the head with respect to the ischial spines of the pelvis. A score of 8 or more generally indicates that the cervix is ready to dilate, (previously the terms 'ripe' or 'favourable' were widely used) and when there is a high chance of spontaneous labour, or response to interventions made to induce labour. For the purposes of this guideline, a Bishop score of less than or equal to 6, or a score greater than 6, was used to help determine choice of pharmacological or mechanical methods to induce labour.\n\n## Dinoprostone\n\nDinoprostone is the international non-proprietary name for prostaglandin E2. Previous versions of this guideline referred to prostaglandin E2, or PGE2, but in order to ensure uniformity with the naming conventions in the BNF, this version refers to this medication as dinoprostone.\n\n## Expectant management\n\nA management approach, also called 'watch and wait', when no medical or surgical treatment is given. The aim is to allow labour to begin naturally.\n\n## Hyperstimulation\n\nThis is overactivity of the uterus as a result of induction of labour. It is variously defined as uterine tachysystole (more than 5 contractions per 10\xa0minutes for at least 20\xa0minutes) and uterine hypersystole/hypertonicity (a contraction lasting at least 2\xa0minutes). These may or may not be associated with changes in the fetal heart rate pattern (persistent decelerations, tachycardia or increased/decreased short term variability).\n\n## Membrane sweeping\n\nMembrane sweeping involves the examining finger passing through the cervix to rotate against the wall of the uterus, to separate the chorionic membrane from the decidua of the uterus. If the cervix will not admit a finger, massaging around the cervix in the vaginal fornices may achieve a similar effect.\n\n## MBRRACE-UK\n\nMothers and babies: reducing risk through audits and confidential enquiries across the UK (MBRRACE-UK) is a series of audits carried out with the aim of identifying causes of maternal and perinatal death and morbidity and making recommendations to inform maternity care and so reduce these poor outcomes.\n\n## Osmotic cervical dilator\n\nA medical device used to dilate the uterine cervix by swelling as it absorbs fluid from surrounding tissue.\n\n## Precipitate labour\n\nA labour that is very quick and short, and the baby is born less than 3 hours after the start of uterine contractions.\n\n## Suspected fetal macrosomia\n\nA baby that is believed to be large for its gestational age, defined for the purposes of this guideline as an estimated fetal weight above the 95th percentile, at or after 36\xa0weeks of pregnancy.\n\n## Unsuccessful induction\n\nUnsuccessful induction is defined as labour not starting after one cycle of treatment.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Prevention of prolonged pregnancy\n\nAt what gestational age should induction of labour be offered in the subgroups of women who may be more likely to experience adverse outcomes if pregnancy continues? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on induction of labour for pregnancy lasting longer than 41 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: induction of labour for prevention of prolonged pregnancy.\n\nLoading. Please wait.\n\n## Prevention of prolonged pregnancy\n\nBased on individual patient data meta-analysis, what is the optimal timing of induction of labour? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on induction of labour for pregnancy lasting longer than 41 weeks\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: induction of labour for prevention of prolonged pregnancy.\n\nLoading. Please wait.\n\n## Preterm prelabour rupture of membranes\n\nWhat are the relative risks and benefits of induced labour versus expectant management in women whose membranes have ruptured spontaneously between 34 and 37\xa0weeks? \n\n## Why this is important\n\nIntrauterine sepsis is more likely to develop in pregnancies that continue after the membranes have ruptured, putting both the woman and the baby at risk. In some such pregnancies, labour begins spontaneously at a variable interval after the membranes have ruptured, avoiding the need for induction. The value of antibiotic therapy and the administration of corticosteroids to the woman is unclear in this situation. A randomised study of active versus expectant management, taking account of time since membrane rupture, gestational age and maternal therapy, would be valuable.\n\n## Intrauterine fetal death after previous caesarean birth\n\nHow should labour be induced in women with intrauterine fetal death who have had a previous caesarean birth, and who choose to be induced? \n\nFor a short explanation of why the committee made the recommendation for research, see the rationale section on induction of labour for intrauterine fetal death after previous caesarean birth\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: induction of labour for intrauterine fetal death after previous caesarean birth.\n\nLoading. Please wait.\n\n## Membrane sweeping\n\nWhat are the effectiveness and acceptability of, and maternal satisfaction with, the following:\n\nmultiple versus once-only membrane sweeping, at varying gestational ages, depending on parity\n\nmembrane sweeping versus cervical massage? \n\n## Why this is important\n\nMembrane sweeping is considered to be a relatively simple intervention that may positively influence the transition from maintenance of pregnancy to the onset of labour, reducing the need for formal induction of labour. However, there are disadvantages, such as possible vaginal bleeding and discomfort. Research into when and how frequently membrane sweeping should be carried out to maximise its effectiveness and acceptability would be of value.\n\n## Vaginal dinoprostone\n\nWhat are the effectiveness, safety and maternal acceptability of:\n\ndifferent regimens of vaginal dinoprostone, stratified by: clinical indications; cervical and membrane status; parity; and previous caesarean birth\n\ndifferent management policies for unsuccessful induction of labour with vaginal dinoprostone (additional dinoprostone, oxytocin, elective caesarean birth or delay of induction, if appropriate). \n\n## Why this is important\n\nDespite extensive studies carried out over the past 30 years to determine the most effective ways of inducing labour with vaginal dinoprostone, uncertainties remain about how best to apply these agents in terms of their dosage and timing. It would be particularly useful to understand more clearly why vaginal dinoprostone is unsuccessful in inducing labour in some women.\n\n## Setting for induction of labour\n\nIs it safe, effective and cost effective to carry out induction of labour in an outpatient setting? What are the advantages and disadvantages of such an approach, taking into account women's views? \n\n## Why this is important\n\nIn line with the way healthcare has developed in many areas of acute care, there is an increasing desire to reduce the time women spend in hospital. Several units are already exploring outpatient induction of labour policies and there is a need to study this approach in order to determine relative risks and benefits, as well as acceptability to women.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Induction of labour for pregnancy lasting longer than 41 weeks\n\nRecommendations 1.1.3 and 1.1.6, and recommendations 1.2.3 to 1.2.5, 1.2.8 and 1.2.9\n\n## Why the committee made the recommendations\n\nBased on their knowledge and experience the committee made recommendations on the advice that should be provided to all women in early pregnancy about mode of birth, the process of inducing labour, and the impact this may have on their place of birth, mode of birth and on their experience of birth. The committee also made recommendations about how these discussions may need to be revisited in later pregnancy, or if women decline induction.\n\nThere was evidence that caesarean birth, perinatal mortality and neonatal intensive care unit admission are reduced by earlier induction of labour (at 41+0 weeks) compared to later induction (at 42+0 weeks or after). However, there was not enough evidence, so the committee made a recommendation for research to identify the optimal timing of induction more precisely.\n\nThe committee were aware that data from the 2020 MBRRACE-UK report on perinatal mortality had shown that babies born to certain groups of women may be at higher risk of stillbirth and chose to highlight this in the guideline. As there was no evidence, the committee made a recommendation for research to identify the optimal timing of induction in groups of women who may be at higher risk of stillbirth.\n\n## How the recommendations might affect practice\n\nThe recommendations decrease the gestational age at which induction of labour is discussed to prevent prolonged pregnancy, and may increase the number of women who undergo induction. The recommendations on monitoring may also increase the number of women who decline induction and then choose to have additional monitoring. Both these factors may increase resource use in the NHS.\n\nReturn to recommendations 1.1.3 and 1.1.6\n\nReturn to recommendations 1.2.3 to 1.2.5, 1.2.8 and 1.2.9\n\n# Induction of labour for prelabour rupture of the membranes\n\nRecommendations 1.2.12, 1.2.15 and 1.2.16\n\n## Why the committee made the recommendations\n\nThe committee were aware of the recommendations in the NICE guideline on neonatal infection that advised immediate induction of labour or caesarean birth after preterm prelabour rupture of the membranes between 34+0 weeks and 37+0 weeks in women with a positive group B streptococcus test, and so added this recommendation to this section of the guideline.\n\nBased on their knowledge and experience of the risks of group B streptococcal infection to the baby after rupture of the membranes, the committee agreed that with prelabour rupture of the membranes after 37+0 weeks in women with a positive group B streptococcus test, immediate induction of labour or caesarean birth would also be recommended.\n\nIn women who did not have a positive group B streptococcus test, but who had prelabour rupture of the membranes after 37+0 weeks, the committee were aware that expectant management for 24\xa0hours was an option as the risk of infection to the baby was low. However, after that period, induction should be advised as the committee were aware that prolonged pregnancy at term after rupture of the membranes can increase risks to the baby, and they therefore advised that birth options should be discussed with women who choose not to have induction of labour after 24\xa0hours.\n\n## How the recommendations might affect practice\n\nThe recommendations will reinforce current practice.\n\nReturn to recommendations\n\n# Induction of labour for suspected fetal macrosomia\n\nRecommendations 1.2.24 and 1.2.25\n\n## Why the committee made the recommendations\n\nThere was some evidence of both benefits and harms for induction of labour and for expectant management in women without diabetes with suspected fetal macrosomia, but there was uncertainty around this evidence, particularly relating to the risk of perineal tears. As there was not enough evidence to recommend one method over another, the committee recommended that women should be provided with information about different modes of birth so they can make an informed decision, and that recruitment into relevant clinical trials should be supported.\n\n## How the recommendations might affect practice\n\nCurrently, there is variation in clinical practice and so the recommendations may mean an increase in consultation time to counsel women appropriately in some areas. This is not expected to lead to a substantial resource impact at national level.\n\nReturn to recommendations\n\n# Induction of labour for intrauterine fetal death after previous caesarean birth\n\nRecommendations 1.2.30 and 1.2.32\n\n## Why the committee made the recommendations\n\nIn the absence of evidence, the committee made recommendations based on their knowledge and experience and also made a recommendation for research on intrauterine fetal death after previous caesarean birth. The committee agreed that the different options for birth should be discussed with women after intrauterine fetal death if they have had a previous caesarean birth, and their choice should be respected. They also agreed that women with IUFD should be cared for on a one-to-one basis and monitored.\n\nThe committee explained that, after intrauterine fetal death, women with a scarred uterus are at increased risk of uterine rupture. This should be taken into account when considering options for birth and if induction is carried out, uterine contractions should be carefully monitored.\n\nThe committee discussed that mifepristone 600\xa0mg daily for 2\xa0days is approved for the induction of labour following intrauterine fetal death when prostaglandin or oxytocin cannot be used, but that no evidence for its safety or efficacy in women with a previous caesarean birth had been identified and so they were unable to recommend it. The committee discussed that in women with intrauterine fetal death and no previous caesarean birth a lower dose of mifepristone was used to sensitise the myometrium to prostaglandin-induced contractions, followed by a prostaglandin (dinoprostone or misoprostol). However, the committee were aware that both dinoprostone and misoprostol are contraindicated after previous caesarean birth and so made a recommendation to state this.\n\nThe committee recognised that mechanical methods of induction may be safe to use in women with a previous caesarean birth, and so they advised that these could be considered. This also brought the recommendations for induction after a previous caesarean birth for women with live babies or after intrauterine fetal death, in line with each other.\n\n## How the recommendations might affect practice\n\nCurrently, there is variation in the management of women after an intrauterine fetal death who have had previous caesarean birth, so the recommendations may mean an increase in consultation time to counsel women appropriately in some areas, and an increase in monitoring to reduce the risk of uterine rupture. This is not expected to lead to a substantial resource impact at national level.\n\nReturn to recommendations\n\n# Methods for induction of labour\n\nRecommendations 1.3.4 to 1.3.10\n\n## Why the committee made the recommendations\n\nThe committee agreed that, in their experience, women value being informed about the reason why certain treatments are offered, and that it should be made clear to women that the possible methods for induction of labour will depend primarily on the readiness of their cervix, which is assessed with a vaginal examination and recorded as the Bishop score.\n\nThere was good evidence that vaginal dinoprostone was effective at promoting vaginal birth within 24\xa0hours for women with a Bishop score of 6 or less, without significantly increasing the risk of adverse outcomes for the woman or her baby. When the different preparations of vaginal dinoprostone were compared, there was little evidence to demonstrate that one preparation was superior to another. Therefore, the committee agreed that it was appropriate to offer a choice of preparation, depending on availability and the woman's preference. There was some evidence that dinoprostone preparations could lead to hyperstimulation with fetal heart rate changes.\n\nMisoprostol was as effective as dinoprostone at promoting vaginal birth within 24\xa0hours. There was evidence showing a risk of hyperstimulation with misoprostol, although this was predominantly with higher doses and vaginal preparations, and the committee took into consideration previous MHRA warnings relating to the misoprostol vaginal insert about this risk. The committee noted that, for the low dose oral preparations of misoprostol, the risk of hyperstimulation appeared to be the same or lower than with the dinoprostone vaginal preparations. Therefore, the committee agreed that misoprostol could be an alternative to dinoprostone for induction of labour, particularly for women who would prefer an oral preparation.\n\nThere was evidence that there was no increased risk of hyperstimulation when using mechanical methods for induction of labour (including osmotic cervical dilators and balloon catheters). Balloon catheters were also effective at promoting vaginal birth within 24\xa0hours and did not appear to markedly increase the risk of other adverse outcomes. There was no evidence for the effectiveness of osmotic cervical dilators at promoting vaginal birth within 24\xa0hours, but they too did not appear to markedly increase the risk of other adverse outcomes. Therefore, the committee agreed that these mechanical methods could be considered for induction of labour for women, particularly when there is a concern about hyperstimulation.\n\nThere was very little evidence for women with a Bishop score of more than 6. However, the committee noted that amniotomy and intravenous oxytocin was the most effective method to promote vaginal birth within 24\xa0hours across the whole population. This was in keeping with their clinical experience, so they agreed that this should be the first choice for induction of labour for women in this group.\n\n## How the recommendations might affect practice\n\nMost hospitals use the recommended methods for induction of labour already, so these recommendations will not result in a significant change of practice. The advice specific to women with a Bishop score of more than 6 should provide more individualised care and standardise practice for this subgroup of women.\n\nReturn to recommendations", 'Context': "Induced labour may be recommended in circumstances when it appears that the benefits outweigh the risks for the mother and baby of continuing with the pregnancy, but with the aim of still enabling a vaginal birth. However, induction has an impact on the birth experience of women as it:\n\nremoves the satisfaction of achieving the more natural birth that many woman hope for\n\nis generally more painful than spontaneous labour\n\nis more likely to lead to additional interventions such as assisted or operative birth, including caesarean birth, and\n\nis more likely to need epidural analgesia.\n\nInduction of labour is a common procedure, with approximately a third of all women in the UK undergoing induction, and there are a variety of methods available using both pharmacological treatments and mechanical methods. The choice of method depends on the readiness of the woman's cervix (assessed using a vaginal examination, and categorised using the Bishop score), whether the membranes have ruptured, and the woman's preferences. The options available should be discussed and this discussion should include:\n\nan awareness of the efficacy and possible adverse effects for the woman and her baby associated with each method, and\n\nthe likelihood that additional interventions (such as emergency caesarean birth) might be needed if the induction is not successful.\n\nWomen can choose not to have induction of labour, and appropriate care should then be offered to optimise the outcome of the pregnancy while respecting the woman's wishes.\n\nThe aim of this guideline is to give advice to healthcare professionals providing obstetric services, and to pregnant women, on the information and support women and their families and birth partners should be offered when making decisions about induction of labour. It also aims to define the circumstances when induction of labour may be appropriate, and identify the most effective way to induce labour, including choice of method, setting, timing, monitoring and pain relief."}
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https://www.nice.org.uk/guidance/ng207
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This guideline covers the circumstances for inducing labour, methods of induction, assessment, monitoring, pain relief and managing complications. It aims to improve advice and care for pregnant women who are thinking about or having induction of labour.
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6b82dc4c416b1b5504e4ab45c97b366a871cbfa7
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nice
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Selpercatinib for treating advanced thyroid cancer with RET alterations
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Selpercatinib for treating advanced thyroid cancer with RET alterations
Evidence-based recommendations on selpercatinib (Retsevmo) for advanced thyroid cancer with RET alterations in people 12 years and older.
# Recommendations
Selpercatinib is recommended for use within the Cancer Drugs Fund, as an option for treating:
advanced RET fusion-positive thyroid cancer in adults who need systemic therapy after sorafenib or lenvatinib
advanced RET-mutant medullary thyroid cancer in people 12 years and older who need systemic therapy after cabozantinib or vandetanib.It is recommended only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect treatment with selpercatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician and the young person and the young person's parents or carers.
Why the committee made these recommendations
People with advanced RET fusion-positive thyroid cancer are usually first offered a partial or full thyroidectomy. This is followed by radioactive iodine and then lenvatinib or sorafenib. People with advanced RET-mutant medullary thyroid cancer are usually offered a partial or full thyroidectomy, followed by cabozantinib.
Clinical trial evidence for selpercatinib is highly uncertain because it is based on an ongoing single-arm trial and not all subpopulations represent NHS practice. The results comparing selpercatinib indirectly with best supportive care are also highly uncertain.
Selpercatinib could be cost effective if more data becomes available from the ongoing trial that shows people live longer with treatment. Data from the trial and NHS practice would also help address the uncertainty about its clinical effectiveness. Selpercatinib is therefore recommended for use in the Cancer Drugs Fund so that more data can be collected.# Information about selpercatinib
# Marketing authorisation indication
Selpercatinib (Retsevmo, Eli Lilly) 'as monotherapy is indicated for the treatment of adults with advanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and or lenvatinib'.
Selpercatinib 'as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RET-mutant medullary thyroid cancer (MTC) who require systemic therapy following prior treatment with cabozantinib and or vandetanib'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The company-estimated cost of a 28‑day cycle of selpercatinib is £8,736.00. The company has a commercial arrangement. This makes selpercatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
cabozantinib is not a relevant comparator for selpercatinib in the rearranged during transfection (RET)-mutant medullary thyroid cancer population
including genetic testing costs in the model is appropriate
time on treatment for selpercatinib in the economic model should be in line with data from LIBRETTO‑001.
It discussed the following issues (issues 2, 3, 4, 5, and 6), which were outstanding after the technical engagement stage. It also discussed the additional issues of whether selpercatinib fulfils the criteria to be considered as a life-extending treatment at the end of life, and the possibility of commissioning selpercatinib through the Cancer Drugs Fund.
# The condition and current treatment
## Advanced thyroid cancer significantly affects quality of life for patients
Clinical experts explained that differentiated thyroid cancer and medullary thyroid cancers are rare. RET-activating fusions and mutations are important in many cancer types, including different types of thyroid cancer. RET mutations in people with advanced medullary thyroid cancer and RET fusions in people with other thyroid cancers are associated with more aggressive disease and poorer outcomes for patients. The patient experts explained that thyroid cancer can be devastating for people and their families, not only because of the shock of the initial diagnosis, but also because of the relative lack of treatment options that are available. One patient expert described the distressing effect of being the parent and carer of 2 young children with RET-mutant medullary thyroid cancer. Initial surgical treatment had resulted in extensive post-operative complications. These had permanently affected their child's appearance, had a lasting effect on self-confidence and were a daily reminder of the disease. Further testing of their relatives revealed more people with the hereditary RET gene mutation who needed treatment for the disease. Another patient expert described how diagnosis in early adulthood and the lack of treatment options had had a big effect on their mental health. Learning that the only treatments available to slow progression were likely to significantly affect day-to-day physical health and might not be tolerable at all because of toxicity contributed to experiences of severe anxiety and depression. The committee concluded that advanced thyroid cancer significantly affects quality of life for patients and carers. A targeted RET inhibitor would offer significant benefit to patients.
The patient and clinical experts explained that there was a significant unmet need for people with RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer. For people with medullary thyroid cancer, initial treatment is a partial or full thyroidectomy, or radiotherapy if the disease is inoperable. NICE's technology appraisal guidance on cabozantinib for treating medullary thyroid cancer recommends its use for unresectable, locally advanced or metastatic disease. Best supportive care is the only option for people with medullary thyroid cancer whose disease progresses on cabozantinib or who cannot tolerate it. NICE's technology appraisal guidance on vandetanib for treating medullary thyroid cancer does not recommend it for use. For people with differentiated thyroid cancer, initial treatment is a partial or full thyroidectomy, followed by radioactive iodine. For those whose disease does not respond to radioactive iodine, NICE's technology appraisal guidance on lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine recommends lenvatinib and sorafenib for treating progressive, locally advanced or metastatic disease. Best supportive care is the only option for people whose disease progresses on lenvatinib or sorafenib or who cannot tolerate them. The patient experts explained that, for people with medullary thyroid cancer, cabozantinib is often very difficult to tolerate because of the side effects. The clinical experts explained that lenvatinib and sorafenib are also associated with significant toxicity, and that a targeted RET inhibitor such as selpercatinib would likely provide clinically meaningful benefit with less toxicity than currently available treatments. The committee understood that patients may choose to have selpercatinib before disease progression because of the poor tolerability of current systemic treatments. The committee agreed that a targeted RET inhibitor would offer significant benefit to patients.
# Clinical evidence
## The main clinical evidence comes from a single-arm study
The main clinical evidence for selpercatinib is from LIBRETTO‑001, an ongoing single-arm, open-label, multicentre phase 1 to 2 trial in people with advanced solid tumours, with RET activations. The primary outcome of the trial was objective response rate. The company presented 3 analysis sets for people with RET-mutant medullary thyroid cancer:
primary analysis set (PAS, n=55): included people who had previously had either cabozantinib, vandetanib, or both
supplementary analysis set (n=88): included people with RET-mutant medullary thyroid cancer who had not had cabozantinib or vandetanib
integrated analysis set (n=124): included a larger group of patients from the PAS.For people with RET fusion-positive thyroid cancer, the trial reported results for people whose disease has been previously treated with a systemic therapy (n=19) and those whose disease was untreated (n=8). Results showed that for people with previously treated medullary thyroid cancer, the objective response rate was 69% and median progression-free survival (PFS) was not estimable. For people with previously treated advanced RET fusion-positive thyroid cancer, the objective response rate was 79%, and median PFS was 20.07 months (95% confidence interval : 9.4 to not estimable). Median overall survival (OS) in all subgroups for RET fusion-positive thyroid cancer and RET-mutant medullary thyroid cancer were also not estimable. Additional efficacy data from a March 2020 data cut was provided by the company. This data represents a larger sample size and an additional 3.5 months of follow up and shows no difference in efficacy compared with the original data cut-off. This data supports the original efficacy results but was not used to inform the company's matching-adjusted indirect treatment comparisons (MAIC) and naive indirect treatment comparisons (ITC) for the RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer populations respectively. The data was not used to inform the base case.
## LIBRETTO-001 subpopulations are not all representative of NHS clinical practice
The ERG explained that in the subset of people with previously treated RET-mutant medullary thyroid cancer over a quarter had had at least 3 previous systemic regimens. The committee noted that the marketing authorisation for selpercatinib for people with RET-mutant medullary thyroid cancer allows its use after cabozantinib or vandetanib. Only cabozantinib is recommended by NICE; therefore, the population seen in NHS clinical practice would only have had 1 previous systemic treatment. Of the 55 people in the primary analysis set (disease previously treated with vandetanib, cabozantinib, or both), the median number of previous therapies was 2 (range between 1 and 8); 18 people (33%) had had vandetanib, 13 (24%) had had cabozantinib, and 24 (44%) had had both. Of the 27 people with RET fusion-positive thyroid cancer, 19 people had a previous systemic treatment, and 8 were identified as not having had systemic therapy. The committee noted the very small number of people with RET fusion-positive thyroid cancer in LIBRETTO‑001 (n=19), and that this population was also not closely aligned with the population who would be seen in clinical practice in the NHS, all of whom would have previously had either sorafenib or lenvatinib. Of the 19 that had previously had systemic treatment, 15 had had either lenvatinib or sorafenib and are therefore aligned with the marketing authorisation for RET fusion-positive thyroid cancer. The committee concluded that the results of the single-arm study were based on small numbers and were of limited relevance to the populations specified in the marketing authorisation and people who would be seen in clinical practice in the NHS.
# Indirect treatment comparisons
## The results of the MAIC for RET-mutant medullary thyroid cancer are uncertain
For RET-mutant medullary thyroid cancer, the company did an unanchored MAIC. The MAIC compared selpercatinib from LIBRETTO‑001 with cabozantinib and placebo (a proxy for best supportive care) from the EXAM trial. The EXAM trial compared cabozantinib with placebo in people with progressive medullary thyroid cancer. The committee noted that the LIBRETTO‑001 and EXAM trials included both people with untreated and treated disease. In the RET-mutant medullary thyroid cancer subgroup of the EXAM trial, clinical-effectiveness results were not reported separately for people with treated or untreated disease. Therefore the MAIC was done using individual patient-level data from the any-line pooled population from LIBRETTO‑001 and summary evidence from the EXAM trial. The committee noted that 79% of people in EXAM had not previously had a multi-kinase inhibitor. Of the people who had had multi-kinase inhibitors, 25% had had 2 or more. The committee understood that the MAIC results now apply to the EXAM population rather than the LIBRETTO‑001 population. The committee noted that because this is a mixed population of people with untreated disease and people who had had more than 1 multi-kinase inhibitor, it is not fully representative of either the population stipulated in the marketing authorisation or those who would be seen in NHS clinical practice (after treatment with cabozantinib only). The committee recalled justification provided in the company submission that the pooled population was preferred over the pre-treated subgroup because it provided a larger patient-level dataset, more closely matched the characteristics of the EXAM trial population, and provided more information about the proportion of people with treated or untreated disease, to better adjust for the differences between the trials. The ERG explained that even with this larger population, the results are based on subgroups with small numbers of people, which affects their reliability. The committee noted the ERG's view that there were additional sources of uncertainty in the MAIC. The baseline characteristics of the RET-mutant subgroups were not available for the placebo arm of the EXAM trial; therefore, the baseline characteristics of the cabozantinib group were assumed to be similar to those of the placebo arm and were used in the MAIC. The company selected only Eastern Cooperative Oncology Group performance status and RET-mutation type (RET M918T) as matching variables in the MAIC. The ERG explained that other important prognostic factors may be missing and therefore the MAIC results are likely to be biased because of unobserved confounding. Also, OS data was not available from EXAM for the RET-mutant subgroup so the data was obtained from the unweighted Kaplan–Meier curves from the RET M918T-positive group (45 people having placebo). The committee noted that the results of the MAIC showed that selpercatinib improves PFS and OS compared with best supportive care (the exact results are confidential and cannot be reported here). The company agreed with the ERG's assessment of the limitations of the MAIC, and suggested that it was not possible to resolve these issues. The committee agreed that these issues could not be resolved and that the MAIC was the only source of data available for decision making. The committee concluded that the MAIC contains multiple sources of uncertainty and therefore the results of the MAIC are uncertain.
## The results of the ITC for RET fusion-positive thyroid cancer are uncertain
For RET fusion-positive thyroid cancer, the company did a naive unanchored ITC. The ITC compared single-arm trial data for selpercatinib from LIBRETTO‑001 with trial data for placebo (a proxy for best supportive care) from the SELECT trial. The SELECT trial compared lenvatinib with placebo in people with radioiodine-refractory differentiated thyroid cancer. The committee noted that no trial data was identified in people with RET fusion-positive thyroid cancer, but that the prognostic significance of RET fusion in thyroid cancer is unclear. So, it is uncertain if data for people with RET-status thyroid cancer (SELECT) is generalisable to RET fusion-positive thyroid cancer (LIBRETTO‑001). The ERG explained that the SELECT trial included predominantly people with untreated disease, with 20.6% having had at least 1 previous therapy, compared with 100% in LIBRETTO‑001. However, in SELECT, the treatment effect on PFS in people with treated disease (hazard ratio 0.22; 95% CI 0.12 to 0.41) was consistent with the overall population (HR 0.21; 95% CI 0.16 to 0.28). Also, subgroup data by line of therapy was not reported for OS in SELECT, so it is unclear if the efficacy of best supportive care is generalisable to the population of interest for this submission. In addition, OS was confounded by crossover in SELECT, with most people who had placebo crossing over to lenvatinib. The ERG stressed that the very small numbers of people in LIBRETTO‑001 (subgroup of people who had had either sorafenib or lenvatinib, n=15), and with no attempt to balance the 2 patient groups, means that PFS is also likely to be highly uncertain. The committee noted that the results of the ITC show that selpercatinib improves PFS and OS compared with best supportive care (the exact results of the ITC are confidential and cannot be reported here). The company agreed with the ERG's assessment of the limitations of the naive unanchored ITC, and suggested that it was not possible to resolve these issues. The committee agreed that these issues could not be resolved and that the ITC was the only source of data available for decision making. The committee concluded that the ITC contains multiple sources of uncertainty and therefore the results of the ITC are uncertain.
# The company's economic model
## The company's model is appropriate for decision making
The company used a partitioned-survival economic model that included 3 health states: pre-progression, post-progression and death. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for thyroid cancer (NICE's technology appraisal guidance on cabozantinib and NICE's technology appraisal guidance on lenvatinib and sorafenib).
# Survival extrapolations
## Modelled progression-free survival in the RET-mutant medullary thyroid cancer population is highly uncertain
To estimate PFS for people with RET-mutant medullary thyroid cancer, the company examined a range of stratified and unstratified parametric functions fitted to the weighted Kaplan–Meier data of the any-line population of LIBRETTO‑001 (generated in the MAIC) and unweighted, pseudo patient-level Kaplan–Meier data for people with RET-mutant medullary thyroid cancer having placebo in EXAM. Because the statistical fit between the PFS functions was so similar, the choice of survival extrapolation was guided by visual fit and clinical plausibility. The company selected the log-logistic for its base case based on clinical expert opinion and because it provided a good visual fit to the early Kaplan–Meier data. The ERG explained that it agreed with the choice of log-logistic, but that it was unable to verify the clinical justification. It emphasised that the wide spread of the alternative parametric functions suggests a very high degree of uncertainty and was associated with a very wide range of incremental cost-effectiveness ratios (ICERs). The committee noted the agreement between the company and the ERG on the choice of the log-logistic extrapolation for PFS, but agreed that this choice was uncertain. The committee concluded that the choice of extrapolation for PFS for RET-mutant medullary thyroid cancer was based on very immature survival data and was therefore highly uncertain.
## Modelled overall survival in the RET-mutant medullary thyroid cancer population is highly uncertain
To estimate OS for people with RET-mutant medullary thyroid cancer, the company maintained that the proportional hazards assumption was not violated, and so its preference was for unstratified proportional hazard functions. The company initially selected an extrapolation based on the Weibull function for its base case. The ERG considered that this choice was overly optimistic for selpercatinib OS, predicting too many people alive at 25 years, and instead preferred to explore alternative extrapolations that included stratified functions. The ERG explained its view that the stratified Weibull function provided the best visual fit, best long-term plausibility for best supportive care, and the most reasonable estimate of the benefit of selpercatinib relative to best supportive care given the very limited evidence and immature data available. The company then replaced the Weibull with the stratified gamma in its base case after receiving additional feedback from a clinical expert who suggested it was clinically plausible. The ERG responded that because of the high degree of uncertainty and the importance of clinical judgement, it had no reason to reject this choice of extrapolation for OS. The clinical experts explained that it was very difficult to predict the most appropriate survival extrapolations for the treatments, and in particular selpercatinib. The committee noted the views of the company and ERG and agreed that it was unclear on what basis the clinical expert consulted by the company had preferred the stratified gamma extrapolation for OS, given the extent of the uncertainty expressed by the clinical experts at the meeting. The committee agreed that the choice of extrapolations for OS using either the stratified gamma or stratified Weibull functions in RET-mutant medullary thyroid cancer was plausible but associated with a very wide range of ICERs. The committee concluded that the choice of extrapolation for OS for RET-mutant medullary thyroid cancer was based on very immature survival data and was therefore highly uncertain.
## Modelled progression-free survival in the RET fusion-positive thyroid cancer population is highly uncertain
To estimate PFS for people with RET fusion-positive thyroid cancer a range of survival functions were fitted to the Kaplan–Meier data for people with previously treated RET fusion-positive thyroid cancer from LIBRETTO‑001 and the Kaplan–Meier data of the intention-to-treat population of people having placebo in SELECT. The stratified Weibull extrapolation was selected for PFS based on feedback from clinical experts. The committee noted that the ERG agreed with this choice but recognised the ERG's view that there was no documented justification for the expert's preference. The committee noted that the plausible extrapolations for PFS did not have such a big effect on the ICER range as was the case for RET-mutant medullary thyroid cancer, but concluded that the choice of the stratified Weibull extrapolation for PFS was uncertain.
## Modelled overall survival in the RET fusion-positive thyroid cancer population is highly uncertain
To estimate OS for people with RET fusion-positive thyroid cancer, a range of parametric functions were explored using data from people with previously treated RET fusion-positive thyroid cancer in LIBRETTO‑001 and the rank preserving structural failure time-adjusted Kaplan–Meier data from the intention-to-treat population having placebo in SELECT. The company considered the results of the extrapolations using stratified functions as implausible, because of the curves often crossing or converging early along the time horizon. The company explored piecewise exponential functions fitted to the data for 0 to 6 months and for 6 months onwards, which was an approach previously accepted in NICE's technology appraisal guidance on lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine. The piecewise exponential model was selected for the company base-case analysis, based on visual fit, external validation with the outcomes seen in LIBRETTO‑001 and SELECT and clinical expert opinion. The ERG emphasised that because of the very limited sample size (subgroup of people who had had either sorafenib or lenvatinib, n=15), immaturity of the data and small number of survival events, there was a high degree of uncertainty around the plausible OS estimates for selpercatinib in this population. The ERG agreed with the company that the extrapolations for OS using most of the stratified functions produced implausible results, because of the early crossing or converging of curves that would suggest only marginal benefit of selpercatinib or favourable results for best supportive care. The committee agreed that there is no plausible clinical reason to expect this. The only stratified function for OS which did not result in crossing curves was the stratified gamma, for which the selpercatinib extrapolation was much less optimistic than the base-case piecewise exponential. The committee noted that predicted OS using the stratified gamma function was likely too pessimistic. For OS, the committee considered that the only plausible extrapolation was piecewise exponential. The committee was reminded that the data on which the PFS and OS extrapolations was based was highly uncertain (see section 3.6). The committee concluded that modelled OS in the RET fusion-positive thyroid cancer population is highly uncertain.
# Utility values in the economic model
## The utility values reported by Fordham et al. (2015) are appropriate
Health-related quality of life data was collected in LIBRETTO‑001 using the EORTC QLQ‑C30 questionnaire. No EQ‑5D data was available from LIBRETTO‑001 and an attempt to map the EORTC QLQ‑C30 to EQ‑5D utilities resulted in implausible results. The committee noted that the literature review done by the company did not identify any health state utility values specific to people with RET-mutant medullary thyroid cancer or RET fusion-positive thyroid cancer. The committee recalled the effect of the disease on parents and carers (see section 3.1). It noted that carer utilities had not been captured by the company for inclusion in the economic model for the medullary thyroid cancer population of people aged between 12 and 18, and agreed that this could be an additional benefit not currently captured in the model. The company selected values from a vignette study done by Fordham et al. (2015) to estimate patient utilities in differentiated thyroid cancer for its base case, and these were also accepted in NICE's technology appraisal on cabozantinib for treating medullary thyroid cancer. The value for progression-free disease was 0.8 and for progressed disease 0.5. The committee noted that clinical expert opinion suggested that the Fordham utility values were reasonable. The company provided alternative values for progressed disease used in NICE's technology appraisal guidance on lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine from the DECISION study (sorafenib compared with best supportive care) and values accepted by the Scottish Medicines Consortium for cabozantinib and sorafenib. The committee noted that the choice of progressed disease value only had a moderate effect on the ICER. The committee was concerned that the Fordham utility values were based on a vignette study, which is not usually accepted by NICE to inform utility values, because they are less robust than EQ‑5D methods. The committee concluded that, in the absence of more appropriate values collected directly from a relevant population, the utility values reported by Fordham et al. (2015) could be accepted as a plausible estimate of utilities.
# End of life
## Selpercatinib does not meet the end-of-life criteria for both populations but the data is highly uncertain
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.
For RET-mutant medullary thyroid cancer, in the RET‑M918T-positive subpopulation of the EXAM trial, the median OS in the placebo arm was 18.9 months (n=45) and the median OS for the intention-to-treat population treated with placebo was 21.1 months (n=111). The EXAM trial included mainly people who had not previously had multi-kinase inhibitor treatment, whereas people with previously treated RET-mutant disease may have worse prognosis than the intention-to-treat placebo arm of the EXAM trial.
For RET fusion-positive thyroid cancer, in the intention-to-treat population of the SELECT trial, the company model predicted a median OS of less than 2 years. This population included predominantly (79.4%) people who had not previously had a tyrosine kinase inhibitor, and so may overestimate survival of a pre-treated population.
For both RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer, the company model predicted an extension to life of greater than 3 months compared with current NHS treatment.The clinical experts agreed with the company that it was plausible that people with previously treated RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer had a short life expectancy of less than 24 months, particularly when people's disease progresses on treatment. The ERG explained that the company's predictions rely on evidence from the economic model that is based on results from highly uncertain analyses (see section 3.5 and section 3.6). The ERG also noted that the company's own model for both populations predicts mean life years for best supportive care of more than 2 years (exact results are confidential). The committee recalled the wording from NICE's guide to the methods of technology appraisal which states that the estimates of the extension to life are sufficiently robust and can be shown or reasonably inferred from either PFS or OS and the assumptions used in the reference case economic modelling are plausible, objective and robust.The committee accepted that for those people whose disease progresses on previous lines of treatment, based on clinical expert opinion, the short life expectancy criteria is likely met. However, for those people who cannot tolerate treatment with cabozantinib or sorafenib or lenvatinib the short life expectancy criteria may not be met. This is because people may choose to have selpercatinib before disease progression because of issues with poor tolerability with previous systemic treatment (see section 3.2). The committee agreed that the survival estimates produced by the economic model are highly uncertain (see section 3.8 to section 3.11). The committee was satisfied that selpercatinib likely extends life by at least 3 months. The committee agreed that selpercatinib is unlikely to meet the end-of-life criteria for the whole population specified in the marketing authorisation and for those who would be seen in NHS clinical practice. The committee concluded that selpercatinib does not meet the end-of-life criteria for both populations but the data is highly uncertain.
# Results of the cost-effectiveness analysis
## Selpercatinib is not recommended for routine use in the NHS
NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. NICE's guide to the methods of technology appraisal also states that consideration of the cost effectiveness of a technology is necessary, but not the sole basis for decision making. The committee considered the rarity of the condition and the lack of effective treatments for people with advanced RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer. It also noted the devastating effect of the disease on children and young people with RET-mutant medullary thyroid cancer and that benefits to carers had not been captured in the economic model (see section 3.1, section 3.2 and section 3.12). Therefore, it agreed that an acceptable ICER for both populations would be around £30,000 per QALY gained. The committee noted that, when considering the commercial arrangements, selpercatinib was plausibly cost effective in both populations, with ICERs around £30,000 per QALY gained (exact ICERs are commercial in confidence and cannot be reported here). The committee recalled that the evidence base was immature and the pivotal trial for selpercatinib was ongoing. It considered that the ICERs are uncertain and could be higher than what NICE normally considers an acceptable use of NHS resources. Therefore, selpercatinib could not be recommended for routine commissioning.
# Cancer Drugs Fund
## Selpercatinib is recommended for the Cancer Drugs Fund
Having concluded that selpercatinib could not be recommended for routine use, the committee then considered if it could be recommended for treating advanced thyroid cancer with RET alterations within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):
The company expressed an interest in selpercatinib being considered for funding through the Cancer Drugs Fund.
The company's model is structurally robust for decision making (see section 3.7)
Data from LIBRETTO‑001 is immature. Median PFS and OS in the pre-treated subgroup for RET-mutant medullary thyroid cancer was not estimable, and median OS in the pre-treated subgroup for RET fusion-positive thyroid cancer was not estimable. OS was a key driver of the cost-effectiveness results.
LIBRETTO‑001 is still ongoing and further data could help reduce uncertainties around long-term PFS and OS
Observational data collection via the Systemic Anti-Cancer Therapy dataset could address some of the clinical uncertainty in PFS and OS for selpercatinib.The committee considered that further data collection in the Cancer Drugs Fund could alleviate some of the uncertainty in the company's estimates. It recognised the rarity of thyroid cancers with RET alterations and that the benefits for carers of children and young people with RET altered thyroid cancers had not been included in the economic model. The committee was satisfied that selpercatinib met the criteria for inclusion in the Cancer Drugs Fund. Therefore, it recommended selpercatinib for use within the Cancer Drugs Fund for treating RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer, if the conditions in the managed access agreement are followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out previously.
|
{'Recommendations': "Selpercatinib is recommended for use within the Cancer Drugs Fund, as an option for treating:\n\nadvanced RET fusion-positive thyroid cancer in adults who need systemic therapy after sorafenib or lenvatinib\n\nadvanced RET-mutant medullary thyroid cancer in people 12\xa0years and older who need systemic therapy after cabozantinib or vandetanib.It is recommended only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect treatment with selpercatinib that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician and the young person and the young person's parents or carers.\n\nWhy the committee made these recommendations\n\nPeople with advanced RET fusion-positive thyroid cancer are usually first offered a partial or full thyroidectomy. This is followed by radioactive iodine and then lenvatinib or sorafenib. People with advanced RET-mutant medullary thyroid cancer are usually offered a partial or full thyroidectomy, followed by cabozantinib.\n\nClinical trial evidence for selpercatinib is highly uncertain because it is based on an ongoing single-arm trial and not all subpopulations represent NHS practice. The results comparing selpercatinib indirectly with best supportive care are also highly uncertain.\n\nSelpercatinib could be cost effective if more data becomes available from the ongoing trial that shows people live longer with treatment. Data from the trial and NHS practice would also help address the uncertainty about its clinical effectiveness. Selpercatinib is therefore recommended for use in the Cancer Drugs Fund so that more data can be collected.", 'Information about selpercatinib': "# Marketing authorisation indication\n\nSelpercatinib (Retsevmo, Eli Lilly) 'as monotherapy is indicated for the treatment of adults with advanced RET fusion-positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and or lenvatinib'.\n\nSelpercatinib 'as monotherapy is indicated for the treatment of adults and adolescents 12\xa0years and older with advanced RET-mutant medullary thyroid cancer (MTC) who require systemic therapy following prior treatment with cabozantinib and or vandetanib'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe company-estimated cost of a 28‑day cycle of selpercatinib is £8,736.00. The company has a commercial arrangement. This makes selpercatinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\ncabozantinib is not a relevant comparator for selpercatinib in the rearranged during transfection (RET)-mutant medullary thyroid cancer population\n\nincluding genetic testing costs in the model is appropriate\n\ntime on treatment for selpercatinib in the economic model should be in line with data from LIBRETTO‑001.\n\nIt discussed the following issues (issues 2, 3, 4, 5, and 6), which were outstanding after the technical engagement stage. It also discussed the additional issues of whether selpercatinib fulfils the criteria to be considered as a life-extending treatment at the end of life, and the possibility of commissioning selpercatinib through the Cancer Drugs Fund.\n\n# The condition and current treatment\n\n## Advanced thyroid cancer significantly affects quality of life for patients\n\nClinical experts explained that differentiated thyroid cancer and medullary thyroid cancers are rare. RET-activating fusions and mutations are important in many cancer types, including different types of thyroid cancer. RET mutations in people with advanced medullary thyroid cancer and RET fusions in people with other thyroid cancers are associated with more aggressive disease and poorer outcomes for patients. The patient experts explained that thyroid cancer can be devastating for people and their families, not only because of the shock of the initial diagnosis, but also because of the relative lack of treatment options that are available. One patient expert described the distressing effect of being the parent and carer of 2\xa0young children with RET-mutant medullary thyroid cancer. Initial surgical treatment had resulted in extensive post-operative complications. These had permanently affected their child's appearance, had a lasting effect on self-confidence and were a daily reminder of the disease. Further testing of their relatives revealed more people with the hereditary RET gene mutation who needed treatment for the disease. Another patient expert described how diagnosis in early adulthood and the lack of treatment options had had a big effect on their mental health. Learning that the only treatments available to slow progression were likely to significantly affect day-to-day physical health and might not be tolerable at all because of toxicity contributed to experiences of severe anxiety and depression. The committee concluded that advanced thyroid cancer significantly affects quality of life for patients and carers. A targeted RET inhibitor would offer significant benefit to patients.\n\nThe patient and clinical experts explained that there was a significant unmet need for people with RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer. For people with medullary thyroid cancer, initial treatment is a partial or full thyroidectomy, or radiotherapy if the disease is inoperable. NICE's technology appraisal guidance on cabozantinib for treating medullary thyroid cancer recommends its use for unresectable, locally advanced or metastatic disease. Best supportive care is the only option for people with medullary thyroid cancer whose disease progresses on cabozantinib or who cannot tolerate it. NICE's technology appraisal guidance on vandetanib for treating medullary thyroid cancer does not recommend it for use. For people with differentiated thyroid cancer, initial treatment is a partial or full thyroidectomy, followed by radioactive iodine. For those whose disease does not respond to radioactive iodine, NICE's technology appraisal guidance on lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine recommends lenvatinib and sorafenib for treating progressive, locally advanced or metastatic disease. Best supportive care is the only option for people whose disease progresses on lenvatinib or sorafenib or who cannot tolerate them. The patient experts explained that, for people with medullary thyroid cancer, cabozantinib is often very difficult to tolerate because of the side effects. The clinical experts explained that lenvatinib and sorafenib are also associated with significant toxicity, and that a targeted RET inhibitor such as selpercatinib would likely provide clinically meaningful benefit with less toxicity than currently available treatments. The committee understood that patients may choose to have selpercatinib before disease progression because of the poor tolerability of current systemic treatments. The committee agreed that a targeted RET inhibitor would offer significant benefit to patients.\n\n# Clinical evidence\n\n## The main clinical evidence comes from a single-arm study\n\nThe main clinical evidence for selpercatinib is from LIBRETTO‑001, an ongoing single-arm, open-label, multicentre phase\xa01 to\xa02 trial in people with advanced solid tumours, with RET activations. The primary outcome of the trial was objective response rate. The company presented 3\xa0analysis sets for people with RET-mutant medullary thyroid cancer:\n\nprimary analysis set (PAS, n=55): included people who had previously had either cabozantinib, vandetanib, or both\n\nsupplementary analysis set (n=88): included people with RET-mutant medullary thyroid cancer who had not had cabozantinib or vandetanib\n\nintegrated analysis set (n=124): included a larger group of patients from the PAS.For people with RET fusion-positive thyroid cancer, the trial reported results for people whose disease has been previously treated with a systemic therapy (n=19) and those whose disease was untreated (n=8). Results showed that for people with previously treated medullary thyroid cancer, the objective response rate was 69% and median progression-free survival (PFS) was not estimable. For people with previously treated advanced RET fusion-positive thyroid cancer, the objective response rate was 79%, and median PFS was 20.07\xa0months (95% confidence interval [CI]: 9.4 to not estimable). Median overall survival (OS) in all subgroups for RET fusion-positive thyroid cancer and RET-mutant medullary thyroid cancer were also not estimable. Additional efficacy data from a March\xa02020 data cut was provided by the company. This data represents a larger sample size and an additional 3.5\xa0months of follow up and shows no difference in efficacy compared with the original data cut-off. This data supports the original efficacy results but was not used to inform the company's matching-adjusted indirect treatment comparisons (MAIC) and naive indirect treatment comparisons (ITC) for the RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer populations respectively. The data was not used to inform the base case.\n\n## LIBRETTO-001 subpopulations are not all representative of NHS clinical practice\n\nThe ERG explained that in the subset of people with previously treated RET-mutant medullary thyroid cancer over a quarter had had at least 3\xa0previous systemic regimens. The committee noted that the marketing authorisation for selpercatinib for people with RET-mutant medullary thyroid cancer allows its use after cabozantinib or vandetanib. Only cabozantinib is recommended by NICE; therefore, the population seen in NHS clinical practice would only have had 1\xa0previous systemic treatment. Of the 55\xa0people in the primary analysis set (disease previously treated with vandetanib, cabozantinib, or both), the median number of previous therapies was 2 (range between\xa01 and 8); 18\xa0people (33%) had had vandetanib, 13 (24%) had had cabozantinib, and 24 (44%) had had both. Of the 27\xa0people with RET fusion-positive thyroid cancer, 19\xa0people had a previous systemic treatment, and 8 were identified as not having had systemic therapy. The committee noted the very small number of people with RET fusion-positive thyroid cancer in LIBRETTO‑001 (n=19), and that this population was also not closely aligned with the population who would be seen in clinical practice in the NHS, all of whom would have previously had either sorafenib or lenvatinib. Of the 19 that had previously had systemic treatment, 15 had had either lenvatinib or sorafenib and are therefore aligned with the marketing authorisation for RET fusion-positive thyroid cancer. The committee concluded that the results of the single-arm study were based on small numbers and were of limited relevance to the populations specified in the marketing authorisation and people who would be seen in clinical practice in the NHS.\n\n# Indirect treatment comparisons\n\n## The results of the MAIC for RET-mutant medullary thyroid cancer are uncertain\n\nFor RET-mutant medullary thyroid cancer, the company did an unanchored MAIC. The MAIC compared selpercatinib from LIBRETTO‑001 with cabozantinib and placebo (a proxy for best supportive care) from the EXAM trial. The EXAM trial compared cabozantinib with placebo in people with progressive medullary thyroid cancer. The committee noted that the LIBRETTO‑001 and EXAM trials included both people with untreated and treated disease. In the RET-mutant medullary thyroid cancer subgroup of the EXAM trial, clinical-effectiveness results were not reported separately for people with treated or untreated disease. Therefore the MAIC was done using individual patient-level data from the any-line pooled population from LIBRETTO‑001 and summary evidence from the EXAM trial. The committee noted that 79% of people in EXAM had not previously had a multi-kinase inhibitor. Of the people who had had multi-kinase inhibitors, 25% had had 2 or more. The committee understood that the MAIC results now apply to the EXAM population rather than the LIBRETTO‑001 population. The committee noted that because this is a mixed population of people with untreated disease and people who had had more than 1\xa0multi-kinase inhibitor, it is not fully representative of either the population stipulated in the marketing authorisation or those who would be seen in NHS clinical practice (after treatment with cabozantinib only). The committee recalled justification provided in the company submission that the pooled population was preferred over the pre-treated subgroup because it provided a larger patient-level dataset, more closely matched the characteristics of the EXAM trial population, and provided more information about the proportion of people with treated or untreated disease, to better adjust for the differences between the trials. The ERG explained that even with this larger population, the results are based on subgroups with small numbers of people, which affects their reliability. The committee noted the ERG's view that there were additional sources of uncertainty in the MAIC. The baseline characteristics of the RET-mutant subgroups were not available for the placebo arm of the EXAM trial; therefore, the baseline characteristics of the cabozantinib group were assumed to be similar to those of the placebo arm and were used in the MAIC. The company selected only Eastern Cooperative Oncology Group performance status and RET-mutation type (RET\xa0M918T) as matching variables in the MAIC. The ERG explained that other important prognostic factors may be missing and therefore the MAIC results are likely to be biased because of unobserved confounding. Also, OS data was not available from EXAM for the RET-mutant subgroup so the data was obtained from the unweighted Kaplan–Meier curves from the RET\xa0M918T-positive group (45\xa0people having placebo). The committee noted that the results of the MAIC showed that selpercatinib improves PFS and OS compared with best supportive care (the exact results are confidential and cannot be reported here). The company agreed with the ERG's assessment of the limitations of the MAIC, and suggested that it was not possible to resolve these issues. The committee agreed that these issues could not be resolved and that the MAIC was the only source of data available for decision making. The committee concluded that the MAIC contains multiple sources of uncertainty and therefore the results of the MAIC are uncertain.\n\n## The results of the ITC for RET fusion-positive thyroid cancer are uncertain\n\nFor RET fusion-positive thyroid cancer, the company did a naive unanchored ITC. The ITC compared single-arm trial data for selpercatinib from LIBRETTO‑001 with trial data for placebo (a proxy for best supportive care) from the SELECT trial. The SELECT trial compared lenvatinib with placebo in people with radioiodine-refractory differentiated thyroid cancer. The committee noted that no trial data was identified in people with RET fusion-positive thyroid cancer, but that the prognostic significance of RET fusion in thyroid cancer is unclear. So, it is uncertain if data for people with RET-status thyroid cancer (SELECT) is generalisable to RET fusion-positive thyroid cancer (LIBRETTO‑001). The ERG explained that the SELECT trial included predominantly people with untreated disease, with 20.6% having had at least 1\xa0previous therapy, compared with 100% in LIBRETTO‑001. However, in SELECT, the treatment effect on PFS in people with treated disease (hazard ratio [HR] 0.22; 95% CI 0.12 to 0.41) was consistent with the overall population (HR 0.21; 95% CI 0.16 to 0.28). Also, subgroup data by line of therapy was not reported for OS in SELECT, so it is unclear if the efficacy of best supportive care is generalisable to the population of interest for this submission. In addition, OS was confounded by crossover in SELECT, with most people who had placebo crossing over to lenvatinib. The ERG stressed that the very small numbers of people in LIBRETTO‑001 (subgroup of people who had had either sorafenib or lenvatinib, n=15), and with no attempt to balance the 2\xa0patient groups, means that PFS is also likely to be highly uncertain. The committee noted that the results of the ITC show that selpercatinib improves PFS and OS compared with best supportive care (the exact results of the ITC are confidential and cannot be reported here). The company agreed with the ERG's assessment of the limitations of the naive unanchored ITC, and suggested that it was not possible to resolve these issues. The committee agreed that these issues could not be resolved and that the ITC was the only source of data available for decision making. The committee concluded that the ITC contains multiple sources of uncertainty and therefore the results of the ITC are uncertain.\n\n# The company's economic model\n\n## The company's model is appropriate for decision making\n\nThe company used a partitioned-survival economic model that included 3\xa0health states: pre-progression, post-progression and death. The committee concluded that the model was generally appropriate and consistent with the models used in other appraisals for thyroid cancer (NICE's technology appraisal guidance on cabozantinib and NICE's technology appraisal guidance on lenvatinib and sorafenib).\n\n# Survival extrapolations\n\n## Modelled progression-free survival in the RET-mutant medullary thyroid cancer population is highly uncertain\n\nTo estimate PFS for people with RET-mutant medullary thyroid cancer, the company examined a range of stratified and unstratified parametric functions fitted to the weighted Kaplan–Meier data of the any-line population of LIBRETTO‑001 (generated in the MAIC) and unweighted, pseudo patient-level Kaplan–Meier data for people with RET-mutant medullary thyroid cancer having placebo in EXAM. Because the statistical fit between the PFS functions was so similar, the choice of survival extrapolation was guided by visual fit and clinical plausibility. The company selected the log-logistic for its base case based on clinical expert opinion and because it provided a good visual fit to the early Kaplan–Meier data. The ERG explained that it agreed with the choice of log-logistic, but that it was unable to verify the clinical justification. It emphasised that the wide spread of the alternative parametric functions suggests a very high degree of uncertainty and was associated with a very wide range of incremental cost-effectiveness ratios (ICERs). The committee noted the agreement between the company and the ERG on the choice of the log-logistic extrapolation for PFS, but agreed that this choice was uncertain. The committee concluded that the choice of extrapolation for PFS for RET-mutant medullary thyroid cancer was based on very immature survival data and was therefore highly uncertain.\n\n## Modelled overall survival in the RET-mutant medullary thyroid cancer population is highly uncertain\n\nTo estimate OS for people with RET-mutant medullary thyroid cancer, the company maintained that the proportional hazards assumption was not violated, and so its preference was for unstratified proportional hazard functions. The company initially selected an extrapolation based on the Weibull function for its base case. The ERG considered that this choice was overly optimistic for selpercatinib OS, predicting too many people alive at 25\xa0years, and instead preferred to explore alternative extrapolations that included stratified functions. The ERG explained its view that the stratified Weibull function provided the best visual fit, best long-term plausibility for best supportive care, and the most reasonable estimate of the benefit of selpercatinib relative to best supportive care given the very limited evidence and immature data available. The company then replaced the Weibull with the stratified gamma in its base case after receiving additional feedback from a clinical expert who suggested it was clinically plausible. The ERG responded that because of the high degree of uncertainty and the importance of clinical judgement, it had no reason to reject this choice of extrapolation for OS. The clinical experts explained that it was very difficult to predict the most appropriate survival extrapolations for the treatments, and in particular selpercatinib. The committee noted the views of the company and ERG and agreed that it was unclear on what basis the clinical expert consulted by the company had preferred the stratified gamma extrapolation for OS, given the extent of the uncertainty expressed by the clinical experts at the meeting. The committee agreed that the choice of extrapolations for OS using either the stratified gamma or stratified Weibull functions in RET-mutant medullary thyroid cancer was plausible but associated with a very wide range of ICERs. The committee concluded that the choice of extrapolation for OS for RET-mutant medullary thyroid cancer was based on very immature survival data and was therefore highly uncertain.\n\n## Modelled progression-free survival in the RET fusion-positive thyroid cancer population is highly uncertain\n\nTo estimate PFS for people with RET fusion-positive thyroid cancer a range of survival functions were fitted to the Kaplan–Meier data for people with previously treated RET fusion-positive thyroid cancer from LIBRETTO‑001 and the Kaplan–Meier data of the intention-to-treat population of people having placebo in SELECT. The stratified Weibull extrapolation was selected for PFS based on feedback from clinical experts. The committee noted that the ERG agreed with this choice but recognised the ERG's view that there was no documented justification for the expert's preference. The committee noted that the plausible extrapolations for PFS did not have such a big effect on the ICER range as was the case for RET-mutant medullary thyroid cancer, but concluded that the choice of the stratified Weibull extrapolation for PFS was uncertain.\n\n## Modelled overall survival in the RET fusion-positive thyroid cancer population is highly uncertain\n\nTo estimate OS for people with RET fusion-positive thyroid cancer, a range of parametric functions were explored using data from people with previously treated RET fusion-positive thyroid cancer in LIBRETTO‑001 and the rank preserving structural failure time-adjusted Kaplan–Meier data from the intention-to-treat population having placebo in SELECT. The company considered the results of the extrapolations using stratified functions as implausible, because of the curves often crossing or converging early along the time horizon. The company explored piecewise exponential functions fitted to the data for 0\xa0to 6\xa0months and for 6\xa0months onwards, which was an approach previously accepted in NICE's technology appraisal guidance on lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine. The piecewise exponential model was selected for the company base-case analysis, based on visual fit, external validation with the outcomes seen in LIBRETTO‑001 and SELECT and clinical expert opinion. The ERG emphasised that because of the very limited sample size (subgroup of people who had had either sorafenib or lenvatinib, n=15), immaturity of the data and small number of survival events, there was a high degree of uncertainty around the plausible OS estimates for selpercatinib in this population. The ERG agreed with the company that the extrapolations for OS using most of the stratified functions produced implausible results, because of the early crossing or converging of curves that would suggest only marginal benefit of selpercatinib or favourable results for best supportive care. The committee agreed that there is no plausible clinical reason to expect this. The only stratified function for OS which did not result in crossing curves was the stratified gamma, for which the selpercatinib extrapolation was much less optimistic than the base-case piecewise exponential. The committee noted that predicted OS using the stratified gamma function was likely too pessimistic. For OS, the committee considered that the only plausible extrapolation was piecewise exponential. The committee was reminded that the data on which the PFS and OS extrapolations was based was highly uncertain (see section\xa03.6). The committee concluded that modelled OS in the RET fusion-positive thyroid cancer population is highly uncertain.\n\n# Utility values in the economic model\n\n## The utility values reported by Fordham et al. (2015) are appropriate\n\nHealth-related quality of life data was collected in LIBRETTO‑001 using the EORTC QLQ‑C30 questionnaire. No EQ‑5D data was available from LIBRETTO‑001 and an attempt to map the EORTC QLQ‑C30 to EQ‑5D utilities resulted in implausible results. The committee noted that the literature review done by the company did not identify any health state utility values specific to people with RET-mutant medullary thyroid cancer or RET fusion-positive thyroid cancer. The committee recalled the effect of the disease on parents and carers (see section\xa03.1). It noted that carer utilities had not been captured by the company for inclusion in the economic model for the medullary thyroid cancer population of people aged between\xa012 and 18, and agreed that this could be an additional benefit not currently captured in the model. The company selected values from a vignette study done by Fordham et al. (2015) to estimate patient utilities in differentiated thyroid cancer for its base case, and these were also accepted in NICE's technology appraisal on cabozantinib for treating medullary thyroid cancer. The value for progression-free disease was 0.8 and for progressed disease 0.5. The committee noted that clinical expert opinion suggested that the Fordham utility values were reasonable. The company provided alternative values for progressed disease used in NICE's technology appraisal guidance on lenvatinib and sorafenib for treating differentiated thyroid cancer after radioactive iodine from the DECISION study (sorafenib compared with best supportive care) and values accepted by the Scottish Medicines Consortium for cabozantinib and sorafenib. The committee noted that the choice of progressed disease value only had a moderate effect on the ICER. The committee was concerned that the Fordham utility values were based on a vignette study, which is not usually accepted by NICE to inform utility values, because they are less robust than EQ‑5D methods. The committee concluded that, in the absence of more appropriate values collected directly from a relevant population, the utility values reported by Fordham et al. (2015) could be accepted as a plausible estimate of utilities.\n\n# End of life\n\n## Selpercatinib does not meet the end-of-life criteria for both populations but the data is highly uncertain\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal.\n\nFor RET-mutant medullary thyroid cancer, in the RET‑M918T-positive subpopulation of the EXAM trial, the median OS in the placebo arm was 18.9\xa0months (n=45) and the median OS for the intention-to-treat population treated with placebo was 21.1\xa0months (n=111). The EXAM trial included mainly people who had not previously had multi-kinase inhibitor treatment, whereas people with previously treated RET-mutant disease may have worse prognosis than the intention-to-treat placebo arm of the EXAM trial.\n\nFor RET fusion-positive thyroid cancer, in the intention-to-treat population of the SELECT trial, the company model predicted a median OS of less than 2\xa0years. This population included predominantly (79.4%) people who had not previously had a tyrosine kinase inhibitor, and so may overestimate survival of a pre-treated population.\n\nFor both RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer, the company model predicted an extension to life of greater than 3\xa0months compared with current NHS treatment.The clinical experts agreed with the company that it was plausible that people with previously treated RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer had a short life expectancy of less than 24\xa0months, particularly when people's disease progresses on treatment. The ERG explained that the company's predictions rely on evidence from the economic model that is based on results from highly uncertain analyses (see section\xa03.5 and section 3.6). The ERG also noted that the company's own model for both populations predicts mean life years for best supportive care of more than 2\xa0years (exact results are confidential). The committee recalled the wording from NICE's guide to the methods of technology appraisal which states that the estimates of the extension to life are sufficiently robust and can be shown or reasonably inferred from either PFS or OS and the assumptions used in the reference case economic modelling are plausible, objective and robust.The committee accepted that for those people whose disease progresses on previous lines of treatment, based on clinical expert opinion, the short life expectancy criteria is likely met. However, for those people who cannot tolerate treatment with cabozantinib or sorafenib or lenvatinib the short life expectancy criteria may not be met. This is because people may choose to have selpercatinib before disease progression because of issues with poor tolerability with previous systemic treatment (see section\xa03.2). The committee agreed that the survival estimates produced by the economic model are highly uncertain (see section\xa03.8 to\xa0section 3.11). The committee was satisfied that selpercatinib likely extends life by at least 3\xa0months. The committee agreed that selpercatinib is unlikely to meet the end-of-life criteria for the whole population specified in the marketing authorisation and for those who would be seen in NHS clinical practice. The committee concluded that selpercatinib does not meet the end-of-life criteria for both populations but the data is highly uncertain.\n\n# Results of the cost-effectiveness analysis\n\n## Selpercatinib is not recommended for routine use in the NHS\n\nNICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. NICE's guide to the methods of technology appraisal also states that consideration of the cost effectiveness of a technology is necessary, but not the sole basis for decision making. The committee considered the rarity of the condition and the lack of effective treatments for people with advanced RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer. It also noted the devastating effect of the disease on children and young people with RET-mutant medullary thyroid cancer and that benefits to carers had not been captured in the economic model (see section\xa03.1, section 3.2 and section 3.12). Therefore, it agreed that an acceptable ICER for both populations would be around £30,000 per QALY gained. The committee noted that, when considering the commercial arrangements, selpercatinib was plausibly cost effective in both populations, with ICERs around £30,000 per QALY gained (exact ICERs are commercial in confidence and cannot be reported here). The committee recalled that the evidence base was immature and the pivotal trial for selpercatinib was ongoing. It considered that the ICERs are uncertain and could be higher than what NICE normally considers an acceptable use of NHS resources. Therefore, selpercatinib could not be recommended for routine commissioning.\n\n# Cancer Drugs Fund\n\n## Selpercatinib is recommended for the Cancer Drugs Fund\n\nHaving concluded that selpercatinib could not be recommended for routine use, the committee then considered if it could be recommended for treating advanced thyroid cancer with RET alterations within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund methods guide (addendum):\n\nThe company expressed an interest in selpercatinib being considered for funding through the Cancer Drugs Fund.\n\nThe company's model is structurally robust for decision making (see section\xa03.7)\n\nData from LIBRETTO‑001 is immature. Median PFS and OS in the pre-treated subgroup for RET-mutant medullary thyroid cancer was not estimable, and median OS in the pre-treated subgroup for RET fusion-positive thyroid cancer was not estimable. OS was a key driver of the cost-effectiveness results.\n\nLIBRETTO‑001 is still ongoing and further data could help reduce uncertainties around long-term PFS and OS\n\nObservational data collection via the Systemic Anti-Cancer Therapy dataset could address some of the clinical uncertainty in PFS and OS for selpercatinib.The committee considered that further data collection in the Cancer Drugs Fund could alleviate some of the uncertainty in the company's estimates. It recognised the rarity of thyroid cancers with RET alterations and that the benefits for carers of children and young people with RET altered thyroid cancers had not been included in the economic model. The committee was satisfied that selpercatinib met the criteria for inclusion in the Cancer Drugs Fund. Therefore, it recommended selpercatinib for use within the Cancer Drugs Fund for treating RET-mutant medullary thyroid cancer and RET fusion-positive thyroid cancer, if the conditions in the managed access agreement are followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions (unless new evidence indicates otherwise), as set out previously."}
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https://www.nice.org.uk/guidance/ta742
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Evidence-based recommendations on selpercatinib (Retsevmo) for advanced thyroid cancer with RET alterations in people 12 years and older.
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b11893fa28a9756584a9d94cc5754132fcabe24c
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nice
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Crizanlizumab for preventing sickle cell crises in sickle cell disease
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Crizanlizumab for preventing sickle cell crises in sickle cell disease
Evidence-based recommendations on crizanlizumab for preventing sickle cell crises in people aged 16 or over with sickle cell disease.
# Recommendations
Crizanlizumab is recommended as an option for preventing recurrent sickle cell crises (vaso-occlusive crises) in people aged 16 or over with sickle cell disease only if the conditions in the managed access agreement are followed.
This recommendation is not intended to affect treatment with crizanlizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Treatments to prevent sickle cell crises include hydroxycarbamide (also known as hydroxyurea), which is taken as a tablet, or regular blood transfusions. Crizanlizumab is a treatment injected into the vein (intravenous, or IV) that people aged 16 or over can take on its own or alongside hydroxycarbamide.
The clinical evidence suggests that people taking crizanlizumab have fewer sickle cell crises in a year than if they have best supportive care with or without hydroxycarbamide. However, because the trial was short and included only a small number of people on the licensed dose of the drug, the long-term benefits are uncertain.
There is also uncertainty about the cost-effectiveness estimates because some of the inputs used in the model do not reflect the clinical evidence. The most likely cost-effectiveness estimate is above what NICE normally considers a cost-effective use of NHS resources. Therefore, the committee could not recommend crizanlizumab for routine use in the NHS.
However, there is an unmet need for effective treatments for people with sickle cell disease. They also face health inequalities because the condition is not well understood, results in disability, and is more common in people of African or African-Caribbean family origin, who tend to have poorer health outcomes than other ethnicities. Access to crizanlizumab may help address these inequalities. Because of this, crizanlizumab is recommended for people with sickle cell disease and recurrent vaso-occlusive crises if more data is collected using a managed access agreement, to address the uncertainties in the evidence. This recommendation will be reviewed based on the data collected.# Information about crizanlizumab
# Marketing authorisation indication
Crizanlizumab (Adakveo, Novartis) is indicated 'for the prevention of recurrent vaso-occlusive crises (VOCs) in sickle cell disease patients aged 16 years and older. It can be given as an add-on therapy to hydroxyurea/hydroxycarbamide (HU/HC) or as monotherapy in patients for whom HU/HC is inappropriate or inadequate'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of crizanlizumab is £1,038 for a 100‑mg vial (excluding VAT; BNF online accessed October 2021). The company has a commercial arrangement. This makes crizanlizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The company's positioning of crizanlizumab is appropriate for the population with recurrent vaso-occlusive crises (VOCs), and in line with the marketing authorisation (issue 1, see technical report page 2).
Based on the positioning of crizanlizumab in the treatment pathway, the relevant comparators are hydroxycarbamide (also known as hydroxyurea) and regular blood transfusions. Allogeneic stem cell transplant is not a relevant comparator (issue 1, see technical report page 2).
The results of the SUSTAIN trial are likely to be generalisable to the target population in England. But the uncertainty around how applicable the SUSTAIN trial results are for those who do not seek medical treatment for VOCs cannot be resolved (issue 3, see technical report page 4).
People are unlikely to have crizanlizumab alongside regular blood transfusions to prevent recurrent VOCs (issue 5, technical report page 7).
The committee discussed the following issues (issues 2, 4, 5, 6 and 7), which were outstanding after the technical engagement stage.
# New treatment option
## People with sickle cell disease who have recurrent VOCs would welcome a new treatment option
VOCs happen when sickle-shaped red blood cells block blood vessels (vaso-occlusion) in different parts of the body. It means not enough oxygen is delivered to tissues and organs, causing ischaemic injuries and excruciating pain. If someone has 2 or more crises a year, they are said to have recurrent VOCs. The patient experts explained that, while they have learnt to avoid common trigger factors, VOCs are unpredictable in terms of when they happen and how severe they are. Recovery can take days to weeks, depending on the cause of the crisis. The patient experts described how this unpredictability can be emotionally distressing, and how it can suddenly prevent them from being able to work or do other planned activities. They explained that severe episodes can often require treatment in hospital, and the build-up of complications over time and resulting organ damage significantly affects their quality of life. Treatments to prevent VOCs in adults include hydroxycarbamide or regular blood transfusions. One patient expert explained that, although hydroxycarbamide had effectively reduced the severity of their crises, they stopped treatment because of the potential toxicity associated with its long-term use. The clinical expert explained that, because hydroxycarbamide is a chemotherapy drug, people often prefer not to take it because they are concerned about serious side effects. Hydroxycarbamide may also affect male fertility and prenatal development during pregnancy. The patient experts explained that there have been no new treatments for sickle cell disease for several decades. There is an unmet need for an effective and well-tolerated treatment that can be taken over a lifetime to reduce VOCs. The committee noted comments received during consultation highlighting that hydroxycarbamide and blood transfusions are not always effective in people with severe disease. Crizanlizumab would be an option for these people, who would otherwise be left without treatment. The patient experts explained that fewer VOCs would mean fewer GP visits and hospital admissions, a reduced risk of organ damage, improved mental health and less time off work. The committee concluded that people with sickle cell disease would welcome a new treatment that reduces the frequency of VOCs and improves their quality of life.
# Comparators
## The relevant comparators are hydroxycarbamide and regular blood transfusions
Standard treatment to prevent VOC is generally best supportive care (for example avoiding trigger factors and maintaining general physical and psychological health) with or without hydroxycarbamide (also known as hydroxyurea). Regular blood transfusions may be considered for a small number of people for whom hydroxycarbamide is inappropriate. The company assumed that people would not have treatment with crizanlizumab alongside regular blood transfusions to prevent VOC. The committee noted that, because crizanlizumab had no effect on haemoglobin or measures of haemolysis in the SUSTAIN trial (the main clinical trial; see section 3.3), combining it with blood transfusions could potentially benefit people with sickle cell disease. The clinical expert highlighted that they were not aware of any data to support combined use. They explained that, because regular blood transfusions substantially reduce the number of sickled red blood cells, this reduces the need for crizanlizumab because of its mechanism of action. The clinical expert described how people can have adverse effects from blood transfusions, such as iron overload, and that clinicians prefer not to combine treatments that may further increase the risk of adverse events. The committee concluded that hydroxycarbamide and regular blood transfusions are the only relevant comparators. It agreed that, although there is a lack of evidence, it was unlikely that people would have crizanlizumab alongside regular blood transfusions to prevent VOCs.
# Clinical effectiveness evidence
## People on crizanlizumab have significantly fewer sickle-cell-related pain crises than people on placebo
The clinical evidence came from SUSTAIN, a double-blind, randomised multicentre trial of crizanlizumab compared with placebo. SUSTAIN treatment centres were in the US, Brazil and Jamaica. The trial had a 52‑week follow up, during which treatment was given. Use of hydroxycarbamide alongside crizanlizumab was permitted in both arms of the trial, but people having regular blood transfusions were excluded. The primary outcome for SUSTAIN was the annual rate of sickle-cell-related pain crises. These were defined as acute episodes of pain caused by a VOC that resulted in a visit to a medical facility and treatment with pain relief medication. The median annual rate of sickle-cell-related pain crises was significantly lower for the licensed dose of crizanlizumab (1.63 per year) than for placebo (2.98 per year; p=0.01). Overall and serious adverse event incidence was comparable across arms.
# Immature SUSTAIN trial data
## Limitations in the trial data mean the long-term clinical effectiveness of crizanlizumab is uncertain
The company submission highlighted the limitations of the SUSTAIN trial, including the small sample size (n=65 for placebo, n=67 for the 5 mg/kg crizanlizumab dose) and short duration (52‑week treatment phase and 6‑week follow up evaluation phase). This did not allow differences in long-term outcomes such as mortality or rare events that occur with low annual frequency, such as acute chest syndrome, to be determined. The SUSTAIN trial also did not provide information on the effect of crizanlizumab in people who do not seek medical treatment for VOCs and instead manage them at home. The committee concluded that the limitations in the trial data mean that the long-term clinical effectiveness of crizanlizumab is uncertain.
# The company's model
## The company's updated model does not resolve the uncertainty about the change in VOC rate over time after crizanlizumab treatment
The eligibility criteria in the SUSTAIN trial included 2 to 10 VOCs in the previous 12 months, and patients were randomised based on VOC rate (2 to 4 or 5 to 10) and by concomitant hydroxycarbamide use (yes or no). The company's original Markov model included 3 main health states: no VOCs, 1 or 2 VOCs, 3 or more VOCs, and a death health state. But the committee understood that, because of the trial's eligibility criteria, SUSTAIN could only provide information about people who had 2 or more VOCs at baseline. The ERG considered that the baseline health state occupancy in the model should reflect the patient population in the trial. The company's model structure meant that transition probabilities could not be accurately estimated because it is not known how patients with less than 2 VOCs would transition after the first year in the model, given the 1‑year cycle length and duration of the trial. The company explained that, because it had trial results at 1 year, it wanted to show that there was a gradual change over that year. It did this by applying a half-cycle correction to the 1‑year cycle length. This meant the distribution of patients at baseline did not match SUSTAIN, and the committee discussed that a monthly cycle length may have been more appropriate. Patients were randomly redistributed to each health state at the end of each cycle, but in the same proportions observed in SUSTAIN so the overall distribution remained the same. The clinical expert explained that because VOCs are unpredictable it is common for people with moderate disease (around 20% to 30%) to fluctuate between a year when they have one hospital admission and a year when they have multiple admissions. However, the committee heard that, with an effective treatment, the clinical expert would expect a trend towards occupying the lower frequency VOC health states beyond the random fluctuations of crises. They explained that the way in which VOC states are classified in the SUSTAIN trial does not reflect clinical practice. The company provided an updated model in response to the appraisal consultation document, which aimed to resolve the committee's concerns about the model structure. This included changing to a monthly cycle length and updating the baseline VOC health state occupancy to match the baseline position of patients in the SUSTAIN trial. The company explained that the baseline health state distribution was estimated using individual patient data from the SUSTAIN trial and included patients with only 2 or more VOCs, in line with the trial eligibility criteria. The ERG noted that the company's updated model continued to use annualised VOC rates to reallocate patients to health states once every 12 cycles, using the same distribution observed at the end of SUSTAIN over the entire model horizon. The committee was concerned that the updated model did not resolve the uncertainty about the change in VOC rate over time after treatment with crizanlizumab compared with placebo. The committee agreed that it would have preferred for the health states in the model to have matched how patients were stratified according to VOC rate in the SUSTAIN trial. It also considered that VOC state occupancy should have been estimated monthly within SUSTAIN, in line with the updated cycle length, to determine crizanlizumab's treatment benefit over time. The committee concluded that the company's updated model structure does not resolve the uncertainty about the change in VOC rate over time after treatment with crizanlizumab.
## Patient weight from SUSTAIN should be used in the model
In the economic model, SUSTAIN trial data was used to inform the treatment effect of crizanlizumab on the frequency of VOC in people with recurrent VOC. Because of the short duration of the SUSTAIN trial, the Hospital Episodes Statistics (HES) database was used to estimate the risk of acute sickle cell disease-related complications or death associated with varying frequency of VOC. In the company's original base case, baseline patient characteristics used in the model for age (mean 37.1) and gender distribution (63% female) were taken from the HES database. Body weights (55 kg for females, 65 kg for males) from NICE's guideline on sickle cell disease, which were based on expert opinion, were used to calculate an average patient body weight of 58.7 kg (adjusted for the proportion of females from the HES data). The company considered that using these data sources was consistent with the natural history data in the model and reflected the characteristics of people with sickle cell disease in the UK. The ERG noted that the HES database and the NICE guideline were representative of all patients with sickle cell disease, not just those who had recurrent VOC. Therefore, the data may include patients who would not have crizanlizumab in clinical practice because they are not eligible according to the marketing authorisation. The ERG considered that patient characteristics should come from SUSTAIN, the main source of treatment efficacy. The committee discussed whether people would have crizanlizumab at a younger age than in the SUSTAIN trial, because this would make them less likely to develop complications later in life if the treatment was effective. The clinical expert explained that sickle cell disease is an inherited condition that is often symptomatic from childhood. Intervening earlier would prevent longer-term complications and organ damage, and minimise its psychological and social effects. The committee noted that the marketing authorisation excluded people under 16 so recommendations for this group were outside its remit. The clinical expert suggested that the ratio of females to males in people with recurrent VOC is likely to be around 50:50 in clinical practice. They explained that children with sickle cell disease tend to have a lower weight because of their chronic ill health and increased metabolic rate. The clinical expert suggested that people with a higher frequency of VOC might be slightly underweight because of their ill health and more frequent hospital admissions. Additional analyses from US data provided by the company at technical engagement indicated that a small proportion of patients with recurrent VOCs (n=729) had an average body weight of 73.6 kg, which was higher than the company's base case. The committee noted that this was lower than the average body weight for the total population of people with sickle cell disease of 84.2 kg (n=11,788). The committee acknowledged that prolonged ill health may affect patient weight, particularly during VOCs, but agreed that it would still expect people's body weight to be greater than in the company's base case. It understood that a higher average patient body weight (60 kg to 80 kg) would increase the dose and number of vials of crizanlizumab needed and subsequent drug wastage. The committee noted that in the HES database most patients had very few or no VOCs per year and the gender distribution was more evenly split in the subgroup of patients with recurrent VOCs than in the company's model. It discussed how in SUSTAIN the mean patient age was lower, the gender distribution ratio was closer to 50%, and body weight was higher than in the company's base case. The committee agreed that using patient characteristics from the SUSTAIN trial would maintain the internal validity of the trial results. It noted that the company considered the trial population to be generalisable to those expected to have crizanlizumab in the NHS. The committee agreed with the ERG's preference to use the age and gender distribution from the HES database to maintain the link between age and gender mix, and complications and mortality estimated from HES data. The committee agreed, however, that the inputs from the HES database may not reflect the population who would receive crizanlizumab in clinical practice. The committee understood that using patient characteristics from SUSTAIN significantly increased the company's base-case incremental cost-effectiveness ratio (ICER). The company updated its base-case assumptions in line with the committee preferences by using patient weight from SUSTAIN in the model. The committee concluded that patient weight from SUSTAIN should be used in the model.
## Hydroxycarbamide use that most likely reflects NHS clinical practice should be used in the model
In the company's original base case, hydroxycarbamide use in the crizanlizumab and standard care arms was assumed to be 14.2%, based on the UK National Haemoglobinopathy Registry annual report 2018 to 2019. The ERG noted that the National Haemoglobinopathy Registry includes all patients with sickle cell disease and that hydroxycarbamide use is likely to be higher in people with recurrent VOCs. It considered that the higher use of hydroxycarbamide from SUSTAIN should be used in the model. The clinical expert explained that the SUSTAIN trial included sites in the US, where hydroxycarbamide use is higher than the UK. The committee discussed how it would be expected that all people with sickle cell disease would have been offered or had hydroxycarbamide for at least 6 months before being considered for crizanlizumab. This is line with guidance from the British Society for Haematology. It is also in line with the company's positioning of crizanlizumab as either an add on to hydroxycarbamide, if it does not adequately reduce VOCs, or as a single treatment if hydroxycarbamide is inappropriate. The clinical expert said that, in people with homozygous sickle cell disease, hydroxycarbamide use is around 30% in people with recurrent VOCs. The committee heard that the clinical expert might expect approximately 50% of people taking hydroxycarbamide to still be on first-line treatment after 6 months. The committee initially considered that hydroxycarbamide use from SUSTAIN should be used in the model, but acknowledged that there is uncertainty around the proportion of people who would have concomitant hydroxycarbamide in England. The company updated its base-case assumptions for hydroxycarbamide use to 30% to reflect the clinical expert's opinion. The committee noted that the company's response to technical engagement included details from an advisory board with UK clinical experts who estimated that hydroxycarbamide use varied between 10% and 50%. The committee heard from the clinical expert that there is some variation in hydroxycarbamide use across England. However, they explained that, for the population that would be considered eligible for crizanlizumab, including people with a high VOC rate, it is usually around 30% in clinical practice. The committee considered that 30% hydroxycarbamide use was in the middle of the range outlined by the company's advisory board, and most likely reflects use in the population who would receive crizanlizumab in the NHS. It concluded that the hydroxycarbamide use that most likely reflects NHS clinical practice should be used in the model.
## There is limited evidence of a prolonged treatment benefit while on treatment and after stopping treatment with crizanlizumab
The company assumed a constant lifetime treatment effect while on treatment with crizanlizumab in its base case. The committee concluded that no evidence was presented to show a prolonged treatment benefit with crizanlizumab after the 52‑week trial duration. Duration of treatment efficacy was a key driver of the cost-effectiveness results, particularly if any waning of the treatment benefit is taken into consideration. The committee noted that, because there is limited long-term data on the efficacy of crizanlizumab, the uncertainty around a prolonged treatment effect could not be resolved. The company's base case also assumed that crizanlizumab's treatment benefit continues for 2 years in all people after stopping treatment. This was based on results from SUCCESSOR, a retrospective chart review of patients who completed the SUSTAIN trial, which reported data from the 52 weeks after SUSTAIN finished, when patients did not have crizanlizumab. The company highlighted that patients who had the licensed dose of crizanlizumab in the SUSTAIN trial who were then followed up in SUCCESSOR had a similar mean annual VOC rate to the SUSTAIN trial. The ERG considered that a gradual waning of treatment effect over the 2 years was more likely, and that this would be the same as 1 year of full treatment effect post-discontinuation. In its base case, it reduced the post-discontinuation benefit to 1 year (in people who completed 1 year of treatment) to align with the data available from SUCCESSOR. The committee discussed how the SUCCESSOR data was uncertain because of the small number of patients who had the licensed crizanlizumab dose (n=15). The data was also uncertain because the patients who agreed to further follow up could have been those who had the best outcomes on treatment. Both of these could bias the results in favour of crizanlizumab. It noted that the SUCCESSOR study included the per-protocol population of the SUSTAIN trial, who had at least 12 of the 14 planned study doses of crizanlizumab. The clinical expert suggested that, because crizanlizumab may reduce inflammation of the endothelium, its treatment effect might continue after stopping the drug. However, they said that this was speculative and would depend on how long the drug stays in the blood after stopping treatment. The committee discussed how the evidence from SUCCESSOR did not provide direct evidence of an ongoing treatment effect after stopping treatment. It acknowledged that it may be possible for a short carryover of treatment effect based on the pharmacokinetic and pharmacodynamic data from the SUSTAIN trial. The company updated its base-case assumptions in line with the committee's preference to remove any efficacy after stopping treatment with crizanlizumab in the model. The committee concluded that, although it was possible that there is some treatment benefit after stopping treatment with crizanlizumab, there is very little evidence to support this.
## A single utility value from SUSTAIN should be used for all VOC health states, with per-event utility decrements applied
The utility values for the VOC health states in the company's model were from an unpublished analysis of a 3‑year US registry study (LEGACY) with an additional utility decrement applied for individual VOCs and complications of sickle cell disease. The value for the utility decrement for VOC events was from a longitudinal study of health-related quality of life in people in the UK with sickle cell disease (Anie et al. 2012). Utility decrements for other sickle cell disease complications were taken from a range of published sources. The company considered that, because health-related quality of life data in SUSTAIN was collected at set time points and not specifically when a VOC occurred, the data may have not fully captured the expected impact of VOCs on quality of life. The company also considered that the trial was too short to show an overall change in health-related quality of life related to sickle cell disease complications and long-term organ damage. It therefore preferred to use the LEGACY study, with its longer follow up. The ERG noted that the company's approach to estimating utility values may overestimate the impact of individual VOCs on health-related quality of life. It considered that it was not appropriate to account for sickle cell disease complications and long-term organ damage through the health state utility value for the VOC groups. This was because they are already accounted for separately in per-event utility decrements. Because patients are randomly distributed between health states, the committee discussed how it would be unlikely that patients moving from a more severe to less severe health state would recover from long-term organ damage. The committee understood that the utility values derived from the SF‑36 data of patients who completed SUSTAIN were similar for each health state but noted slightly higher utility values for states with more VOCs. The committee did not think this was plausible, so agreed with the ERG's approach of applying a single utility value across all 3 VOC health states to capture health-related quality of life between VOC events (as a weighted average from SUSTAIN), with additional per-event decrements applied for each individual VOC and complication. This significantly increased the company's base-case ICER. Most of the SF‑36 questionnaires were administered outside of a recall period that included a VOC event. However, the committee noted that some patients in SUSTAIN had a VOC within the recall window of the SF‑36 survey so the company could have estimated the VOC utility decrement from SUSTAIN. The company did not provide any new evidence to support its preferred approach to deriving utility values in response to the appraisal consultation document. At the second committee meeting the clinical expert noted that people with recurrent VOCs are unlikely to all have the same utility values. The committee noted that because the ERG's preferred method of estimating utilities included a decrement for each VOC, it was satisfied the differences between VOCs had been adequately captured. The committee concluded that the ERG's method for estimating utility values was more appropriate than the company's method. This is because it reduced the risk that VOC events are double counted and better represented health-related quality of life in people with recurrent VOCs.
## Drug wastage should be included in the model
The company's original base case assumed drug wastage for each administration of crizanlizumab. In response to the appraisal consultation document, the company's revised base case assumed no drug wastage in the model. The company explained that this change was because it assumed there would be vial sharing in clinical practice, and that this had been validated by its clinical expert. The committee heard how crizanlizumab would likely be administered in a specialist centre which would mean that it may be possible to minimise some wastage. It discussed that, based on the patient weight from the SUSTAIN trial and the recommended licensed dose of crizanlizumab, drug wastage is expected because only 1 vial size is available. The committee considered that crizanlizumab could be prepared in an aseptic pharmacy facility before being administered and then stored for up to 24 hours. It noted that this process may be time consuming and costly. The committee discussed how someone may not be able to attend their infusion appointment after crizanlizumab had been prepared, which would further increase the likelihood of drug wastage. It recognised that vial sharing may be complex and problematic for crizanlizumab because the dose administered depends on a person's weight, and monthly infusions would need to be scheduled. The committee considered that drug wastage was highly likely with each administration of crizanlizumab. It concluded that drug wastage should be included the model.
# Cost-effectiveness estimates
## The company's updated base case does not reflect the committee's preferred assumptions
In response to consultation, the company incorporated the following assumptions into its base case:
patient weight from SUSTAIN
patient age and gender mix from the HES database (to maintain the link between age and gender mix and complications and mortality estimated using HES data)
hydroxycarbamide use at 30% to reflect NHS practice
removing post-discontinuation efficacy
using differential utility values for each VOC health state from LEGACY, with per-event utility decrements applied
no drug wastage assumed for each administration of crizanlizumab.The committee noted that the company's updated base case did not include its preferred assumptions on:
using the ERG's approach to calculate a single utility value (based on SUSTAIN) for all 3 health states with per-event decrements for individual VOCs and complications
including drug wastage for each administration of crizanlizumab.The committee discussed the results of its preferred analysis, which were commercial in confidence. It noted that the deterministic ICER was slightly more than £30,000 per quality-adjusted life year (QALY) gained. It also noted that the ICER could be substantially higher because of the immature SUSTAIN trial data, uncertainty around the model input parameters, and remaining issues with the model structure. The committee was aware that crizanlizumab's cost effectiveness was highly sensitive to changes in certain parameters in the company's base case, which were associated with uncertainty. These included age, weight and gender distribution, hydroxycarbamide use, duration of treatment effect during and after stopping treatment, and the choice of utility values.
## The deterministic ICERs should be used for decision making
The committee noted that the company's revised base-case probabilistic ICERs were considerably lower than the revised deterministic base-case ICERs. The company considered this to be partly because varying patient weight in the probabilistic sensitivity analysis resulted in fewer vials of crizanlizumab administered for some iterations. The committee discussed how it was unclear why none of the probabilistic sensitivity analyses included a higher patient weight (which requires more crizanlizumab vials) than in SUSTAIN. The ERG explained that, in the company's original submission, certain parameters had not been included in the probabilistic sensitivity analysis, including the proportion of patients in each VOC state and the number of VOC events per health state. When these parameters were included in the probabilistic sensitivity analysis, the probabilistic and deterministic results differed much more substantially. The ERG explained that when patient weight was removed from the probabilistic sensitivity analysis, it still resulted in a large difference between the deterministic and probabilistic ICERs. The committee understood that the ERG was unable to identify the reasons for the discrepancy in the cost-effectiveness results. The committee was concerned that the probabilistic ICERs were highly uncertain. It concluded that in this instance the deterministic results should be used for decision making.
# Other factors
## Health inequalities were considered in the committee's decision making
The committee considered potential equalities issues raised by the company, experts and patient groups:
The patient experts explained that sickle cell disease is not widely understood, including among healthcare professionals, which often results in poor hospital care and stigma around seeking pain relief for crises.
The committee also heard that, because a significant proportion of patients with sickle cell disease may also be registered disabled because of ill health associated with their disease, for example strokes, chronic leg or foot ulcers and osteonecrosis, there can be problems accessing treatment.
The committee heard how the condition is more common in people of African or African-Caribbean family origin and that as a group these people tend to have poorer health outcomes than other ethnicities.The committee noted that these issues had been strongly reiterated in comments received in response to the appraisal consultation document. The committee discussed each of the equality issues raised. It noted that any recommendation for crizanlizumab would be unable to address the issues related to poor hospital care and stigma around seeking pain relief and that these were beyond the remit of a technology appraisal. It discussed potential issues around access to treatments for sickle cell disease in people with registered disabilities. It noted that if crizanlizumab were recommended, healthcare professionals should consider if reasonable adjustments can be made to enable access to crizanlizumab for people who do not receive hospital management of their VOCs or who may have difficulty travelling to hospital because of disability. The committee also acknowledged the potential health inequalities faced by people with this condition, and was mindful that the principles that guide the development of NICE guidance and standards included the aim to reduce health inequalities. The committee noted that sickle cell disease is mostly seen in certain minority ethnic populations, and was concerned to hear that consultees said that those populations suffered worse health outcomes and barriers to treatment. The committee concluded that it would consider these issues in its decision making.
## The benefits of crizanlizumab are captured in the cost-effectiveness analysis
The company considers crizanlizumab to be innovative because it is a well tolerated and effective treatment for preventing VOCs in people with sickle cell disease. The committee considered other comments from patient groups highlighting the limited research and development in sickle cell disease compared with other orphan diseases. It acknowledged the limited research into the disease area and noted that crizanlizumab is the first drug to receive a marketing authorisation for treating the disease in several years. The committee recognised that the conditional regulatory approval of crizanlizumab was important to people with sickle cell disease. But it concluded that it had not been presented with evidence of any additional benefits that could not be captured in the QALY.
# Conclusion
## Crizanlizumab is not recommended for routine use in the NHS
The committee recalled that the most plausible ICER for crizanlizumab was above £30,000 per QALY gained. It also noted that there were issues with the model structure and that multiple model parameters were highly uncertain, which could lead to a plausible ICER that is considerably higher. NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Above a most plausible ICER of £30,000 per QALY gained, the guide to the methods of technology appraisal notes that an increasingly stronger case will need to be identified for supporting the technology as an effective use of NHS resources. NICE's guide to the methods of technology appraisal also states that consideration of the cost effectiveness of a technology is a necessary, but not the sole, basis for decision-making. The committee was willing to be flexible, taking into consideration the significant unmet need for effective treatments in people with sickle cell disease, and NICE's aim of reducing health inequalities (see section 3.13). The committee said that in theory it would be willing to accept an ICER slightly more than what is usually acceptable if it addresses such health inequalities. However, it noted that departing from NICE's usual range needs to be done with caution, as it risks displacing funding from more cost-effective treatments elsewhere in the NHS, with an overall net loss of health gain (see the principles that guide the development of NICE guidance and standards). Previously, substantial departures from the usual threshold have been accepted only under policies that were subject to formal public consultation before their adoption. The committee concluded that it was willing to be flexible when considering uncertainty, noting that a conditional marketing authorisation has been granted for crizanlizumab, which requires further data to be collected through several ongoing clinical trials. The committee concluded that, despite applying flexibilities, the ICER was above what NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that crizanlizumab could not be recommended for routine commissioning.
# Managed access proposal
## A managed access agreement has been proposed by the company
Having concluded that crizanlizumab could not be recommended for routine use, the committee then considered the company's proposal for ongoing data collection through a managed access agreement, which could help address some of the uncertainties. The company identified 2 sources of evidence that it considered could resolve the committee's uncertainties. The STAND trial is a phase 3 randomised placebo-controlled trial with UK patients. It is examining the efficacy and safety of crizanlizumab, with or without hydroxycarbamide, in patients aged 12 years and over with a history of VOC. The committee noted that the primary analysis of the trial is due to report in 2023. The company considered that the trial would provide data on:
longer-term efficacy (with data up to 3 years)
crizanlizumab's impact on the longer-term consequences of sickle cell disease
duration of treatment effect
utility values after treatment with crizanlizumab.Another source of prospective data was the National Haemoglobinopathy Registry. The company proposed that the registry would collect data on people having crizanlizumab in clinical practice, including:
the frequency of VOCs that lead to hospitalisation while on crizanlizumab
healthcare utilisation
age, gender mix and weight of people with sickle cell disease who have recurrent VOCs in the UK
concomitant hydroxycarbamide use in people with sickle cell disease and recurrent VOCs in the UK.
## A managed access agreement could address uncertainties
The committee agreed that data from the STAND trial and the National Haemoglobinopathy Registry collected through a managed access agreement may be enough to address the current uncertainties in the evidence base for crizanlizumab. It also acknowledged the need to manage the risks to the NHS because of the identified uncertainties. It considered the details of the company's proposed eligibility criteria in the managed access agreement and concluded that they were clinically achievable. The committee recognised the limited data available in people with sickle cell disease and that collecting more data could reduce the uncertainty around crizanlizumab's clinical and cost effectiveness.
## Crizanlizumab is recommended for treating sickle cell disease within a managed access agreement
The high levels of uncertainty about crizanlizumab's long-term clinical effectiveness means that there would be a substantial financial risk to the NHS if the committee was to recommend it for routine use when it may not be cost effective. The committee noted that the risk to the NHS is reduced through the proposed managed access agreement. The committee took into account a range of factors in its decision making, including the unmet need of the disease and health inequalities faced by people with sickle cell disease. The committee was willing to be flexible in its considerations around uncertainty, particularly if access could be managed in a way that reduced the risk to the NHS. The committee was satisfied that further data collection through a managed access arrangement could gather enough evidence on longer-term effectiveness of crizanlizumab. It concluded that crizanlizumab met the criteria to be considered for use with managed access. It recommended crizanlizumab for preventing recurrent VOCs in sickle cell disease patients aged 16 years and older if the conditions in the managed access agreement are followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions as set out in this section, unless new evidence indicates otherwise.
|
{'Recommendations': 'Crizanlizumab is recommended as an option for preventing recurrent sickle cell crises (vaso-occlusive crises) in people aged\xa016 or over with sickle cell disease only if the conditions in the managed access agreement are followed.\n\nThis recommendation is not intended to affect treatment with crizanlizumab that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nTreatments to prevent sickle cell crises include hydroxycarbamide (also known as hydroxyurea), which is taken as a tablet, or regular blood transfusions. Crizanlizumab is a treatment injected into the vein (intravenous, or IV) that people aged\xa016 or over can take on its own or alongside hydroxycarbamide.\n\nThe clinical evidence suggests that people taking crizanlizumab have fewer sickle cell crises in a year than if they have best supportive care with or without hydroxycarbamide. However, because the trial was short and included only a small number of people on the licensed dose of the drug, the long-term benefits are uncertain.\n\nThere is also uncertainty about the cost-effectiveness estimates because some of the inputs used in the model do not reflect the clinical evidence. The most likely cost-effectiveness estimate is above what NICE normally considers a cost-effective use of NHS resources. Therefore, the committee could not recommend crizanlizumab for routine use in the NHS.\n\nHowever, there is an unmet need for effective treatments for people with sickle cell disease. They also face health inequalities because the condition is not well understood, results in disability, and is more common in people of African or African-Caribbean family origin, who tend to have poorer health outcomes than other ethnicities. Access to crizanlizumab may help address these inequalities. Because of this, crizanlizumab is recommended for people with sickle cell disease and recurrent vaso-occlusive crises if more data is collected using a managed access agreement, to address the uncertainties in the evidence. This recommendation will be reviewed based on the data collected.', 'Information about crizanlizumab': "# Marketing authorisation indication\n\nCrizanlizumab (Adakveo, Novartis) is indicated 'for the prevention of recurrent vaso-occlusive crises (VOCs) in sickle cell disease patients aged 16\xa0years and older. It can be given as an add-on therapy to hydroxyurea/hydroxycarbamide (HU/HC) or as monotherapy in patients for whom HU/HC is inappropriate or inadequate'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of crizanlizumab is £1,038 for a 100‑mg vial (excluding VAT; BNF online accessed October\xa02021). The company has a commercial arrangement. This makes crizanlizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe company's positioning of crizanlizumab is appropriate for the population with recurrent vaso-occlusive crises (VOCs), and in line with the marketing authorisation (issue\xa01, see technical report page\xa02).\n\nBased on the positioning of crizanlizumab in the treatment pathway, the relevant comparators are hydroxycarbamide (also known as hydroxyurea) and regular blood transfusions. Allogeneic stem cell transplant is not a relevant comparator (issue\xa01, see technical report page\xa02).\n\nThe results of the SUSTAIN trial are likely to be generalisable to the target population in England. But the uncertainty around how applicable the SUSTAIN trial results are for those who do not seek medical treatment for VOCs cannot be resolved (issue\xa03, see technical report page\xa04).\n\nPeople are unlikely to have crizanlizumab alongside regular blood transfusions to prevent recurrent VOCs (issue\xa05, technical report page\xa07).\n\nThe committee discussed the following issues (issues\xa02, 4, 5, 6 and 7), which were outstanding after the technical engagement stage.\n\n# New treatment option\n\n## People with sickle cell disease who have recurrent VOCs would welcome a new treatment option\n\nVOCs happen when sickle-shaped red blood cells block blood vessels (vaso-occlusion) in different parts of the body. It means not enough oxygen is delivered to tissues and organs, causing ischaemic injuries and excruciating pain. If someone has 2 or more crises a year, they are said to have recurrent VOCs. The patient experts explained that, while they have learnt to avoid common trigger factors, VOCs are unpredictable in terms of when they happen and how severe they are. Recovery can take days to weeks, depending on the cause of the crisis. The patient experts described how this unpredictability can be emotionally distressing, and how it can suddenly prevent them from being able to work or do other planned activities. They explained that severe episodes can often require treatment in hospital, and the build-up of complications over time and resulting organ damage significantly affects their quality of life. Treatments to prevent VOCs in adults include hydroxycarbamide or regular blood transfusions. One patient expert explained that, although hydroxycarbamide had effectively reduced the severity of their crises, they stopped treatment because of the potential toxicity associated with its long-term use. The clinical expert explained that, because hydroxycarbamide is a chemotherapy drug, people often prefer not to take it because they are concerned about serious side effects. Hydroxycarbamide may also affect male fertility and prenatal development during pregnancy. The patient experts explained that there have been no new treatments for sickle cell disease for several decades. There is an unmet need for an effective and well-tolerated treatment that can be taken over a lifetime to reduce VOCs. The committee noted comments received during consultation highlighting that hydroxycarbamide and blood transfusions are not always effective in people with severe disease. Crizanlizumab would be an option for these people, who would otherwise be left without treatment. The patient experts explained that fewer VOCs would mean fewer GP visits and hospital admissions, a reduced risk of organ damage, improved mental health and less time off work. The committee concluded that people with sickle cell disease would welcome a new treatment that reduces the frequency of VOCs and improves their quality of life.\n\n# Comparators\n\n## The relevant comparators are hydroxycarbamide and regular blood transfusions\n\nStandard treatment to prevent VOC is generally best supportive care (for example avoiding trigger factors and maintaining general physical and psychological health) with or without hydroxycarbamide (also known as hydroxyurea). Regular blood transfusions may be considered for a small number of people for whom hydroxycarbamide is inappropriate. The company assumed that people would not have treatment with crizanlizumab alongside regular blood transfusions to prevent VOC. The committee noted that, because crizanlizumab had no effect on haemoglobin or measures of haemolysis in the SUSTAIN trial (the main clinical trial; see section 3.3), combining it with blood transfusions could potentially benefit people with sickle cell disease. The clinical expert highlighted that they were not aware of any data to support combined use. They explained that, because regular blood transfusions substantially reduce the number of sickled red blood cells, this reduces the need for crizanlizumab because of its mechanism of action. The clinical expert described how people can have adverse effects from blood transfusions, such as iron overload, and that clinicians prefer not to combine treatments that may further increase the risk of adverse events. The committee concluded that hydroxycarbamide and regular blood transfusions are the only relevant comparators. It agreed that, although there is a lack of evidence, it was unlikely that people would have crizanlizumab alongside regular blood transfusions to prevent VOCs.\n\n# Clinical effectiveness evidence\n\n## People on crizanlizumab have significantly fewer sickle-cell-related pain crises than people on placebo\n\nThe clinical evidence came from SUSTAIN, a double-blind, randomised multicentre trial of crizanlizumab compared with placebo. SUSTAIN treatment centres were in the US, Brazil and Jamaica. The trial had a 52‑week follow up, during which treatment was given. Use of hydroxycarbamide alongside crizanlizumab was permitted in both arms of the trial, but people having regular blood transfusions were excluded. The primary outcome for SUSTAIN was the annual rate of sickle-cell-related pain crises. These were defined as acute episodes of pain caused by a VOC that resulted in a visit to a medical facility and treatment with pain relief medication. The median annual rate of sickle-cell-related pain crises was significantly lower for the licensed dose of crizanlizumab (1.63 per year) than for placebo (2.98 per year; p=0.01). Overall and serious adverse event incidence was comparable across arms.\n\n# Immature SUSTAIN trial data\n\n## Limitations in the trial data mean the long-term clinical effectiveness of crizanlizumab is uncertain\n\nThe company submission highlighted the limitations of the SUSTAIN trial, including the small sample size (n=65 for placebo, n=67 for the 5\xa0mg/kg crizanlizumab dose) and short duration (52‑week treatment phase and 6‑week follow up evaluation phase). This did not allow differences in long-term outcomes such as mortality or rare events that occur with low annual frequency, such as acute chest syndrome, to be determined. The SUSTAIN trial also did not provide information on the effect of crizanlizumab in people who do not seek medical treatment for VOCs and instead manage them at home. The committee concluded that the limitations in the trial data mean that the long-term clinical effectiveness of crizanlizumab is uncertain.\n\n# The company's model\n\n## The company's updated model does not resolve the uncertainty about the change in VOC rate over time after crizanlizumab treatment\n\nThe eligibility criteria in the SUSTAIN trial included 2 to 10\xa0VOCs in the previous 12\xa0months, and patients were randomised based on VOC rate (2\xa0to\xa04 or 5\xa0to\xa010) and by concomitant hydroxycarbamide use (yes or no). The company's original Markov model included 3\xa0main health states: no VOCs, 1 or 2\xa0VOCs, 3 or more VOCs, and a death health state. But the committee understood that, because of the trial's eligibility criteria, SUSTAIN could only provide information about people who had 2 or more VOCs at baseline. The ERG considered that the baseline health state occupancy in the model should reflect the patient population in the trial. The company's model structure meant that transition probabilities could not be accurately estimated because it is not known how patients with less than 2\xa0VOCs would transition after the first year in the model, given the 1‑year cycle length and duration of the trial. The company explained that, because it had trial results at 1\xa0year, it wanted to show that there was a gradual change over that year. It did this by applying a half-cycle correction to the 1‑year cycle length. This meant the distribution of patients at baseline did not match SUSTAIN, and the committee discussed that a monthly cycle length may have been more appropriate. Patients were randomly redistributed to each health state at the end of each cycle, but in the same proportions observed in SUSTAIN so the overall distribution remained the same. The clinical expert explained that because VOCs are unpredictable it is common for people with moderate disease (around 20% to 30%) to fluctuate between a year when they have one hospital admission and a year when they have multiple admissions. However, the committee heard that, with an effective treatment, the clinical expert would expect a trend towards occupying the lower frequency VOC health states beyond the random fluctuations of crises. They explained that the way in which VOC states are classified in the SUSTAIN trial does not reflect clinical practice. The company provided an updated model in response to the appraisal consultation document, which aimed to resolve the committee's concerns about the model structure. This included changing to a monthly cycle length and updating the baseline VOC health state occupancy to match the baseline position of patients in the SUSTAIN trial. The company explained that the baseline health state distribution was estimated using individual patient data from the SUSTAIN trial and included patients with only 2 or more VOCs, in line with the trial eligibility criteria. The ERG noted that the company's updated model continued to use annualised VOC rates to reallocate patients to health states once every 12\xa0cycles, using the same distribution observed at the end of SUSTAIN over the entire model horizon. The committee was concerned that the updated model did not resolve the uncertainty about the change in VOC rate over time after treatment with crizanlizumab compared with placebo. The committee agreed that it would have preferred for the health states in the model to have matched how patients were stratified according to VOC rate in the SUSTAIN trial. It also considered that VOC state occupancy should have been estimated monthly within SUSTAIN, in line with the updated cycle length, to determine crizanlizumab's treatment benefit over time. The committee concluded that the company's updated model structure does not resolve the uncertainty about the change in VOC rate over time after treatment with crizanlizumab.\n\n## Patient weight from SUSTAIN should be used in the model\n\nIn the economic model, SUSTAIN trial data was used to inform the treatment effect of crizanlizumab on the frequency of VOC in people with recurrent VOC. Because of the short duration of the SUSTAIN trial, the Hospital Episodes Statistics (HES) database was used to estimate the risk of acute sickle cell disease-related complications or death associated with varying frequency of VOC. In the company's original base case, baseline patient characteristics used in the model for age (mean 37.1) and gender distribution (63% female) were taken from the HES database. Body weights (55\xa0kg for females, 65\xa0kg for males) from NICE's guideline on sickle cell disease, which were based on expert opinion, were used to calculate an average patient body weight of 58.7\xa0kg (adjusted for the proportion of females from the HES data). The company considered that using these data sources was consistent with the natural history data in the model and reflected the characteristics of people with sickle cell disease in the UK. The ERG noted that the HES database and the NICE guideline were representative of all patients with sickle cell disease, not just those who had recurrent VOC. Therefore, the data may include patients who would not have crizanlizumab in clinical practice because they are not eligible according to the marketing authorisation. The ERG considered that patient characteristics should come from SUSTAIN, the main source of treatment efficacy. The committee discussed whether people would have crizanlizumab at a younger age than in the SUSTAIN trial, because this would make them less likely to develop complications later in life if the treatment was effective. The clinical expert explained that sickle cell disease is an inherited condition that is often symptomatic from childhood. Intervening earlier would prevent longer-term complications and organ damage, and minimise its psychological and social effects. The committee noted that the marketing authorisation excluded people under\xa016 so recommendations for this group were outside its remit. The clinical expert suggested that the ratio of females to males in people with recurrent VOC is likely to be around 50:50 in clinical practice. They explained that children with sickle cell disease tend to have a lower weight because of their chronic ill health and increased metabolic rate. The clinical expert suggested that people with a higher frequency of VOC might be slightly underweight because of their ill health and more frequent hospital admissions. Additional analyses from US data provided by the company at technical engagement indicated that a small proportion of patients with recurrent VOCs (n=729) had an average body weight of 73.6\xa0kg, which was higher than the company's base case. The committee noted that this was lower than the average body weight for the total population of people with sickle cell disease of 84.2\xa0kg (n=11,788). The committee acknowledged that prolonged ill health may affect patient weight, particularly during VOCs, but agreed that it would still expect people's body weight to be greater than in the company's base case. It understood that a higher average patient body weight (60\xa0kg to 80\xa0kg) would increase the dose and number of vials of crizanlizumab needed and subsequent drug wastage. The committee noted that in the HES database most patients had very few or no VOCs per year and the gender distribution was more evenly split in the subgroup of patients with recurrent VOCs than in the company's model. It discussed how in SUSTAIN the mean patient age was lower, the gender distribution ratio was closer to 50%, and body weight was higher than in the company's base case. The committee agreed that using patient characteristics from the SUSTAIN trial would maintain the internal validity of the trial results. It noted that the company considered the trial population to be generalisable to those expected to have crizanlizumab in the NHS. The committee agreed with the ERG's preference to use the age and gender distribution from the HES database to maintain the link between age and gender mix, and complications and mortality estimated from HES data. The committee agreed, however, that the inputs from the HES database may not reflect the population who would receive crizanlizumab in clinical practice. The committee understood that using patient characteristics from SUSTAIN significantly increased the company's base-case incremental cost-effectiveness ratio (ICER). The company updated its base-case assumptions in line with the committee preferences by using patient weight from SUSTAIN in the model. The committee concluded that patient weight from SUSTAIN should be used in the model.\n\n## Hydroxycarbamide use that most likely reflects NHS clinical practice should be used in the model\n\nIn the company's original base case, hydroxycarbamide use in the crizanlizumab and standard care arms was assumed to be 14.2%, based on the UK National Haemoglobinopathy Registry annual report 2018 to 2019. The ERG noted that the National Haemoglobinopathy Registry includes all patients with sickle cell disease and that hydroxycarbamide use is likely to be higher in people with recurrent VOCs. It considered that the higher use of hydroxycarbamide from SUSTAIN should be used in the model. The clinical expert explained that the SUSTAIN trial included sites in the US, where hydroxycarbamide use is higher than the UK. The committee discussed how it would be expected that all people with sickle cell disease would have been offered or had hydroxycarbamide for at least 6\xa0months before being considered for crizanlizumab. This is line with guidance from the British Society for Haematology. It is also in line with the company's positioning of crizanlizumab as either an add on to hydroxycarbamide, if it does not adequately reduce VOCs, or as a single treatment if hydroxycarbamide is inappropriate. The clinical expert said that, in people with homozygous sickle cell disease, hydroxycarbamide use is around 30% in people with recurrent VOCs. The committee heard that the clinical expert might expect approximately 50% of people taking hydroxycarbamide to still be on first-line treatment after 6\xa0months. The committee initially considered that hydroxycarbamide use from SUSTAIN should be used in the model, but acknowledged that there is uncertainty around the proportion of people who would have concomitant hydroxycarbamide in England. The company updated its base-case assumptions for hydroxycarbamide use to 30% to reflect the clinical expert's opinion. The committee noted that the company's response to technical engagement included details from an advisory board with UK clinical experts who estimated that hydroxycarbamide use varied between 10% and 50%. The committee heard from the clinical expert that there is some variation in hydroxycarbamide use across England. However, they explained that, for the population that would be considered eligible for crizanlizumab, including people with a high VOC rate, it is usually around 30% in clinical practice. The committee considered that 30% hydroxycarbamide use was in the middle of the range outlined by the company's advisory board, and most likely reflects use in the population who would receive crizanlizumab in the NHS. It concluded that the hydroxycarbamide use that most likely reflects NHS clinical practice should be used in the model.\n\n## There is limited evidence of a prolonged treatment benefit while on treatment and after stopping treatment with crizanlizumab\n\nThe company assumed a constant lifetime treatment effect while on treatment with crizanlizumab in its base case. The committee concluded that no evidence was presented to show a prolonged treatment benefit with crizanlizumab after the 52‑week trial duration. Duration of treatment efficacy was a key driver of the cost-effectiveness results, particularly if any waning of the treatment benefit is taken into consideration. The committee noted that, because there is limited long-term data on the efficacy of crizanlizumab, the uncertainty around a prolonged treatment effect could not be resolved. The company's base case also assumed that crizanlizumab's treatment benefit continues for 2\xa0years in all people after stopping treatment. This was based on results from SUCCESSOR, a retrospective chart review of patients who completed the SUSTAIN trial, which reported data from the 52\xa0weeks after SUSTAIN finished, when patients did not have crizanlizumab. The company highlighted that patients who had the licensed dose of crizanlizumab in the SUSTAIN trial who were then followed up in SUCCESSOR had a similar mean annual VOC rate to the SUSTAIN trial. The ERG considered that a gradual waning of treatment effect over the 2\xa0years was more likely, and that this would be the same as 1\xa0year of full treatment effect post-discontinuation. In its base case, it reduced the post-discontinuation benefit to 1\xa0year (in people who completed 1\xa0year of treatment) to align with the data available from SUCCESSOR. The committee discussed how the SUCCESSOR data was uncertain because of the small number of patients who had the licensed crizanlizumab dose (n=15). The data was also uncertain because the patients who agreed to further follow up could have been those who had the best outcomes on treatment. Both of these could bias the results in favour of crizanlizumab. It noted that the SUCCESSOR study included the per-protocol population of the SUSTAIN trial, who had at least 12 of the 14 planned study doses of crizanlizumab. The clinical expert suggested that, because crizanlizumab may reduce inflammation of the endothelium, its treatment effect might continue after stopping the drug. However, they said that this was speculative and would depend on how long the drug stays in the blood after stopping treatment. The committee discussed how the evidence from SUCCESSOR did not provide direct evidence of an ongoing treatment effect after stopping treatment. It acknowledged that it may be possible for a short carryover of treatment effect based on the pharmacokinetic and pharmacodynamic data from the SUSTAIN trial. The company updated its base-case assumptions in line with the committee's preference to remove any efficacy after stopping treatment with crizanlizumab in the model. The committee concluded that, although it was possible that there is some treatment benefit after stopping treatment with crizanlizumab, there is very little evidence to support this.\n\n## A single utility value from SUSTAIN should be used for all VOC health states, with per-event utility decrements applied\n\nThe utility values for the VOC health states in the company's model were from an unpublished analysis of a 3‑year US registry study (LEGACY) with an additional utility decrement applied for individual VOCs and complications of sickle cell disease. The value for the utility decrement for VOC events was from a longitudinal study of health-related quality of life in people in the UK with sickle cell disease (Anie et al. 2012). Utility decrements for other sickle cell disease complications were taken from a range of published sources. The company considered that, because health-related quality of life data in SUSTAIN was collected at set time points and not specifically when a VOC occurred, the data may have not fully captured the expected impact of VOCs on quality of life. The company also considered that the trial was too short to show an overall change in health-related quality of life related to sickle cell disease complications and long-term organ damage. It therefore preferred to use the LEGACY study, with its longer follow up. The ERG noted that the company's approach to estimating utility values may overestimate the impact of individual VOCs on health-related quality of life. It considered that it was not appropriate to account for sickle cell disease complications and long-term organ damage through the health state utility value for the VOC groups. This was because they are already accounted for separately in per-event utility decrements. Because patients are randomly distributed between health states, the committee discussed how it would be unlikely that patients moving from a more severe to less severe health state would recover from long-term organ damage. The committee understood that the utility values derived from the SF‑36 data of patients who completed SUSTAIN were similar for each health state but noted slightly higher utility values for states with more VOCs. The committee did not think this was plausible, so agreed with the ERG's approach of applying a single utility value across all 3\xa0VOC health states to capture health-related quality of life between VOC events (as a weighted average from SUSTAIN), with additional per-event decrements applied for each individual VOC and complication. This significantly increased the company's base-case ICER. Most of the SF‑36 questionnaires were administered outside of a recall period that included a VOC event. However, the committee noted that some patients in SUSTAIN had a VOC within the recall window of the SF‑36 survey so the company could have estimated the VOC utility decrement from SUSTAIN. The company did not provide any new evidence to support its preferred approach to deriving utility values in response to the appraisal consultation document. At the second committee meeting the clinical expert noted that people with recurrent VOCs are unlikely to all have the same utility values. The committee noted that because the ERG's preferred method of estimating utilities included a decrement for each VOC, it was satisfied the differences between VOCs had been adequately captured. The committee concluded that the ERG's method for estimating utility values was more appropriate than the company's method. This is because it reduced the risk that VOC events are double counted and better represented health-related quality of life in people with recurrent VOCs.\n\n## Drug wastage should be included in the model\n\nThe company's original base case assumed drug wastage for each administration of crizanlizumab. In response to the appraisal consultation document, the company's revised base case assumed no drug wastage in the model. The company explained that this change was because it assumed there would be vial sharing in clinical practice, and that this had been validated by its clinical expert. The committee heard how crizanlizumab would likely be administered in a specialist centre which would mean that it may be possible to minimise some wastage. It discussed that, based on the patient weight from the SUSTAIN trial and the recommended licensed dose of crizanlizumab, drug wastage is expected because only 1\xa0vial size is available. The committee considered that crizanlizumab could be prepared in an aseptic pharmacy facility before being administered and then stored for up to 24\xa0hours. It noted that this process may be time consuming and costly. The committee discussed how someone may not be able to attend their infusion appointment after crizanlizumab had been prepared, which would further increase the likelihood of drug wastage. It recognised that vial sharing may be complex and problematic for crizanlizumab because the dose administered depends on a person's weight, and monthly infusions would need to be scheduled. The committee considered that drug wastage was highly likely with each administration of crizanlizumab. It concluded that drug wastage should be included the model.\n\n# Cost-effectiveness estimates\n\n## The company's updated base case does not reflect the committee's preferred assumptions\n\nIn response to consultation, the company incorporated the following assumptions into its base case:\n\npatient weight from SUSTAIN\n\npatient age and gender mix from the HES database (to maintain the link between age and gender mix and complications and mortality estimated using HES data)\n\nhydroxycarbamide use at 30% to reflect NHS practice\n\nremoving post-discontinuation efficacy\n\nusing differential utility values for each VOC health state from LEGACY, with per-event utility decrements applied\n\nno drug wastage assumed for each administration of crizanlizumab.The committee noted that the company's updated base case did not include its preferred assumptions on:\n\nusing the ERG's approach to calculate a single utility value (based on SUSTAIN) for all 3\xa0health states with per-event decrements for individual VOCs and complications\n\nincluding drug wastage for each administration of crizanlizumab.The committee discussed the results of its preferred analysis, which were commercial in confidence. It noted that the deterministic ICER was slightly more than £30,000 per quality-adjusted life year (QALY) gained. It also noted that the ICER could be substantially higher because of the immature SUSTAIN trial data, uncertainty around the model input parameters, and remaining issues with the model structure. The committee was aware that crizanlizumab's cost effectiveness was highly sensitive to changes in certain parameters in the company's base case, which were associated with uncertainty. These included age, weight and gender distribution, hydroxycarbamide use, duration of treatment effect during and after stopping treatment, and the choice of utility values.\n\n## The deterministic ICERs should be used for decision making\n\nThe committee noted that the company's revised base-case probabilistic ICERs were considerably lower than the revised deterministic base-case ICERs. The company considered this to be partly because varying patient weight in the probabilistic sensitivity analysis resulted in fewer vials of crizanlizumab administered for some iterations. The committee discussed how it was unclear why none of the probabilistic sensitivity analyses included a higher patient weight (which requires more crizanlizumab vials) than in SUSTAIN. The ERG explained that, in the company's original submission, certain parameters had not been included in the probabilistic sensitivity analysis, including the proportion of patients in each VOC state and the number of VOC events per health state. When these parameters were included in the probabilistic sensitivity analysis, the probabilistic and deterministic results differed much more substantially. The ERG explained that when patient weight was removed from the probabilistic sensitivity analysis, it still resulted in a large difference between the deterministic and probabilistic ICERs. The committee understood that the ERG was unable to identify the reasons for the discrepancy in the cost-effectiveness results. The committee was concerned that the probabilistic ICERs were highly uncertain. It concluded that in this instance the deterministic results should be used for decision making.\n\n# Other factors\n\n## Health inequalities were considered in the committee's decision making\n\nThe committee considered potential equalities issues raised by the company, experts and patient groups:\n\nThe patient experts explained that sickle cell disease is not widely understood, including among healthcare professionals, which often results in poor hospital care and stigma around seeking pain relief for crises.\n\nThe committee also heard that, because a significant proportion of patients with sickle cell disease may also be registered disabled because of ill health associated with their disease, for example strokes, chronic leg or foot ulcers and osteonecrosis, there can be problems accessing treatment.\n\nThe committee heard how the condition is more common in people of African or African-Caribbean family origin and that as a group these people tend to have poorer health outcomes than other ethnicities.The committee noted that these issues had been strongly reiterated in comments received in response to the appraisal consultation document. The committee discussed each of the equality issues raised. It noted that any recommendation for crizanlizumab would be unable to address the issues related to poor hospital care and stigma around seeking pain relief and that these were beyond the remit of a technology appraisal. It discussed potential issues around access to treatments for sickle cell disease in people with registered disabilities. It noted that if crizanlizumab were recommended, healthcare professionals should consider if reasonable adjustments can be made to enable access to crizanlizumab for people who do not receive hospital management of their VOCs or who may have difficulty travelling to hospital because of disability. The committee also acknowledged the potential health inequalities faced by people with this condition, and was mindful that the principles that guide the development of NICE guidance and standards included the aim to reduce health inequalities. The committee noted that sickle cell disease is mostly seen in certain minority ethnic populations, and was concerned to hear that consultees said that those populations suffered worse health outcomes and barriers to treatment. The committee concluded that it would consider these issues in its decision making.\n\n## The benefits of crizanlizumab are captured in the cost-effectiveness analysis\n\nThe company considers crizanlizumab to be innovative because it is a well tolerated and effective treatment for preventing VOCs in people with sickle cell disease. The committee considered other comments from patient groups highlighting the limited research and development in sickle cell disease compared with other orphan diseases. It acknowledged the limited research into the disease area and noted that crizanlizumab is the first drug to receive a marketing authorisation for treating the disease in several years. The committee recognised that the conditional regulatory approval of crizanlizumab was important to people with sickle cell disease. But it concluded that it had not been presented with evidence of any additional benefits that could not be captured in the QALY.\n\n# Conclusion\n\n## Crizanlizumab is not recommended for routine use in the NHS\n\nThe committee recalled that the most plausible ICER for crizanlizumab was above £30,000 per QALY gained. It also noted that there were issues with the model structure and that multiple model parameters were highly uncertain, which could lead to a plausible ICER that is considerably higher. NICE's guide to the methods of technology appraisal notes that, above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. Above a most plausible ICER of £30,000 per QALY gained, the guide to the methods of technology appraisal notes that an increasingly stronger case will need to be identified for supporting the technology as an effective use of NHS resources. NICE's guide to the methods of technology appraisal also states that consideration of the cost effectiveness of a technology is a necessary, but not the sole, basis for decision-making. The committee was willing to be flexible, taking into consideration the significant unmet need for effective treatments in people with sickle cell disease, and NICE's aim of reducing health inequalities (see section 3.13). The committee said that in theory it would be willing to accept an ICER slightly more than what is usually acceptable if it addresses such health inequalities. However, it noted that departing from NICE's usual range needs to be done with caution, as it risks displacing funding from more cost-effective treatments elsewhere in the NHS, with an overall net loss of health gain (see the principles that guide the development of NICE guidance and standards). Previously, substantial departures from the usual threshold have been accepted only under policies that were subject to formal public consultation before their adoption. The committee concluded that it was willing to be flexible when considering uncertainty, noting that a conditional marketing authorisation has been granted for crizanlizumab, which requires further data to be collected through several ongoing clinical trials. The committee concluded that, despite applying flexibilities, the ICER was above what NICE normally considers an acceptable use of NHS resources. Therefore, it concluded that crizanlizumab could not be recommended for routine commissioning.\n\n# Managed access proposal\n\n## A managed access agreement has been proposed by the company\n\nHaving concluded that crizanlizumab could not be recommended for routine use, the committee then considered the company's proposal for ongoing data collection through a managed access agreement, which could help address some of the uncertainties. The company identified 2\xa0sources of evidence that it considered could resolve the committee's uncertainties. The STAND trial is a phase\xa03 randomised placebo-controlled trial with UK patients. It is examining the efficacy and safety of crizanlizumab, with or without hydroxycarbamide, in patients aged 12\xa0years and over with a history of VOC. The committee noted that the primary analysis of the trial is due to report in 2023. The company considered that the trial would provide data on:\n\nlonger-term efficacy (with data up to 3\xa0years)\n\ncrizanlizumab's impact on the longer-term consequences of sickle cell disease\n\nduration of treatment effect\n\nutility values after treatment with crizanlizumab.Another source of prospective data was the National Haemoglobinopathy Registry. The company proposed that the registry would collect data on people having crizanlizumab in clinical practice, including:\n\nthe frequency of VOCs that lead to hospitalisation while on crizanlizumab\n\nhealthcare utilisation\n\nage, gender mix and weight of people with sickle cell disease who have recurrent VOCs in the UK\n\nconcomitant hydroxycarbamide use in people with sickle cell disease and recurrent VOCs in the UK.\n\n## A managed access agreement could address uncertainties\n\nThe committee agreed that data from the STAND trial and the National Haemoglobinopathy Registry collected through a managed access agreement may be enough to address the current uncertainties in the evidence base for crizanlizumab. It also acknowledged the need to manage the risks to the NHS because of the identified uncertainties. It considered the details of the company's proposed eligibility criteria in the managed access agreement and concluded that they were clinically achievable. The committee recognised the limited data available in people with sickle cell disease and that collecting more data could reduce the uncertainty around crizanlizumab's clinical and cost effectiveness.\n\n## Crizanlizumab is recommended for treating sickle cell disease within a managed access agreement\n\nThe high levels of uncertainty about crizanlizumab's long-term clinical effectiveness means that there would be a substantial financial risk to the NHS if the committee was to recommend it for routine use when it may not be cost effective. The committee noted that the risk to the NHS is reduced through the proposed managed access agreement. The committee took into account a range of factors in its decision making, including the unmet need of the disease and health inequalities faced by people with sickle cell disease. The committee was willing to be flexible in its considerations around uncertainty, particularly if access could be managed in a way that reduced the risk to the NHS. The committee was satisfied that further data collection through a managed access arrangement could gather enough evidence on longer-term effectiveness of crizanlizumab. It concluded that crizanlizumab met the criteria to be considered for use with managed access. It recommended crizanlizumab for preventing recurrent VOCs in sickle cell disease patients aged 16\xa0years and older if the conditions in the managed access agreement are followed. When the guidance is next reviewed, the company should use the committee's preferred assumptions as set out in this section, unless new evidence indicates otherwise."}
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https://www.nice.org.uk/guidance/ta743
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Evidence-based recommendations on crizanlizumab for preventing sickle cell crises in people aged 16 or over with sickle cell disease.
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becda314f626192776ec1603430f38926c13ee47
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nice
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Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management
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Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management
This guideline covers diagnosing and managing myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) in children, young people and adults. It aims to improve awareness and understanding about ME/CFS and when to suspect it, so that people are diagnosed earlier. It includes recommendations on diagnosis, assessment and care planning, safeguarding, access to care and managing ME/CFS and its symptoms.
# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
# Box 1 Severity of ME/CFS
Unless stated otherwise, these recommendations apply to everyone with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) regardless of symptom severity. There are also additional considerations in the section on care for people with severe or very severe ME/CFS.
Definitions of severity are not clear cut because individual symptoms vary widely in severity and people may have some symptoms more severely than others. The definitions below provide a guide to the level of impact of symptoms on everyday functioning.
Mild ME/CFS
People with mild ME/CFS care for themselves and do some light domestic tasks (sometimes needing support) but may have difficulties with mobility. Most are still working or in education, but to do this they have probably stopped all leisure and social pursuits. They often have reduced hours, take days off and use the weekend to cope with the rest of the week.
Moderate ME/CFS
People with moderate ME/CFS have reduced mobility and are restricted in all activities of daily living, although they may have peaks and troughs in their level of symptoms and ability to do activities. They have usually stopped work or education, and need rest periods, often resting in the afternoon for 1 or 2 hours. Their sleep at night is generally poor quality and disturbed.
Severe ME/CFS
People with severe ME/CFS are unable to do any activity for themselves or can carry out minimal daily tasks only (such as face washing or cleaning teeth). They have severe cognitive difficulties and may depend on a wheelchair for mobility. They are often unable to leave the house or have a severe and prolonged after-effect if they do so. They may also spend most of their time in bed and are often extremely sensitive to light and sound.
Very severe ME/CFS
People with very severe ME/CFS are in bed all day and dependent on care. They need help with personal hygiene and eating, and are very sensitive to sensory stimuli. Some people may not be able to swallow and may need to be tube fed.
# Principles of care for people with ME/CFS
Also see the section on care for people with severe or very severe ME/CFS.
## Awareness of ME/CFS and its impact
Be aware that ME/CFS:
is a complex, chronic medical condition affecting multiple body systems and its pathophysiology is still being investigated
affects everyone differently and its impact varies widely – for some people symptoms still allow them to carry out some activities, whereas for others they cause substantial incapacity
is a fluctuating condition in which a person's symptoms can change unpredictably in nature and severity over a day, week or longer
can affect different aspects of the lives of both people with ME/CFS and their families and carers, including activities of daily living, family life, social life, emotional wellbeing, work and education.
Recognise that people with ME/CFS may have experienced prejudice and disbelief and could feel stigmatised by people (including family, friends, health and social care professionals, and teachers) who do not understand their illness. Take into account:
the impact this may have on a child, young person or adult with ME/CFS
that people with ME/CFS may have lost trust in health and social care services and be hesitant about involving them.
## Approach to delivering care
Health and social care professionals should:
take time to build supportive, trusting and empathetic relationships
acknowledge to the person the reality of living with ME/CFS and how symptoms could affect them
use a person-centred approach to care and assessment
involve families and carers (as appropriate) in discussions and care planning if the person with ME/CFS chooses to include them
be sensitive to the person's socioeconomic, cultural and ethnic background, beliefs and values, and their gender identity and sexual orientation, and think about how these might influence their experience, understanding and choice of management.
Recognise that people with ME/CFS need:
timely and accurate diagnosis so they get appropriate care for their symptoms
regular monitoring and review, particularly when their symptoms are worsening, changing or are severe (see the section on managing flare-ups in symptoms and relapse and review in primary care).
Explain to people with ME/CFS and their family or carers (as appropriate) that they can decline or withdraw from any part of their care and support plan and this will not affect access to any other aspects of their care. They can begin or return to this part of their plan if they wish to.
When working with children and young people with ME/CFS, ensure their voice is heard by:
taking a child-centred approach, with the communication focusing on them
discussing and regularly reviewing with them how they want to be involved in decisions about their care
taking into account that they may find it difficult to communicate and describe their symptoms and may need their parents or carers (as appropriate) to help them
recognising that they may need to be seen on more than 1 occasion to gain trust (with or without their parents or carers, as appropriate).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles of care for people with ME/CFS .
Full details of the evidence and the committee's discussion are in:
evidence review A: information, education and support for people with ME/CFS and their families and carers
evidence review C: accessing health and social care services
appendix 2: involving adults with severe ME/CFS.
Other supporting evidence and discussion can be found in evidence review B: information, education and support for health and social care professionals and appendix 1: involving children and young people.
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# Suspecting ME/CFS
Explain to people presenting with possible symptoms of ME/CFS that there currently is no diagnostic test for ME/CFS and it is recognised on clinical grounds alone.
Suspect ME/CFS if:
the person has had all of the persistent symptoms in box 2 for a minimum of 6 weeks in adults and 4 weeks in children and young people and
the person's ability to engage in occupational, educational, social or personal activities is significantly reduced from pre‑illness levels and
symptoms are not explained by another condition.
## Box 2 Symptoms for suspecting ME/CFS
All of these symptoms should be present:
Debilitating fatigue that is worsened by activity, is not caused by excessive cognitive, physical, emotional or social exertion, and is not significantly relieved by rest.
Post-exertional malaise after activity in which the worsening of symptoms:
is often delayed in onset by hours or days
is disproportionate to the activity
has a prolonged recovery time that may last hours, days, weeks or longer.
Unrefreshing sleep or sleep disturbance (or both), which may include:
feeling exhausted, feeling flu-like and stiff on waking
broken or shallow sleep, altered sleep pattern or hypersomnia.
Cognitive difficulties (sometimes described as 'brain fog'), which may include problems finding words or numbers, difficulty in speaking, slowed responsiveness, short-term memory problems, and difficulty concentrating or multitasking.
If ME/CFS is suspected, carry out:
a medical assessment (including symptoms and history, comorbidities, overall physical and mental health)
a physical examination
an assessment of the impact of symptoms on psychological and social wellbeing
investigations to exclude other diagnoses, for example (but not limited to):
urinalysis for protein, blood and glucose
full blood count
urea and electrolytes
liver function
thyroid function
erythrocyte sedimentation rate or plasma viscosity
C-reactive protein
calcium and phosphate
HbA1c
serum ferritin
coeliac screening
creatine kinase.Use clinical judgement to decide on additional investigations to exclude other diagnoses (for example, vitamin D, vitamin B12 and folate levels; serological tests if there is a history of infection; and 9am cortisol for adrenal insufficiency).
Be aware that the following symptoms may also be associated with, but are not exclusive to, ME/CFS:
-rthostatic intolerance and autonomic dysfunction, including dizziness, palpitations, fainting, nausea on standing or sitting upright from a reclining position
temperature hypersensitivity resulting in profuse sweating, chills, hot flushes, or feeling very cold
neuromuscular symptoms, including twitching and myoclonic jerks
flu-like symptoms, including sore throat, tender glands, nausea, chills or muscle aches
intolerance to alcohol, or to certain foods and chemicals
heightened sensory sensitivities, including to light, sound, touch, taste and smell
pain, including pain on touch, myalgia, headaches, eye pain, abdominal pain or joint pain without acute redness, swelling or effusion.
Primary healthcare professionals should consider seeking advice from an appropriate specialist if there is uncertainty about interpreting signs and symptoms and whether an early referral is needed. For children and young people, consider seeking advice from a paediatrician.
When ME/CFS is suspected:
continue with any assessments needed to exclude or identify other conditions
give the person advice on managing their symptoms in line with the section on advice for people with suspected ME/CFS.
## Referring children and young people with suspected ME/CFS
When ME/CFS is suspected in a child or young person based on the criteria in recommendation 1.2.2 and the assessment in recommendation 1.2.3:
refer them to a paediatrician for further assessment and investigation for ME/CFS and other conditions
start to work with the child or young person's place of education or training to support flexible adjustments or adaptations.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on suspecting ME/CFS .
Full details of the evidence and the committee's discussion are in evidence review D: identifying and diagnosing ME/CFS.
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# Advice for people with suspected ME/CFS
When ME/CFS is suspected, give people personalised advice about managing their symptoms. Also advise them:
not to use more energy than they perceive they have − they should manage their daily activity and not 'push through' their symptoms
to rest and convalesce as needed (this might mean making changes to their daily routine, including work, school and other activities)
to maintain a healthy balanced diet, with adequate fluid intake.
Explain to people with suspected ME/CFS that their diagnosis can only be confirmed after 3 months of persistent symptoms. Reassure them that they can return for a review before that if they develop new or worsened symptoms, and ensure that they know who to contact for advice.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on advice for people with suspected ME/CFS .
Full details of the evidence and the committee's discussion are in evidence review E: management strategies before diagnosis.
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# Diagnosis
Diagnose ME/CFS in a child, young person or adult who has the symptoms in recommendation 1.2.2 that have persisted for 3 months and are not explained by another condition.
Primary healthcare professionals should consider seeking advice from an appropriate specialist if there is uncertainty about interpreting signs and symptoms at 3 months and whether further investigations are needed.
Refer adults directly to an ME/CFS specialist team (see box 3) to confirm their diagnosis and develop a care and support plan.
Refer children and young people who have been diagnosed with ME/CFS after assessment by a paediatrician (based on the criteria in recommendation 1.2.2) directly to a paediatric ME/CFS specialist team (see box 3) to confirm their diagnosis and develop a care and support plan.
## Box 3 ME/CFS specialist team
Specialist teams consist of a range of healthcare professionals with training and experience in assessing, diagnosing, treating and managing ME/CFS. They commonly have medically trained clinicians from a variety of specialisms (including rheumatology, rehabilitation medicine, endocrinology, infectious diseases, neurology, immunology, general practice and paediatrics) as well as access to other healthcare professionals specialising in ME/CFS. These may include physiotherapists, exercise physiologists, occupational therapists, dietitians, and clinical or counselling psychologists.
Children and young people are likely to be cared for under local or regional paediatric teams that have experience of working with children and young people with ME/CFS in collaboration with ME/CFS specialist centres.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis .
Full details of the evidence and the committee's discussion are in evidence review D: identifying and diagnosing ME/CFS.
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# Assessment and care and support planning by an ME/CFS specialist team
Also see the section on care for people with severe or very severe ME/CFS.
Carry out and record a holistic assessment to confirm the person's diagnosis of ME/CFS and inform their care and support plan. This should include:
a medical assessment (including relevant symptoms and history, comorbidities, overall physical and mental health, anything that is known to exacerbate or alleviate symptoms, and sleep quality)
physical functioning
the impact of symptoms on psychological, emotional and social wellbeing
current and past experiences of medicines (including tolerance and sensitivities), vitamins and mineral supplements
dietary assessment (including weight history before and after their diagnosis of ME/CFS, use of restrictive and alternative diets, and access to shopping and cooking).
Develop and agree a personalised care and support plan with the person with ME/CFS and their family or carers (as appropriate) informed by their holistic assessment. Include the following, depending on the person's needs:
information and support needs (see the section on information and support)
support for activities of daily living (see the section on access to care and support and recommendation 1.6.8 on accessing social care)
mobility and daily living aids and adaptations to increase or maintain independence (see the recommendations on aids and adaptations)
education, training or employment support needs (see the section on supporting people with ME/CFS in work, education and training)
self-management strategies, including energy management (see the recommendations on energy management)
physical functioning and mobility (see the recommendations on physical functioning and mobility)
managing ME/CFS and symptom management, including medicines management (see recommendations 1.12.1 to 1.12.26 on managing symptoms)
guidance on managing flare-ups and relapses (see the section on managing flare-ups in symptoms and relapses)
details of the health and social care professionals involved in the person's care, and who to contact (see recommendation 1.10.3).
Recognise that the person with ME/CFS is in charge of the aims of their care and support plan.
Give the person and their family or carers (as appropriate) a copy of their care and support plan and share a copy with their GP.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and care and support planning by an ME/CFS specialist team .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS and evidence review A: information, education and support for people with ME/CFS and their families and carers.
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# Information and support
## Communication
Ensure information is provided to people with ME/CFS and their family or carers (as appropriate):
in a variety of formats, such as written materials, electronic and audio, and suitable for their needs (for example, in their preferred language or an accessible version)
both in person in clinical settings and for them to use at home.Follow the principles on communication, information giving and shared decision making in the NICE guidelines on patient experience in adult NHS services, people's experience in adult social care services and shared decision making.
When providing information for children and young people with ME/CFS, take into account their age and level of understanding, symptoms and any disabilities or communication needs. Use interactive formats such as:
-ne-to-one or group discussion
written materials and pictures
play, art and music activities
digital media, for example video or interactive apps.
## Information about ME/CFS
Give people with ME/CFS and their family or carers (as appropriate) up-to-date information about ME/CFS as soon as it is suspected. Tailor information to people's circumstances, including their symptoms, the severity of their condition and how long they have had ME/CFS. Ask people regularly if they would like more information or to revisit discussions.
Explain that ME/CFS:
is a fluctuating medical condition that affects everyone differently, in which symptoms and their severity can change over a day, week or longer
varies in long-term outlook from person to person – although a proportion of people recover or have a long period of remission, many will need to adapt to living with ME/CFS
varies widely in its impact on people's lives, and can affect their daily activities, family and social life, and work or education (these impacts may be severe)
can be worsened by particular triggers – these can be known or new triggers or in some cases there is no clear trigger
can be self-managed with support and advice (see the section on energy management)
can involve flare-ups and relapses even if symptoms are well managed, so planning for these should be part of the energy management plan.
Explain to children and young people with ME/CFS and their parents or carers (as appropriate) that the outlook is better in children and young people than in adults.
Give people with ME/CFS and their family or carers (as appropriate) information about:
self-help groups, support groups and other local and national resources for people with ME/CFS
where to access advice about financial support, including applying for benefits.
## Social care
Discuss sensitively with the person and their family or carers (as appropriate) how social care may benefit them. Explain that it can help the person living with ME/CFS as well as provide a route to support for families and carers through a formal carer's assessment. Also see recommendations 1.8.5 and 1.8.6 on maintaining independence.
Explain to people with ME/CFS and their family or carers (as appropriate) how to self-refer for a social care needs assessment from their local authority. Offer to make the referral for them if they prefer.
Advise children and young people with moderate ME/CFS or severe or very severe ME/CFS and their parents or carers (as appropriate) that they may be entitled to support from children's social care as children in need because of their disability.
## Supporting families and carers of people with ME/CFS
Follow recommendations in the NICE guideline on supporting adult carers on identifying, assessing and meeting the caring, physical and mental health needs of families and carers.
Advise families and carers about the right to assessment and support for their own needs, as follows:
parents and carers of children and young people under 16 with ME/CFS, according to the Children and Families Act 2014
young carers, according to the Young Carers (Needs Assessment) Regulations 2015.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support .
Full details of the evidence and the committee's discussion are in evidence review A: information, education and support for people with ME/CFS and their families and carers.
Other supporting evidence and discussion can be found in:
evidence review B: information, education and support for health and social care professionals
evidence review C: accessing health and social care services
appendix 1: involving children and young people.
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# Safeguarding
Recognise that people with ME/CFS, particularly those with severe or very severe ME/CFS, are at risk of their symptoms being confused with signs of abuse or neglect.
If a person with confirmed or suspected ME/CFS needs a safeguarding assessment, directly involve health and social care professionals who have training and experience in ME/CFS as soon as possible.
If a person with confirmed or suspected ME/CFS needs to be assessed under the Mental Health Act 1983 or the Mental Capacity Act 2005, directly involve health and social care professionals who have training and experience in ME/CFS as soon as possible.
Recognise that the following are not necessarily signs of abuse or neglect in children and young people with confirmed or suspected ME/CFS:
physical symptoms that do not fit a commonly recognised illness pattern
more than 1 child or family member having ME/CFS
disagreeing with, declining or withdrawing from any part of their care and support plan, either by them or by their parents or carers on their behalf
parents or carers acting as advocates and communicating on their behalf
reduced or non-attendance at school.
Be aware that recognising and responding to possible child abuse and neglect (maltreatment) is complex and should be considered in the same way for children and young people with confirmed or suspected ME/CFS as with any child with a chronic illness or disability. Follow the NICE guidelines on child maltreatment and child abuse and neglect.
Offer children and young people with ME/CFS a review of their care and support plan at least every 6 months, and more frequently if needed, depending on the severity and complexity of their symptoms.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safeguarding .
Full details of the evidence and the committee's discussion are in evidence review B: information, education and support for health and social care professionals.
Other supporting evidence and discussion can be found in evidence review A: information, education and support for people with ME/CFS and their families and carers and appendix 1: involving children and young people.
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# Access to care and support
Also see the section on care for people with severe or very severe ME/CFS.
Health and social care organisations should ensure that people with ME/CFS can use their services by:
adapting the timing, length and frequency of all appointments to the person's needs
taking into account physical accessibility, such as how far the person has to travel, whether there is suitable transport and parking, and where rooms are for appointments
taking into account sensitivities to light, sound, touch, pain, temperature extremes or smells
providing care flexibly to the person's needs, such as by online or phone consultations or making home visits.
If a person with ME/CFS misses an appointment:
do not discharge them for not attending because it could be due to their symptoms worsening
discuss why they could not attend and how the multidisciplinary team can support them.
Be aware that people with ME/CFS are unlikely to be seen at their worst because:
debilitating symptoms or the risk that their symptoms will worsen may prevent people from leaving their home
cognitive difficulties may often mean people wait until they feel they can speak and explain clearly before contacting services.
## Hospital care
For improving access to hospital inpatient and outpatient care for people with ME/CFS, see recommendation 1.8.1.
Discuss with people who need inpatient care whether any aspects of where their care will be provided could cause problems for them, including:
where a bed is situated on a ward (if possible, aim to provide a single room)
the accessibility of toilets and washrooms
environmental factors such as lighting, sound, heating and smells.
## Maintaining independence
Also see the recommendations on social care and supporting families and carers of people with ME/CFS.
If a person with ME/CFS needs support at home, carry out a social care needs assessment. As a minimum, record and provide information and support on:
activities of daily living
mobility, including transferring from bed to chair, access to and use of toilet and washing facilities, use of stairs, and access to outside space
dexterity and balance, including avoiding falls
their home, including environmental controls to reduce light levels, sound levels and temperature fluctuations
the feasibility of equipment and adaptations
access to technology, including internet access
where to get financial support and advice, for example signposting to advice on money management and making personalised arrangements with banks or the Post Office to access personal finances, and how to claim carers' and disability benefits and grants.
Give families and carers information on how to access training and resources about caring for the person with ME/CFS (see the NICE guideline on supporting adult carers).
Enable prompt assessment for funding for home adaptation. If the person is not eligible for funding, continue to offer information and support in arranging home adaptations.
For people with moderate ME/CFS or severe or very severe ME/CFS, consider providing or recommending aids and adaptations (such as a wheelchair, blue badge or stairlift) that could help them maintain their independence and improve their quality of life, taking into account the risks and benefits. Include these in the person's care and support plan.
Provide aids and adaptations identified in the person's social care needs assessment without delay, so that people with ME/CFS can carry out activities of daily living and maintain their quality of life as much as possible.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to care and support .
Full details of the evidence and the committee's discussion are in evidence review C: accessing health and social care services.
Other supporting evidence and discussion can be found in evidence review A: information, education and support for people with ME/CFS and their families and carers and appendix 2: involving adults with severe ME/CFS.
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# Supporting people with ME/CFS in work, education and training
Offer to liaise on the person's behalf (with their informed consent) with employers, education providers and support services. Give them information about ME/CFS and discuss the person's care and support plan and any adjustments needed.
Advise and discuss with people with ME/CFS that:
they may be able to access reasonable adjustments or adaptations (in line with the Equality Act 2010) to help them continue or return to work or education
there may be times when they are unable to continue with work or education
some people find that going back to work, school or college worsens their symptoms.
Health and social care professionals should follow the Department for Education's guidance on supporting pupils at school with medical conditions or equivalent statutory guidance.
Health and social care professionals should work with training and education services to:
provide information about ME/CFS and the needs and impairments of children and young people with ME/CFS, including the need for a balance of activities in their life
discuss the child or young person's care and support plan so that everyone has a common understanding of their priorities, hopes and plans
discuss a flexible approach to training and education – this could include adjustments to the school day, online learning or education at home and using assistive equipment.
Give parents and carers information about education, health and care (EHC) plans and how to request one from their local authority.
Advise children and young people with ME/CFS and their parents or carers (as appropriate) that:
training or education should not be the only activity they undertake
they should aim to find a balance between the time they spend on education or training, home and family life, and social activities.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people with ME/CFS in work, education and training .
Full details of the evidence and the committee's discussion are in evidence review A: information, education and support for people with ME/CFS and their families and carers and appendix 1: involving children and young people.
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# Multidisciplinary care
Provide care for people with ME/CFS using a coordinated multidisciplinary approach. Based on the person's needs, include access to health and social care professionals with expertise in the following as a minimum, with additional expertise depending on symptoms:
medical assessment and diagnosis
developing personalised care and support plans
self-management strategies, including energy management
symptom management, including prescribing and medicines management
managing flare-ups and relapses
activities of daily living, including dental health
psychological, emotional and social wellbeing, including family and sexual relationships
diet and nutrition
mobility, avoiding falls and problems from loss of dexterity, including access to aids and rehabilitation services
social care and support
support to engage in work, education, social activities and hobbies.
Care for people whose ME/CFS is managed in primary care should be supported by advice and direct clinical consultation from an ME/CFS specialist team.
Give adults, children and young people with ME/CFS and their family or carers (as appropriate) a named contact in their primary care and/or ME/CFS specialist team to coordinate their care and support plan, help them access services and support them during periods of relapse.
Provide children and young people with ME/CFS and their family or carers (as appropriate) with details of a named professional in the ME/CFS specialist team who they can contact with any concerns about the child or young person's health, education or social life.
## Moving into adults' services
For young adults with ME/CFS moving from children's to adults' services, manage transitions in line with the NICE guideline on transition from children's to adults' services for young people using health or social care services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multidisciplinary care .
Full details of the evidence and the committee's discussion are in evidence review I: multidisciplinary care and evidence review C: accessing health and social care services.
Other supporting evidence and discussion can be found in evidence review A: information, education and support for people with ME/CFS and their families and carers and appendix 1: involving children and young people.
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# Managing ME/CFS
Be aware that ME/CFS symptoms can be managed but there is currently no cure (non-pharmacological or pharmacological) for ME/CFS.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on managing ME/CFS .
Full details of the evidence and the committee's discussion are in evidence review F: pharmacological interventions and evidence review G: non- pharmacological management of ME/CFS.
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## Energy management
Also see the section on care for people with severe or very severe ME/CFS.
Discuss with people with ME/CFS the principles of energy management, the potential benefits and risks and what they should expect. Explain that it:
is not curative
is a self-management strategy led by the person themselves with support from a healthcare professional in an ME/CFS specialist team
includes all types of activity (cognitive, physical, emotional and social) and takes into account overall level of activity
helps people learn to use the amount of energy they have while reducing their risk of post-exertional malaise or worsening their symptoms by exceeding their limits
recognises that each person has a different and fluctuating energy limit and they are experts in judging their own limits
can include help from a healthcare professional to recognise when they are approaching their limit (children and young people in particular may find it harder to judge their limits and can overreach them)
uses a flexible, tailored approach so that activity is never automatically increased but is maintained or adjusted (upwards after a period of stability or downwards when symptoms are worse)
is a long-term approach − it can take weeks, months or sometimes even years to reach stabilisation or to increase tolerance or activity.
Help people with ME/CFS develop a plan for energy management as part of their care and support plan. Support them to establish realistic expectations and develop goals that are meaningful to them. Discuss and record the following in the plan along with anything else that is important to the person:
cognitive activity
mobility and other physical activity
ability to undertake activities of daily living
psychological, emotional and social demands, including family and sexual relationships
rest and relaxation (both quality and duration)
sleep quality and duration
effect of environmental factors, including sensory stimulation.
Work with the person to establish an individual activity pattern within their current energy limits that minimises their symptoms. For example:
agree a sustainable level of activity as the first step, which may mean reducing activity
plan periods of rest and activity, and incorporate the need for pre-emptive rest
alternate and vary between different types of activity and break activities into small chunks.
Agree how often to review the person's energy management plan with them and revise it if needed.
Advise people with ME/CFS how to manage flare-ups and relapses (see the section on managing flare-ups in symptoms and relapse).
Make self-monitoring of activity as easy as possible by taking advantage of any tools the person already uses, such as an activity tracker, phone heart-rate monitor or diary.
Refer people with ME/CFS to a physiotherapist or occupational therapist working in an ME/CFS specialist team if they:
have difficulties caused by reduced physical activity or mobility (also see the sections on physical functioning and mobility and care for people with severe or very severe ME/CFS) or
feel ready to progress their physical activity beyond their current activities of daily living (see the section on physical activity and exercise) or
would like to incorporate a physical activity or exercise programme into managing their ME/CFS (see the section on incorporating physical activity and exercise).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on energy management .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
Other supporting evidence and discussion can be found in evidence review A: information, education and support for people with ME/CFS and their families and carers and appendix 2: involving adults with severe ME/CFS.
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## Incorporating physical activity and exercise
Do not advise people with ME/CFS to undertake exercise that is not part of a programme overseen by an ME/CFS specialist team, such as telling them to go to the gym or exercise more, because this may worsen their symptoms.
Only consider a personalised physical activity or exercise programme for people with ME/CFS who:
feel ready to progress their physical activity beyond their current activities of daily living or
would like to incorporate physical activity or exercise into managing their ME/CFS.
Tell people about the risks and benefits of physical activity and exercise programmes. Explain that some people with ME/CFS have found that they can make their symptoms worse, for some people it makes no difference and others find them helpful.
If a physical activity or exercise programme is offered, it should be overseen by a physiotherapist in an ME/CFS specialist team.
If a person with ME/CFS takes up the offer of a personalised physical activity or exercise programme, agree a programme with them that involves the following and review it regularly:
establishing their physical activity baseline at a level that does not worsen their symptoms
initially reducing physical activity to be below their baseline level
maintaining this successfully for a period of time before attempting to increase it
making flexible adjustments to their physical activity (up or down as needed) to help them gradually improve their physical abilities while staying within their energy limits
recognising a flare-up or relapse early and outlining how to manage it.
Do not offer people with ME/CFS:
any therapy based on physical activity or exercise as a cure for ME/CFS
generalised physical activity or exercise programmes – this includes programmes developed for healthy people or people with other illnesses
any programme that does not follow the approach in recommendation 1.11.13 or that uses fixed incremental increases in physical activity or exercise, for example, graded exercise therapy (see box 4)
physical activity or exercise programmes that are based on deconditioning and exercise avoidance theories as perpetuating ME/CFS.
## Box 4 Graded exercise therapy definition
Graded exercise therapy is a term used in varying ways by different services supporting people with ME/CFS.
In this guideline, graded exercise therapy is defined as first establishing an individual's baseline of achievable exercise or physical activity, then making fixed incremental increases in the time spent being physically active. This definition of graded exercise therapy reflects the descriptions given in the evidence that was reviewed, and it is this approach that the guideline says should not be undertaken.
An individualised approach that should be taken for people with ME/CFS who choose to undertake a physical activity or exercise programme is described in recommendations 1.11.10 to 1.11.13.
Agree with the person how to adjust their physical activity during a flare‑up or relapse. This should include:
providing access to review and support from a physiotherapist in an ME/CFS specialist team
stabilising their symptoms by reducing physical activity to within their current energy limits
-nly once symptoms stabilise and the person feels able to resume physical activity, establishing a new physical activity baseline.
Advise people with ME/CFS after a flare‑up that the time it takes to return to the level of physical activity they had before varies from person to person.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on incorporating physical activity and exercise .
Full details of the evidence and the committee's discussion are in:
evidence review G: non-pharmacological management of ME/CFS
evidence review A: information, education and support for people with ME/CFS and their families and carers
appendix 1: involving children and young people.
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# Symptom management for people with ME/CFS
Refer to relevant NICE guidance for managing symptoms that are not covered in this section, taking into account the recommendations in the sections on principles of care for people with ME/CFS, access to care and support and energy management.
## Rest and sleep
Advise people with ME/CFS:
about the role of rest in ME/CFS
that rest periods are part of all management strategies for ME/CFS
how to introduce rest periods into their daily routine, including how often and for how long, as appropriate for each person
that relaxation techniques at the beginning of each rest period could be helpful.
Give people with ME/CFS personalised sleep management advice that includes:
explaining the role and effect of sleep disturbance in ME/CFS
identifying the common changes in sleep patterns seen in ME/CFS (such as broken or shallow sleep, altered sleep pattern or hypersomnia)
developing good sleep habits
taking into account the need for rest in the day, and balancing this against how the person is sleeping at night
introducing changes to sleep patterns gradually.
If sleep management strategies do not improve the person's sleep and rest, think about the possibility of an underlying sleep disorder or dysfunction and whether to refer to an appropriate specialist.
Review the use of rest periods and sleep management strategies regularly as part of the person's care and support plan.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rest and sleep .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Physical functioning and mobility
Include strategies to maintain and prevent deterioration of physical functioning and mobility in the care and support plans of people with ME/CFS. These strategies may need to be carried out in small amounts and spread out throughout the day. Think about including the following:
joint mobility
muscle flexibility
balance
postural and positional support
muscle function
bone health
cardiovascular health.
Assess at every contact people with severe or very severe ME/CFS or those with prolonged periods of immobility for:
areas at risk of pressure ulcers (see the NICE guideline on pressure ulcers)
deep vein thrombosis (see the NICE guideline on venous thromboembolic diseases)
risk of contractures.
Give people with ME/CFS and their family or carers (as appropriate) information, advice and support on how to recognise and prevent possible complications of long-term immobility.
Give families and carers information, advice and support on how to help people with ME/CFS follow their care and support plan in relation to physical functioning and mobility. This may include:
bed mobility
moving from lying to sitting to standing
transferring from bed to chair
using mobility aids
walking
joint mobility
muscle stretching
muscle strength
balance
going up and down stairs.For training to provide care and support, see NICE's guideline on supporting adult carers.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical functioning and mobility .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Orthostatic intolerance
Be aware that people with ME/CFS may experience orthostatic intolerance, including postural orthostatic tachycardia syndrome (POTS).
Medicine for orthostatic intolerance in people with ME/CFS should only be prescribed or overseen by a healthcare professional with expertise in orthostatic intolerance.
Refer people with orthostatic intolerance to secondary care if their symptoms are severe or worsening, or there are concerns that another condition may be the cause.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on orthostatic intolerance .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Pain
Be aware that pain is a symptom commonly associated with ME/CFS.
Investigate and manage the person's pain according to best practice, referring to specialist pain services if appropriate.
Refer to the following for advice on treating neuropathic pain or headaches:
NICE's guideline on neuropathic pain in adults
NICE's guideline on headaches in over 12s.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Medicines
Do not offer any medicines or supplements to cure ME/CFS.
Offer people with ME/CFS a medication review in line with the NICE guidelines on medicines adherence and medicines optimisation.
Take into account when prescribing that people with ME/CFS may be more intolerant of drug treatment. Consider:
starting medicines at a lower dose than in usual clinical practice
gradually increasing the dose if the medicine is tolerated.
Drug treatment for the symptoms associated with ME/CFS for children and young people should only be started under guidance or supervision from a medical professional trained and experienced in paediatric prescribing.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on medicines .
Full details of the evidence and the committee's discussion are in evidence review F: pharmacological interventions.
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## Dietary management and strategies
Also see the section on care for people with severe or very severe ME/CFS.
Emphasise to people with ME/CFS the importance of adequate fluid intake and a well-balanced diet according to the NHS eat well guide.
Work with the person and their family or carers (as appropriate) to find ways of minimising complications caused by gastrointestinal symptoms (such as nausea), changes to appetite, swallowing difficulties, sore throat or difficulties with buying, preparing and eating food.
Encourage people with ME/CFS who have nausea to keep up adequate fluid intake and advise them to try to eat regularly, taking small amounts often. Explain that not eating or drinking may increase their nausea.
Refer people with ME/CFS for a dietetic assessment by a dietitian with a special interest in ME/CFS if they are:
losing weight and at risk of malnutrition
gaining weight
following a restrictive diet.
Be aware that people with ME/CFS may be at risk of vitamin D deficiency, especially those who are housebound or bedbound. For advice on vitamin D supplementation, see the NICE guideline on vitamin D.
Explain to people with ME/CFS that there is not enough evidence to support routinely taking vitamin and mineral supplements as a cure for ME/CFS or for managing symptoms. If they choose to take a vitamin or supplement, explain the potential side effects of taking doses of vitamins and minerals above the recommended daily amount.
Refer children and young people with ME/CFS who are losing weight or have faltering growth or dietary restrictions to a paediatric dietitian with a special interest in ME/CFS.
For advice on food allergies in children, see the NICE guideline on food allergy in under 19s.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on dietary management and strategies .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Lightning Process
Do not offer the Lightning Process, or therapies based on it, to people with ME/CFS.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on the Lightning Process .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Cognitive behavioural therapy
Also see the section on care for people with severe or very severe ME/CFS.
Discuss cognitive behavioural therapy (CBT) with adults, children and young people with ME/CFS (and their parents or carers, as appropriate). Explain:
its principles, including that it may help them manage their symptoms but it is not curative (see box 5) and
any potential benefits and risks.
## Box 5 Cognitive behavioural therapy
The committee wanted to highlight that cognitive behavioural therapy (CBT) has sometimes been assumed to be a cure for ME/CFS. However, it should only be offered to support people who live with ME/CFS to manage their symptoms, improve their functioning and reduce the distress associated with having a chronic illness.
Only offer CBT to adults, children and young people with ME/CFS if, after discussing it (see recommendation 1.12.28), they would like to use it to support them in managing their symptoms.
For children and young people with ME/CFS who would like to use CBT:
involve parents or carers (as appropriate) in the therapy wherever possible
adapt the therapy to the child or young person's cognitive and emotional stage of development.Also see the section on principles of care for people with ME/CFS (including the additional principles of care for children and young people with ME/CFS).
CBT should only be delivered by a healthcare professional with appropriate training and experience in CBT for ME/CFS, and under the clinical supervision of someone with expertise in CBT for ME/CFS.
Explain that CBT for people with ME/CFS:
aims to improve their quality of life, including functioning, and reduce the distress associated with having a chronic illness
does not assume people have 'abnormal' illness beliefs and behaviours as an underlying cause of their ME/CFS, but recognises that thoughts, feelings, behaviours and physiology interact with each other.
Explain what CBT involves so people know what to expect. Tell them that it:
takes a non-judgemental, supportive approach to the person's experience of their symptoms and the challenges these present
is a collaborative, structured, time-limited intervention that focuses on the difficulties people are having at that time
involves working closely with their therapist to establish strategies to work towards goals and priorities that they have chosen themselves
takes into account how symptoms are individual to each person, can fluctuate in severity and may change over time.
CBT for people with ME/CFS should include the following components:
developing a shared understanding with the person about the main difficulties and challenges they face
exploring the personal meaning of their symptoms and illness, and how this might relate to how they manage their symptoms
developing a self-management plan
working together to adapt and refine self-management strategies to improve the person's functioning and quality of life, for example their sleep, activity and rest
reviewing their plan regularly to see if their self-management strategies need to be adapted, for example if their symptoms or functioning change
developing a therapy blueprint collaboratively with their therapist at the end of therapy.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on cognitive behavioural therapy .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS and appendix 2: involving adults with severe ME/CFS.
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# Managing coexisting conditions
Be aware that other conditions may coexist with ME/CFS and should be investigated and managed according to best practice.
When managing coexisting conditions in people with ME/CFS, take into account the recommendations in the sections on principles of care for people with ME/CFS, access to care and support and energy management.
For recommendations on multimorbidity, thyroid disease and irritable bowel syndrome in adults, refer to the:
NICE guideline on multimorbidity
NICE guideline on thyroid disease
NICE guideline on irritable bowel syndrome in adults.
For recommendations on identifying and treating associated or comorbid anxiety, depression or mood disorders, see the:
NICE guideline on depression in adults
NICE guideline on depression in adults with a chronic physical health problem
NICE guideline on depression in children and young people
NICE guideline on generalised anxiety disorder and panic disorder in adults
NICE guideline on common mental health problems.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing coexisting conditions .
Full details of the evidence and the committee's discussion are in evidence review D: identifying and diagnosing ME/CFS.
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# Managing flare-ups in symptoms and relapse
Explain that flare-ups and relapses can happen in ME/CFS even if the person's symptoms are well managed.
Tell people with ME/CFS that:
they are likely to be having a flare‑up if they experience a worsening of their symptoms beyond their normal day-to-day variation, which lasts a few days
a relapse is when there is a sustained and marked exacerbation of ME/CFS symptoms lasting longer than a flare‑up and needing substantial and sustained adjustment of energy management.
Include guidance on managing flare‑ups and relapses in the person's care and support plan.
Evaluate and investigate any new symptoms or a change in symptoms and do not assume they are caused by the person's ME/CFS.
Discuss and agree self-management strategies with the person with ME/CFS to help them respond promptly if they have a flare‑up or relapse, and record these in their care and support plan. This should include:
For a flare‑up:
identifying possible triggers, such as acute illness or overexertion (in some cases, there may be no clear trigger)
temporarily reducing their activity levels
monitoring symptoms, recognising that although flare‑ups are transient, some will develop into a relapse
not returning to usual activity levels until the flare‑up has resolved.
For a relapse:
reducing, or even stopping, some activities
increasing the frequency or duration of rest periods
reassessing energy limits to stabilise symptoms.
If a flare-up or relapse cannot be managed using the person's self-management strategies outlined in their care and support plan or they are worried about new symptoms or a change in symptoms, advise the person to contact their named contact in primary care or the ME/CFS specialist team.
When a person with ME/CFS has a relapse, review their care and support plan with them (if needed), and discuss and agree a course of action, taking into account:
possible causes of the relapse, if known
the nature of the symptoms
the severity and duration of the relapse (bearing in mind this can be years).
## After a flare-up or relapse
Once a flare‑up or relapse has resolved or stabilised, discuss with the person:
whether their care and support plan needs to be reviewed and adjusted to reflect their current symptoms and energy limit if this is different from before the flare‑up or relapse (for people participating in physical activity or exercise programmes, see recommendations 1.11.15 and 1.11.16)
their experience of the flare‑up or relapse to determine whether strategies can be put in place to manage potential triggers in the future.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing flare-ups in symptoms and relapse .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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# Review in primary care
Offer adults with ME/CFS a review of their care and support plan in primary care at least once a year.
Offer children and young people with ME/CFS a review of their care and support plan at least every 6 months.
Arrange more frequent primary care reviews for children, young people and adults with ME/CFS as needed, depending on the severity and complexity of their symptoms, and the effectiveness of any symptom management.
When carrying out a review in primary care, ensure you have access to the person's care and support plan and any clinical communications from the ME/CFS specialist team (including their discharge letter, if relevant).
As part of the review, discuss with the person with ME/CFS (and their family or carers, as appropriate) and record as a minimum:
their condition, including any changes in their illness and the impact of this
symptoms, including whether they have experienced new symptoms
self-management − ask about their energy management plan and (if relevant) their physical activity or exercise programme
who is helping them and how they provide support
psychological, emotional and social wellbeing
any future plans − ask if the person is considering any changes or if they have any challenges ahead.
Refer the person with ME/CFS to their named contact in the ME/CFS specialist team if there are any new or deteriorating aspects of their condition.
Consider seeking advice from an appropriate specialist if there is uncertainty about interpreting signs and symptoms and whether a referral is needed.
Evaluate and investigate whether new symptoms, or a change in symptoms, are due to the person's ME/CFS or whether they are due to another condition.
## Additional principles for children and young people
Ensure reviews are carried out or overseen by a paediatrician with expertise in ME/CFS. Involve other appropriate specialists as needed.
When deciding how often reviews or reassessment might be needed for children and young people with ME/CFS, take into account:
their developmental stage
transitions, such as changing schools or exams
the severity and complexity of symptoms
the effectiveness of any symptom management.Also see recommendation 1.1.6 on ensuring the child's voice is heard and on involving their parents or carers.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on review in primary care .
Full details of the evidence and the committee's discussion are in evidence review J: monitoring and reviewing people with ME/CFS.
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# Training for health and social care professionals
Health and social care providers should ensure that all staff delivering care to people with ME/CFS receive training relevant to their role so they can provide care in line with this guideline. Training should include:
helping them to understand what ME/CFS is and its diagnosis and management
the experiences of people with ME/CFS.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on training for health and social care professionals .
Full details of the evidence and the committee's discussion are in evidence review B: information, education and support for health and social care professionals.
Other supporting evidence and discussion can be found in evidence review A: information, education and support for people with ME/CFS and their families and carers and appendix 2: involving adults with severe ME/CFS.
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# Care for people with severe or very severe ME/CFS
This section supplements the rest of the guideline with additional considerations for people with severe or very severe ME/CFS.
## Awareness of severe and very severe ME/CFS and its impact
Also see the main section on principles of care for people with ME/CFS.
Be aware that people with severe or very severe ME/CFS may experience the following symptoms that significantly affect their lives, including their mobility, emotional wellbeing and ability to interact with others and care for themselves:
severe and constant pain, which can have muscular, arthralgic or neuropathic features
hypersensitivity to light, sound, touch, movement, temperature extremes and smells
extreme weakness, with severely reduced movement
reduced ability or inability to speak or swallow
cognitive difficulties that limit the person's ability to communicate and take in written or verbal communication
sleep disturbance such as unrefreshing sleep, hypersomnia and altered sleep pattern
gastrointestinal difficulties such as nausea, incontinence, constipation and bloating
neurological symptoms such as double vision and other visual disorders, dizziness
-rthostatic intolerance and autonomic dysfunction, such as postural orthostatic tachycardia syndrome (POTS) and postural hypotension.
Recognise that symptoms of severe or very severe ME/CFS may mean that people:
need a low-stimulus environment, for example a dark quiet room with interaction at a level of their choice (this may be little or no social interaction)
are housebound or bedbound and may need support with all activities of daily living, including aids and adaptations to assist mobility and independence in activities of daily living (for example, a wheelchair)
need careful physical contact when supported with activities of daily living, taking into account possible sensitivity to touch
cannot communicate without support and may need to choose someone to be their advocate and communicate for them
are unable to eat and digest food easily and may need support with hydration and nutrition (see the recommendations on dietary management and strategies)
have problems accessing information, for example because of difficulty with screens, sound and light sensitivity, headaches affecting their ability to read, or brain fog affecting their concentration.
Personal care and support for people with severe or very severe ME/CFS should be carried out by health and social care practitioners who are:
known to the person and their family or carers wherever possible
aware of the person's needs.
Risk assess each interaction with a person with severe or very severe ME/CFS in advance to ensure its benefits will outweigh the risks (for example, worsening their symptoms) to the person. For people with very severe ME/CFS, think about discussing this with the person's family or carers on their behalf (if appropriate), while keeping the focus of the engagement on the person with ME/CFS.
## Assessment and care and support planning by an ME/CFS specialist team
Also see the main section on assessment and care and support planning by an ME/CFS specialist team.
Offer home visits to people with severe or very severe ME/CFS to carry out their holistic assessment and develop their care and support plan.
## Access to care and support
Also see the main section on access to care and support.
Service providers should be proactive and flexible in delivering services to people with severe or very severe ME/CFS, who may have particular difficulty accessing services and articulating their needs. This could include home visits, online or phone consultations, supplying written communication, and supporting their applications for aids and appliances.
When planning hospital care for people with severe or very severe ME/CFS:
discuss with the person (and their family or carers, as appropriate) what to expect when they come into hospital
aim to minimise discomfort and post-exertional malaise during transfer to hospital, for example by planning the route in advance, avoiding noisy areas and admitting them straight to the ward on arrival
discuss the person's care and support plan with them, including information on comorbidities, intolerances and sensitivities, to plan any reasonable adjustments that are needed
aim to provide a single room if possible
keep stimuli to a minimum, for example by:
seeing them one-to-one
using calm movements and gestures
not duplicating assessments
being cautious about the pressure of touch
keeping lights dimmed
reducing sound
keeping a stable temperature
minimising smells.
## Managing ME/CFS
Also see the main section on managing ME/CFS.
Also see the main section on energy management.
Refer people with severe or very severe ME/CFS to a physiotherapist or occupational therapist working in an ME/CFS specialist team for support on developing energy management plans.
When agreeing energy management plans with people with severe or very severe ME/CFS (and their family or carers, as appropriate), take into account the need to make any changes in activity smaller and any increases (if possible) much slower.
## Symptom management
Also see the main section on symptom management for people with ME/CFS.
Refer people with severe or very severe ME/CFS for a dietetic assessment by a dietitian with a special interest in ME/CFS.
Monitor people with severe or very severe ME/CFS who are at risk of malnutrition or unintentional weight loss because of:
restrictive diets
poor appetite, for example linked with altered taste, smell and texture
food intolerances
nausea
difficulty swallowing and chewing.Follow the recommendations on screening for malnutrition and indications for nutrition support, in the NICE guideline on nutrition support for adults.
Give advice to support people with severe or very severe ME/CFS, which could include:
eating little and often
having nourishing drinks and snacks, including food fortification
finding easier ways of eating to conserve energy, such as food with softer textures
using modified eating aids, particularly if someone has difficulty chewing or swallowing
-ral nutrition support and enteral feeding.
## Cognitive behavioural therapy
Healthcare professionals delivering CBT to people with severe or very severe ME/CFS should adjust the process and pace of CBT to meet the person's needs. This might include shorter, less frequent sessions and longer-term goals.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care for people with severe or very severe ME/CFS .
Full details of the evidence and the committee's discussion are in:
evidence review A: information, education and support for people with ME/CFS and their families and carers
appendix 1: involving children and young people
evidence review B: information, education and support for health and social care professionals
evidence review C: accessing health and social care services
evidence review G: non-pharmacological management of ME/CFS
evidence review I: multidisciplinary care
evidence review J: monitoring and reviewing people with ME/CFS.
Other supporting evidence and discussion can be found in evidence review A: information, education and support for people with ME/CFS and their families and carers and appendix 2: involving adults with severe ME/CFS.
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# Terms used in this guideline
For other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.
## Activity
Any effort that uses energy, which includes cognitive, emotional and social activity as well as physical activity. Different activities combine and interact to cause a cumulative impact for the person.
## Advocate
In this guideline, the role of an advocate is to support a vulnerable or disadvantaged person with ME/CFS and ensure that their rights are being upheld in a health and social care context. They are chosen by the person with ME/CFS and could be a family member, carer, friend or an independent advocate. They make sure that the person is heard.
## Care and support plan
The personalised collaborative care and support plan is developed by the ME/CFS specialist team based on a holistic assessment. It is the basis for other assessments and plans in areas such as social care, energy management, physical activity, physical functioning and mobility, cognitive behavioural therapy and dietary management.
## Carers
In this guideline, a carer refers to someone who provides unpaid care and support to a family member, partner or friend with ME/CFS. This is distinct from care workers who are employed to provide support.
## Children and young people
In this guideline, children and young people are aged under 18 (adults are 18 and above).
## Energy limit
The amount of energy a person has to do all activities without triggering an increase or worsening of their symptoms.
## Energy management
A self-management strategy that involves a person with ME/CFS managing their activities to stay within their energy limit, with support from a healthcare professional.
## Exercise
Exercise is planned, structured, repetitive and purposeful activity focused on improvement or maintenance of 1 or more components of physical fitness. Exercise is a subcategory of physical activity.
## Fatigue
Fatigue in ME/CFS typically has the following components:
feeling flu-like, especially in the early days of the illness
restlessness or feeling 'wired but tired'
low energy or a lack of physical energy to start or finish activities of daily living and the sensation of being 'physically drained'
cognitive fatigue that worsens existing difficulties
rapid loss of muscle strength or stamina after starting an activity, causing for example, sudden weakness, clumsiness, lack of coordination, and being unable to repeat physical effort consistently.
## Flare-up
A worsening of symptoms, more than would be accounted for by normal day-to-day variation, that affects the person's ability to perform their usual activities. Flare‑ups may occur spontaneously or be triggered by another illness, overexertion or other triggers. Flare‑ups usually occur as part of post-exertional malaise but it is possible for other symptoms, such as pain, to flare-up without post-exertional malaise. The worsening of symptoms is transient and flare‑ups typically resolve after a few days, either spontaneously or in response to temporary changes in energy management or a change in treatment. A relapse lasts longer than a flare‑up.
## Graded exercise therapy
In this guideline, graded exercise therapy is defined as establishing a baseline of achievable exercise or physical activity and then making fixed incremental increases in the time spent being physically active. It is a therapy based on the deconditioning and exercise avoidance theories of ME/CFS. These theories assume that ME/CFS is perpetuated by reversible physiological changes of deconditioning and avoidance of activity. These changes result in the deconditioning being maintained and an increased perception of effort, leading to further inactivity. This definition of graded exercise therapy reflects the descriptions of it included in evidence review G: non-pharmacological management of ME/CFS.
## ME/CFS specialist team
These teams consist of a range of healthcare professionals with expertise in assessing, diagnosing, treating and managing ME/CFS. They commonly have medically trained clinicians from a variety of specialisms (including rheumatology, rehabilitation medicine, endocrinology, infectious diseases, neurology, immunology, general practice and paediatrics) as well as access to other healthcare professionals specialising in ME/CFS. These may include physiotherapists, exercise physiologists, occupational therapists, dietitians, and clinical or counselling psychologists. Children and young people are likely to be cared for under local or regional paediatric teams that have experience working with children and young people with ME/CFS in collaboration with ME/CFS specialist centres.
## Orthostatic intolerance
A clinical condition in which symptoms such as light-headedness, near-fainting or fainting, impaired concentration, headaches, dimming or blurring of vision, forceful beating of the heart, palpitations, tremulousness and chest pain occur or worsen on standing up and are improved (although not necessarily resolved) by sitting or lying down. Orthostatic intolerance may include postural orthostatic tachycardia syndrome (POTS), which is a significant rise in pulse rate when moving from lying to standing, and postural hypotension, which is a significant fall in blood pressure when moving from lying to standing. People with severe orthostatic intolerance may find they are unable to sit up for any length of time.
## Physical activity
Any bodily movement produced by skeletal muscles that results in energy expenditure. It should not be confused with exercise. Physical activity in daily life can be categorised into occupational, sports, conditioning, household or other activities, and can be done during leisure time, to get around or as part of a person's work. See World Health Organization advice on physical activity. Physical activity has a health benefit for most people and many conditions, but in people with ME/CFS, physical activity may make their symptoms worsen.
## Physical functioning and mobility
The process of incorporating into daily activities a level of movement that helps to maintain joint and muscle flexibility without worsening symptoms of ME/CFS. This aims to support people to have as much independence as possible in their activities, ranging from personal hygiene to activities of daily living, working and social interaction. Such movement is undertaken within the person's energy limits and avoids pushing through their boundaries of tolerance.
## Post-exertional malaise
The worsening of symptoms that can follow minimal cognitive, physical, emotional or social activity, or activity that could previously be tolerated. Symptoms can typically worsen 12 to 48 hours after activity and last for days or even weeks, sometimes leading to a relapse. Post-exertional malaise may also be referred to as post-exertional symptom exacerbation.
## Relapse
A sustained and marked exacerbation of symptoms lasting longer than a flare‑up and needing a substantial and sustained adjustment to the person's energy management. It may not be clear in the early stages of a symptom exacerbation whether it is a flare‑up or a relapse. Relapses can lead to a long-term reduction in the person's energy limits.
## Special interest in ME/CFS
A special interest in ME/CFS refers to a healthcare professional who is not working in an ME/CFS specialist team service but has knowledge and experience in this area.
## Therapy blueprint
This summarises the therapy and provides a basis for future independent self-management. The blueprint may include the therapy formulation, strategies that have been helpful, 'warning signs' and triggers of flare‑ups and how to manage them, and goals for the future. It is important that the therapy blueprint is led by the person themselves and is in their own words, supported by guidance from the therapist.
## Unrefreshing sleep
Unrefreshing sleep means sleep that is non-restorative. Even after a full night's sleep, people do not feel refreshed. People with ME/CFS often report waking up exhausted and feeling as if they have not slept at all, no matter how long they were asleep.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Diagnostic tests
What diagnostic tests are clinically and cost effective in people with suspected myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS)?
For a short explanation of why the committee made this recommendation, see the rationale section on suspecting ME/CFS .
Full details of the evidence and the committee's discussion are in evidence review D: identifying and diagnosing ME/CFS.
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## A core outcome set
What core set of relevant health outcome measures should be used for trials of treatments for ME/CFS and managing symptoms of ME/CFS?
For a short explanation of why the committee made this recommendation, see the rationale section on managing ME/CFS .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Diagnostic criteria
In people with suspected ME/CFS, how effective is the NICE 2021 consensus-based diagnostic criteria in identifying people with ME/CFS?
For a short explanation of why the committee made this recommendation, see the rationale section on suspecting ME/CFS .
Full details of the evidence and the committee's discussion are in evidence review D: identifying and diagnosing ME/CFS.
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# Other recommendations for research
## Self-monitoring management strategies
What is the clinical and cost effectiveness of self-monitoring strategies and techniques in guiding energy management?
For a short explanation of why the committee made this recommendation, see the rationale section on energy management .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Sleep management strategies
What is the clinical and cost effectiveness of sleep management strategies in managing ME/CFS?
For a short explanation of why the committee made this recommendation, see the rationale section on rest and sleep .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
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## Dietary strategies
What is the clinical and cost effectiveness of dietary strategies in managing ME/CFS?
For a short explanation of why the committee made this recommendation, see the rationale section on dietary management and strategies .
Full details of the evidence and the committee's discussion are in evidence review G: non-pharmacological management of ME/CFS.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Principles of care for people with ME/CFS
Recommendations 1.1.1 to 1.1.6
## Why the committee made the recommendations
Common themes across the qualitative evidence showed a lack of belief about myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) as a real condition by health and social care professionals, and a lack of understanding about what it is and the impact it has. The committee used this evidence to make recommendations to raise awareness about ME/CFS. One strong theme showed how experiencing a lack of understanding and prejudice can lead to people losing trust in health and social care services. The committee agreed that health and social care professionals need to take into account the impact of not being believed when building relationships with people with ME/CFS and their families. The committee considered this particularly relevant to children and young people and made separate recommendations highlighting communication with children.
The evidence showed this loss of trust can be compounded when people with ME/CFS have negative experiences of healthcare services if they decline treatments that have been offered to them. This was a strong theme in the evidence for children and young people. The committee agreed that declining a specific treatment should not affect other areas of the person's care.
The qualitative evidence also showed that one of the barriers to good ME/CFS management was a late diagnosis and a lack of monitoring, and this reflected the committee's experience.
## How the recommendations might affect practice
These overarching principles will improve consistency of best practice and do not need any additional resources to deliver.
Return to recommendations
# Suspecting ME/CFS
Recommendations 1.2.1 to 1.2.7
## Why the committee made the recommendations
The committee took into account both the lack of evidence on diagnostic tests and the evidence that people value realistic advice about ME/CFS (particularly around diagnosis) when making the recommendation to explain how the condition is recognised.
The committee acknowledged there is ongoing discussion in the ME/CFS community about which diagnostic criteria should be used to identify and diagnose ME/CFS. The committee made a recommendation for key symptoms based on the evidence review of the current diagnostic criteria, but no 1 set of criteria was agreed to be better overall. The factors influencing these discussions are the broadness of the inclusion criteria, the definition of some of the symptoms, and the usability of the criteria as a clinical tool. There are concerns that many of the existing criteria do not accurately identify people with or without ME/CFS. Based on both the evidence and their experience, the committee agreed that the Institute of Medicine's 2015 criteria had the best balance of inclusion and exclusion of all the reviewed criteria, but it needed to be adapted for optimal use. In particular, the committee felt that the 6‑month delay should be reduced so that management could start earlier, and that fatigue and post-exertional malaise should be defined clearly to make it easier to interpret the revised criteria.
Based on their experience, the committee decided that a diagnosis of ME/CFS should be suspected if people have all 4 key symptoms (debilitating fatigue, post-exertional malaise, unrefreshing sleep or sleep disturbance , and cognitive difficulties) for a minimum of 6 weeks in adults and 4 weeks in children and young people. The committee agreed it would be unusual for an acute illness, including a viral illness, to persist longer than this in someone who has all 4 key symptoms. They emphasised it is the combination and interaction of the symptoms that is critical in distinguishing ME/CFS from other conditions and illness.
Currently, because there are no validated diagnostic criteria for ME/CFS, this leads to confusion about which criteria to use. The committee agreed to make a recommendation for research on diagnostic criteria to inform future guidance.
In addition to the 4 key symptoms, the committee noted that many of the criteria used to define ME/CFS also include other symptoms that are commonly experienced by people with ME/CFS. They agreed that although these symptoms are not crucial to a diagnosis, they are important for understanding ME/CFS and helping to manage symptoms, so they made a recommendation to raise awareness of them.
No evidence was identified for any tests or specific signs and symptoms as predictors of a later diagnosis of ME/CFS. Accurate diagnostic tests that correctly identify ME/CFS will support healthcare professionals to identify people who have ME/CFS and rule out those who do not. The committee made a recommendation for research on diagnostic tests to help identify effective diagnostic tests for ME/CFS that will facilitate early diagnosis and potentially lead to better outcomes for people with ME/CFS. They hoped this research would inform future guidance.
In outlining key areas for assessment, the committee agreed that although they could not give a list of standard tests, it was important to carry out investigations to exclude other potential diagnoses. They listed some examples of tests that could be done to exclude reversible conditions with similar symptoms to ME/CFS and that are often missed.
The committee discussed the non-specific nature and common presentation of some ME/CFS symptoms (for example, cognitive difficulties such as brain fog), which make it difficult to diagnose and distinguish from other conditions. This has led to misdiagnosis, missed diagnosis, and delays in the diagnosis of ME/CFS and of other conditions. Because of this, the committee agreed it is important that when a healthcare professional suspects ME/CFS, they should also consider alternative explanatory diagnoses or coexisting conditions. They should investigate these and refer to an appropriate specialist if they are unsure. The committee also agreed that diagnosis can be reviewed if symptoms change or new symptoms emerge.
The evidence and the committee's experience suggested that managing symptoms early may prevent them getting worse and the person's health deteriorating. To reflect this, the committee recommended advice on symptom management for people as soon as ME/CFS is suspected.
The committee agreed that to avoid any disruption to education, once ME/CFS is suspected in a child or young person, their place of education should be contacted to advise about flexible adjustments or adaptations.
## How the recommendations might affect practice
There is variation in practice and no single set of criteria is used clinically, with a 'mix and match' approach used alongside clinical experience. These recommendations will standardise practice and it is not believed they will have any impact on resource use or training.
There will be no change to the current practice of diagnosing ME/CFS based on clinical assessment and history and performing tests for differential diagnoses as appropriate.
The recommendations aim to raise awareness of symptoms and associated conditions that should raise suspicion of ME/CFS, particularly among healthcare professionals with limited knowledge about ME/CFS. This could increase the number of people with suspected ME/CFS who are then referred to an ME/CFS specialist team, but it will help to ensure they get appropriate care and better outcomes.
The recommendation that children and young people with suspected ME/CFS should be referred to a paediatrician after 4 weeks is earlier than in current practice. However, referring earlier for further assessment will help children and young people to get appropriate care sooner by identifying and excluding other conditions as well as ME/CFS, improving their outcomes.
Return to recommendations
# Advice for people with suspected ME/CFS
Recommendations 1.3.1 and 1.3.2
## Why the committee made the recommendations
There was limited clinical evidence on management strategies for people with suspected ME/CFS. The qualitative evidence and the committee's experience suggested that managing symptoms early may prevent them from getting worse and the person's health deteriorating. To reflect this, the committee made a recommendation to give people advice on symptom management drawn from their own knowledge and experience.
The qualitative evidence suggested this can be an anxious time for people with suspected ME/CFS and the committee agreed it was important for people to know who to contact if their symptoms change.
## How the recommendations might affect practice
Providing the advice in these recommendations would not impose a significant cost on the NHS. If this advice leads to fewer people with deteriorating symptoms, the recommendations would be highly cost effective.
Return to recommendations
# Diagnosis
Recommendations 1.4.1 to 1.4.4
## Why the committee made the recommendations
The committee agreed that although a 6‑month delay before diagnosis is built into the Institute of Medicine criteria, the criteria could be safely amended by reducing this period to 3 months. The committee saw removing this delay as useful because it might enable earlier management and could potentially improve longer-term outcomes.
Reflecting the common theme across the evidence about a lack of knowledge of ME/CFS and evidence that non-specialists in ME/CFS are not confident about diagnosing and managing ME/CFS, the committee recommended referring people with ME/CFS to an ME/CFS specialist team at 3 months to confirm their diagnosis and develop a care and support plan.
## How the recommendations might affect practice
The duration of symptoms before diagnosis can take place has been reduced but the criteria are now stricter, requiring that 4 different sets of symptoms are all present in order to suspect ME/CFS. The impact therefore will not necessarily be an increase in referrals but for people to receive their diagnosis earlier, which will bring forward their assessment and care plan. Earlier access to appropriate advice and care could prevent disease progression and therefore might lead to some resource savings in the longer term.
Return to recommendations
# Assessment and care and support planning by an ME/CFS specialist team
Recommendations 1.5.1 to 1.5.4
## Why the committee made the recommendations
The committee agreed that the key to managing ME/CFS symptoms successfully is having a collaborative personalised care and support plan. This should be developed based on a holistic assessment as soon as the person's diagnosis is confirmed. The committee agreed that a medical assessment should be part of this assessment, typically requiring access to a medically trained clinician. A copy of the care and support plan can be shared with primary care and a copy held by the person themselves, and it can be referred to in situations such as planning an admission to hospital. In the committee's experience, this approach to assessment and planning is common in ME/CFS specialist teams.
The committee outlined key areas to assess what support might be needed, based on their experience. The committee noted that the key areas to assess and the support needed will depend on the person's severity of ME/CFS, the impact of their symptoms and their needs. Once the care and support plan is agreed, it then provides a basis for the more detailed assessments and plans outlined in specific interventions in the guideline, such as social care needs assessments, energy management, physical functioning and mobility, cognitive behavioural therapy (CBT) and dietary management.
## How the recommendations might affect practice
Carrying out a holistic assessment and developing a care and support plan is already current practice in ME/CFS specialist services, although there may be more referrals to the specialist service resulting from these recommendations. However, having a care and support plan will facilitate people's care and may lead to better outcomes. If assessment is carried out early and a care plan is implemented, it could reduce resource use in the longer term by preventing progression of disease.
Return to recommendations
# Information and support
Recommendations 1.6.1 to 1.6.11
## Why the committee made the recommendations
Qualitative evidence showed that people with ME/CFS valued information from health and social care practitioners in formats that took into account the way symptoms such as 'brain fog' affected their capacity to take in and remember information. The committee highlighted formats that were reported as useful.
The evidence showed people with ME/CFS and their families and carers valued general information about ME/CFS that they could use themselves and share with others (families, friends, employers and practitioners), particularly around the time of diagnosis and the early stages of ME/CFS. This enabled them to develop accurate expectations about the future, relieve distress caused by the general lack of information and educate others. The evidence suggested people with ME/CFS wanted realistic information about what ME/CFS is and how it might affect them in the future, and this formed the basis of the recommendations outlining the key characteristics of ME/CFS.
The recommendation noting that the long-term outlook can be better in children and young people was based on the committee's experience.
The evidence supported the committee's view that information about ME/CFS and advice about other support is not easily available from health and social care services, and they agreed that people would benefit from information from local and national support groups.
Evidence suggested that people with ME/CFS needed practical support, both for themselves and their carers. The committee considered that some people may have reservations about engaging with social care, after experiencing disbelief about their illness and the impact it has on their day-to-day functioning. For this reason, the committee emphasised the need for sensitivity when talking to people and their families about social care support.
The committee made recommendations signposting to different assessments and support that could be helpful. In their experience, health and social care professionals did not always know what support is available to families and carers of people with ME/CFS, so the committee also referred to the NICE guideline on supporting adult carers.
## How the recommendations might affect practice
The recommendations are in line with the general principles for providing information already established in the existing NICE guideline on patient experience in the NHS and so were not considered likely to have any additional impact on practice.
Return to recommendations
# Safeguarding
Recommendations 1.7.1 to 1.7.6
## Why the committee made the recommendations
The committee recognised that safeguarding is a particular issue in ME/CFS in a way that is different from other chronic illnesses and disabilities because people with ME/CFS commonly report that they are not believed. No evidence was identified on safeguarding in ME/CFS, but the committee agreed it was very important to make recommendations based on consensus. The recommendations address some of the misconceptions on this topic and highlight the need for expertise in ME/CFS when carrying out safeguarding assessments.
The committee emphasised the need for frequent review of children and young people with ME/CFS (in line with recommendations 1.15.2 and 1.15.3). The importance of appropriate review is also highlighted in the NICE guidelines on child maltreatment and child abuse and neglect.
The committee noted that although safeguarding is not solely about children and young people, most of the concerns they were aware of related to children and young people with ME/CFS so they made separate recommendations for this group.
## How the recommendations might affect practice
The recommendations will improve consistency of best practice and do not need any additional resources to deliver.
Return to recommendations
# Access to care and support
Recommendations 1.8.1 to 1.8.9
## Why the committee made the recommendations
The evidence showed that people with ME/CFS can have difficulty using healthcare services, particularly because of physical accessibility and the time constraints of appointments. This can make it more difficult to get the support and treatment they need. The committee were also aware that common sensitivities in ME/CFS, such as to light and sound, can make it challenging to travel to and attend appointments and to receive inpatient care. The committee made recommendations to improve access to care based on these potential barriers.
The committee discussed the unpredictable and fluctuating nature of ME/CFS and the risk that people will be discharged from a service if they miss appointments when their symptoms worsen. They made a recommendation based on consensus to address the lack of awareness about this in health and social care services.
There was limited evidence directly addressing the barriers and facilitators to accessing social care. However, the committee agreed this was an important area of care and they could draw conclusions from the evidence on healthcare and use their own experience to make recommendations.
ME/CFS can affect a person's ability to carry out activities of daily living and maintain their independence and quality of life. The committee agreed that everyone with ME/CFS should be asked how their symptoms affect their independence and then a social care needs assessment carried out if necessary. Using their experience, the committee outlined the topics for assessment and discussion.
The committee also made further recommendations based on their own knowledge and experience, including that:
many families and carers do not know the most appropriate ways to support someone with ME/CFS and need advice on this
people with ME/CFS often have difficulty getting the equipment they need to support their activities of daily living and maintain their quality of life.
## How the recommendations might affect practice
Some of these recommendations might need extra staff time or other healthcare resource use, for example to offer flexible appointments and home visits, make adjustments during inpatient stays and provide access to aids and adaptations. However, for equity reasons, people with ME/CFS need the same access to healthcare and support as other NHS patients that is commensurate with the severity of their illness.
Return to recommendations
# Supporting people with ME/CFS in work, education and training
Recommendations 1.9.1 to 1.9.6
## Why the committee made the recommendations
The evidence showed a lack of support with education and training for children and young people with ME/CFS and their families and carers, and this can result in some children or young people leaving education. This reflected the committee's experience and they agreed that many of the themes in the evidence could also be applied to people in work.
The common theme of lack of knowledge and understanding about ME/CFS was echoed in this evidence with a lack of awareness about the impact that a high-stimulus environment (such as a school) can have on someone with ME/CFS. There was a lack of understanding about the need for a flexible approach to education with possible adjustments. The committee agreed that better communication between health and social care professionals and training and education services is key to develop a shared understanding of the needs and impairments of people with ME/CFS and how to provide them with appropriate educational support.
## How the recommendations might affect practice
The recommendations will improve consistency of best practice and do not need any additional resources to deliver.
Return to recommendations
# Multidisciplinary care
Recommendations 1.10.1 to 1.10.5
## Why the committee made the recommendations
There was limited evidence on the composition of a multidisciplinary team, but based on their experience, the committee agreed that good care for people with ME/CFS results from access to an integrated team of health and social care professionals who are trained and experienced in diagnosing and managing ME/CFS.
The fluctuating nature of ME/CFS means that people's support needs can change, so access to different expertise is needed at different times. The committee agreed that medical assessment and diagnosis would typically require access to an ME/CFS specialist physician or a GP with a special interest in ME/CFS. The committee agreed to make recommendations on providing a coordinated multidisciplinary approach and to identify the expertise that should be available.
In the committee's experience, care for most people with ME/CFS can be managed in primary care after their diagnosis is confirmed and they have a care and support plan agreed. However, the committee acknowledged the lack of confidence that non-specialists can have in managing ME/CFS and they recommended support from an ME/CFS specialist team.
The qualitative evidence showed that people with ME/CFS valued continuity of care and the committee agreed that having a single point of contact in their care team would avoid needing to have contact and appointments with multiple professionals which, for some people, could worsen their health.
## How the recommendations might affect practice
The recommendations on the ME/CFS specialist multidisciplinary team, providing a named contact and giving support to primary care services may need resources. Current provision of ME/CFS specialist teams is very uneven across the country and increased staffing may be needed in some areas if there are more referrals. The specialist team will need to cover different areas of expertise, but most people will only need access to some elements and only at specific times. However, faster access to diagnosis and appropriate care should lead to better symptom management and to substantially better outcomes for people with ME/CFS and so might reduce health and care costs in the longer term.
Allocating a single point of contact to people with ME/CFS is not routine practice across the NHS. This could be implemented differently in different regions according to local service structures and may not necessarily need the addition of new staff. It could improve the efficiency of care for people with ME/CFS by reducing the burden of repeated appointments.
Return to recommendations
# Managing ME/CFS
Recommendation 1.11.1
## Why the committee made the recommendation
Overall, the evidence for non-pharmacological and pharmacological interventions for ME/CFS was heterogenous and inconclusive, with limited evidence for any single intervention, and this supported the committee's experience. The committee were aware of claims that have been made about cures for ME/CFS and that there is often a financial cost to people with ME/CFS when they pursue these. To address this, the committee agreed to raise awareness in the recommendations of the current lack of a cure for ME/CFS.
There is considerable controversy over the outcome measures used in trials of treatments for ME/CFS and managing symptoms. Inconsistency in outcomes used and concerns over the validity of some outcome measures in an ME/CFS population makes it difficult to combine and compare results from different trials, limiting the ability to draw conclusions on the clinical and cost effectiveness of interventions. The committee made a recommendation for research on core outcome sets to enable the direct comparison of treatments for ME/CFS and symptom management and to shape and optimise ME/CFS trial design.
## How the recommendation might affect practice
The recommendations reflect current practice so no effect on resources is anticipated.
Return to recommendation
# Energy management
Recommendations 1.11.2 to 1.11.8
## Why the committee made the recommendations
The committee discussed how the controversy over graded exercise therapy had resulted in confusion over what support should be available to people with ME/CFS to safely manage their level of activity, including physical activity or exercise. They agreed it was important to provide clarity of information and clear guidance around energy management, physical activity and exercise to people with ME/CFS. The committee also agreed people need clear information about services available to them to support the development of energy management plans.
Based on their experience, the committee agreed that energy management is one of the most important tools that people with ME/CFS have to support them in living with the symptoms of ME/CFS. They agreed that people with ME/CFS should have access to support from an ME/CFS specialist team to develop a plan for energy management.
The committee listed the components of energy management and what an assessment and plan would include, noting that the key component is understanding the principle of using energy in a way to minimise post-exertional malaise. They recommended a detailed assessment that takes into account all areas of current activity and evaluation of rest and sleep, to establish an individual activity pattern within the person's current energy limit. The committee noted that energy management is not a physical activity or exercise programme, although the principles of energy management do apply to physical activity and exercise programmes.
To avoid potential harms by energy management being wrongly applied to people with ME/CFS without adequate support and expertise, the committee recommended that in specific circumstances, people with ME/CFS should be referred to a physiotherapist or occupational therapist in an ME/CFS specialist team.
There was a lack of effectiveness evidence on strategies and tools to support people to self-monitor activity management. The committee considered the qualitative evidence and their own experience of the benefits of using strategies and tools to monitor activity alongside the potential harms of increasing the burden on the person and causing them additional anxiety about their activity levels. The committee decided to recommend that activity recording should be as easy as possible, and people should take advantage of tools they are already using. The committee also decided to make a recommendation for research on self-monitoring management strategies to help determine which strategies and techniques are effective.
## How the recommendations might affect practice
The energy management plan forms part of the care and support plan and is part of ME/CFS specialist care. Appropriate energy management supports people to stay within their energy limits and aims to prevent their symptoms from worsening. It also supports them to increase their activity if possible. If this helps people maintain or improve their health this will be highly cost effective.
Return to recommendations
# Incorporating physical activity and exercise
Recommendations 1.11.9 to 1.11.16
## Why the committee made the recommendations
The committee agreed that clarity of information and clear guidance on energy management in relation to all activity should be available to people with ME/CFS. The committee also agreed that people need clear information about services available to them, and particularly the specific circumstances in which a personalised physical activity or exercise programme could be considered by a person with ME/CFS.
In the committee's experience, people with ME/CFS have had varying results from physical activity and exercise programmes. The committee agreed it was important to discuss this with people with ME/CFS and to explain to them the possible risks and benefits.
Because of the harms reported by people with ME/CFS in the qualitative evidence, as well as the committee's experience of the effects when people exceed their energy limits, the committee recommended that people with ME/CFS should not undertake a physical activity or exercise programme unless it is overseen by a physiotherapist who has training and expertise in ME/CFS.
The committee outlined what a personalised physical activity or exercise programme should, and should not, include. In developing recommendations on the content, approach and delivery of physical activity and exercise programmes, the committee considered the benefits and harms associated with graded exercise therapy that had been reported with ME/CFS across the quantitative and qualitative evidence, alongside their own experiences. They recognised that different definitions of the term 'graded exercise therapy' are used, and as a result the content and application of graded exercise therapy programmes differ. This has resulted in confusion. Taking into account descriptions of graded exercise therapy in the evidence they reviewed, the committee included a definition in this guideline to clarify what graded exercise therapy is intended to mean in the recommendation.
The committee concluded any programme using fixed incremental increases in physical activity or exercise (for example, graded exercise therapy), or physical activity or exercise programmes that are based on deconditioning and exercise avoidance theories, should not be offered to people with ME/CFS. The committee also wanted to reinforce that there is no therapy based on physical activity or exercise that is effective as a cure for ME/CFS.
For people with ME/CFS who do choose to take part in a physical activity or exercise programme, this should follow the principles set out in this section and the energy management section.
## How the recommendations might affect practice
These recommendations should prevent inappropriate or unstructured physical activity or exercise programmes from worsening people's symptoms. The referral to a physiotherapist or occupational therapist in an ME/CFS specialist team may need increased resources. However, this should not impose a significant cost on the NHS and if it leads to fewer people with deteriorating symptoms, it will be highly cost effective.
Return to recommendations
# Rest and sleep
Recommendations 1.12.1 to 1.12.4
## Why the committee made the recommendations
The committee considered that giving advice on planning rest and activity was a fundamental part of any management strategy. In their experience, understanding the role of rest and how to introduce rest periods was important in successful energy management.
There was a lack of evidence for sleep management, but the committee recognised that difficulty with sleep was an area of concern for many people with ME/CFS. The committee discussed making recommendations based on consensus for providing advice for people with ME/CFS and agreed they could recommend general advice for sleep management. They noted that there are common sleep patterns in people with ME/CFS that need to be considered when giving advice about sleep management. In addition, they made a recommendation for research on sleep management strategies.
## How the recommendations might affect practice
The recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.
Return to recommendations
# Physical functioning and mobility
Recommendations 1.12.5 to 1.12.8
## Why the committee made the recommendations
The committee discussed that people with ME/CFS can have reduced or limited mobility and, in their experience, this can lead to health problems. Physical functioning and mobility should therefore be assessed and included in the person's care and support plan.
The committee agreed that people with ME/CFS who are immobile need information to help them recognise and prevent the possible complications of long-term immobility, for example in relation to bone health and skin problems. In the committee's experience, families and carers are given only limited information about these areas of care (for example, how to transfer someone from a bed to a chair) and it would have helped them.
## How the recommendations might affect practice
The recommendations are already established in other NICE guidance and should not impose a significant cost on the NHS. If they lead to fewer people with deteriorating symptoms, they will be highly cost effective.
Return to recommendations
# Orthostatic intolerance
Recommendations 1.12.9 to 1.12.11
## Why the committee made the recommendations
Orthostatic intolerance is identified as one of the symptoms commonly associated with, but not exclusive to, ME/CFS (see the section on suspecting ME/CFS). In the committee's experience, although not everyone with ME/CFS experiences orthostatic intolerance, it is very common and the symptoms can be hard to differentiate from other ME/CFS symptoms.
Based on consensus, the committee made recommendations to raise awareness that people with ME/CFS may experience orthostatic intolerance, and to clarify when people with orthostatic intolerance should be referred to secondary care.
The committee did not make any recommendations on managing orthostatic intolerance because this can involve advice on diet, daily activities and activity support and needs to be tailored to each person, taking into account their other ME/CFS symptoms.
The committee recommended that medicines should only be prescribed or overseen by a clinician with expertise in orthostatic intolerance because the medicines that are usually prescribed can worsen other symptoms in people with ME/CFS.
## How the recommendations might affect practice
The recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.
Return to recommendations
# Pain
Recommendations 1.12.12 to 1.12.14
## Why the committee made the recommendations
Pain is identified as one of the symptoms commonly associated with, but not exclusive to, ME/CFS (see the section on suspecting ME/CFS). The committee agreed that pain is a common symptom in people with ME/CFS and is particularly intense in people with severe or very severe ME/CFS. The lack of evidence meant they could not recommend any interventions, but they did refer to the NICE guidelines on neuropathic pain and headaches. The committee also made consensus-based recommendations to raise awareness about pain in ME/CFS and what action to take.
## How the recommendations might affect practice
The recommendation referring to other NICE guidance should not have a resource impact as those recommendations are already established. The other recommendations should not impose a significant cost on the NHS and if they lead to fewer people deteriorating then they would be highly cost effective.
Return to recommendations
# Medicines
Recommendations 1.12.15 to 1.12.18
## Why the committee made the recommendations
The evidence for any pharmacological interventions for ME/CFS was inconclusive, with limited evidence for any one medicine, and this supported the committee's experience. The committee were aware of claims that have been made about cures for ME/CFS and there is often a financial cost to people with ME/CFS when these are pursued. The committee considered it was important to highlight that medicines or supplements should not be offered as a cure for ME/CFS.
The committee recognised that medicines can be useful for people with ME/CFS to manage their symptoms. The committee agreed that people with ME/CFS may be more intolerant of drug treatment, so they decided to raise awareness of this. To reduce the risk of harm, the committee discussed using a cautious approach to medicines prescribing, which includes starting the medicine at a lower dose than in usual clinical practice and monitoring how the person's symptoms respond before adjusting the dose.
The committee discussed medicines management for children and young people, noting the potential for harm, which led them to recommend that prescribing should be initiated under the supervision of a paediatrician with expertise in ME/CFS.
## How the recommendations might affect practice
The recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.
Return to recommendations
# Dietary management and strategies
Recommendations 1.12.19 to 1.12.26
## Why the committee made the recommendations
There was not enough evidence to make a recommendation for a particular dietary strategy for ME/CFS. However, the committee agreed some general recommendations to ensure that people with ME/CFS get appropriate support related to diet. This included guidance on when to refer someone to a dietitian with a special interest in ME/CFS. The committee also referred to other relevant NICE guidance.
The committee recognised that difficulties with diet and nutrition was an area of concern for many people with ME/CFS. They discussed making consensus-based recommendations for providing dietary strategies for people with ME/CFS, but they agreed it was hard to be confident in making recommendations when there was no evidence and a lack of consensus in the area, so they made a recommendation for research on dietary strategies.
## How the recommendations might affect practice
The recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.
Return to recommendations
# Lightning Process
Recommendation 1.12.27
## Why the committee made the recommendation
The committee discussed the limited evidence on the Lightning Process. They acknowledged that although some benefit was demonstrated and aspects of it, such as goal setting, practical examples and applications and peer support, were found to be helpful, the qualitative evidence on people's experiences of the therapy varied and raised some concerns. In the qualitative evidence, some people reported negative experiences to do with the confusing nature of the educational component, the intensity of the sessions, and the secrecy surrounding the therapy. While in the SMILE trial children under 16 were accompanied by parents, the committee were particularly concerned about the reported secrecy of the Lightning Process in the qualitative evidence and the lack of public information on the implementation of the process in practice. The committee agreed the transparency of any intervention is important and noted that in the qualitative evidence it was reported that people had been specifically encouraged not to talk about the therapy. The committee agreed this was an inappropriate and unusual message to give, particularly to children and young people.
The committee discussed concerns that the Lightning Process encourages people with ME/CFS to ignore and 'push through' their symptoms and this could potentially cause harm. In the qualitative evidence, some participants reported they had received advice they could do what they wanted. The committee noted they had made clear recommendations on the principles of energy management and this advice appears at odds with these principles.
Overall, the committee considered there was a lack of clarity around the implementation of the Lightning Process in practice and some concerning issues raised in the qualitative evidence. As a result, the committee agreed the Lightning Process should not be offered to people with ME/CFS.
## How the recommendation might affect practice
The Lightning Process is not offered as part of current practice so this recommendation will maintain current practice.
Return to recommendation
# Cognitive behavioural therapy
Recommendations 1.12.28 to 1.12.34
## Why the committee made the recommendations
The quantitative and qualitative evidence was mixed for adults, children and young people, and this reflected the committee's experience. Based on criticisms in the qualitative evidence of cognitive behavioural therapy (CBT) being described as a 'treatment' (cure) for ME/CFS, the committee considered it was important to highlight that CBT is not a cure for ME/CFS and should not be offered as such. Instead, it aims to improve wellbeing and quality of life, and may be useful in supporting people who live with ME/CFS to manage their symptoms and reduce the distress associated with having a chronic illness. It should therefore only be offered in this context, and after people have been fully informed about its principles and aims. The committee agreed if a child or young person would like to use CBT, it was important to adapt the therapy taking into account their cognitive and emotional maturity.
The qualitative evidence showed that people with ME/CFS have found CBT useful when delivered by a therapist who understands ME/CFS, but also that there is the potential for harm when it is inappropriately delivered. To avoid this, the committee made the recommendation about who should deliver CBT and the clinical supervision they should have.
The committee also made recommendations based on their experience to explain the principles of CBT for people with ME/CFS and what people should expect if they decide to consider CBT.
## How the recommendations might affect practice
CBT is currently provided for people with ME/CFS in specialist ME/CFS services. The recommendations clarify when CBT should be offered to people with ME/CFS. They should not have an impact on NHS resource and costs.
Return to recommendations
# Managing coexisting conditions
Recommendations 1.13.1 to 1.13.4
## Why the committee made the recommendations
The evidence on the diagnostic criteria identified that some conditions are common in people with ME/CFS and this reflected the committee's experience. The committee made recommendations to highlight this and referred to relevant NICE guidance.
## How the recommendations might affect practice
The recommendations should not impose a significant cost on the NHS.
Return to recommendations
# Managing flare-ups in symptoms and relapse
Recommendations 1.14.1 to 1.14.8
## Why the committee made the recommendations
In the committee's experience, flare‑ups and relapse are a common part of ME/CFS. The committee considered it important to give people information about what a flare‑up is, how to recognise one and how they can lead to a relapse if activity is not monitored and adjusted.
The committee discussed the importance of recognising when a flare‑up has moved to a relapse and that it needs to prompt a review of their care and support plan. It is also possible that a relapse may lead to someone moving to a more severe form of ME/CFS. Part of the review of the care and support plan is to consider what the causes of relapse might have been and to consider this when revising the plan.
## How the recommendations might affect practice
The recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.
Return to recommendations
# Review in primary care
Recommendations 1.15.1 to 1.15.10
## Why the committee made the recommendations
The evidence showed that people with ME/CFS did not always receive follow‑up or review of their care, but those who did valued this. This reflected the committee's experience, so they recommended at least annual reviews for adults.
The committee agreed that children and young people need more frequent review to take into account changes in their ME/CFS as they develop. They also wanted to highlight the importance of involving a paediatrician.
The committee outlined areas for discussion during the review, including asking people how much support they had to carry out their activities of daily living. This was because, in the committee's experience, this is an area often overlooked and the input of family and carers is often not acknowledged. The committee noted that if any problems are identified, advice should be sought from an appropriate specialist.
## How the recommendations might affect practice
There is variation in practice and some people with ME/CFS, including those with severe or very severe ME/CFS, do not get a clinical review routinely, so for some this will be a change in practice. These recommendations are in line with other long-term conditions and support equity of access to care for people with ME/CFS. Routine follow‑up might not be present everywhere but most people with ME/CFS already have regular contact with their primary care teams, so there is not expected to be a large resource impact.
Return to recommendations
# Training for health and social care professionals
Recommendation 1.16.1
## Why the committee made the recommendation
A strong theme in the evidence was the lack of knowledge, understanding and up-to-date training that health and social care professionals have about ME/CFS. This was reflected in the committee's experience, so they recommended that all health and social care staff who deliver care to people with ME/CFS should be trained so they are able to provide the care in this guideline.
## How the recommendation might affect practice
Training and education in ME/CFS are not widespread and this will be a change in practice, so there will be a resource impact from the cost of providing this training. Improving knowledge and awareness about ME/CFS will support identifying ME/CFS earlier, which should improve people's care and lead to better outcomes.
Return to recommendation
# Care for people with severe or very severe ME/CFS
Recommendations 1.17.1 to 1.17.13
## Awareness of severe and very severe ME/CFS and its impact
People with severe or very severe ME/CFS were named as a group for special consideration in the guideline scope. Evidence relating to people with severe ME/CFS reinforced the committee's experience that this group of people are often neglected, and the severity of their symptoms misunderstood, and with every recommendation the committee considered whether different or additional recommendations were needed for this group. The rationale and impact sections for these recommendations are below. These additional considerations for people with severe or very severe ME/CFS were placed in a separate section to make sure they could be easily found within the guideline.
Return to recommendations
## Assessment and care and support planning by an ME/CFS specialist team
Based on the evidence about problems with accessing services, the committee made a recommendation for a home visit to people with severe or very severe ME/CFS to carry out the assessment.
There may be an increased number of home visits for people with severe or very severe ME/CFS. However, this will provide equity of access to care for this group who are usually housebound.
Return to recommendation
## Access to care and support
The committee were aware that difficulties accessing care are intensified in people with severe or very severe ME/CFS, particularly when they need hospital care. The evidence showed that as a result of this, some people with severe or very severe ME/CFS have little contact and support from health and social care services. To address this, the committee highlighted the flexibility and specific support needed by people with severe or very severe ME/CFS.
There may be an increased number of home visits for people with severe or very severe ME/CFS. However, this will provide equity of access to care for this group who are usually housebound. Some of these costs may be offset by the ability to provide online consultations when appropriate. The emphasis in this guideline on timely diagnosis and referral to an ME/CFS specialist team for a personalised care and support plan aims to minimise the number of people who may progress to severe ME/CFS.
Return to recommendations
## Energy management
The committee agreed that if energy management strategies are inappropriately applied in people with severe or very severe ME/CFS, this will increase the potential for harm. To reflect this, they recommended specialist physiotherapy advice and additional care for people with severe or very severe ME/CFS who have chosen to develop an energy management plan.
The energy management plan forms part of the care and support plan and is a usual part of ME/CFS specialist care. Appropriate energy management supports people to stay within their energy limits and aims to prevent their symptoms from worsening. It also supports them to increase their activity if possible. If this helps people maintain or improve their health, this will be highly cost effective.
Return to recommendations
## Dietary management and strategies
The committee considered that people with severe or very severe ME/CFS are particularly at risk of problems associated with eating and are likely to need additional support and referral to a dietitian who has a special interest in ME/CFS. The committee also used their own experience to recommend some general dietary advice that could be helpful for people with severe or very severe ME/CFS.
## How the recommendations might affect practice
The recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.
Return to recommendations
## Cognitive behavioural therapy
None of the clinical evidence included or reflected the needs of people with severe or very severe ME/CFS, and the qualitative evidence was mixed, with some people reporting benefit and others harm. The committee recognised that CBT could be supportive for people with severe or very severe ME/CFS in some circumstances, but because of the severity of their symptoms, it is important to be more flexible and adapt the delivery of CBT to accommodate people's limitations.
CBT is currently provided for people with ME/CFS in specialist ME/CFS services. The recommendations clarify when CBT should be offered to people with ME/CFS. They should not have an impact on NHS resource and costs.
Return to recommendation# Context
The terms myalgic encephalomyelitis (ME; or encephalopathy), chronic fatigue syndrome (CFS), CFS/ME and ME/CFS have all been used for this condition and are not clearly defined. There is little pathological evidence of brain inflammation, which makes the term 'myalgic encephalomyelitis' problematic. Myalgic encephalomyelitis is classified under diseases of the nervous system in the SNOMED CT and ICD10 (G93.3). Many people with ME/CFS consider the name 'chronic fatigue syndrome' too broad, simplistic and judgemental. For consistency, the abbreviation ME/CFS is used in this guideline.
Recent data from the UK Biobank suggest that there are over 250,000 people in England and Wales with ME/CFS, with about 2.4 times as many women affected as men. ME/CFS can affect people of all ages. It is a complex, multi-system, chronic medical condition that has considerable personal, social and economic consequences and a significant impact on a person's quality of life, including their psychological, emotional and social wellbeing.
Everyday life for people with ME/CFS, their family and carers is disrupted and unpredictable. Many people with the condition are unemployed, and less than a fifth work full-time. Approximately 25% have severe disease and are housebound or bedbound. The quality of life of people with ME/CFS is lower than that of many people with other severe chronic conditions, including multiple sclerosis and some forms of cancer.
It is not clear what causes ME/CFS. In many cases, symptoms are thought to have been triggered by an infection but it is not simple post-illness fatigue. It lasts longer and even minimal mental or physical activity can make symptoms worse.
There is no diagnostic test or universally accepted definition for ME/CFS. People with the condition report delays in diagnosis, and many healthcare professionals lack the confidence and knowledge to recognise, diagnose and manage it. Fatigue associated with another chronic disease may be confused with ME/CFS and some practitioners are reluctant to positively diagnose ME/CFS when no other causes are found.
People with ME/CFS report a lack of belief and acknowledgement from health and social care professionals about their condition and related problems, which may lead them to be dissatisfied with care and to disengage from services. There are added issues for children and young people if illness makes school attendance difficult, bringing families to the attention of educational and social care services.
NICE produced a guideline on CFS/ME in 2007. That guideline made recommendations on cognitive behavioural therapy and graded exercise therapy. Both treatments are controversial for this condition, and there are disagreements and uncertainty about their effectiveness among both people with ME/CFS and health providers. The evidence for the effects of other commonly prescribed therapies has also been questioned.
There is unequal access to ME/CFS specialist services across England and Wales with some areas reporting very limited access. It is important this inequity of access is addressed.
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{'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\n# Box 1 Severity of ME/CFS\n\nUnless stated otherwise, these recommendations apply to everyone with myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) regardless of symptom severity. There are also additional considerations in the section on care for people with severe or very severe ME/CFS.\n\nDefinitions of severity are not clear cut because individual symptoms vary widely in severity and people may have some symptoms more severely than others. The definitions below provide a guide to the level of impact of symptoms on everyday functioning.\n\nMild ME/CFS\n\nPeople with mild ME/CFS care for themselves and do some light domestic tasks (sometimes needing support) but may have difficulties with mobility. Most are still working or in education, but to do this they have probably stopped all leisure and social pursuits. They often have reduced hours, take days off and use the weekend to cope with the rest of the week.\n\nModerate ME/CFS\n\nPeople with moderate ME/CFS have reduced mobility and are restricted in all activities of daily living, although they may have peaks and troughs in their level of symptoms and ability to do activities. They have usually stopped work or education, and need rest periods, often resting in the afternoon for 1\xa0or\xa02\xa0hours. Their sleep at night is generally poor quality and disturbed.\n\nSevere ME/CFS\n\nPeople with severe ME/CFS are unable to do any activity for themselves or can carry out minimal daily tasks only (such as face washing or cleaning teeth). They have severe cognitive difficulties and may depend on a wheelchair for mobility. They are often unable to leave the house or have a severe and prolonged after-effect if they do so. They may also spend most of their time in bed and are often extremely sensitive to light and sound.\n\nVery severe ME/CFS\n\nPeople with very severe ME/CFS are in bed all day and dependent on care. They need help with personal hygiene and eating, and are very sensitive to sensory stimuli. Some people may not be able to swallow and may need to be tube fed.\n\n# Principles of care for people with ME/CFS\n\nAlso see the section on care for people with severe or very severe ME/CFS.\n\n## Awareness of ME/CFS and its impact\n\nBe aware that ME/CFS:\n\nis a complex, chronic medical condition affecting multiple body systems and its pathophysiology is still being investigated\n\naffects everyone differently and its impact varies widely – for some people symptoms still allow them to carry out some activities, whereas for others they cause substantial incapacity\n\nis a fluctuating condition in which a person's symptoms can change unpredictably in nature and severity over a day, week or longer\n\ncan affect different aspects of the lives of both people with ME/CFS and their families and carers, including activities of daily living, family life, social life, emotional wellbeing, work and education.\n\nRecognise that people with ME/CFS may have experienced prejudice and disbelief and could feel stigmatised by people (including family, friends, health and social care professionals, and teachers) who do not understand their illness. Take into account:\n\nthe impact this may have on a child, young person or adult with ME/CFS\n\nthat people with ME/CFS may have lost trust in health and social care services and be hesitant about involving them.\n\n## Approach to delivering care\n\nHealth and social care professionals should:\n\ntake time to build supportive, trusting and empathetic relationships\n\nacknowledge to the person the reality of living with ME/CFS and how symptoms could affect them\n\nuse a person-centred approach to care and assessment\n\ninvolve families and carers (as appropriate) in discussions and care planning if the person with ME/CFS chooses to include them\n\nbe sensitive to the person's socioeconomic, cultural and ethnic background, beliefs and values, and their gender identity and sexual orientation, and think about how these might influence their experience, understanding and choice of management.\n\nRecognise that people with ME/CFS need:\n\ntimely and accurate diagnosis so they get appropriate care for their symptoms\n\nregular monitoring and review, particularly when their symptoms are worsening, changing or are severe (see the section on managing flare-ups in symptoms and relapse and review in primary care).\n\nExplain to people with ME/CFS and their family or carers (as appropriate) that they can decline or withdraw from any part of their care and support plan and this will not affect access to any other aspects of their care. They can begin or return to this part of their plan if they wish to.\n\nWhen working with children and young people with ME/CFS, ensure their voice is heard by:\n\ntaking a child-centred approach, with the communication focusing on them\n\ndiscussing and regularly reviewing with them how they want to be involved in decisions about their care\n\ntaking into account that they may find it difficult to communicate and describe their symptoms and may need their parents or carers (as appropriate) to help them\n\nrecognising that they may need to be seen on more than 1\xa0occasion to gain trust (with or without their parents or carers, as appropriate).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on principles of care for people with ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: information, education and support for people with ME/CFS and their families and carers\n\nevidence review\xa0C: accessing health and social care services\n\nappendix\xa02: involving adults with severe ME/CFS.\n\nOther supporting evidence and discussion can be found in evidence review\xa0B: information, education and support for health and social care professionals and appendix\xa01: involving children and young people.\n\nLoading. Please wait.\n\n# Suspecting ME/CFS\n\nExplain to people presenting with possible symptoms of ME/CFS that there currently is no diagnostic test for ME/CFS and it is recognised on clinical grounds alone.\n\nSuspect ME/CFS if:\n\nthe person has had all of the persistent symptoms in box\xa02 for a minimum of 6\xa0weeks in adults and 4\xa0weeks in children and young people\xa0and\n\nthe person's ability to engage in occupational, educational, social or personal activities is significantly reduced from pre‑illness levels and\n\nsymptoms are not explained by another condition.\n\n## Box 2 Symptoms for suspecting ME/CFS\n\nAll of these symptoms should be present:\n\nDebilitating fatigue that is worsened by activity, is not caused by excessive cognitive, physical, emotional or social exertion, and is not significantly relieved by rest.\n\nPost-exertional malaise after activity in which the worsening of symptoms:\n\n\n\nis often delayed in onset by hours or days\n\nis disproportionate to the activity\n\nhas a prolonged recovery time that may last hours, days, weeks or longer.\n\n\n\nUnrefreshing sleep or sleep disturbance (or both), which may include:\n\n\n\nfeeling exhausted, feeling flu-like and stiff on waking\n\nbroken or shallow sleep, altered sleep pattern or hypersomnia.\n\n\n\nCognitive difficulties (sometimes described as 'brain fog'), which may include problems finding words or numbers, difficulty in speaking, slowed responsiveness, short-term memory problems, and difficulty concentrating or multitasking.\n\nIf ME/CFS is suspected, carry out:\n\na medical assessment (including symptoms and history, comorbidities, overall physical and mental health)\n\na physical examination\n\nan assessment of the impact of symptoms on psychological and social wellbeing\n\ninvestigations to exclude other diagnoses, for example (but not limited to):\n\n\n\nurinalysis for protein, blood and glucose\n\nfull blood count\n\nurea and electrolytes\n\nliver function\n\nthyroid function\n\nerythrocyte sedimentation rate or plasma viscosity\n\nC-reactive protein\n\ncalcium and phosphate\n\nHbA1c\n\nserum ferritin\n\ncoeliac screening\n\ncreatine kinase.Use clinical judgement to decide on additional investigations to exclude other diagnoses (for example, vitamin\xa0D, vitamin\xa0B12 and folate levels; serological tests if there is a history of infection; and 9am cortisol for adrenal insufficiency).\n\n\n\nBe aware that the following symptoms may also be associated with, but are not exclusive to, ME/CFS:\n\northostatic intolerance and autonomic dysfunction, including dizziness, palpitations, fainting, nausea on standing or sitting upright from a reclining position\n\ntemperature hypersensitivity resulting in profuse sweating, chills, hot flushes, or feeling very cold\n\nneuromuscular symptoms, including twitching and myoclonic jerks\n\nflu-like symptoms, including sore throat, tender glands, nausea, chills or muscle aches\n\nintolerance to alcohol, or to certain foods and chemicals\n\nheightened sensory sensitivities, including to light, sound, touch, taste and smell\n\npain, including pain on touch, myalgia, headaches, eye pain, abdominal pain or joint pain without acute redness, swelling or effusion.\n\nPrimary healthcare professionals should consider seeking advice from an appropriate specialist if there is uncertainty about interpreting signs and symptoms and whether an early referral is needed. For children and young people, consider seeking advice from a paediatrician.\n\nWhen ME/CFS is suspected:\n\ncontinue with any assessments needed to exclude or identify other conditions\n\ngive the person advice on managing their symptoms in line with the section on advice for people with suspected ME/CFS.\n\n## Referring children and young people with suspected ME/CFS\n\nWhen ME/CFS is suspected in a child or young person based on the criteria in recommendation 1.2.2 and the assessment in recommendation\xa01.2.3:\n\nrefer them to a paediatrician for further assessment and investigation for ME/CFS and other conditions\n\nstart to work with the child or young person's place of education or training to support flexible adjustments or adaptations.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on suspecting ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: identifying and diagnosing ME/CFS.\n\nLoading. Please wait.\n\n# Advice for people with suspected ME/CFS\n\nWhen ME/CFS is suspected, give people personalised advice about managing their symptoms. Also advise them:\n\nnot to use more energy than they perceive they have − they should manage their daily activity and not 'push through' their symptoms\n\nto rest and convalesce as needed (this might mean making changes to their daily routine, including work, school and other activities)\n\nto maintain a healthy balanced diet, with adequate fluid intake.\n\nExplain to people with suspected ME/CFS that their diagnosis can only be confirmed after 3\xa0months of persistent symptoms. Reassure them that they can return for a review before that if they develop new or worsened symptoms, and ensure that they know who to contact for advice.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on advice for people with suspected ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: management strategies before diagnosis.\n\nLoading. Please wait.\n\n# Diagnosis\n\nDiagnose ME/CFS in a child, young person or adult who has the symptoms in recommendation 1.2.2 that have persisted for 3\xa0months and are not explained by another condition.\n\nPrimary healthcare professionals should consider seeking advice from an appropriate specialist if there is uncertainty about interpreting signs and symptoms at 3\xa0months and whether further investigations are needed.\n\nRefer adults directly to an ME/CFS specialist team (see box 3) to confirm their diagnosis and develop a care and support plan.\n\nRefer children and young people who have been diagnosed with ME/CFS after assessment by a paediatrician (based on the criteria in recommendation 1.2.2) directly to a paediatric ME/CFS specialist team (see box 3) to confirm their diagnosis and develop a care and support plan.\n\n## Box 3 ME/CFS specialist team\n\nSpecialist teams consist of a range of healthcare professionals with training and experience in assessing, diagnosing, treating and managing ME/CFS. They commonly have medically trained clinicians from a variety of specialisms (including rheumatology, rehabilitation medicine, endocrinology, infectious diseases, neurology, immunology, general practice and paediatrics) as well as access to other healthcare professionals specialising in ME/CFS. These may include physiotherapists, exercise physiologists, occupational therapists, dietitians, and clinical or counselling psychologists.\n\nChildren and young people are likely to be cared for under local or regional paediatric teams that have experience of working with children and young people with ME/CFS in collaboration with ME/CFS specialist centres.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on diagnosis\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: identifying and diagnosing ME/CFS.\n\nLoading. Please wait.\n\n# Assessment and care and support planning by an ME/CFS specialist team\n\nAlso see the section on care for people with severe or very severe ME/CFS.\n\nCarry out and record a holistic assessment to confirm the person's diagnosis of ME/CFS and inform their care and support plan. This should include:\n\na medical assessment (including relevant symptoms and history, comorbidities, overall physical and mental health, anything that is known to exacerbate or alleviate symptoms, and sleep quality)\n\nphysical functioning\n\nthe impact of symptoms on psychological, emotional and social wellbeing\n\ncurrent and past experiences of medicines (including tolerance and sensitivities), vitamins and mineral supplements\n\ndietary assessment (including weight history before and after their diagnosis of ME/CFS, use of restrictive and alternative diets, and access to shopping and cooking).\n\nDevelop and agree a personalised care and support plan with the person with ME/CFS and their family or carers (as appropriate) informed by their holistic assessment. Include the following, depending on the person's needs:\n\ninformation and support needs (see the section on information and support)\n\nsupport for activities of daily living (see the section on access to care and support and recommendation 1.6.8 on accessing social care)\n\nmobility and daily living aids and adaptations to increase or maintain independence (see the recommendations on aids and adaptations)\n\neducation, training or employment support needs (see the section on supporting people with ME/CFS in work, education and training)\n\nself-management strategies, including energy management (see the recommendations on energy management)\n\nphysical functioning and mobility (see the recommendations on physical functioning and mobility)\n\nmanaging ME/CFS and symptom management, including medicines management (see recommendations 1.12.1 to 1.12.26 on managing symptoms)\n\nguidance on managing flare-ups and relapses (see the section on managing flare-ups in symptoms and relapses)\n\ndetails of the health and social care professionals involved in the person's care, and who to contact (see recommendation 1.10.3).\n\nRecognise that the person with ME/CFS is in charge of the aims of their care and support plan.\n\nGive the person and their family or carers (as appropriate) a copy of their care and support plan and share a copy with their GP.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on assessment and care and support planning by an ME/CFS specialist team\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS and evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers.\n\nLoading. Please wait.\n\n# Information and support\n\n## Communication\n\nEnsure information is provided to people with ME/CFS and their family or carers (as appropriate):\n\nin a variety of formats, such as written materials, electronic and audio, and suitable for their needs (for example, in their preferred language or an accessible version)\n\nboth in person in clinical settings and for them to use at home.Follow the principles on communication, information giving and shared decision making in the NICE guidelines on patient experience in adult NHS services, people's experience in adult social care services and shared decision making.\n\nWhen providing information for children and young people with ME/CFS, take into account their age and level of understanding, symptoms and any disabilities or communication needs. Use interactive formats such as:\n\none-to-one or group discussion\n\nwritten materials and pictures\n\nplay, art and music activities\n\ndigital media, for example video or interactive apps.\n\n## Information about ME/CFS\n\nGive people with ME/CFS and their family or carers (as appropriate) up-to-date information about ME/CFS as soon as it is suspected. Tailor information to people's circumstances, including their symptoms, the severity of their condition and how long they have had ME/CFS. Ask people regularly if they would like more information or to revisit discussions.\n\nExplain that ME/CFS:\n\nis a fluctuating medical condition that affects everyone differently, in which symptoms and their severity can change over a day, week or longer\n\nvaries in long-term outlook from person to person – although a proportion of people recover or have a long period of remission, many will need to adapt to living with ME/CFS\n\nvaries widely in its impact on people's lives, and can affect their daily activities, family and social life, and work or education (these impacts may be severe)\n\ncan be worsened by particular triggers – these can be known or new triggers or in some cases there is no clear trigger\n\ncan be self-managed with support and advice (see the section on energy management)\n\ncan involve flare-ups and relapses even if symptoms are well managed, so planning for these should be part of the energy management plan.\n\nExplain to children and young people with ME/CFS and their parents or carers (as appropriate) that the outlook is better in children and young people than in adults.\n\nGive people with ME/CFS and their family or carers (as appropriate) information about:\n\nself-help groups, support groups and other local and national resources for people with ME/CFS\n\nwhere to access advice about financial support, including applying for benefits.\n\n## Social care\n\nDiscuss sensitively with the person and their family or carers (as appropriate) how social care may benefit them. Explain that it can help the person living with ME/CFS as well as provide a route to support for families and carers through a formal carer's assessment. Also see recommendations 1.8.5 and 1.8.6 on maintaining independence.\n\nExplain to people with ME/CFS and their family or carers (as appropriate) how to self-refer for a social care needs assessment from their local authority. Offer to make the referral for them if they prefer.\n\nAdvise children and young people with moderate ME/CFS or severe or very severe ME/CFS and their parents or carers (as appropriate) that they may be entitled to support from children's social care as children in need because of their disability.\n\n## Supporting families and carers of people with ME/CFS\n\nFollow recommendations in the NICE guideline on supporting adult carers on identifying, assessing and meeting the caring, physical and mental health needs of families and carers.\n\nAdvise families and carers about the right to assessment and support for their own needs, as follows:\n\nparents and carers of children and young people under\xa016 with ME/CFS, according to the Children and Families Act 2014\n\nyoung carers, according to the Young Carers (Needs Assessment) Regulations 2015.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on information and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers.\n\nOther supporting evidence and discussion can be found in:\n\nevidence review\xa0B: information, education and support for health and social care professionals\n\nevidence review\xa0C: accessing health and social care services\n\nappendix\xa01: involving children and young people.\n\nLoading. Please wait.\n\n# Safeguarding\n\nRecognise that people with ME/CFS, particularly those with severe or very severe ME/CFS, are at risk of their symptoms being confused with signs of abuse or neglect.\n\nIf a person with confirmed or suspected ME/CFS needs a safeguarding assessment, directly involve health and social care professionals who have training and experience in ME/CFS as soon as possible.\n\nIf a person with confirmed or suspected ME/CFS needs to be assessed under the Mental Health Act 1983 or the Mental Capacity Act 2005, directly involve health and social care professionals who have training and experience in ME/CFS as soon as possible.\n\nRecognise that the following are not necessarily signs of abuse or neglect in children and young people with confirmed or suspected ME/CFS:\n\nphysical symptoms that do not fit a commonly recognised illness pattern\n\nmore than 1\xa0child or family member having ME/CFS\n\ndisagreeing with, declining or withdrawing from any part of their care and support plan, either by them or by their parents or carers on their behalf\n\nparents or carers acting as advocates and communicating on their behalf\n\nreduced or non-attendance at school.\n\nBe aware that recognising and responding to possible child abuse and neglect (maltreatment) is complex and should be considered in the same way for children and young people with confirmed or suspected ME/CFS as with any child with a chronic illness or disability. Follow the NICE guidelines on child maltreatment and child abuse and neglect.\n\nOffer children and young people with ME/CFS a review of their care and support plan at least every 6\xa0months, and more frequently if needed, depending on the severity and complexity of their symptoms.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safeguarding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information, education and support for health and social care professionals.\n\nOther supporting evidence and discussion can be found in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers and appendix\xa01: involving children and young people.\n\nLoading. Please wait.\n\n# Access to care and support\n\nAlso see the section on care for people with severe or very severe ME/CFS.\n\nHealth and social care organisations should ensure that people with ME/CFS can use their services by:\n\nadapting the timing, length and frequency of all appointments to the person's needs\n\ntaking into account physical accessibility, such as how far the person has to travel, whether there is suitable transport and parking, and where rooms are for appointments\n\ntaking into account sensitivities to light, sound, touch, pain, temperature extremes or smells\n\nproviding care flexibly to the person's needs, such as by online or phone consultations or making home visits.\n\nIf a person with ME/CFS misses an appointment:\n\ndo not discharge them for not attending because it could be due to their symptoms worsening\n\ndiscuss why they could not attend and how the multidisciplinary team can support them.\n\nBe aware that people with ME/CFS are unlikely to be seen at their worst because:\n\ndebilitating symptoms or the risk that their symptoms will worsen may prevent people from leaving their home\n\ncognitive difficulties may often mean people wait until they feel they can speak and explain clearly before contacting services.\n\n## Hospital care\n\nFor improving access to hospital inpatient and outpatient care for people with ME/CFS, see recommendation 1.8.1.\n\nDiscuss with people who need inpatient care whether any aspects of where their care will be provided could cause problems for them, including:\n\nwhere a bed is situated on a ward (if possible, aim to provide a single room)\n\nthe accessibility of toilets and washrooms\n\nenvironmental factors such as lighting, sound, heating and smells.\n\n## Maintaining independence\n\nAlso see the recommendations on social care and supporting families and carers of people with ME/CFS.\n\nIf a person with ME/CFS needs support at home, carry out a social care needs assessment. As a minimum, record and provide information and support on:\n\nactivities of daily living\n\nmobility, including transferring from bed to chair, access to and use of toilet and washing facilities, use of stairs, and access to outside space\n\ndexterity and balance, including avoiding falls\n\ntheir home, including environmental controls to reduce light levels, sound levels and temperature fluctuations\n\nthe feasibility of equipment and adaptations\n\naccess to technology, including internet access\n\nwhere to get financial support and advice, for example signposting to advice on money management and making personalised arrangements with banks or the Post Office to access personal finances, and how to claim carers' and disability benefits and grants.\n\nGive families and carers information on how to access training and resources about caring for the person with ME/CFS (see the NICE guideline on supporting adult carers).\n\nEnable prompt assessment for funding for home adaptation. If the person is not eligible for funding, continue to offer information and support in arranging home adaptations.\n\nFor people with moderate ME/CFS or severe or very severe ME/CFS, consider providing or recommending aids and adaptations (such as a wheelchair, blue badge or stairlift) that could help them maintain their independence and improve their quality of life, taking into account the risks and benefits. Include these in the person's care and support plan.\n\nProvide aids and adaptations identified in the person's social care needs assessment without delay, so that people with ME/CFS can carry out activities of daily living and maintain their quality of life as much as possible.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on access to care and support\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0C: accessing health and social care services.\n\nOther supporting evidence and discussion can be found in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers and appendix\xa02: involving adults with severe ME/CFS.\n\nLoading. Please wait.\n\n# Supporting people with ME/CFS in work, education and training\n\nOffer to liaise on the person's behalf (with their informed consent) with employers, education providers and support services. Give them information about ME/CFS and discuss the person's care and support plan and any adjustments needed.\n\nAdvise and discuss with people with ME/CFS that:\n\nthey may be able to access reasonable adjustments or adaptations (in line with the Equality Act 2010) to help them continue or return to work or education\n\nthere may be times when they are unable to continue with work or education\n\nsome people find that going back to work, school or college worsens their symptoms.\n\nHealth and social care professionals should follow the Department for Education's guidance on supporting pupils at school with medical conditions or equivalent statutory guidance.\n\nHealth and social care professionals should work with training and education services to:\n\nprovide information about ME/CFS and the needs and impairments of children and young people with ME/CFS, including the need for a balance of activities in their life\n\ndiscuss the child or young person's care and support plan so that everyone has a common understanding of their priorities, hopes and plans\n\ndiscuss a flexible approach to training and education – this could include adjustments to the school day, online learning or education at home and using assistive equipment.\n\nGive parents and carers information about education, health and care (EHC) plans and how to request one from their local authority.\n\nAdvise children and young people with ME/CFS and their parents or carers (as appropriate) that:\n\ntraining or education should not be the only activity they undertake\n\nthey should aim to find a balance between the time they spend on education or training, home and family life, and social activities.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting people with ME/CFS in work, education and training\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers and appendix\xa01: involving children and young people.\n\nLoading. Please wait.\n\n# Multidisciplinary care\n\nProvide care for people with ME/CFS using a coordinated multidisciplinary approach. Based on the person's needs, include access to health and social care professionals with expertise in the following as a minimum, with additional expertise depending on symptoms:\n\nmedical assessment and diagnosis\n\ndeveloping personalised care and support plans\n\nself-management strategies, including energy management\n\nsymptom management, including prescribing and medicines management\n\nmanaging flare-ups and relapses\n\nactivities of daily living, including dental health\n\npsychological, emotional and social wellbeing, including family and sexual relationships\n\ndiet and nutrition\n\nmobility, avoiding falls and problems from loss of dexterity, including access to aids and rehabilitation services\n\nsocial care and support\n\nsupport to engage in work, education, social activities and hobbies.\n\nCare for people whose ME/CFS is managed in primary care should be supported by advice and direct clinical consultation from an ME/CFS specialist team.\n\nGive adults, children and young people with ME/CFS and their family or carers (as appropriate) a named contact in their primary care and/or ME/CFS specialist team to coordinate their care and support plan, help them access services and support them during periods of relapse.\n\nProvide children and young people with ME/CFS and their family or carers (as appropriate) with details of a named professional in the ME/CFS specialist team who they can contact with any concerns about the child or young person's health, education or social life.\n\n## Moving into adults' services\n\nFor young adults with ME/CFS moving from children's to adults' services, manage transitions in line with the NICE guideline on transition from children's to adults' services for young people using health or social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on multidisciplinary care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: multidisciplinary care and evidence review\xa0C: accessing health and social care services.\n\nOther supporting evidence and discussion can be found in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers and appendix\xa01: involving children and young people.\n\nLoading. Please wait.\n\n# Managing ME/CFS\n\nBe aware that ME/CFS symptoms can be managed but there is currently no cure (non-pharmacological or pharmacological) for ME/CFS.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on managing ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pharmacological interventions and evidence review\xa0G: non- pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Energy management\n\nAlso see the section on care for people with severe or very severe ME/CFS.\n\nDiscuss with people with ME/CFS the principles of energy management, the potential benefits and risks and what they should expect. Explain that it:\n\nis not curative\n\nis a self-management strategy led by the person themselves with support from a healthcare professional in an ME/CFS specialist team\n\nincludes all types of activity (cognitive, physical, emotional and social) and takes into account overall level of activity\n\nhelps people learn to use the amount of energy they have while reducing their risk of post-exertional malaise or worsening their symptoms by exceeding their limits\n\nrecognises that each person has a different and fluctuating energy limit and they are experts in judging their own limits\n\ncan include help from a healthcare professional to recognise when they are approaching their limit (children and young people in particular may find it harder to judge their limits and can overreach them)\n\nuses a flexible, tailored approach so that activity is never automatically increased but is maintained or adjusted (upwards after a period of stability or downwards when symptoms are worse)\n\nis a long-term approach − it can take weeks, months or sometimes even years to reach stabilisation or to increase tolerance or activity.\n\nHelp people with ME/CFS develop a plan for energy management as part of their care and support plan. Support them to establish realistic expectations and develop goals that are meaningful to them. Discuss and record the following in the plan along with anything else that is important to the person:\n\ncognitive activity\n\nmobility and other physical activity\n\nability to undertake activities of daily living\n\npsychological, emotional and social demands, including family and sexual relationships\n\nrest and relaxation (both quality and duration)\n\nsleep quality and duration\n\neffect of environmental factors, including sensory stimulation.\n\nWork with the person to establish an individual activity pattern within their current energy limits that minimises their symptoms. For example:\n\nagree a sustainable level of activity as the first step, which may mean reducing activity\n\nplan periods of rest and activity, and incorporate the need for pre-emptive rest\n\nalternate and vary between different types of activity and break activities into small chunks.\n\nAgree how often to review the person's energy management plan with them and revise it if needed.\n\nAdvise people with ME/CFS how to manage flare-ups and relapses (see the section on managing flare-ups in symptoms and relapse).\n\nMake self-monitoring of activity as easy as possible by taking advantage of any tools the person already uses, such as an activity tracker, phone heart-rate monitor or diary.\n\nRefer people with ME/CFS to a physiotherapist or occupational therapist working in an ME/CFS specialist team if they:\n\nhave difficulties caused by reduced physical activity or mobility (also see the sections on physical functioning and mobility and care for people with severe or very severe ME/CFS) or\n\nfeel ready to progress their physical activity beyond their current activities of daily living (see the section on physical activity and exercise) or\n\nwould like to incorporate a physical activity or exercise programme into managing their ME/CFS (see the section on incorporating physical activity and exercise).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on energy management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nOther supporting evidence and discussion can be found in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers and appendix\xa02: involving adults with severe ME/CFS.\n\nLoading. Please wait.\n\n## Incorporating physical activity and exercise\n\nDo not advise people with ME/CFS to undertake exercise that is not part of a programme overseen by an ME/CFS specialist team, such as telling them to go to the gym or exercise more, because this may worsen their symptoms.\n\nOnly consider a personalised physical activity or exercise programme for people with ME/CFS who:\n\nfeel ready to progress their physical activity beyond their current activities of daily living or\n\nwould like to incorporate physical activity or exercise into managing their ME/CFS.\n\nTell people about the risks and benefits of physical activity and exercise programmes. Explain that some people with ME/CFS have found that they can make their symptoms worse, for some people it makes no difference and others find them helpful.\n\nIf a physical activity or exercise programme is offered, it should be overseen by a physiotherapist in an ME/CFS specialist team.\n\nIf a person with ME/CFS takes up the offer of a personalised physical activity or exercise programme, agree a programme with them that involves the following and review it regularly:\n\nestablishing their physical activity baseline at a level that does not worsen their symptoms\n\ninitially reducing physical activity to be below their baseline level\n\nmaintaining this successfully for a period of time before attempting to increase it\n\nmaking flexible adjustments to their physical activity (up or down as needed) to help them gradually improve their physical abilities while staying within their energy limits\n\nrecognising a flare-up or relapse early and outlining how to manage it.\n\nDo not offer people with ME/CFS:\n\nany therapy based on physical activity or exercise as a cure for ME/CFS\n\ngeneralised physical activity or exercise programmes – this includes programmes developed for healthy people or people with other illnesses\n\nany programme that does not follow the approach in recommendation 1.11.13 or that uses fixed incremental increases in physical activity or exercise, for example, graded exercise therapy (see box 4)\n\nphysical activity or exercise programmes that are based on deconditioning and exercise avoidance theories as perpetuating ME/CFS.\n\n## Box 4 Graded exercise therapy definition\n\nGraded exercise therapy is a term used in varying ways by different services supporting people with ME/CFS.\n\nIn this guideline, graded exercise therapy is defined as first establishing an individual's baseline of achievable exercise or physical activity, then making fixed incremental increases in the time spent being physically active. This definition of graded exercise therapy reflects the descriptions given in the evidence that was reviewed, and it is this approach that the guideline says should not be undertaken.\n\nAn individualised approach that should be taken for people with ME/CFS who choose to undertake a physical activity or exercise programme is described in recommendations 1.11.10 to 1.11.13.\n\nAgree with the person how to adjust their physical activity during a flare‑up or relapse. This should include:\n\nproviding access to review and support from a physiotherapist in an ME/CFS specialist team\n\nstabilising their symptoms by reducing physical activity to within their current energy limits\n\nonly once symptoms stabilise and the person feels able to resume physical activity, establishing a new physical activity baseline.\n\nAdvise people with ME/CFS after a flare‑up that the time it takes to return to the level of physical activity they had before varies from person to person.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on incorporating physical activity and exercise\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: non-pharmacological management of ME/CFS\n\nevidence review\xa0A: information, education and support for people with ME/CFS and their families and carers\n\nappendix\xa01: involving children and young people.\n\nLoading. Please wait.\n\n# Symptom management for people with ME/CFS\n\nRefer to relevant NICE guidance for managing symptoms that are not covered in this section, taking into account the recommendations in the sections on principles of care for people with ME/CFS, access to care and support and energy management.\n\n## Rest and sleep\n\nAdvise people with ME/CFS:\n\nabout the role of rest in ME/CFS\n\nthat rest periods are part of all management strategies for ME/CFS\n\nhow to introduce rest periods into their daily routine, including how often and for how long, as appropriate for each person\n\nthat relaxation techniques at the beginning of each rest period could be helpful.\n\nGive people with ME/CFS personalised sleep management advice that includes:\n\nexplaining the role and effect of sleep disturbance in ME/CFS\n\nidentifying the common changes in sleep patterns seen in ME/CFS (such as broken or shallow sleep, altered sleep pattern or hypersomnia)\n\ndeveloping good sleep habits\n\ntaking into account the need for rest in the day, and balancing this against how the person is sleeping at night\n\nintroducing changes to sleep patterns gradually.\n\nIf sleep management strategies do not improve the person's sleep and rest, think about the possibility of an underlying sleep disorder or dysfunction and whether to refer to an appropriate specialist.\n\nReview the use of rest periods and sleep management strategies regularly as part of the person's care and support plan.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on rest and sleep\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Physical functioning and mobility\n\nInclude strategies to maintain and prevent deterioration of physical functioning and mobility in the care and support plans of people with ME/CFS. These strategies may need to be carried out in small amounts and spread out throughout the day. Think about including the following:\n\njoint mobility\n\nmuscle flexibility\n\nbalance\n\npostural and positional support\n\nmuscle function\n\nbone health\n\ncardiovascular health.\n\nAssess at every contact people with severe or very severe ME/CFS or those with prolonged periods of immobility for:\n\nareas at risk of pressure ulcers (see the NICE guideline on pressure ulcers)\n\ndeep vein thrombosis (see the NICE guideline on venous thromboembolic diseases)\n\nrisk of contractures.\n\nGive people with ME/CFS and their family or carers (as appropriate) information, advice and support on how to recognise and prevent possible complications of long-term immobility.\n\nGive families and carers information, advice and support on how to help people with ME/CFS follow their care and support plan in relation to physical functioning and mobility. This may include:\n\nbed mobility\n\nmoving from lying to sitting to standing\n\ntransferring from bed to chair\n\nusing mobility aids\n\nwalking\n\njoint mobility\n\nmuscle stretching\n\nmuscle strength\n\nbalance\n\ngoing up and down stairs.For training to provide care and support, see NICE's guideline on supporting adult carers.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical functioning and mobility\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Orthostatic intolerance\n\nBe aware that people with ME/CFS may experience orthostatic intolerance, including postural orthostatic tachycardia syndrome (POTS).\n\nMedicine for orthostatic intolerance in people with ME/CFS should only be prescribed or overseen by a healthcare professional with expertise in orthostatic intolerance.\n\nRefer people with orthostatic intolerance to secondary care if their symptoms are severe or worsening, or there are concerns that another condition may be the cause.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on orthostatic intolerance\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Pain\n\nBe aware that pain is a symptom commonly associated with ME/CFS.\n\nInvestigate and manage the person's pain according to best practice, referring to specialist pain services if appropriate.\n\nRefer to the following for advice on treating neuropathic pain or headaches:\n\nNICE's guideline on neuropathic pain in adults\n\nNICE's guideline on headaches in over 12s.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on pain\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Medicines\n\nDo not offer any medicines or supplements to cure ME/CFS.\n\nOffer people with ME/CFS a medication review in line with the NICE guidelines on medicines adherence and medicines optimisation.\n\nTake into account when prescribing that people with ME/CFS may be more intolerant of drug treatment. Consider:\n\nstarting medicines at a lower dose than in usual clinical practice\n\ngradually increasing the dose if the medicine is tolerated.\n\nDrug treatment for the symptoms associated with ME/CFS for children and young people should only be started under guidance or supervision from a medical professional trained and experienced in paediatric prescribing.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on medicines\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: pharmacological interventions.\n\nLoading. Please wait.\n\n## Dietary management and strategies\n\nAlso see the section on care for people with severe or very severe ME/CFS.\n\nEmphasise to people with ME/CFS the importance of adequate fluid intake and a well-balanced diet according to the NHS eat well guide.\n\nWork with the person and their family or carers (as appropriate) to find ways of minimising complications caused by gastrointestinal symptoms (such as nausea), changes to appetite, swallowing difficulties, sore throat or difficulties with buying, preparing and eating food.\n\nEncourage people with ME/CFS who have nausea to keep up adequate fluid intake and advise them to try to eat regularly, taking small amounts often. Explain that not eating or drinking may increase their nausea.\n\nRefer people with ME/CFS for a dietetic assessment by a dietitian with a special interest in ME/CFS if they are:\n\nlosing weight and at risk of malnutrition\n\ngaining weight\n\nfollowing a restrictive diet.\n\nBe aware that people with ME/CFS may be at risk of vitamin\xa0D deficiency, especially those who are housebound or bedbound. For advice on vitamin\xa0D supplementation, see the NICE guideline on vitamin\xa0D.\n\nExplain to people with ME/CFS that there is not enough evidence to support routinely taking vitamin and mineral supplements as a cure for ME/CFS or for managing symptoms. If they choose to take a vitamin or supplement, explain the potential side effects of taking doses of vitamins and minerals above the recommended daily amount.\n\nRefer children and young people with ME/CFS who are losing weight or have faltering growth or dietary restrictions to a paediatric dietitian with a special interest in ME/CFS.\n\nFor advice on food allergies in children, see the NICE guideline on food allergy in under 19s.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on dietary management and strategies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Lightning Process\n\nDo not offer the Lightning Process, or therapies based on it, to people with ME/CFS.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on the Lightning Process\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Cognitive behavioural therapy\n\nAlso see the section on care for people with severe or very severe ME/CFS.\n\nDiscuss cognitive behavioural therapy (CBT) with adults, children and young people with ME/CFS (and their parents or carers, as appropriate). Explain:\n\nits principles, including that it may help them manage their symptoms but it is not curative (see box 5) and\n\nany potential benefits and risks.\n\n## Box 5 Cognitive behavioural therapy\n\nThe committee wanted to highlight that cognitive behavioural therapy (CBT) has sometimes been assumed to be a cure for ME/CFS. However, it should only be offered to support people who live with ME/CFS to manage their symptoms, improve their functioning and reduce the distress associated with having a chronic illness.\n\nOnly offer CBT to adults, children and young people with ME/CFS if, after discussing it (see recommendation 1.12.28), they would like to use it to support them in managing their symptoms.\n\nFor children and young people with ME/CFS who would like to use CBT:\n\ninvolve parents or carers (as appropriate) in the therapy wherever possible\n\nadapt the therapy to the child or young person's cognitive and emotional stage of development.Also see the section on principles of care for people with ME/CFS (including the additional principles of care for children and young people with ME/CFS).\n\nCBT should only be delivered by a healthcare professional with appropriate training and experience in CBT for ME/CFS, and under the clinical supervision of someone with expertise in CBT for ME/CFS.\n\nExplain that CBT for people with ME/CFS:\n\naims to improve their quality of life, including functioning, and reduce the distress associated with having a chronic illness\n\ndoes not assume people have 'abnormal' illness beliefs and behaviours as an underlying cause of their ME/CFS, but recognises that thoughts, feelings, behaviours and physiology interact with each other.\n\nExplain what CBT involves so people know what to expect. Tell them that it:\n\ntakes a non-judgemental, supportive approach to the person's experience of their symptoms and the challenges these present\n\nis a collaborative, structured, time-limited intervention that focuses on the difficulties people are having at that time\n\ninvolves working closely with their therapist to establish strategies to work towards goals and priorities that they have chosen themselves\n\ntakes into account how symptoms are individual to each person, can fluctuate in severity and may change over time.\n\nCBT for people with ME/CFS should include the following components:\n\ndeveloping a shared understanding with the person about the main difficulties and challenges they face\n\nexploring the personal meaning of their symptoms and illness, and how this might relate to how they manage their symptoms\n\ndeveloping a self-management plan\n\nworking together to adapt and refine self-management strategies to improve the person's functioning and quality of life, for example their sleep, activity and rest\n\nreviewing their plan regularly to see if their self-management strategies need to be adapted, for example if their symptoms or functioning change\n\ndeveloping a therapy blueprint collaboratively with their therapist at the end of therapy.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on cognitive behavioural therapy\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS and appendix\xa02: involving adults with severe ME/CFS.\n\nLoading. Please wait.\n\n# Managing coexisting conditions\n\nBe aware that other conditions may coexist with ME/CFS and should be investigated and managed according to best practice.\n\nWhen managing coexisting conditions in people with ME/CFS, take into account the recommendations in the sections on principles of care for people with ME/CFS, access to care and support and energy management.\n\nFor recommendations on multimorbidity, thyroid disease and irritable bowel syndrome in adults, refer to the:\n\nNICE guideline on multimorbidity\n\nNICE guideline on thyroid disease\n\nNICE guideline on irritable bowel syndrome in adults.\n\nFor recommendations on identifying and treating associated or comorbid anxiety, depression or mood disorders, see the:\n\nNICE guideline on depression in adults\n\nNICE guideline on depression in adults with a chronic physical health problem\n\nNICE guideline on depression in children and young people\n\nNICE guideline on generalised anxiety disorder and panic disorder in adults\n\nNICE guideline on common mental health problems.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing coexisting conditions\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: identifying and diagnosing ME/CFS.\n\nLoading. Please wait.\n\n# Managing flare-ups in symptoms and relapse\n\nExplain that flare-ups and relapses can happen in ME/CFS even if the person's symptoms are well managed.\n\nTell people with ME/CFS that:\n\nthey are likely to be having a flare‑up if they experience a worsening of their symptoms beyond their normal day-to-day variation, which lasts a few days\n\na relapse is when there is a sustained and marked exacerbation of ME/CFS symptoms lasting longer than a flare‑up and needing substantial and sustained adjustment of energy management.\n\nInclude guidance on managing flare‑ups and relapses in the person's care and support plan.\n\nEvaluate and investigate any new symptoms or a change in symptoms and do not assume they are caused by the person's ME/CFS.\n\nDiscuss and agree self-management strategies with the person with ME/CFS to help them respond promptly if they have a flare‑up or relapse, and record these in their care and support plan. This should include:\n\nFor a flare‑up:\n\n\n\nidentifying possible triggers, such as acute illness or overexertion (in some cases, there may be no clear trigger)\n\ntemporarily reducing their activity levels\n\nmonitoring symptoms, recognising that although flare‑ups are transient, some will develop into a relapse\n\nnot returning to usual activity levels until the flare‑up has resolved.\n\n\n\nFor a relapse:\n\n\n\nreducing, or even stopping, some activities\n\nincreasing the frequency or duration of rest periods\n\nreassessing energy limits to stabilise symptoms.\n\n\n\nIf a flare-up or relapse cannot be managed using the person's self-management strategies outlined in their care and support plan or they are worried about new symptoms or a change in symptoms, advise the person to contact their named contact in primary care or the ME/CFS specialist team.\n\nWhen a person with ME/CFS has a relapse, review their care and support plan with them (if needed), and discuss and agree a course of action, taking into account:\n\npossible causes of the relapse, if known\n\nthe nature of the symptoms\n\nthe severity and duration of the relapse (bearing in mind this can be years).\n\n## After a flare-up or relapse\n\nOnce a flare‑up or relapse has resolved or stabilised, discuss with the person:\n\nwhether their care and support plan needs to be reviewed and adjusted to reflect their current symptoms and energy limit if this is different from before the flare‑up or relapse (for people participating in physical activity or exercise programmes, see recommendations 1.11.15 and 1.11.16)\n\ntheir experience of the flare‑up or relapse to determine whether strategies can be put in place to manage potential triggers in the future.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on managing flare-ups in symptoms and relapse\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n# Review in primary care\n\nOffer adults with ME/CFS a review of their care and support plan in primary care at least once a year.\n\nOffer children and young people with ME/CFS a review of their care and support plan at least every 6\xa0months.\n\nArrange more frequent primary care reviews for children, young people and adults with ME/CFS as needed, depending on the severity and complexity of their symptoms, and the effectiveness of any symptom management.\n\nWhen carrying out a review in primary care, ensure you have access to the person's care and support plan and any clinical communications from the ME/CFS specialist team (including their discharge letter, if relevant).\n\nAs part of the review, discuss with the person with ME/CFS (and their family or carers, as appropriate) and record as a minimum:\n\ntheir condition, including any changes in their illness and the impact of this\n\nsymptoms, including whether they have experienced new symptoms\n\nself-management − ask about their energy management plan and (if relevant) their physical activity or exercise programme\n\nwho is helping them and how they provide support\n\npsychological, emotional and social wellbeing\n\nany future plans − ask if the person is considering any changes or if they have any challenges ahead.\n\nRefer the person with ME/CFS to their named contact in the ME/CFS specialist team if there are any new or deteriorating aspects of their condition.\n\nConsider seeking advice from an appropriate specialist if there is uncertainty about interpreting signs and symptoms and whether a referral is needed.\n\nEvaluate and investigate whether new symptoms, or a change in symptoms, are due to the person's ME/CFS or whether they are due to another condition.\n\n## Additional principles for children and young people\n\nEnsure reviews are carried out or overseen by a paediatrician with expertise in ME/CFS. Involve other appropriate specialists as needed.\n\nWhen deciding how often reviews or reassessment might be needed for children and young people with ME/CFS, take into account:\n\ntheir developmental stage\n\ntransitions, such as changing schools or exams\n\nthe severity and complexity of symptoms\n\nthe effectiveness of any symptom management.Also see recommendation 1.1.6 on ensuring the child's voice is heard and on involving their parents or carers.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on review in primary care\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: monitoring and reviewing people with ME/CFS.\n\nLoading. Please wait.\n\n# Training for health and social care professionals\n\nHealth and social care providers should ensure that all staff delivering care to people with ME/CFS receive training relevant to their role so they can provide care in line with this guideline. Training should include:\n\nhelping them to understand what ME/CFS is and its diagnosis and management\n\nthe experiences of people with ME/CFS.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on training for health and social care professionals\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: information, education and support for health and social care professionals.\n\nOther supporting evidence and discussion can be found in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers and appendix\xa02: involving adults with severe ME/CFS.\n\nLoading. Please wait.\n\n# Care for people with severe or very severe ME/CFS\n\nThis section supplements the rest of the guideline with additional considerations for people with severe or very severe ME/CFS.\n\n## Awareness of severe and very severe ME/CFS and its impact\n\nAlso see the main section on principles of care for people with ME/CFS.\n\nBe aware that people with severe or very severe ME/CFS may experience the following symptoms that significantly affect their lives, including their mobility, emotional wellbeing and ability to interact with others and care for themselves:\n\nsevere and constant pain, which can have muscular, arthralgic or neuropathic features\n\nhypersensitivity to light, sound, touch, movement, temperature extremes and smells\n\nextreme weakness, with severely reduced movement\n\nreduced ability or inability to speak or swallow\n\ncognitive difficulties that limit the person's ability to communicate and take in written or verbal communication\n\nsleep disturbance such as unrefreshing sleep, hypersomnia and altered sleep pattern\n\ngastrointestinal difficulties such as nausea, incontinence, constipation and bloating\n\nneurological symptoms such as double vision and other visual disorders, dizziness\n\northostatic intolerance and autonomic dysfunction, such as postural orthostatic tachycardia syndrome (POTS) and postural hypotension.\n\nRecognise that symptoms of severe or very severe ME/CFS may mean that people:\n\nneed a low-stimulus environment, for example a dark quiet room with interaction at a level of their choice (this may be little or no social interaction)\n\nare housebound or bedbound and may need support with all activities of daily living, including aids and adaptations to assist mobility and independence in activities of daily living (for example, a wheelchair)\n\nneed careful physical contact when supported with activities of daily living, taking into account possible sensitivity to touch\n\ncannot communicate without support and may need to choose someone to be their advocate and communicate for them\n\nare unable to eat and digest food easily and may need support with hydration and nutrition (see the recommendations on dietary management and strategies)\n\nhave problems accessing information, for example because of difficulty with screens, sound and light sensitivity, headaches affecting their ability to read, or brain fog affecting their concentration.\n\nPersonal care and support for people with severe or very severe ME/CFS should be carried out by health and social care practitioners who are:\n\nknown to the person and their family or carers wherever possible\n\naware of the person's needs.\n\nRisk assess each interaction with a person with severe or very severe ME/CFS in advance to ensure its benefits will outweigh the risks (for example, worsening their symptoms) to the person. For people with very severe ME/CFS, think about discussing this with the person's family or carers on their behalf (if appropriate), while keeping the focus of the engagement on the person with ME/CFS.\n\n## Assessment and care and support planning by an ME/CFS specialist team\n\nAlso see the main section on assessment and care and support planning by an ME/CFS specialist team.\n\nOffer home visits to people with severe or very severe ME/CFS to carry out their holistic assessment and develop their care and support plan.\n\n## Access to care and support\n\nAlso see the main section on access to care and support.\n\nService providers should be proactive and flexible in delivering services to people with severe or very severe ME/CFS, who may have particular difficulty accessing services and articulating their needs. This could include home visits, online or phone consultations, supplying written communication, and supporting their applications for aids and appliances.\n\nWhen planning hospital care for people with severe or very severe ME/CFS:\n\ndiscuss with the person (and their family or carers, as appropriate) what to expect when they come into hospital\n\naim to minimise discomfort and post-exertional malaise during transfer to hospital, for example by planning the route in advance, avoiding noisy areas and admitting them straight to the ward on arrival\n\ndiscuss the person's care and support plan with them, including information on comorbidities, intolerances and sensitivities, to plan any reasonable adjustments that are needed\n\naim to provide a single room if possible\n\nkeep stimuli to a minimum, for example by:\n\n\n\nseeing them one-to-one\n\nusing calm movements and gestures\n\nnot duplicating assessments\n\nbeing cautious about the pressure of touch\n\nkeeping lights dimmed\n\nreducing sound\n\nkeeping a stable temperature\n\nminimising smells.\n\n\n\n## Managing ME/CFS\n\nAlso see the main section on managing ME/CFS.\n\nAlso see the main section on energy management.\n\nRefer people with severe or very severe ME/CFS to a physiotherapist or occupational therapist working in an ME/CFS specialist team for support on developing energy management plans.\n\nWhen agreeing energy management plans with people with severe or very severe ME/CFS (and their family or carers, as appropriate), take into account the need to make any changes in activity smaller and any increases (if possible) much slower.\n\n## Symptom management\n\nAlso see the main section on symptom management for people with ME/CFS.\n\nRefer people with severe or very severe ME/CFS for a dietetic assessment by a dietitian with a special interest in ME/CFS.\n\nMonitor people with severe or very severe ME/CFS who are at risk of malnutrition or unintentional weight loss because of:\n\nrestrictive diets\n\npoor appetite, for example linked with altered taste, smell and texture\n\nfood intolerances\n\nnausea\n\ndifficulty swallowing and chewing.Follow the recommendations on screening for malnutrition and indications for nutrition support, in the NICE guideline on nutrition support for adults.\n\nGive advice to support people with severe or very severe ME/CFS, which could include:\n\neating little and often\n\nhaving nourishing drinks and snacks, including food fortification\n\nfinding easier ways of eating to conserve energy, such as food with softer textures\n\nusing modified eating aids, particularly if someone has difficulty chewing or swallowing\n\noral nutrition support and enteral feeding.\n\n## Cognitive behavioural therapy\n\nHealthcare professionals delivering CBT to people with severe or very severe ME/CFS should adjust the process and pace of CBT to meet the person's needs. This might include shorter, less frequent sessions and longer-term goals.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on care for people with severe or very severe ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: information, education and support for people with ME/CFS and their families and carers\n\nappendix\xa01: involving children and young people\n\nevidence review\xa0B: information, education and support for health and social care professionals\n\nevidence review\xa0C: accessing health and social care services\n\nevidence review\xa0G: non-pharmacological management of ME/CFS\n\nevidence review\xa0I: multidisciplinary care\n\nevidence review\xa0J: monitoring and reviewing people with ME/CFS.\n\nOther supporting evidence and discussion can be found in evidence review\xa0A: information, education and support for people with ME/CFS and their families and carers and appendix\xa02: involving adults with severe ME/CFS.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nFor other definitions, see the NICE glossary and the Think Local, Act Personal Care and Support Jargon Buster.\n\n## Activity\n\nAny effort that uses energy, which includes cognitive, emotional and social activity as well as physical activity. Different activities combine and interact to cause a cumulative impact for the person.\n\n## Advocate\n\nIn this guideline, the role of an advocate is to support a vulnerable or disadvantaged person with ME/CFS and ensure that their rights are being upheld in a health and social care context. They are chosen by the person with ME/CFS and could be a family member, carer, friend or an independent advocate. They make sure that the person is heard.\n\n## Care and support plan\n\nThe personalised collaborative care and support plan is developed by the ME/CFS specialist team based on a holistic assessment. It is the basis for other assessments and plans in areas such as social care, energy management, physical activity, physical functioning and mobility, cognitive behavioural therapy and dietary management.\n\n## Carers\n\nIn this guideline, a carer refers to someone who provides unpaid care and support to a family member, partner or friend with ME/CFS. This is distinct from care workers who are employed to provide support.\n\n## Children and young people\n\nIn this guideline, children and young people are aged under\xa018 (adults are 18\xa0and above).\n\n## Energy limit\n\nThe amount of energy a person has to do all activities without triggering an increase or worsening of their symptoms.\n\n## Energy management\n\nA self-management strategy that involves a person with ME/CFS managing their activities to stay within their energy limit, with support from a healthcare professional.\n\n## Exercise\n\nExercise is planned, structured, repetitive and purposeful activity focused on improvement or maintenance of 1\xa0or more components of physical fitness. Exercise is a subcategory of physical activity.\n\n## Fatigue\n\nFatigue in ME/CFS typically has the following components:\n\nfeeling flu-like, especially in the early days of the illness\n\nrestlessness or feeling 'wired but tired'\n\nlow energy or a lack of physical energy to start or finish activities of daily living and the sensation of being 'physically drained'\n\ncognitive fatigue that worsens existing difficulties\n\nrapid loss of muscle strength or stamina after starting an activity, causing for example, sudden weakness, clumsiness, lack of coordination, and being unable to repeat physical effort consistently.\n\n## Flare-up\n\nA worsening of symptoms, more than would be accounted for by normal day-to-day variation, that affects the person's ability to perform their usual activities. Flare‑ups may occur spontaneously or be triggered by another illness, overexertion or other triggers. Flare‑ups usually occur as part of post-exertional malaise but it is possible for other symptoms, such as pain, to flare-up without post-exertional malaise. The worsening of symptoms is transient and flare‑ups typically resolve after a few days, either spontaneously or in response to temporary changes in energy management or a change in treatment. A relapse lasts longer than a flare‑up.\n\n## Graded exercise therapy\n\nIn this guideline, graded exercise therapy is defined as establishing a baseline of achievable exercise or physical activity and then making fixed incremental increases in the time spent being physically active. It is a therapy based on the deconditioning and exercise avoidance theories of ME/CFS. These theories assume that ME/CFS is perpetuated by reversible physiological changes of deconditioning and avoidance of activity. These changes result in the deconditioning being maintained and an increased perception of effort, leading to further inactivity. This definition of graded exercise therapy reflects the descriptions of it included in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\n## ME/CFS specialist team\n\nThese teams consist of a range of healthcare professionals with expertise in assessing, diagnosing, treating and managing ME/CFS. They commonly have medically trained clinicians from a variety of specialisms (including rheumatology, rehabilitation medicine, endocrinology, infectious diseases, neurology, immunology, general practice and paediatrics) as well as access to other healthcare professionals specialising in ME/CFS. These may include physiotherapists, exercise physiologists, occupational therapists, dietitians, and clinical or counselling psychologists. Children and young people are likely to be cared for under local or regional paediatric teams that have experience working with children and young people with ME/CFS in collaboration with ME/CFS specialist centres.\n\n## Orthostatic intolerance\n\nA clinical condition in which symptoms such as light-headedness, near-fainting or fainting, impaired concentration, headaches, dimming or blurring of vision, forceful beating of the heart, palpitations, tremulousness and chest pain occur or worsen on standing up and are improved (although not necessarily resolved) by sitting or lying down. Orthostatic intolerance may include postural orthostatic tachycardia syndrome (POTS), which is a significant rise in pulse rate when moving from lying to standing, and postural hypotension, which is a significant fall in blood pressure when moving from lying to standing. People with severe orthostatic intolerance may find they are unable to sit up for any length of time.\n\n## Physical activity\n\nAny bodily movement produced by skeletal muscles that results in energy expenditure. It should not be confused with exercise. Physical activity in daily life can be categorised into occupational, sports, conditioning, household or other activities, and can be done during leisure time, to get around or as part of a person's work. See World Health Organization advice on physical activity. Physical activity has a health benefit for most people and many conditions, but in people with ME/CFS, physical activity may make their symptoms worsen.\n\n## Physical functioning and mobility\n\nThe process of incorporating into daily activities a level of movement that helps to maintain joint and muscle flexibility without worsening symptoms of ME/CFS. This aims to support people to have as much independence as possible in their activities, ranging from personal hygiene to activities of daily living, working and social interaction. Such movement is undertaken within the person's energy limits and avoids pushing through their boundaries of tolerance.\n\n## Post-exertional malaise\n\nThe worsening of symptoms that can follow minimal cognitive, physical, emotional or social activity, or activity that could previously be tolerated. Symptoms can typically worsen 12\xa0to 48\xa0hours after activity and last for days or even weeks, sometimes leading to a relapse. Post-exertional malaise may also be referred to as post-exertional symptom exacerbation.\n\n## Relapse\n\nA sustained and marked exacerbation of symptoms lasting longer than a flare‑up and needing a substantial and sustained adjustment to the person's energy management. It may not be clear in the early stages of a symptom exacerbation whether it is a flare‑up or a relapse. Relapses can lead to a long-term reduction in the person's energy limits.\n\n## Special interest in ME/CFS\n\nA special interest in ME/CFS refers to a healthcare professional who is not working in an ME/CFS specialist team service but has knowledge and experience in this area.\n\n## Therapy blueprint\n\nThis summarises the therapy and provides a basis for future independent self-management. The blueprint may include the therapy formulation, strategies that have been helpful, 'warning signs' and triggers of flare‑ups and how to manage them, and goals for the future. It is important that the therapy blueprint is led by the person themselves and is in their own words, supported by guidance from the therapist.\n\n## Unrefreshing sleep\n\nUnrefreshing sleep means sleep that is non-restorative. Even after a full night's sleep, people do not feel refreshed. People with ME/CFS often report waking up exhausted and feeling as if they have not slept at all, no matter how long they were asleep.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Diagnostic tests\n\nWhat diagnostic tests are clinically and cost effective in people with suspected myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS)?\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on suspecting ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: identifying and diagnosing ME/CFS.\n\nLoading. Please wait.\n\n## A core outcome set\n\nWhat core set of relevant health outcome measures should be used for trials of treatments for ME/CFS and managing symptoms of ME/CFS?\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on managing ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Diagnostic criteria\n\nIn people with suspected ME/CFS, how effective is the NICE 2021 consensus-based diagnostic criteria in identifying people with ME/CFS?\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on suspecting ME/CFS\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: identifying and diagnosing ME/CFS.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Self-monitoring management strategies\n\nWhat is the clinical and cost effectiveness of self-monitoring strategies and techniques in guiding energy management?\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on energy management\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Sleep management strategies\n\nWhat is the clinical and cost effectiveness of sleep management strategies in managing ME/CFS?\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on rest and sleep\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.\n\n## Dietary strategies\n\nWhat is the clinical and cost effectiveness of dietary strategies in managing ME/CFS?\n\nFor a short explanation of why the committee made this recommendation, see the rationale section on dietary management and strategies\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: non-pharmacological management of ME/CFS.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Principles of care for people with ME/CFS\n\nRecommendations 1.1.1 to 1.1.6\n\n## Why the committee made the recommendations\n\nCommon themes across the qualitative evidence showed a lack of belief about myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) as a real condition by health and social care professionals, and a lack of understanding about what it is and the impact it has. The committee used this evidence to make recommendations to raise awareness about ME/CFS. One strong theme showed how experiencing a lack of understanding and prejudice can lead to people losing trust in health and social care services. The committee agreed that health and social care professionals need to take into account the impact of not being believed when building relationships with people with ME/CFS and their families. The committee considered this particularly relevant to children and young people and made separate recommendations highlighting communication with children.\n\nThe evidence showed this loss of trust can be compounded when people with ME/CFS have negative experiences of healthcare services if they decline treatments that have been offered to them. This was a strong theme in the evidence for children and young people. The committee agreed that declining a specific treatment should not affect other areas of the person's care.\n\nThe qualitative evidence also showed that one of the barriers to good ME/CFS management was a late diagnosis and a lack of monitoring, and this reflected the committee's experience.\n\n## How the recommendations might affect practice\n\nThese overarching principles will improve consistency of best practice and do not need any additional resources to deliver.\n\nReturn to recommendations\n\n# Suspecting ME/CFS\n\nRecommendations 1.2.1 to 1.2.7\n\n## Why the committee made the recommendations\n\nThe committee took into account both the lack of evidence on diagnostic tests and the evidence that people value realistic advice about ME/CFS (particularly around diagnosis) when making the recommendation to explain how the condition is recognised.\n\nThe committee acknowledged there is ongoing discussion in the ME/CFS community about which diagnostic criteria should be used to identify and diagnose ME/CFS. The committee made a recommendation for key symptoms based on the evidence review of the current diagnostic criteria, but no 1\xa0set of criteria was agreed to be better overall. The factors influencing these discussions are the broadness of the inclusion criteria, the definition of some of the symptoms, and the usability of the criteria as a clinical tool. There are concerns that many of the existing criteria do not accurately identify people with or without ME/CFS. Based on both the evidence and their experience, the committee agreed that the Institute of Medicine's 2015 criteria had the best balance of inclusion and exclusion of all the reviewed criteria, but it needed to be adapted for optimal use. In particular, the committee felt that the 6‑month delay should be reduced so that management could start earlier, and that fatigue and post-exertional malaise should be defined clearly to make it easier to interpret the revised criteria.\n\nBased on their experience, the committee decided that a diagnosis of ME/CFS should be suspected if people have all 4\xa0key symptoms (debilitating fatigue, post-exertional malaise, unrefreshing sleep or sleep disturbance [or both], and cognitive difficulties) for a minimum of 6\xa0weeks in adults and 4\xa0weeks in children and young people. The committee agreed it would be unusual for an acute illness, including a viral illness, to persist longer than this in someone who has all 4\xa0key symptoms. They emphasised it is the combination and interaction of the symptoms that is critical in distinguishing ME/CFS from other conditions and illness.\n\nCurrently, because there are no validated diagnostic criteria for ME/CFS, this leads to confusion about which criteria to use. The committee agreed to make a recommendation for research on diagnostic criteria to inform future guidance.\n\nIn addition to the 4\xa0key symptoms, the committee noted that many of the criteria used to define ME/CFS also include other symptoms that are commonly experienced by people with ME/CFS. They agreed that although these symptoms are not crucial to a diagnosis, they are important for understanding ME/CFS and helping to manage symptoms, so they made a recommendation to raise awareness of them.\n\nNo evidence was identified for any tests or specific signs and symptoms as predictors of a later diagnosis of ME/CFS. Accurate diagnostic tests that correctly identify ME/CFS will support healthcare professionals to identify people who have ME/CFS and rule out those who do not. The committee made a recommendation for research on diagnostic tests to help identify effective diagnostic tests for ME/CFS that will facilitate early diagnosis and potentially lead to better outcomes for people with ME/CFS. They hoped this research would inform future guidance.\n\nIn outlining key areas for assessment, the committee agreed that although they could not give a list of standard tests, it was important to carry out investigations to exclude other potential diagnoses. They listed some examples of tests that could be done to exclude reversible conditions with similar symptoms to ME/CFS and that are often missed.\n\nThe committee discussed the non-specific nature and common presentation of some ME/CFS symptoms (for example, cognitive difficulties such as brain fog), which make it difficult to diagnose and distinguish from other conditions. This has led to misdiagnosis, missed diagnosis, and delays in the diagnosis of ME/CFS and of other conditions. Because of this, the committee agreed it is important that when a healthcare professional suspects ME/CFS, they should also consider alternative explanatory diagnoses or coexisting conditions. They should investigate these and refer to an appropriate specialist if they are unsure. The committee also agreed that diagnosis can be reviewed if symptoms change or new symptoms emerge.\n\nThe evidence and the committee's experience suggested that managing symptoms early may prevent them getting worse and the person's health deteriorating. To reflect this, the committee recommended advice on symptom management for people as soon as ME/CFS is suspected.\n\nThe committee agreed that to avoid any disruption to education, once ME/CFS is suspected in a child or young person, their place of education should be contacted to advise about flexible adjustments or adaptations.\n\n## How the recommendations might affect practice\n\nThere is variation in practice and no single set of criteria is used clinically, with a 'mix and match' approach used alongside clinical experience. These recommendations will standardise practice and it is not believed they will have any impact on resource use or training.\n\nThere will be no change to the current practice of diagnosing ME/CFS based on clinical assessment and history and performing tests for differential diagnoses as appropriate.\n\nThe recommendations aim to raise awareness of symptoms and associated conditions that should raise suspicion of ME/CFS, particularly among healthcare professionals with limited knowledge about ME/CFS. This could increase the number of people with suspected ME/CFS who are then referred to an ME/CFS specialist team, but it will help to ensure they get appropriate care and better outcomes.\n\nThe recommendation that children and young people with suspected ME/CFS should be referred to a paediatrician after 4\xa0weeks is earlier than in current practice. However, referring earlier for further assessment will help children and young people to get appropriate care sooner by identifying and excluding other conditions as well as ME/CFS, improving their outcomes.\n\nReturn to recommendations\n\n# Advice for people with suspected ME/CFS\n\nRecommendations 1.3.1 and 1.3.2\n\n## Why the committee made the recommendations\n\nThere was limited clinical evidence on management strategies for people with suspected ME/CFS. The qualitative evidence and the committee's experience suggested that managing symptoms early may prevent them from getting worse and the person's health deteriorating. To reflect this, the committee made a recommendation to give people advice on symptom management drawn from their own knowledge and experience.\n\nThe qualitative evidence suggested this can be an anxious time for people with suspected ME/CFS and the committee agreed it was important for people to know who to contact if their symptoms change.\n\n## How the recommendations might affect practice\n\nProviding the advice in these recommendations would not impose a significant cost on the NHS. If this advice leads to fewer people with deteriorating symptoms, the recommendations would be highly cost effective.\n\nReturn to recommendations\n\n# Diagnosis\n\nRecommendations 1.4.1 to 1.4.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that although a 6‑month delay before diagnosis is built into the Institute of Medicine criteria, the criteria could be safely amended by reducing this period to 3\xa0months. The committee saw removing this delay as useful because it might enable earlier management and could potentially improve longer-term outcomes.\n\nReflecting the common theme across the evidence about a lack of knowledge of ME/CFS and evidence that non-specialists in ME/CFS are not confident about diagnosing and managing ME/CFS, the committee recommended referring people with ME/CFS to an ME/CFS specialist team at 3\xa0months to confirm their diagnosis and develop a care and support plan.\n\n## How the recommendations might affect practice\n\nThe duration of symptoms before diagnosis can take place has been reduced but the criteria are now stricter, requiring that 4\xa0different sets of symptoms are all present in order to suspect ME/CFS. The impact therefore will not necessarily be an increase in referrals but for people to receive their diagnosis earlier, which will bring forward their assessment and care plan. Earlier access to appropriate advice and care could prevent disease progression and therefore might lead to some resource savings in the longer term.\n\nReturn to recommendations\n\n# Assessment and care and support planning by an ME/CFS specialist team\n\nRecommendations 1.5.1 to 1.5.4\n\n## Why the committee made the recommendations\n\nThe committee agreed that the key to managing ME/CFS symptoms successfully is having a collaborative personalised care and support plan. This should be developed based on a holistic assessment as soon as the person's diagnosis is confirmed. The committee agreed that a medical assessment should be part of this assessment, typically requiring access to a medically trained clinician. A copy of the care and support plan can be shared with primary care and a copy held by the person themselves, and it can be referred to in situations such as planning an admission to hospital. In the committee's experience, this approach to assessment and planning is common in ME/CFS specialist teams.\n\nThe committee outlined key areas to assess what support might be needed, based on their experience. The committee noted that the key areas to assess and the support needed will depend on the person's severity of ME/CFS, the impact of their symptoms and their needs. Once the care and support plan is agreed, it then provides a basis for the more detailed assessments and plans outlined in specific interventions in the guideline, such as social care needs assessments, energy management, physical functioning and mobility, cognitive behavioural therapy (CBT) and dietary management.\n\n## How the recommendations might affect practice\n\nCarrying out a holistic assessment and developing a care and support plan is already current practice in ME/CFS specialist services, although there may be more referrals to the specialist service resulting from these recommendations. However, having a care and support plan will facilitate people's care and may lead to better outcomes. If assessment is carried out early and a care plan is implemented, it could reduce resource use in the longer term by preventing progression of disease.\n\nReturn to recommendations\n\n# Information and support\n\nRecommendations 1.6.1 to 1.6.11\n\n## Why the committee made the recommendations\n\nQualitative evidence showed that people with ME/CFS valued information from health and social care practitioners in formats that took into account the way symptoms such as 'brain fog' affected their capacity to take in and remember information. The committee highlighted formats that were reported as useful.\n\nThe evidence showed people with ME/CFS and their families and carers valued general information about ME/CFS that they could use themselves and share with others (families, friends, employers and practitioners), particularly around the time of diagnosis and the early stages of ME/CFS. This enabled them to develop accurate expectations about the future, relieve distress caused by the general lack of information and educate others. The evidence suggested people with ME/CFS wanted realistic information about what ME/CFS is and how it might affect them in the future, and this formed the basis of the recommendations outlining the key characteristics of ME/CFS.\n\nThe recommendation noting that the long-term outlook can be better in children and young people was based on the committee's experience.\n\nThe evidence supported the committee's view that information about ME/CFS and advice about other support is not easily available from health and social care services, and they agreed that people would benefit from information from local and national support groups.\n\nEvidence suggested that people with ME/CFS needed practical support, both for themselves and their carers. The committee considered that some people may have reservations about engaging with social care, after experiencing disbelief about their illness and the impact it has on their day-to-day functioning. For this reason, the committee emphasised the need for sensitivity when talking to people and their families about social care support.\n\nThe committee made recommendations signposting to different assessments and support that could be helpful. In their experience, health and social care professionals did not always know what support is available to families and carers of people with ME/CFS, so the committee also referred to the NICE guideline on supporting adult carers.\n\n## How the recommendations might affect practice\n\nThe recommendations are in line with the general principles for providing information already established in the existing NICE guideline on patient experience in the NHS and so were not considered likely to have any additional impact on practice.\n\nReturn to recommendations\n\n# Safeguarding\n\nRecommendations 1.7.1 to 1.7.6\n\n## Why the committee made the recommendations\n\nThe committee recognised that safeguarding is a particular issue in ME/CFS in a way that is different from other chronic illnesses and disabilities because people with ME/CFS commonly report that they are not believed. No evidence was identified on safeguarding in ME/CFS, but the committee agreed it was very important to make recommendations based on consensus. The recommendations address some of the misconceptions on this topic and highlight the need for expertise in ME/CFS when carrying out safeguarding assessments.\n\nThe committee emphasised the need for frequent review of children and young people with ME/CFS (in line with recommendations 1.15.2 and 1.15.3). The importance of appropriate review is also highlighted in the NICE guidelines on child maltreatment and child abuse and neglect.\n\nThe committee noted that although safeguarding is not solely about children and young people, most of the concerns they were aware of related to children and young people with ME/CFS so they made separate recommendations for this group.\n\n## How the recommendations might affect practice\n\nThe recommendations will improve consistency of best practice and do not need any additional resources to deliver.\n\nReturn to recommendations\n\n# Access to care and support\n\nRecommendations 1.8.1 to 1.8.9\n\n## Why the committee made the recommendations\n\nThe evidence showed that people with ME/CFS can have difficulty using healthcare services, particularly because of physical accessibility and the time constraints of appointments. This can make it more difficult to get the support and treatment they need. The committee were also aware that common sensitivities in ME/CFS, such as to light and sound, can make it challenging to travel to and attend appointments and to receive inpatient care. The committee made recommendations to improve access to care based on these potential barriers.\n\nThe committee discussed the unpredictable and fluctuating nature of ME/CFS and the risk that people will be discharged from a service if they miss appointments when their symptoms worsen. They made a recommendation based on consensus to address the lack of awareness about this in health and social care services.\n\nThere was limited evidence directly addressing the barriers and facilitators to accessing social care. However, the committee agreed this was an important area of care and they could draw conclusions from the evidence on healthcare and use their own experience to make recommendations.\n\nME/CFS can affect a person's ability to carry out activities of daily living and maintain their independence and quality of life. The committee agreed that everyone with ME/CFS should be asked how their symptoms affect their independence and then a social care needs assessment carried out if necessary. Using their experience, the committee outlined the topics for assessment and discussion.\n\nThe committee also made further recommendations based on their own knowledge and experience, including that:\n\nmany families and carers do not know the most appropriate ways to support someone with ME/CFS and need advice on this\n\npeople with ME/CFS often have difficulty getting the equipment they need to support their activities of daily living and maintain their quality of life.\n\n## How the recommendations might affect practice\n\nSome of these recommendations might need extra staff time or other healthcare resource use, for example to offer flexible appointments and home visits, make adjustments during inpatient stays and provide access to aids and adaptations. However, for equity reasons, people with ME/CFS need the same access to healthcare and support as other NHS patients that is commensurate with the severity of their illness.\n\nReturn to recommendations\n\n# Supporting people with ME/CFS in work, education and training\n\nRecommendations 1.9.1 to 1.9.6\n\n## Why the committee made the recommendations\n\nThe evidence showed a lack of support with education and training for children and young people with ME/CFS and their families and carers, and this can result in some children or young people leaving education. This reflected the committee's experience and they agreed that many of the themes in the evidence could also be applied to people in work.\n\nThe common theme of lack of knowledge and understanding about ME/CFS was echoed in this evidence with a lack of awareness about the impact that a high-stimulus environment (such as a school) can have on someone with ME/CFS. There was a lack of understanding about the need for a flexible approach to education with possible adjustments. The committee agreed that better communication between health and social care professionals and training and education services is key to develop a shared understanding of the needs and impairments of people with ME/CFS and how to provide them with appropriate educational support.\n\n## How the recommendations might affect practice\n\nThe recommendations will improve consistency of best practice and do not need any additional resources to deliver.\n\nReturn to recommendations\n\n# Multidisciplinary care\n\nRecommendations 1.10.1 to 1.10.5\n\n## Why the committee made the recommendations\n\nThere was limited evidence on the composition of a multidisciplinary team, but based on their experience, the committee agreed that good care for people with ME/CFS results from access to an integrated team of health and social care professionals who are trained and experienced in diagnosing and managing ME/CFS.\n\nThe fluctuating nature of ME/CFS means that people's support needs can change, so access to different expertise is needed at different times. The committee agreed that medical assessment and diagnosis would typically require access to an ME/CFS specialist physician or a GP with a special interest in ME/CFS. The committee agreed to make recommendations on providing a coordinated multidisciplinary approach and to identify the expertise that should be available.\n\nIn the committee's experience, care for most people with ME/CFS can be managed in primary care after their diagnosis is confirmed and they have a care and support plan agreed. However, the committee acknowledged the lack of confidence that non-specialists can have in managing ME/CFS and they recommended support from an ME/CFS specialist team.\n\nThe qualitative evidence showed that people with ME/CFS valued continuity of care and the committee agreed that having a single point of contact in their care team would avoid needing to have contact and appointments with multiple professionals which, for some people, could worsen their health.\n\n## How the recommendations might affect practice\n\nThe recommendations on the ME/CFS specialist multidisciplinary team, providing a named contact and giving support to primary care services may need resources. Current provision of ME/CFS specialist teams is very uneven across the country and increased staffing may be needed in some areas if there are more referrals. The specialist team will need to cover different areas of expertise, but most people will only need access to some elements and only at specific times. However, faster access to diagnosis and appropriate care should lead to better symptom management and to substantially better outcomes for people with ME/CFS and so might reduce health and care costs in the longer term.\n\nAllocating a single point of contact to people with ME/CFS is not routine practice across the NHS. This could be implemented differently in different regions according to local service structures and may not necessarily need the addition of new staff. It could improve the efficiency of care for people with ME/CFS by reducing the burden of repeated appointments.\n\nReturn to recommendations\n\n# Managing ME/CFS\n\nRecommendation 1.11.1\n\n## Why the committee made the recommendation\n\nOverall, the evidence for non-pharmacological and pharmacological interventions for ME/CFS was heterogenous and inconclusive, with limited evidence for any single intervention, and this supported the committee's experience. The committee were aware of claims that have been made about cures for ME/CFS and that there is often a financial cost to people with ME/CFS when they pursue these. To address this, the committee agreed to raise awareness in the recommendations of the current lack of a cure for ME/CFS.\n\nThere is considerable controversy over the outcome measures used in trials of treatments for ME/CFS and managing symptoms. Inconsistency in outcomes used and concerns over the validity of some outcome measures in an ME/CFS population makes it difficult to combine and compare results from different trials, limiting the ability to draw conclusions on the clinical and cost effectiveness of interventions. The committee made a recommendation for research on core outcome sets to enable the direct comparison of treatments for ME/CFS and symptom management and to shape and optimise ME/CFS trial design.\n\n## How the recommendation might affect practice\n\nThe recommendations reflect current practice so no effect on resources is anticipated.\n\nReturn to recommendation\n\n# Energy management\n\nRecommendations 1.11.2 to 1.11.8\n\n## Why the committee made the recommendations\n\nThe committee discussed how the controversy over graded exercise therapy had resulted in confusion over what support should be available to people with ME/CFS to safely manage their level of activity, including physical activity or exercise. They agreed it was important to provide clarity of information and clear guidance around energy management, physical activity and exercise to people with ME/CFS. The committee also agreed people need clear information about services available to them to support the development of energy management plans.\n\nBased on their experience, the committee agreed that energy management is one of the most important tools that people with ME/CFS have to support them in living with the symptoms of ME/CFS. They agreed that people with ME/CFS should have access to support from an ME/CFS specialist team to develop a plan for energy management.\n\nThe committee listed the components of energy management and what an assessment and plan would include, noting that the key component is understanding the principle of using energy in a way to minimise post-exertional malaise. They recommended a detailed assessment that takes into account all areas of current activity and evaluation of rest and sleep, to establish an individual activity pattern within the person's current energy limit. The committee noted that energy management is not a physical activity or exercise programme, although the principles of energy management do apply to physical activity and exercise programmes.\n\nTo avoid potential harms by energy management being wrongly applied to people with ME/CFS without adequate support and expertise, the committee recommended that in specific circumstances, people with ME/CFS should be referred to a physiotherapist or occupational therapist in an ME/CFS specialist team.\n\nThere was a lack of effectiveness evidence on strategies and tools to support people to self-monitor activity management. The committee considered the qualitative evidence and their own experience of the benefits of using strategies and tools to monitor activity alongside the potential harms of increasing the burden on the person and causing them additional anxiety about their activity levels. The committee decided to recommend that activity recording should be as easy as possible, and people should take advantage of tools they are already using. The committee also decided to make a recommendation for research on self-monitoring management strategies to help determine which strategies and techniques are effective.\n\n## How the recommendations might affect practice\n\nThe energy management plan forms part of the care and support plan and is part of ME/CFS specialist care. Appropriate energy management supports people to stay within their energy limits and aims to prevent their symptoms from worsening. It also supports them to increase their activity if possible. If this helps people maintain or improve their health this will be highly cost effective.\n\nReturn to recommendations\n\n# Incorporating physical activity and exercise\n\nRecommendations 1.11.9 to 1.11.16\n\n## Why the committee made the recommendations\n\nThe committee agreed that clarity of information and clear guidance on energy management in relation to all activity should be available to people with ME/CFS. The committee also agreed that people need clear information about services available to them, and particularly the specific circumstances in which a personalised physical activity or exercise programme could be considered by a person with ME/CFS.\n\nIn the committee's experience, people with ME/CFS have had varying results from physical activity and exercise programmes. The committee agreed it was important to discuss this with people with ME/CFS and to explain to them the possible risks and benefits.\n\nBecause of the harms reported by people with ME/CFS in the qualitative evidence, as well as the committee's experience of the effects when people exceed their energy limits, the committee recommended that people with ME/CFS should not undertake a physical activity or exercise programme unless it is overseen by a physiotherapist who has training and expertise in ME/CFS.\n\nThe committee outlined what a personalised physical activity or exercise programme should, and should not, include. In developing recommendations on the content, approach and delivery of physical activity and exercise programmes, the committee considered the benefits and harms associated with graded exercise therapy that had been reported with ME/CFS across the quantitative and qualitative evidence, alongside their own experiences. They recognised that different definitions of the term 'graded exercise therapy' are used, and as a result the content and application of graded exercise therapy programmes differ. This has resulted in confusion. Taking into account descriptions of graded exercise therapy in the evidence they reviewed, the committee included a definition in this guideline to clarify what graded exercise therapy is intended to mean in the recommendation.\n\nThe committee concluded any programme using fixed incremental increases in physical activity or exercise (for example, graded exercise therapy), or physical activity or exercise programmes that are based on deconditioning and exercise avoidance theories, should not be offered to people with ME/CFS. The committee also wanted to reinforce that there is no therapy based on physical activity or exercise that is effective as a cure for ME/CFS.\n\nFor people with ME/CFS who do choose to take part in a physical activity or exercise programme, this should follow the principles set out in this section and the energy management section.\n\n## How the recommendations might affect practice\n\nThese recommendations should prevent inappropriate or unstructured physical activity or exercise programmes from worsening people's symptoms. The referral to a physiotherapist or occupational therapist in an ME/CFS specialist team may need increased resources. However, this should not impose a significant cost on the NHS and if it leads to fewer people with deteriorating symptoms, it will be highly cost effective.\n\nReturn to recommendations\n\n# Rest and sleep\n\nRecommendations 1.12.1 to 1.12.4\n\n## Why the committee made the recommendations\n\nThe committee considered that giving advice on planning rest and activity was a fundamental part of any management strategy. In their experience, understanding the role of rest and how to introduce rest periods was important in successful energy management.\n\nThere was a lack of evidence for sleep management, but the committee recognised that difficulty with sleep was an area of concern for many people with ME/CFS. The committee discussed making recommendations based on consensus for providing advice for people with ME/CFS and agreed they could recommend general advice for sleep management. They noted that there are common sleep patterns in people with ME/CFS that need to be considered when giving advice about sleep management. In addition, they made a recommendation for research on sleep management strategies.\n\n## How the recommendations might affect practice\n\nThe recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.\n\nReturn to recommendations\n\n# Physical functioning and mobility\n\nRecommendations 1.12.5 to 1.12.8\n\n## Why the committee made the recommendations\n\nThe committee discussed that people with ME/CFS can have reduced or limited mobility and, in their experience, this can lead to health problems. Physical functioning and mobility should therefore be assessed and included in the person's care and support plan.\n\nThe committee agreed that people with ME/CFS who are immobile need information to help them recognise and prevent the possible complications of long-term immobility, for example in relation to bone health and skin problems. In the committee's experience, families and carers are given only limited information about these areas of care (for example, how to transfer someone from a bed to a chair) and it would have helped them.\n\n## How the recommendations might affect practice\n\nThe recommendations are already established in other NICE guidance and should not impose a significant cost on the NHS. If they lead to fewer people with deteriorating symptoms, they will be highly cost effective.\n\nReturn to recommendations\n\n# Orthostatic intolerance\n\nRecommendations 1.12.9 to 1.12.11\n\n## Why the committee made the recommendations\n\nOrthostatic intolerance is identified as one of the symptoms commonly associated with, but not exclusive to, ME/CFS (see the section on suspecting ME/CFS). In the committee's experience, although not everyone with ME/CFS experiences orthostatic intolerance, it is very common and the symptoms can be hard to differentiate from other ME/CFS symptoms.\n\nBased on consensus, the committee made recommendations to raise awareness that people with ME/CFS may experience orthostatic intolerance, and to clarify when people with orthostatic intolerance should be referred to secondary care.\n\nThe committee did not make any recommendations on managing orthostatic intolerance because this can involve advice on diet, daily activities and activity support and needs to be tailored to each person, taking into account their other ME/CFS symptoms.\n\nThe committee recommended that medicines should only be prescribed or overseen by a clinician with expertise in orthostatic intolerance because the medicines that are usually prescribed can worsen other symptoms in people with ME/CFS.\n\n## How the recommendations might affect practice\n\nThe recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.\n\nReturn to recommendations\n\n# Pain\n\nRecommendations 1.12.12 to 1.12.14\n\n## Why the committee made the recommendations\n\nPain is identified as one of the symptoms commonly associated with, but not exclusive to, ME/CFS (see the section on suspecting ME/CFS). The committee agreed that pain is a common symptom in people with ME/CFS and is particularly intense in people with severe or very severe ME/CFS. The lack of evidence meant they could not recommend any interventions, but they did refer to the NICE guidelines on neuropathic pain and headaches. The committee also made consensus-based recommendations to raise awareness about pain in ME/CFS and what action to take.\n\n## How the recommendations might affect practice\n\nThe recommendation referring to other NICE guidance should not have a resource impact as those recommendations are already established. The other recommendations should not impose a significant cost on the NHS and if they lead to fewer people deteriorating then they would be highly cost effective.\n\nReturn to recommendations\n\n# Medicines\n\nRecommendations 1.12.15 to 1.12.18\n\n## Why the committee made the recommendations\n\nThe evidence for any pharmacological interventions for ME/CFS was inconclusive, with limited evidence for any one medicine, and this supported the committee's experience. The committee were aware of claims that have been made about cures for ME/CFS and there is often a financial cost to people with ME/CFS when these are pursued. The committee considered it was important to highlight that medicines or supplements should not be offered as a cure for ME/CFS.\n\nThe committee recognised that medicines can be useful for people with ME/CFS to manage their symptoms. The committee agreed that people with ME/CFS may be more intolerant of drug treatment, so they decided to raise awareness of this. To reduce the risk of harm, the committee discussed using a cautious approach to medicines prescribing, which includes starting the medicine at a lower dose than in usual clinical practice and monitoring how the person's symptoms respond before adjusting the dose.\n\nThe committee discussed medicines management for children and young people, noting the potential for harm, which led them to recommend that prescribing should be initiated under the supervision of a paediatrician with expertise in ME/CFS.\n\n## How the recommendations might affect practice\n\nThe recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.\n\nReturn to recommendations\n\n# Dietary management and strategies\n\nRecommendations 1.12.19 to 1.12.26\n\n## Why the committee made the recommendations\n\nThere was not enough evidence to make a recommendation for a particular dietary strategy for ME/CFS. However, the committee agreed some general recommendations to ensure that people with ME/CFS get appropriate support related to diet. This included guidance on when to refer someone to a dietitian with a special interest in ME/CFS. The committee also referred to other relevant NICE guidance.\n\nThe committee recognised that difficulties with diet and nutrition was an area of concern for many people with ME/CFS. They discussed making consensus-based recommendations for providing dietary strategies for people with ME/CFS, but they agreed it was hard to be confident in making recommendations when there was no evidence and a lack of consensus in the area, so they made a recommendation for research on dietary strategies.\n\n## How the recommendations might affect practice\n\nThe recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.\n\nReturn to recommendations\n\n# Lightning Process\n\nRecommendation 1.12.27\n\n## Why the committee made the recommendation\n\nThe committee discussed the limited evidence on the Lightning Process. They acknowledged that although some benefit was demonstrated and aspects of it, such as goal setting, practical examples and applications and peer support, were found to be helpful, the qualitative evidence on people's experiences of the therapy varied and raised some concerns. In the qualitative evidence, some people reported negative experiences to do with the confusing nature of the educational component, the intensity of the sessions, and the secrecy surrounding the therapy. While in the SMILE trial children under 16 were accompanied by parents, the committee were particularly concerned about the reported secrecy of the Lightning Process in the qualitative evidence and the lack of public information on the implementation of the process in practice. The committee agreed the transparency of any intervention is important and noted that in the qualitative evidence it was reported that people had been specifically encouraged not to talk about the therapy. The committee agreed this was an inappropriate and unusual message to give, particularly to children and young people.\n\nThe committee discussed concerns that the Lightning Process encourages people with ME/CFS to ignore and 'push through' their symptoms and this could potentially cause harm. In the qualitative evidence, some participants reported they had received advice they could do what they wanted. The committee noted they had made clear recommendations on the principles of energy management and this advice appears at odds with these principles.\n\nOverall, the committee considered there was a lack of clarity around the implementation of the Lightning Process in practice and some concerning issues raised in the qualitative evidence. As a result, the committee agreed the Lightning Process should not be offered to people with ME/CFS.\n\n## How the recommendation might affect practice\n\nThe Lightning Process is not offered as part of current practice so this recommendation will maintain current practice.\n\nReturn to recommendation\n\n# Cognitive behavioural therapy\n\nRecommendations 1.12.28 to 1.12.34\n\n## Why the committee made the recommendations\n\nThe quantitative and qualitative evidence was mixed for adults, children and young people, and this reflected the committee's experience. Based on criticisms in the qualitative evidence of cognitive behavioural therapy (CBT) being described as a 'treatment' (cure) for ME/CFS, the committee considered it was important to highlight that CBT is not a cure for ME/CFS and should not be offered as such. Instead, it aims to improve wellbeing and quality of life, and may be useful in supporting people who live with ME/CFS to manage their symptoms and reduce the distress associated with having a chronic illness. It should therefore only be offered in this context, and after people have been fully informed about its principles and aims. The committee agreed if a child or young person would like to use CBT, it was important to adapt the therapy taking into account their cognitive and emotional maturity.\n\nThe qualitative evidence showed that people with ME/CFS have found CBT useful when delivered by a therapist who understands ME/CFS, but also that there is the potential for harm when it is inappropriately delivered. To avoid this, the committee made the recommendation about who should deliver CBT and the clinical supervision they should have.\n\nThe committee also made recommendations based on their experience to explain the principles of CBT for people with ME/CFS and what people should expect if they decide to consider CBT.\n\n## How the recommendations might affect practice\n\nCBT is currently provided for people with ME/CFS in specialist ME/CFS services. The recommendations clarify when CBT should be offered to people with ME/CFS. They should not have an impact on NHS resource and costs.\n\nReturn to recommendations\n\n# Managing coexisting conditions\n\nRecommendations 1.13.1 to 1.13.4\n\n## Why the committee made the recommendations\n\nThe evidence on the diagnostic criteria identified that some conditions are common in people with ME/CFS and this reflected the committee's experience. The committee made recommendations to highlight this and referred to relevant NICE guidance.\n\n## How the recommendations might affect practice\n\nThe recommendations should not impose a significant cost on the NHS.\n\nReturn to recommendations\n\n# Managing flare-ups in symptoms and relapse\n\nRecommendations 1.14.1 to 1.14.8\n\n## Why the committee made the recommendations\n\nIn the committee's experience, flare‑ups and relapse are a common part of ME/CFS. The committee considered it important to give people information about what a flare‑up is, how to recognise one and how they can lead to a relapse if activity is not monitored and adjusted.\n\nThe committee discussed the importance of recognising when a flare‑up has moved to a relapse and that it needs to prompt a review of their care and support plan. It is also possible that a relapse may lead to someone moving to a more severe form of ME/CFS. Part of the review of the care and support plan is to consider what the causes of relapse might have been and to consider this when revising the plan.\n\n## How the recommendations might affect practice\n\nThe recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.\n\nReturn to recommendations\n\n# Review in primary care\n\nRecommendations 1.15.1 to 1.15.10\n\n## Why the committee made the recommendations\n\nThe evidence showed that people with ME/CFS did not always receive follow‑up or review of their care, but those who did valued this. This reflected the committee's experience, so they recommended at least annual reviews for adults.\n\nThe committee agreed that children and young people need more frequent review to take into account changes in their ME/CFS as they develop. They also wanted to highlight the importance of involving a paediatrician.\n\nThe committee outlined areas for discussion during the review, including asking people how much support they had to carry out their activities of daily living. This was because, in the committee's experience, this is an area often overlooked and the input of family and carers is often not acknowledged. The committee noted that if any problems are identified, advice should be sought from an appropriate specialist.\n\n## How the recommendations might affect practice\n\nThere is variation in practice and some people with ME/CFS, including those with severe or very severe ME/CFS, do not get a clinical review routinely, so for some this will be a change in practice. These recommendations are in line with other long-term conditions and support equity of access to care for people with ME/CFS. Routine follow‑up might not be present everywhere but most people with ME/CFS already have regular contact with their primary care teams, so there is not expected to be a large resource impact.\n\nReturn to recommendations\n\n# Training for health and social care professionals\n\nRecommendation 1.16.1\n\n## Why the committee made the recommendation\n\nA strong theme in the evidence was the lack of knowledge, understanding and up-to-date training that health and social care professionals have about ME/CFS. This was reflected in the committee's experience, so they recommended that all health and social care staff who deliver care to people with ME/CFS should be trained so they are able to provide the care in this guideline.\n\n## How the recommendation might affect practice\n\nTraining and education in ME/CFS are not widespread and this will be a change in practice, so there will be a resource impact from the cost of providing this training. Improving knowledge and awareness about ME/CFS will support identifying ME/CFS earlier, which should improve people's care and lead to better outcomes.\n\nReturn to recommendation\n\n# Care for people with severe or very severe ME/CFS\n\nRecommendations 1.17.1 to 1.17.13\n\n## Awareness of severe and very severe ME/CFS and its impact\n\nPeople with severe or very severe ME/CFS were named as a group for special consideration in the guideline scope. Evidence relating to people with severe ME/CFS reinforced the committee's experience that this group of people are often neglected, and the severity of their symptoms misunderstood, and with every recommendation the committee considered whether different or additional recommendations were needed for this group. The rationale and impact sections for these recommendations are below. These additional considerations for people with severe or very severe ME/CFS were placed in a separate section to make sure they could be easily found within the guideline.\n\nReturn to recommendations\n\n## Assessment and care and support planning by an ME/CFS specialist team\n\nBased on the evidence about problems with accessing services, the committee made a recommendation for a home visit to people with severe or very severe ME/CFS to carry out the assessment.\n\nThere may be an increased number of home visits for people with severe or very severe ME/CFS. However, this will provide equity of access to care for this group who are usually housebound.\n\nReturn to recommendation\n\n## Access to care and support\n\nThe committee were aware that difficulties accessing care are intensified in people with severe or very severe ME/CFS, particularly when they need hospital care. The evidence showed that as a result of this, some people with severe or very severe ME/CFS have little contact and support from health and social care services. To address this, the committee highlighted the flexibility and specific support needed by people with severe or very severe ME/CFS.\n\nThere may be an increased number of home visits for people with severe or very severe ME/CFS. However, this will provide equity of access to care for this group who are usually housebound. Some of these costs may be offset by the ability to provide online consultations when appropriate. The emphasis in this guideline on timely diagnosis and referral to an ME/CFS specialist team for a personalised care and support plan aims to minimise the number of people who may progress to severe ME/CFS.\n\nReturn to recommendations\n\n## Energy management\n\nThe committee agreed that if energy management strategies are inappropriately applied in people with severe or very severe ME/CFS, this will increase the potential for harm. To reflect this, they recommended specialist physiotherapy advice and additional care for people with severe or very severe ME/CFS who have chosen to develop an energy management plan.\n\nThe energy management plan forms part of the care and support plan and is a usual part of ME/CFS specialist care. Appropriate energy management supports people to stay within their energy limits and aims to prevent their symptoms from worsening. It also supports them to increase their activity if possible. If this helps people maintain or improve their health, this will be highly cost effective.\n\nReturn to recommendations\n\n## Dietary management and strategies\n\nThe committee considered that people with severe or very severe ME/CFS are particularly at risk of problems associated with eating and are likely to need additional support and referral to a dietitian who has a special interest in ME/CFS. The committee also used their own experience to recommend some general dietary advice that could be helpful for people with severe or very severe ME/CFS.\n\n## How the recommendations might affect practice\n\nThe recommendations should not impose a significant cost on the NHS and if they lead to fewer people with deteriorating symptoms, they will be highly cost effective.\n\nReturn to recommendations\n\n## Cognitive behavioural therapy\n\nNone of the clinical evidence included or reflected the needs of people with severe or very severe ME/CFS, and the qualitative evidence was mixed, with some people reporting benefit and others harm. The committee recognised that CBT could be supportive for people with severe or very severe ME/CFS in some circumstances, but because of the severity of their symptoms, it is important to be more flexible and adapt the delivery of CBT to accommodate people's limitations.\n\nCBT is currently provided for people with ME/CFS in specialist ME/CFS services. The recommendations clarify when CBT should be offered to people with ME/CFS. They should not have an impact on NHS resource and costs.\n\nReturn to recommendation", 'Context': "The terms myalgic encephalomyelitis (ME; or encephalopathy), chronic fatigue syndrome (CFS), CFS/ME and ME/CFS have all been used for this condition and are not clearly defined. There is little pathological evidence of brain inflammation, which makes the term 'myalgic encephalomyelitis' problematic. Myalgic encephalomyelitis is classified under diseases of the nervous system in the SNOMED\xa0CT and ICD10 (G93.3). Many people with ME/CFS consider the name 'chronic fatigue syndrome' too broad, simplistic and judgemental. For consistency, the abbreviation ME/CFS is used in this guideline.\n\nRecent data from the UK Biobank suggest that there are over 250,000\xa0people in England and Wales with ME/CFS, with about 2.4\xa0times as many women affected as men. ME/CFS can affect people of all ages. It is a complex, multi-system, chronic medical condition that has considerable personal, social and economic consequences and a significant impact on a person's quality of life, including their psychological, emotional and social wellbeing.\n\nEveryday life for people with ME/CFS, their family and carers is disrupted and unpredictable. Many people with the condition are unemployed, and less than a fifth work full-time. Approximately 25% have severe disease and are housebound or bedbound. The quality of life of people with ME/CFS is lower than that of many people with other severe chronic conditions, including multiple sclerosis and some forms of cancer.\n\nIt is not clear what causes ME/CFS. In many cases, symptoms are thought to have been triggered by an infection but it is not simple post-illness fatigue. It lasts longer and even minimal mental or physical activity can make symptoms worse.\n\nThere is no diagnostic test or universally accepted definition for ME/CFS. People with the condition report delays in diagnosis, and many healthcare professionals lack the confidence and knowledge to recognise, diagnose and manage it. Fatigue associated with another chronic disease may be confused with ME/CFS and some practitioners are reluctant to positively diagnose ME/CFS when no other causes are found.\n\nPeople with ME/CFS report a lack of belief and acknowledgement from health and social care professionals about their condition and related problems, which may lead them to be dissatisfied with care and to disengage from services. There are added issues for children and young people if illness makes school attendance difficult, bringing families to the attention of educational and social care services.\n\nNICE produced a guideline on CFS/ME in 2007. That guideline made recommendations on cognitive behavioural therapy and graded exercise therapy. Both treatments are controversial for this condition, and there are disagreements and uncertainty about their effectiveness among both people with ME/CFS and health providers. The evidence for the effects of other commonly prescribed therapies has also been questioned.\n\nThere is unequal access to ME/CFS specialist services across England and Wales with some areas reporting very limited access. It is important this inequity of access is addressed."}
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https://www.nice.org.uk/guidance/ng206
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This guideline covers diagnosing and managing myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome (ME/CFS) in children, young people and adults. It aims to improve awareness and understanding about ME/CFS and when to suspect it, so that people are diagnosed earlier. It includes recommendations on diagnosis, assessment and care planning, safeguarding, access to care and managing ME/CFS and its symptoms.
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48ffea1018caa17ada8e04e974fa92fc4ac5f5e3
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nice
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Apalutamide with androgen deprivation therapy for treating high-risk hormone-relapsed non-metastatic prostate cancer
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Apalutamide with androgen deprivation therapy for treating high-risk hormone-relapsed non-metastatic prostate cancer
Evidence-based recommendations on apalutamide with androgen deprivation therapy for treating high-risk hormone-relapsed non-metastatic prostate cancer in adults.
# Recommendations
Apalutamide plus androgen deprivation therapy (ADT) is recommended, within its marketing authorisation, as an option for treating hormone‑relapsed non‑metastatic prostate cancer that is at high risk of metastasising in adults. High risk is defined as a blood prostate-specific antigen (PSA) level that has doubled in 10 months or less on continuous ADT. It is recommended only if the company provides apalutamide according to the commercial arrangement.
Why the committee made these recommendations
Hormone-relapsed non-metastatic prostate cancer is usually treated with ADT alone or with darolutamide plus ADT.
Clinical trial evidence suggests that, compared with placebo plus ADT, apalutamide plus ADT increases the time until the disease spreads and how long people live. The cost‑effectiveness estimates are within what NICE considers to be an acceptable use of NHS resources. So, apalutamide plus ADT is recommended.# Information about apalutamide
# Marketing authorisation indication
Apalutamide (Erleada, Janssen) is indicated 'in adult men for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price for apalutamide is £2,735 per pack of 112 tablets, each containing 60 mg of the active ingredient (excluding VAT; BNF online, March 2021). The company has a commercial arrangement (simple discount patient access scheme). This makes apalutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway
## Only 1 newer androgen receptor inhibitor would be used in the prostate cancer treatment pathway
NICE recommends the newer (second-generation) androgen receptor inhibitors enzalutamide plus androgen deprivation therapy (ADT), and darolutamide plus ADT, or abiraterone plus prednisone or prednisolone plus ADT (hereafter abiraterone in combination) for treating hormone-sensitive metastatic or hormone-relapsed non-metastatic prostate cancer at multiple positions in the treatment pathway:
NICE's technology appraisal guidance on darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer
NICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer
NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated
NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated
NICE's technology appraisal guidance on abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen
NICE's technology appraisal guidance on enzalutamide for metastatic hormone-relapsed prostate cancer previously treated with a docetaxel-containing regimen.People have treatment with a second‑generation androgen receptor inhibitor until disease progression, docetaxel for up to 6 cycles, and ADT indefinitely. Apalutamide is another second‑generation androgen receptor inhibitor. The Cancer Drugs Fund clinical lead explained that a person will have only 1 of these drugs in the NHS prostate cancer treatment pathway. The clinical experts confirmed that this is because of the similar way the drugs work, and probable resistance to drugs in the same group when used one after another. For example, if prostate cancer metastasises on apalutamide plus ADT, it would be expected to be resistant to subsequent treatment with enzalutamide plus ADT or abiraterone plus ADT. The Cancer Drugs Fund clinical lead confirmed that NHS England would not commission enzalutamide plus ADT or abiraterone plus ADT after apalutamide plus ADT. The committee concluded that in the NHS people with prostate cancer would be offered only 1 newer androgen receptor inhibitor.
# Clinical management
## People would value additional treatments for hormone-relapsed non-metastatic disease
Treatment for hormone-relapsed non-metastatic prostate cancer is ADT alone or darolutamide plus ADT. Treatment aims to delay metastasis, which is associated with reduced quality of life and survival. The patient experts explained that anxiety about cancer metastasising causes psychological distress, which adds to debilitating symptoms such as fatigue, pain, and urinary and bowel problems. Apalutamide plus ADT has more than one indication; the one being appraised is for treating hormone-relapsed non-metastatic prostate cancer that is at high risk of metastasising. This is the same indication appraised in NICE's technology appraisal guidance on enzalutamide and darolutamide plus ADT. But, NICE does not recommend enzalutamide for this population, and NICE had not yet recommended darolutamide at the start of this appraisal. So, as per NICE processes, darolutamide plus ADT was not considered a relevant comparator for decision making. The committee concluded that people with hormone-relapsed non-metastatic prostate cancer would value additional treatment options.
# Clinical evidence
## The SPARTAN results are in line with planned analyses
SPARTAN was a phase 3, randomised, multicentre trial comparing apalutamide plus ADT (n=806) with placebo plus ADT (n=401) for hormone‑relapsed non‑metastatic prostate cancer. The trial population had adenocarcinoma of the prostate that was hormone relapsed and at high risk of metastasis. High risk was defined as a blood prostate-specific antigen (PSA) doubling time of 10 months or less during continuous ADT before randomisation. The committee considered that the participants in SPARTAN reflected people in NHS clinical practice reasonably well. The primary endpoint of SPARTAN was metastases-free survival, that is, the time from randomisation to confirmed evidence of metastasis or death from any cause. The committee appreciated that this reflected progression-free survival, with metastases indicating progression. Secondary endpoints included overall survival. Exploratory endpoints included time to progression-free survival on the first subsequent treatment taken for metastatic disease (PFS2) and health‑related quality of life, measured using the EQ‑5D questionnaire and the Functional Assessment of Cancer Therapy Prostate Module (FACT‑P). PFS2 measures the time from metastasis to the next disease progression on the treatment that people have after the trial treatment. The committee was aware that although PFS2 and EQ‑5D were exploratory endpoints, the company used them in its cost-effectiveness modelling. The final analysis for metastases-free survival and an interim analysis for overall survival and PFS2 were done in May 2017. At this time, most people's cancer had metastasised and the metastases-free survival endpoint had been met. In May 2017, the trial was unblinded and people who had placebo plus ADT could cross over to have apalutamide plus ADT if their cancer had not metastasised. The final analyses of overall survival and PFS2 were done in February 2020. After progression to metastatic disease, people could have abiraterone plus prednisone or prednisolone (from now on referred to as abiraterone in combination) or enzalutamide as subsequent treatment, as well as other treatments (see section 3.1). The committee concluded that the results were in line with the trial's planned analyses.
## In SPARTAN, apalutamide plus ADT is clinically effective compared with placebo plus ADT
In SPARTAN:
median metastases-free survival for people randomised to apalutamide plus ADT was 40.5 months and for people randomised to placebo plus ADT it was 15.7 months (hazard ratio 0.30, 95% confidence interval 0.24 to 0.36)
median overall survival for people randomised to apalutamide plus ADT was 73.9 months and for people randomised to placebo plus ADT it was 59.9 months (hazard ratio 0.78, 95% CI 0.64 to 0.96)
median PFS2 for people randomised to apalutamide plus ADT was 55.6 months and for people randomised to placebo plus ADT it was 41.2 months (hazard ratio considered academic in confidence by the company so cannot be reported here)
mean change in EQ‑5D‑3L visual analogue score showed improvements in the apalutamide plus ADT arm compared with the placebo plus ADT arm at cycles 21 (mean difference 3.03) and 25 (mean difference 3.28), p<0.05.The committee concluded that apalutamide plus ADT extended metastases-free survival, overall survival, PFS2 and health-related quality of life when compared with placebo plus ADT, and was clinically effective.
## The modified RPSFTM is appropriate for decision making, but there is still uncertainty
The results for overall survival and PFS2 (reported as hazard ratios in SPARTAN) were adjusted to reflect the treatment effect that would be seen in NHS practice. This is because in the trial people randomised to:
placebo plus ADT crossed over to apalutamide plus ADT
apalutamide plus ADT went on to have abiraterone plus ADT or enzalutamide plus ADT.The committee discussed both situations. In SPARTAN, 76 people (19.0%) randomised to placebo plus ADT crossed over to apalutamide plus ADT. The company explained that this could underestimate the relative benefit of apalutamide plus ADT for overall survival and PFS2. This was because some people progressed or died only after the trial was unblinded (see section 3.3). However, the committee recognised that people with non‑metastatic disease in NHS practice who have ADT alone (as in the placebo plus ADT arm of SPARTAN) could have abiraterone in combination or enzalutamide as treatments after their disease had metastasised. This would mean that the trial endpoints may not need to be adjusted if these endpoints occurred after metastasis. The committee also recognised that, in the NHS, people can have only 1 newer androgen receptor inhibitor in the prostate cancer treatment pathway (see section 3.1). Because more people randomised to apalutamide had a second newer androgen receptor inhibitor, the trial results may have overestimated apalutamide plus ADT's apparent effectiveness on PFS2 and overall survival, if having a second newer androgen receptor inhibitor is beneficial. The company considered that the number of people who had a second newer androgen receptor inhibitor is academic in confidence and cannot be reported here. The clinical expert explained that having a second newer androgen receptor inhibitor is unlikely to extend life, but might be associated with adverse effects. The committee appreciated that this type of switching might not bias survival estimates, but it was possible that people could have had a better response to the treatment if they had not had a second newer androgen receptor inhibitor. The company considered several different methods for adjusting. These included the rank preserving structural failure time model (RPSFTM), iterative parameter estimation (IPE), inverse probability of censoring weights (IPCW) and 2‑stage estimation. The company chose to use a modified version of the RPSFTM (Diels et al. 2019). The company explained that it did not have enough data to estimate the multiple parameters needed for the RPSFTM and IPE methods, and the IPCW method provided counterintuitive and clinically implausible results. The company also said that the 2‑stage method was not viable because of the lack of data and the need for a 'secondary baseline' before changing to apalutamide plus ADT or having a second newer androgen receptor inhibitor. The committee questioned whether it was necessary to adjust the results because of the likely minimal effect of multiple lines of newer treatments. It appreciated that the modified RPSFTM appeared to be reasonable but it was more like a 2‑stage method using aspects of all the adjustment approaches, and propensity weighting. It also considered that the IPCW and 2‑stage methods could have been appropriate, if appropriately specified. So, at its first meeting the committee asked that the company explore alternative approaches. At consultation, the company explained that it did not have time to explore alternative approaches. It reiterated its view that the modified RPSFTM was the most appropriate method. The committee was disappointed that the company chose not to explore alternative approaches. But it noted that the adjusted and unadjusted results were similar, which reduced the risks associated with this uncertainty. It concluded that the modified RPSFTM was acceptable for decision making.
## Using data from COU-AA-302 to estimate the effect of a second newer androgen receptor inhibitor and to adjust for survival causes uncertainty
The company manufactures abiraterone as well as apalutamide, and acknowledged that it can access individual patient data from trials of abiraterone in combination for hormone-relapsed metastatic disease. To estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor in SPARTAN using the modified RPSFTM, the company used data from another trial, COU‑AA‑302, later in the treatment pathway. COU‑AA‑302 was a randomised trial comparing abiraterone plus prednisone with placebo plus prednisone in people with hormone-relapsed metastatic prostate cancer who had not had cytotoxic chemotherapy. The ERG explained that it could not verify the results of the modified RPSFTM because the company had not provided the requested individual patient data. Although the ERG agreed with using the COU‑AA‑302 and SPARTAN data, it noted that the survival benefit of abiraterone in combination may be underestimated. This was because people randomised to placebo plus prednisone in the trial could cross over to have abiraterone in combination at unblinding. To address the ERG's concern, the company estimated the survival benefits of abiraterone based on the COU‑AA‑302 trial's interim and final analysis data. This showed that the final analysis data may be affected by crossover from placebo to abiraterone. For the interim data, the bias should be small because only 3 people (0.55% of the 542 originally randomised to the placebo plus prednisone arm) had crossed over to abiraterone plus prednisone at this stage. The ERG considered that using the COU-AA-302 interim or final analysis data had a minimal effect on the adjusted hazard ratios for overall survival. It noted that the active treatment in COU-AA-302 had a considerably bigger effect on progression-free survival (used by the company to adjust PFS2) than on overall survival. Therefore, adjusting PFS2 in COU-AA-302 would have a bigger effect on the adjusted hazard ratios and would likely increase the cost-effectiveness estimates. At consultation, the company said that progression-free survival in COU‑AA-302 was not affected by crossover from placebo to abiraterone. However, the ERG noted that 17% (93 of 542) of people initially randomised to the placebo plus prednisone arm went on have abiraterone plus prednisone. Because a substantial number of people crossed over, progression-free survival could have been affected by crossover. The company also presented unadjusted results for both crossover and having a second androgen receptor inhibitor, and adjusted results for having a newer androgen receptor inhibitor only. This had a small effect on the results, which the committee noted. It concluded that using COU‑AA‑302 data to estimate the effect of a second newer androgen receptor inhibitor caused uncertainty, but was unlikely to affect the results much.
## Adjusting for the survival benefit of having more than 1 newer androgen receptor inhibitor may be unnecessary
The committee noted that COU‑AA‑302 included only people who had never had a newer androgen receptor inhibitor. So, using this data to adjust for the impact of a second newer androgen receptor inhibitor would 'over adjust' the overall survival of people having a second newer androgen receptor inhibitor in SPARTAN. This is because it is unlikely that a second newer androgen receptor inhibitor is as effective as the first one. Because more people in the apalutamide plus ADT arm of SPARTAN had a second newer androgen receptor inhibitor, adjusting for this treatment with COU-AA-302 data could bias against apalutamide plus ADT. The committee agreed that using COU‑AA‑302 data to estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor caused uncertainty (see section 3.6). It noted that using an appropriately specified IPCW or 2‑stage adjustment method applied to SPARTAN may have avoided the potential bias with estimating the effect of a second newer androgen receptor inhibitor based on data from COU‑AA‑302. Also, the committee understood that only 1 newer androgen receptor inhibitor would be used in the NHS prostate cancer treatment pathway (see section 3.1). Because they are unlikely to be effective when used again, it may be unnecessary to adjust the SPARTAN survival estimates. The committee agreed that considering a scenario in which people who had a second newer androgen receptor inhibitor survived longer than if they had followed the NHS treatment pathway could be reasonable. However, the committee also recalled the possibility of adverse effects from multiple lines of newer androgen receptor inhibitors. At consultation, the company presented unadjusted results for both crossover and having a second newer androgen receptor inhibitor, and adjusted results for a second newer androgen receptor inhibitor only. This had only a small effect on the results, which the committee noted. The committee concluded that it was uncertain if adjusting for the survival benefit of having a second newer androgen receptor inhibitor was necessary, but the impact of this on results was likely to be limited.
## How the company adjusts for crossover in SPARTAN from placebo plus ADT to apalutamide plus ADT may bias results
The committee considered whether the adjusted or the unadjusted hazard ratios for overall survival and PFS2 were more appropriate for decision making. When adjusting for crossover from the placebo plus ADT arm to the apalutamide plus ADT arm, the company assumed that people had no treatment after placebo plus ADT. But, in clinical practice, people are likely to be offered a newer androgen receptor inhibitor including abiraterone plus ADT or enzalutamide plus ADT as their next treatment. The committee considered that this part of the company's analysis could have biased against placebo plus ADT. It considered that an analysis that did not adjust survival estimates for crossover could be reasonable, if it was assumed that apalutamide has similar effectiveness to abiraterone and enzalutamide. At consultation, the company highlighted that unblinding rather than progression drove crossover in SPARTAN so it considered adjusting to be appropriate. The committee recognised that adjusting for metastases-free survival could also be appropriate when crossover could occur before metastases. It also considered that, after disease metastasis, treatment with one of these therapies would still be expected in the NHS, making adjustment for overall survival inappropriate. To explore this uncertainty, the company did scenario analyses with and without adjusting for crossover. The committee concluded that it would take these results into account in its decision making.
## Both adjusted and unadjusted hazard ratios for overall survival and PFS2 from SPARTAN can be considered for decision making
The company explained that the adjusted hazard ratio (0.77, 95% CI 0.64 to 0.94) and unadjusted hazard ratio (0.78, 95% CI 0.64 to 0.96) using the modified RPSFTM for overall survival were similar. The adjusted and unadjusted results for PFS2 were also similar to each other. The committee considered that this might be because the company had adjusted both arms of SPARTAN. The company explained that it considered the newer androgen receptor inhibitors the bigger driver of the adjustment results because the benefit of multiple lines of these treatments is small. In their base cases, the company and the ERG used the adjusted hazard ratios for overall survival and PFS2 to adjust for the effect of crossover and having a second androgen receptor inhibitor. Although the difference was minor, the committee took into account both the adjusted and unadjusted hazard ratios for overall survival and PFS2 in its decision making.
## SPARTAN is generalisable to NHS practice for people with hormone-relapsed non-metastatic disease
Unlike in the NHS, people in SPARTAN could have multiple newer androgen receptor inhibitors (see section 3.3). Although the effect of this on overall survival was likely to be minimal, the committee noted that people might have adverse effects (see section 3.5). The committee noted that SPARTAN was a large high‑quality trial measuring relevant outcomes. It concluded that, although the treatments people had in SPARTAN did not reflect NHS practice, the trial was otherwise generalisable to NHS practice for people with hormone-relapsed non‑metastatic disease.
# Adverse effects
## Adverse effects with apalutamide are tolerable
The clinical experts explained that apalutamide plus ADT is well tolerated. Rash and hypothyroidism have been reported and are manageable. The committee concluded that adverse effects with apalutamide plus ADT are tolerable.
# Economic model
## The model structure is appropriate for decision making
To estimate the cost effectiveness of apalutamide plus ADT compared with placebo plus ADT, the company used a partitioned survival model with health states for progression-free survival, progressed disease and death. After disease progression, people could have up to 3 lines of therapy and their health-related quality of life could decline. The company used PFS2 to inform the probability of moving between the first and second treatments for metastatic disease. The company used mean duration in each health state to assign people to the remaining health states. In the progression-free survival health state, people could be on or off treatment as determined by trial data on time to stopping treatment. The company used SPARTAN to estimate efficacy (metastases-free survival and overall survival). The committee concluded that the model structure was appropriate for decision making.
# Modelling the SPARTAN data
## In SPARTAN, extrapolating metastases-free survival using a Weibull model is uncertain
Because the decision problem specified a lifetime time horizon (32 years), the company sought data to estimate what would have happened had the SPARTAN trial lasted longer. The company did not identify any studies that provided longer‑term data for metastases-free survival to extrapolate beyond the duration of SPARTAN. It therefore explored a range of curves reflecting hazard functions including generalised gamma and Weibull. Most curves modelling metastases‑free survival provided a good fit to the observed data, but the committee recognised the data was of limited duration. The company asked for clinical advice. The advice it received suggested that the Weibull model was the most plausible for both apalutamide plus ADT and placebo plus ADT, although the Weibull function could underestimate metastases‑free survival at 10 years for apalutamide plus ADT. The clinical expert at the committee meeting estimated that only 1% to 2% of people having ADT alone as first treatment would be free of metastases at 5 to 10 years, suggesting that the Weibull model was a good fit to the observed data. In its base case, the company used the Weibull model to extrapolate metastases‑free survival, and fitted the curves independently to each arm. The ERG also chose the Weibull to model metastases-free survival. However, clinical expert advice to the ERG suggested that none of the models adequately captured metastases-free survival. This was because most curves underestimated the proportion of people who remain metastases free on ADT alone at 5 and 10 years. The exception was the generalised gamma model, which had a clinically implausible long tail to the curve and may overestimate the proportion who remain metastases free on apalutamide plus ADT. The ERG explained that the choice of the model had a large effect on the cost-effectiveness results. It suggested that more flexible models may be appropriate. The committee was aware that metastases-free survival was not adjusted for crossover because this endpoint was reached before people could switch to the other treatment arm (see section 3.3). The committee agreed that, because of the uncertainty associated with the Weibull model, it would have liked to see a more flexible model fitted to extrapolate metastases-free survival beyond the trial duration. At consultation, the company declined to explore flexible approaches. It said that these might be more uncertain than standard parametric models, because of their complexity and number of assumptions. It also said that a flexible approach needed a clinical or statistical reason to justify the time point at which the curves flex, which it considered did not exist. The committee concluded that the company's approach to extrapolating metastases-free survival was uncertain, which the committee factored into its decision making.
## In SPARTAN, extrapolating overall survival using a generalised gamma model is appropriate, but treatment effect beyond the trial is uncertain
The company used a systematic review (Aly et al. 2018) to identify clinical trial data that it could use to extrapolate overall survival in SPARTAN. It found 3 clinical trials with similar populations to SPARTAN, which it referred to as historical data. But, it did not use this data to extrapolate overall survival because SPARTAN had longer follow up than the historical studies. The company assessed if the proportional hazards assumption held for overall survival. The log‑cumulative hazard plot for overall survival in both arms of SPARTAN showed that the curves were relatively parallel over time. The company said that the proportional hazards assumption held based on Schoenfeld residual testing, and the company considered it appropriate to apply jointly fitted models in its original model. That is, rather than fitting survival models to each treatment independently the company fitted 1 survival model to all data, and then generated treatment-specific survival curves by using the treatment group as a covariate. The company chose a Weibull distribution to extrapolate overall survival because of its clinical plausibility. However, the ERG could not verify that proportional hazards would hold in the extrapolated part of the survival curves because of lack of evidence. It noted that the survival estimates from SPARTAN, on which the proportional hazards assumption was tested, were immature. It considered that using models fitted to the treatment arms separately (independently) would be more appropriate. During technical engagement before the first committee meeting, an expert advised the ERG that both Weibull curves were likely underestimated overall survival at 10 years, and possibly at 15 years. The ERG noted that generalised gamma models have a good visual fit to the observed data, and better statistical fits (lower Akaike information criterion or Bayesian information criterion scores) compared with the Weibull models. After technical engagement, both the company and the ERG used the jointly fitted generalised gamma models in their base cases. The committee was aware that the company had adjusted overall survival for crossover and having a second newer androgen receptor inhibitor. The committee concluded that extrapolating overall survival using the generalised gamma model was appropriate, but the treatment effect beyond the trial was uncertain.
## In SPARTAN, extrapolating PFS2 using a Weibull model is appropriate, but estimates are based on immature data
The company, having assessed that the proportional hazards assumption held for PFS2, applied the Weibull models fitted jointly to both treatments in its base case based on the statistical fits and clinical plausibility. The ERG also jointly fitted Weibull models in its base case, although it noted that the estimates were likely to be uncertain because PFS2 data for apalutamide plus ADT in SPARTAN was relatively immature. The committee concluded that the company and ERG's approach to modelling PFS2 was broadly appropriate but agreed that it was based on immature data.
## Treatment effect waning affects the cost-effectiveness results
The company considered that the benefits of apalutamide plus ADT did not wane over time, so it did not apply any treatment effect waning in its base case. It justified this by noting there was no evidence in SPARTAN that the overall survival curves for both treatments converge over time. The ERG explored treatment effect waning, but considered it unclear from the hazard plots if treatment benefit declined. Because the treatment effect did not wane in abiraterone clinical trials with longer follow up, the ERG's clinical experts did not expect treatment effect waning with apalutamide. However, a study in advanced prostate cancer (Antonarakis et al. 2016) suggested that resistance to newer androgen receptor inhibitors was likely to develop with time. The ERG noted that it was unclear if the study results were generalisable to hormone-relapsed non‑metastatic disease. The ERG also noted that resistance to abiraterone or enzalutamide does not necessarily imply that there would be a treatment waning effect for apalutamide. It considered that there was not enough evidence to assess the best approach to estimate the duration of treatment benefits. The Cancer Drugs Fund clinical lead noted that, in practice, most newer hormonal treatments for prostate cancer lose effectiveness over time. The committee was aware that both the company and the ERG had explored treatment waning in scenarios before technical engagement. The effect on the incremental cost‑effectiveness ratio (ICER) was an increase of around £2,000 per quality‑adjusted life year (QALY) gained when varying treatment effect waning from 100% to 0% for a duration of 5 years and 10 years. The committee concluded that treatment effect waning affected the cost-effectiveness results.
# Treatment costs
## The costs of apalutamide are appropriately captured in the model
The company offered apalutamide to the NHS at a discount, and increased the discount during the appraisal. The committee was aware that duration of treatment determines cost. People have apalutamide plus ADT until disease progression, or until they can no longer tolerate it or choose to stop. The company explained that data reflecting time‑to‑treatment discontinuation was available from the SPARTAN data cut of February 2020. But, the company chose to model time on treatment using data on time to metastases (metastases-free survival) from an earlier data cut in May 2017. The company explained that it did this because several of the extrapolations for time-to-treatment discontinuation crossed the metastases-free survival curves towards the end of SPARTAN. The committee considered that the best measure of treatment duration was the data measuring time-to-treatment discontinuation. The company explained that the costs used in the model were informed by the minimum of either time‑to‑treatment discontinuation until progression, or metastases‑free survival curves. The company therefore capped the costs. During the first committee meeting, it noted that this might have underestimated the cost of apalutamide in the model. However, at consultation the company stated that it now believed that the costs of treatment had been fully captured. The company also provided a scenario analysis with time on treatment equal to progression-free survival. The ERG confirmed that it agreed with the company's approach in its base case, because no one with progressed disease remains on treatment. The ERG considered the company's base case would not underestimate the costs of apalutamide. The committee concluded that the costs of apalutamide were appropriately captured in the company's model.
# Utility values
## The company's utility values are broadly appropriate
The company assumed that health-related quality of life declines over time because simulated people in the model have disease progression and move onto subsequent lines of therapy (see section 3.12). The company's utility value for having first-line treatment for hormone-relapsed metastatic prostate cancer was from SPARTAN using the EQ‑5D‑3L. The utility values are considered confidential by the company so cannot be reported here. For second- and third-line treatments for hormone-relapsed metastatic prostate cancer, the company originally used external data from NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA387). This was because a limited number of people completed the EQ‑5D‑3L questionnaire after developing metastases in SPARTAN. The company derived the utility values for second- and third-line treatments from the first treatment by applying a 'relative decline ratio'. It did this by estimating the relative decline in utility in TA387 between first- and second-line treatments for metastatic disease, and first- and third-line treatments for metastatic disease. It then applied these ratios to the progressed utility value from SPARTAN to estimate utilities for second- and third-line hormone-relapsed metastatic prostate cancer. The company also adjusted the derived utility values to account for population differences between SPARTAN and TA387. The company noted that it did this in line with the method described in the NICE Decision Support Unit's technical support document 12 on the use of health state utility values in decision models. The ERG had concerns with the company's adjusted utility values:
They were much lower than those used in NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA377) and enzalutamide for hormone-relapsed non-metastatic prostate cancer (TA580). The utility values were 0.658 and 0.612 in TA377 and 0.8 and 0.688 in TA580, for health states reflecting second- and third-line treatments of hormone‑relapsed metastatic prostate cancer.
It was unclear which line of treatment generated the utility values reported in TA387.
By applying a 'relative decline ratio', the company assumed that the utility values would decrease by the same relative proportion between first- and second-line treatments for hormone-relapsed metastatic prostate cancer (as in TA387). But the committee considered that this assumption may not be appropriate given the different populations in this appraisal (hormone-relapsed non-metastatic disease) and in TA387 (hormone-relapsed metastatic disease before chemotherapy is indicated).In its base case, the ERG used the utility values from TA377 without adjusting them. The patient experts reiterated the effect of psychological distress (see section 3.2) and worry about a treatment's loss of efficacy. The clinical expert was aware that EQ‑5D, measured in SPARTAN, included questions on anxiety and depression and agreed with the company's utility values. The committee agreed that this disease was associated with a significant effect on quality of life. However, it was concerned with the lack of consistency with utility values used in related technology appraisals. Also, the Cancer Drugs Fund clinical lead explained that the ERG's unadjusted utility values better fitted what had been seen in other disease areas with multiple lines of treatment. Therefore, the committee agreed that, on balance, the ERG's utility values had a higher face validity than the company's adjusted utility values. At consultation, the company updated its base case using unadjusted utility values from TA377 for second- and third‑line hormone-relapsed metastatic prostate cancer. The committee concluded that the unadjusted utility values from TA377 were most appropriate for decision making.
# End of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company did not make a case for end of life in its submission. The committee concluded that the end of life criteria were not met for apalutamide in hormone-relapsed non-metastatic prostate cancer.
# Cost-effectiveness estimates
## An acceptable ICER would be in the middle of the range normally considered cost effective, or lower
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The data is immature for overall survival and PFS2 and the appropriate extrapolation model for metastases-free survival was uncertain. The committee also takes into account other factors, and it was aware that NICE has recommended darolutamide plus ADT for this population (see section 3.22). Therefore, the committee agreed that an acceptable ICER would be in the middle of the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).
## Apalutamide is cost effective for hormone-relapsed non-metastatic disease
Because of confidential commercial arrangements for apalutamide and other treatments in the pathway, the cost-effectiveness estimates cannot be reported here. At consultation, the company updated its base case with the committee's preferred assumptions, which were also the ERG's preferred assumptions. These included:
adjusting for the effect of crossover and having a second androgen receptor inhibitor on overall survival and PFS2 (see section 3.8)
using unadjusted utility values for second- and third-line hormone-relapsed metastatic prostate cancer (see section 3.18).At consultation, the company also explored scenarios for some of the uncertainties identified by the committee, including:
not adjusting treatment effect for either crossover or having a second newer androgen receptor inhibitor
adjusting treatment effect for a second newer androgen receptor inhibitor only (and not crossover)
setting time on treatment as equal to progression-free survival (see section 3.17).The company also presented a probabilistic base-case ICER. It acknowledged that it had chosen not to explore several key uncertainties during consultation. These included exploring methods of adjustment other than the modified RPSFTM, and extrapolating metastases-free survival using a flexible model. The company further increased its discount for apalutamide. The committee considered that the ICER that most closely reflected its preferred assumptions was below the middle of the range of £20,000 to £30,000 per QALY gained. Therefore, apalutamide is recommended as a cost-effective use of NHS resources for treating hormone-relapsed non-metastatic prostate cancer.
# Innovation
## Apalutamide plus ADT is not innovative for high-risk hormone-relapsed non-metastatic prostate cancer
Darolutamide, a new androgen receptor inhibitor that was not available when this appraisal started, is now an option with ADT for treating hormone-relapsed non-metastatic prostate cancer at high risk of developing metastatic disease in the NHS. The recommended dose of darolutamide, an oral treatment, is twice daily; the recommended dose of apalutamide is once daily (as 4 tablets). The committee considered this to be an advantage, but not enough to consider apalutamide plus ADT a step-change in treatment and therefore innovative.
# Equality issues
## The recommendations apply to all people with prostate cancer
The committee noted that, as in previous NICE technology appraisals of prostate cancer treatments, its recommendations should apply to all people with prostate cancer. It further noted that a person can have a prostate but not identify as a man. Gender reassignment is a protected characteristic under the Equality Act 2010. No other equality issues were raised for hormone-relapsed non-metastatic prostate cancer.
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{'Recommendations': 'Apalutamide plus androgen deprivation therapy (ADT) is recommended, within its marketing authorisation, as an option for treating hormone‑relapsed non‑metastatic prostate cancer that is at high risk of metastasising in adults. High risk is defined as a blood prostate-specific antigen (PSA) level that has doubled in 10\xa0months or less on continuous ADT. It is recommended only if the company provides apalutamide according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nHormone-relapsed non-metastatic prostate cancer is usually treated with ADT alone or with darolutamide plus ADT.\n\nClinical trial evidence suggests that, compared with placebo plus ADT, apalutamide plus ADT increases the time until the disease spreads and how long people live. The cost‑effectiveness estimates are within what NICE considers to be an acceptable use of NHS resources. So, apalutamide plus ADT is recommended.', 'Information about apalutamide': "# Marketing authorisation indication\n\nApalutamide (Erleada, Janssen) is indicated 'in adult men for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price for apalutamide is £2,735 per pack of 112\xa0tablets, each containing 60\xa0mg of the active ingredient (excluding VAT; BNF online, March\xa02021). The company has a commercial arrangement (simple discount patient access scheme). This makes apalutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Only 1\xa0newer androgen receptor inhibitor would be used in the prostate cancer treatment pathway\n\nNICE recommends the newer (second-generation) androgen receptor inhibitors enzalutamide plus androgen deprivation therapy (ADT), and darolutamide plus ADT, or abiraterone plus prednisone or prednisolone plus ADT (hereafter abiraterone in combination) for treating hormone-sensitive metastatic or hormone-relapsed non-metastatic prostate cancer at multiple positions in the treatment pathway:\n\nNICE's technology appraisal guidance on darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer\n\nNICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer\n\nNICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated\n\nNICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated\n\nNICE's technology appraisal guidance on abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen\n\nNICE's technology appraisal guidance on enzalutamide for metastatic hormone-relapsed prostate cancer previously treated with a docetaxel-containing regimen.People have treatment with a second‑generation androgen receptor inhibitor until disease progression, docetaxel for up to 6\xa0cycles, and ADT indefinitely. Apalutamide is another second‑generation androgen receptor inhibitor. The Cancer Drugs Fund clinical lead explained that a person will have only 1 of these drugs in the NHS prostate cancer treatment pathway. The clinical experts confirmed that this is because of the similar way the drugs work, and probable resistance to drugs in the same group when used one after another. For example, if prostate cancer metastasises on apalutamide plus ADT, it would be expected to be resistant to subsequent treatment with enzalutamide plus ADT or abiraterone plus ADT. The Cancer Drugs Fund clinical lead confirmed that NHS England would not commission enzalutamide plus ADT or abiraterone plus ADT after apalutamide plus ADT. The committee concluded that in the NHS people with prostate cancer would be offered only 1 newer androgen receptor inhibitor.\n\n# Clinical management\n\n## People would value additional treatments for hormone-relapsed non-metastatic disease\n\nTreatment for hormone-relapsed non-metastatic prostate cancer is ADT alone or darolutamide plus ADT. Treatment aims to delay metastasis, which is associated with reduced quality of life and survival. The patient experts explained that anxiety about cancer metastasising causes psychological distress, which adds to debilitating symptoms such as fatigue, pain, and urinary and bowel problems. Apalutamide plus ADT has more than one indication; the one being appraised is for treating hormone-relapsed non-metastatic prostate cancer that is at high risk of metastasising. This is the same indication appraised in NICE's technology appraisal guidance on enzalutamide and darolutamide plus ADT. But, NICE does not recommend enzalutamide for this population, and NICE had not yet recommended darolutamide at the start of this appraisal. So, as per NICE processes, darolutamide plus ADT was not considered a relevant comparator for decision making. The committee concluded that people with hormone-relapsed non-metastatic prostate cancer would value additional treatment options.\n\n# Clinical evidence\n\n## The SPARTAN results are in line with planned analyses\n\nSPARTAN was a phase\xa03, randomised, multicentre trial comparing apalutamide plus ADT (n=806) with placebo plus ADT (n=401) for hormone‑relapsed non‑metastatic prostate cancer. The trial population had adenocarcinoma of the prostate that was hormone relapsed and at high risk of metastasis. High risk was defined as a blood prostate-specific antigen (PSA) doubling time of 10\xa0months or less during continuous ADT before randomisation. The committee considered that the participants in SPARTAN reflected people in NHS clinical practice reasonably well. The primary endpoint of SPARTAN was metastases-free survival, that is, the time from randomisation to confirmed evidence of metastasis or death from any cause. The committee appreciated that this reflected progression-free survival, with metastases indicating progression. Secondary endpoints included overall survival. Exploratory endpoints included time to progression-free survival on the first subsequent treatment taken for metastatic disease (PFS2) and health‑related quality of life, measured using the EQ‑5D questionnaire and the Functional Assessment of Cancer Therapy Prostate Module (FACT‑P). PFS2 measures the time from metastasis to the next disease progression on the treatment that people have after the trial treatment. The committee was aware that although PFS2 and EQ‑5D were exploratory endpoints, the company used them in its cost-effectiveness modelling. The final analysis for metastases-free survival and an interim analysis for overall survival and PFS2 were done in May\xa02017. At this time, most people's cancer had metastasised and the metastases-free survival endpoint had been met. In May\xa02017, the trial was unblinded and people who had placebo plus ADT could cross over to have apalutamide plus ADT if their cancer had not metastasised. The final analyses of overall survival and PFS2 were done in February\xa02020. After progression to metastatic disease, people could have abiraterone plus prednisone or prednisolone (from now on referred to as abiraterone in combination) or enzalutamide as subsequent treatment, as well as other treatments (see section\xa03.1). The committee concluded that the results were in line with the trial's planned analyses.\n\n## In SPARTAN, apalutamide plus ADT is clinically effective compared with placebo plus ADT\n\nIn SPARTAN:\n\nmedian metastases-free survival for people randomised to apalutamide plus ADT was 40.5\xa0months and for people randomised to placebo plus ADT it was 15.7\xa0months (hazard ratio 0.30, 95% confidence interval [CI] 0.24 to 0.36)\n\nmedian overall survival for people randomised to apalutamide plus ADT was 73.9\xa0months and for people randomised to placebo plus ADT it was 59.9\xa0months (hazard ratio 0.78, 95% CI 0.64 to 0.96)\n\nmedian PFS2 for people randomised to apalutamide plus ADT was 55.6\xa0months and for people randomised to placebo plus ADT it was 41.2\xa0months (hazard ratio considered academic in confidence by the company so cannot be reported here)\n\nmean change in EQ‑5D‑3L visual analogue score showed improvements in the apalutamide plus ADT arm compared with the placebo plus ADT arm at cycles\xa021 (mean difference\xa03.03) and 25 (mean difference 3.28), p<0.05.The committee concluded that apalutamide plus ADT extended metastases-free survival, overall survival, PFS2 and health-related quality of life when compared with placebo plus ADT, and was clinically effective.\n\n## The modified RPSFTM is appropriate for decision making, but there is still uncertainty\n\nThe results for overall survival and PFS2 (reported as hazard ratios in SPARTAN) were adjusted to reflect the treatment effect that would be seen in NHS practice. This is because in the trial people randomised to:\n\nplacebo plus ADT crossed over to apalutamide plus ADT\n\napalutamide plus ADT went on to have abiraterone plus ADT or enzalutamide plus ADT.The committee discussed both situations. In SPARTAN, 76\xa0people (19.0%) randomised to placebo plus ADT crossed over to apalutamide plus ADT. The company explained that this could underestimate the relative benefit of apalutamide plus ADT for overall survival and PFS2. This was because some people progressed or died only after the trial was unblinded (see section\xa03.3). However, the committee recognised that people with non‑metastatic disease in NHS practice who have ADT alone (as in the placebo plus ADT arm of SPARTAN) could have abiraterone in combination or enzalutamide as treatments after their disease had metastasised. This would mean that the trial endpoints may not need to be adjusted if these endpoints occurred after metastasis. The committee also recognised that, in the NHS, people can have only 1\xa0newer androgen receptor inhibitor in the prostate cancer treatment pathway (see section\xa03.1). Because more people randomised to apalutamide had a second newer androgen receptor inhibitor, the trial results may have overestimated apalutamide plus ADT's apparent effectiveness on PFS2 and overall survival, if having a second newer androgen receptor inhibitor is beneficial. The company considered that the number of people who had a second newer androgen receptor inhibitor is academic in confidence and cannot be reported here. The clinical expert explained that having a second newer androgen receptor inhibitor is unlikely to extend life, but might be associated with adverse effects. The committee appreciated that this type of switching might not bias survival estimates, but it was possible that people could have had a better response to the treatment if they had not had a second newer androgen receptor inhibitor. The company considered several different methods for adjusting. These included the rank preserving structural failure time model (RPSFTM), iterative parameter estimation (IPE), inverse probability of censoring weights (IPCW) and 2‑stage estimation. The company chose to use a modified version of the RPSFTM (Diels et al. 2019). The company explained that it did not have enough data to estimate the multiple parameters needed for the RPSFTM and IPE methods, and the IPCW method provided counterintuitive and clinically implausible results. The company also said that the 2‑stage method was not viable because of the lack of data and the need for a 'secondary baseline' before changing to apalutamide plus ADT or having a second newer androgen receptor inhibitor. The committee questioned whether it was necessary to adjust the results because of the likely minimal effect of multiple lines of newer treatments. It appreciated that the modified RPSFTM appeared to be reasonable but it was more like a 2‑stage method using aspects of all the adjustment approaches, and propensity weighting. It also considered that the IPCW and 2‑stage methods could have been appropriate, if appropriately specified. So, at its first meeting the committee asked that the company explore alternative approaches. At consultation, the company explained that it did not have time to explore alternative approaches. It reiterated its view that the modified RPSFTM was the most appropriate method. The committee was disappointed that the company chose not to explore alternative approaches. But it noted that the adjusted and unadjusted results were similar, which reduced the risks associated with this uncertainty. It concluded that the modified RPSFTM was acceptable for decision making.\n\n## Using data from COU-AA-302 to estimate the effect of a second newer androgen receptor inhibitor and to adjust for survival causes uncertainty\n\nThe company manufactures abiraterone as well as apalutamide, and acknowledged that it can access individual patient data from trials of abiraterone in combination for hormone-relapsed metastatic disease. To estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor in SPARTAN using the modified RPSFTM, the company used data from another trial, COU‑AA‑302, later in the treatment pathway. COU‑AA‑302 was a randomised trial comparing abiraterone plus prednisone with placebo plus prednisone in people with hormone-relapsed metastatic prostate cancer who had not had cytotoxic chemotherapy. The ERG explained that it could not verify the results of the modified RPSFTM because the company had not provided the requested individual patient data. Although the ERG agreed with using the COU‑AA‑302 and SPARTAN data, it noted that the survival benefit of abiraterone in combination may be underestimated. This was because people randomised to placebo plus prednisone in the trial could cross over to have abiraterone in combination at unblinding. To address the ERG's concern, the company estimated the survival benefits of abiraterone based on the COU‑AA‑302 trial's interim and final analysis data. This showed that the final analysis data may be affected by crossover from placebo to abiraterone. For the interim data, the bias should be small because only 3\xa0people (0.55% of the 542 originally randomised to the placebo plus prednisone arm) had crossed over to abiraterone plus prednisone at this stage. The ERG considered that using the COU-AA-302 interim or final analysis data had a minimal effect on the adjusted hazard ratios for overall survival. It noted that the active treatment in COU-AA-302 had a considerably bigger effect on progression-free survival (used by the company to adjust PFS2) than on overall survival. Therefore, adjusting PFS2 in COU-AA-302 would have a bigger effect on the adjusted hazard ratios and would likely increase the cost-effectiveness estimates. At consultation, the company said that progression-free survival in COU‑AA-302 was not affected by crossover from placebo to abiraterone. However, the ERG noted that 17% (93 of 542) of people initially randomised to the placebo plus prednisone arm went on have abiraterone plus prednisone. Because a substantial number of people crossed over, progression-free survival could have been affected by crossover. The company also presented unadjusted results for both crossover and having a second androgen receptor inhibitor, and adjusted results for having a newer androgen receptor inhibitor only. This had a small effect on the results, which the committee noted. It concluded that using COU‑AA‑302 data to estimate the effect of a second newer androgen receptor inhibitor caused uncertainty, but was unlikely to affect the results much.\n\n## Adjusting for the survival benefit of having more than 1\xa0newer androgen receptor inhibitor may be unnecessary\n\nThe committee noted that COU‑AA‑302 included only people who had never had a newer androgen receptor inhibitor. So, using this data to adjust for the impact of a second newer androgen receptor inhibitor would 'over adjust' the overall survival of people having a second newer androgen receptor inhibitor in SPARTAN. This is because it is unlikely that a second newer androgen receptor inhibitor is as effective as the first one. Because more people in the apalutamide plus ADT arm of SPARTAN had a second newer androgen receptor inhibitor, adjusting for this treatment with COU-AA-302 data could bias against apalutamide plus ADT. The committee agreed that using COU‑AA‑302 data to estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor caused uncertainty (see section\xa03.6). It noted that using an appropriately specified IPCW or 2‑stage adjustment method applied to SPARTAN may have avoided the potential bias with estimating the effect of a second newer androgen receptor inhibitor based on data from COU‑AA‑302. Also, the committee understood that only 1 newer androgen receptor inhibitor would be used in the NHS prostate cancer treatment pathway (see section\xa03.1). Because they are unlikely to be effective when used again, it may be unnecessary to adjust the SPARTAN survival estimates. The committee agreed that considering a scenario in which people who had a second newer androgen receptor inhibitor survived longer than if they had followed the NHS treatment pathway could be reasonable. However, the committee also recalled the possibility of adverse effects from multiple lines of newer androgen receptor inhibitors. At consultation, the company presented unadjusted results for both crossover and having a second newer androgen receptor inhibitor, and adjusted results for a second newer androgen receptor inhibitor only. This had only a small effect on the results, which the committee noted. The committee concluded that it was uncertain if adjusting for the survival benefit of having a second newer androgen receptor inhibitor was necessary, but the impact of this on results was likely to be limited.\n\n## How the company adjusts for crossover in SPARTAN from placebo plus ADT to apalutamide plus ADT may bias results\n\nThe committee considered whether the adjusted or the unadjusted hazard ratios for overall survival and PFS2 were more appropriate for decision making. When adjusting for crossover from the placebo plus ADT arm to the apalutamide plus ADT arm, the company assumed that people had no treatment after placebo plus ADT. But, in clinical practice, people are likely to be offered a newer androgen receptor inhibitor including abiraterone plus ADT or enzalutamide plus ADT as their next treatment. The committee considered that this part of the company's analysis could have biased against placebo plus ADT. It considered that an analysis that did not adjust survival estimates for crossover could be reasonable, if it was assumed that apalutamide has similar effectiveness to abiraterone and enzalutamide. At consultation, the company highlighted that unblinding rather than progression drove crossover in SPARTAN so it considered adjusting to be appropriate. The committee recognised that adjusting for metastases-free survival could also be appropriate when crossover could occur before metastases. It also considered that, after disease metastasis, treatment with one of these therapies would still be expected in the NHS, making adjustment for overall survival inappropriate. To explore this uncertainty, the company did scenario analyses with and without adjusting for crossover. The committee concluded that it would take these results into account in its decision making.\n\n## Both adjusted and unadjusted hazard ratios for overall survival and PFS2 from SPARTAN can be considered for decision making\n\nThe company explained that the adjusted hazard ratio (0.77, 95% CI 0.64 to 0.94) and unadjusted hazard ratio (0.78, 95%\xa0CI 0.64 to 0.96) using the modified RPSFTM for overall survival were similar. The adjusted and unadjusted results for PFS2 were also similar to each other. The committee considered that this might be because the company had adjusted both arms of SPARTAN. The company explained that it considered the newer androgen receptor inhibitors the bigger driver of the adjustment results because the benefit of multiple lines of these treatments is small. In their base cases, the company and the ERG used the adjusted hazard ratios for overall survival and PFS2 to adjust for the effect of crossover and having a second androgen receptor inhibitor. Although the difference was minor, the committee took into account both the adjusted and unadjusted hazard ratios for overall survival and PFS2 in its decision making.\n\n## SPARTAN is generalisable to NHS practice for people with hormone-relapsed non-metastatic disease\n\nUnlike in the NHS, people in SPARTAN could have multiple newer androgen receptor inhibitors (see section\xa03.3). Although the effect of this on overall survival was likely to be minimal, the committee noted that people might have adverse effects (see section\xa03.5). The committee noted that SPARTAN was a large high‑quality trial measuring relevant outcomes. It concluded that, although the treatments people had in SPARTAN did not reflect NHS practice, the trial was otherwise generalisable to NHS practice for people with hormone-relapsed non‑metastatic disease.\n\n# Adverse effects\n\n## Adverse effects with apalutamide are tolerable\n\nThe clinical experts explained that apalutamide plus ADT is well tolerated. Rash and hypothyroidism have been reported and are manageable. The committee concluded that adverse effects with apalutamide plus ADT are tolerable.\n\n# Economic model\n\n## The model structure is appropriate for decision making\n\nTo estimate the cost effectiveness of apalutamide plus ADT compared with placebo plus ADT, the company used a partitioned survival model with health states for progression-free survival, progressed disease and death. After disease progression, people could have up to 3\xa0lines of therapy and their health-related quality of life could decline. The company used PFS2 to inform the probability of moving between the first and second treatments for metastatic disease. The company used mean duration in each health state to assign people to the remaining health states. In the progression-free survival health state, people could be on or off treatment as determined by trial data on time to stopping treatment. The company used SPARTAN to estimate efficacy (metastases-free survival and overall survival). The committee concluded that the model structure was appropriate for decision making.\n\n# Modelling the SPARTAN data\n\n## In SPARTAN, extrapolating metastases-free survival using a Weibull model is uncertain\n\nBecause the decision problem specified a lifetime time horizon (32\xa0years), the company sought data to estimate what would have happened had the SPARTAN trial lasted longer. The company did not identify any studies that provided longer‑term data for metastases-free survival to extrapolate beyond the duration of SPARTAN. It therefore explored a range of curves reflecting hazard functions including generalised gamma and Weibull. Most curves modelling metastases‑free survival provided a good fit to the observed data, but the committee recognised the data was of limited duration. The company asked for clinical advice. The advice it received suggested that the Weibull model was the most plausible for both apalutamide plus ADT and placebo plus ADT, although the Weibull function could underestimate metastases‑free survival at 10\xa0years for apalutamide plus ADT. The clinical expert at the committee meeting estimated that only 1% to 2% of people having ADT alone as first treatment would be free of metastases at 5 to 10\xa0years, suggesting that the Weibull model was a good fit to the observed data. In its base case, the company used the Weibull model to extrapolate metastases‑free survival, and fitted the curves independently to each arm. The ERG also chose the Weibull to model metastases-free survival. However, clinical expert advice to the ERG suggested that none of the models adequately captured metastases-free survival. This was because most curves underestimated the proportion of people who remain metastases free on ADT alone at 5 and 10\xa0years. The exception was the generalised gamma model, which had a clinically implausible long tail to the curve and may overestimate the proportion who remain metastases free on apalutamide plus ADT. The ERG explained that the choice of the model had a large effect on the cost-effectiveness results. It suggested that more flexible models may be appropriate. The committee was aware that metastases-free survival was not adjusted for crossover because this endpoint was reached before people could switch to the other treatment arm (see section\xa03.3). The committee agreed that, because of the uncertainty associated with the Weibull model, it would have liked to see a more flexible model fitted to extrapolate metastases-free survival beyond the trial duration. At consultation, the company declined to explore flexible approaches. It said that these might be more uncertain than standard parametric models, because of their complexity and number of assumptions. It also said that a flexible approach needed a clinical or statistical reason to justify the time point at which the curves flex, which it considered did not exist. The committee concluded that the company's approach to extrapolating metastases-free survival was uncertain, which the committee factored into its decision making.\n\n## In SPARTAN, extrapolating overall survival using a generalised gamma model is appropriate, but treatment effect beyond the trial is uncertain\n\nThe company used a systematic review (Aly et al. 2018) to identify clinical trial data that it could use to extrapolate overall survival in SPARTAN. It found 3\xa0clinical trials with similar populations to SPARTAN, which it referred to as historical data. But, it did not use this data to extrapolate overall survival because SPARTAN had longer follow up than the historical studies. The company assessed if the proportional hazards assumption held for overall survival. The log‑cumulative hazard plot for overall survival in both arms of SPARTAN showed that the curves were relatively parallel over time. The company said that the proportional hazards assumption held based on Schoenfeld residual testing, and the company considered it appropriate to apply jointly fitted models in its original model. That is, rather than fitting survival models to each treatment independently the company fitted 1\xa0survival model to all data, and then generated treatment-specific survival curves by using the treatment group as a covariate. The company chose a Weibull distribution to extrapolate overall survival because of its clinical plausibility. However, the ERG could not verify that proportional hazards would hold in the extrapolated part of the survival curves because of lack of evidence. It noted that the survival estimates from SPARTAN, on which the proportional hazards assumption was tested, were immature. It considered that using models fitted to the treatment arms separately (independently) would be more appropriate. During technical engagement before the first committee meeting, an expert advised the ERG that both Weibull curves were likely underestimated overall survival at 10\xa0years, and possibly at 15\xa0years. The ERG noted that generalised gamma models have a good visual fit to the observed data, and better statistical fits (lower Akaike information criterion or Bayesian information criterion scores) compared with the Weibull models. After technical engagement, both the company and the ERG used the jointly fitted generalised gamma models in their base cases. The committee was aware that the company had adjusted overall survival for crossover and having a second newer androgen receptor inhibitor. The committee concluded that extrapolating overall survival using the generalised gamma model was appropriate, but the treatment effect beyond the trial was uncertain.\n\n## In SPARTAN, extrapolating PFS2 using a Weibull model is appropriate, but estimates are based on immature data\n\nThe company, having assessed that the proportional hazards assumption held for PFS2, applied the Weibull models fitted jointly to both treatments in its base case based on the statistical fits and clinical plausibility. The ERG also jointly fitted Weibull models in its base case, although it noted that the estimates were likely to be uncertain because PFS2 data for apalutamide plus ADT in SPARTAN was relatively immature. The committee concluded that the company and ERG's approach to modelling PFS2 was broadly appropriate but agreed that it was based on immature data.\n\n## Treatment effect waning affects the cost-effectiveness results\n\nThe company considered that the benefits of apalutamide plus ADT did not wane over time, so it did not apply any treatment effect waning in its base case. It justified this by noting there was no evidence in SPARTAN that the overall survival curves for both treatments converge over time. The ERG explored treatment effect waning, but considered it unclear from the hazard plots if treatment benefit declined. Because the treatment effect did not wane in abiraterone clinical trials with longer follow up, the ERG's clinical experts did not expect treatment effect waning with apalutamide. However, a study in advanced prostate cancer (Antonarakis et al. 2016) suggested that resistance to newer androgen receptor inhibitors was likely to develop with time. The ERG noted that it was unclear if the study results were generalisable to hormone-relapsed non‑metastatic disease. The ERG also noted that resistance to abiraterone or enzalutamide does not necessarily imply that there would be a treatment waning effect for apalutamide. It considered that there was not enough evidence to assess the best approach to estimate the duration of treatment benefits. The Cancer Drugs Fund clinical lead noted that, in practice, most newer hormonal treatments for prostate cancer lose effectiveness over time. The committee was aware that both the company and the ERG had explored treatment waning in scenarios before technical engagement. The effect on the incremental cost‑effectiveness ratio (ICER) was an increase of around £2,000 per quality‑adjusted life year (QALY) gained when varying treatment effect waning from 100% to 0% for a duration of 5\xa0years and 10\xa0years. The committee concluded that treatment effect waning affected the cost-effectiveness results.\n\n# Treatment costs\n\n## The costs of apalutamide are appropriately captured in the model\n\nThe company offered apalutamide to the NHS at a discount, and increased the discount during the appraisal. The committee was aware that duration of treatment determines cost. People have apalutamide plus ADT until disease progression, or until they can no longer tolerate it or choose to stop. The company explained that data reflecting time‑to‑treatment discontinuation was available from the SPARTAN data cut of February\xa02020. But, the company chose to model time on treatment using data on time to metastases (metastases-free survival) from an earlier data cut in May\xa02017. The company explained that it did this because several of the extrapolations for time-to-treatment discontinuation crossed the metastases-free survival curves towards the end of SPARTAN. The committee considered that the best measure of treatment duration was the data measuring time-to-treatment discontinuation. The company explained that the costs used in the model were informed by the minimum of either time‑to‑treatment discontinuation until progression, or metastases‑free survival curves. The company therefore capped the costs. During the first committee meeting, it noted that this might have underestimated the cost of apalutamide in the model. However, at consultation the company stated that it now believed that the costs of treatment had been fully captured. The company also provided a scenario analysis with time on treatment equal to progression-free survival. The ERG confirmed that it agreed with the company's approach in its base case, because no one with progressed disease remains on treatment. The ERG considered the company's base case would not underestimate the costs of apalutamide. The committee concluded that the costs of apalutamide were appropriately captured in the company's model.\n\n# Utility values\n\n## The company's utility values are broadly appropriate\n\nThe company assumed that health-related quality of life declines over time because simulated people in the model have disease progression and move onto subsequent lines of therapy (see section\xa03.12). The company's utility value for having first-line treatment for hormone-relapsed metastatic prostate cancer was from SPARTAN using the EQ‑5D‑3L. The utility values are considered confidential by the company so cannot be reported here. For second- and third-line treatments for hormone-relapsed metastatic prostate cancer, the company originally used external data from NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA387). This was because a limited number of people completed the EQ‑5D‑3L questionnaire after developing metastases in SPARTAN. The company derived the utility values for second- and third-line treatments from the first treatment by applying a 'relative decline ratio'. It did this by estimating the relative decline in utility in TA387 between first- and second-line treatments for metastatic disease, and first- and third-line treatments for metastatic disease. It then applied these ratios to the progressed utility value from SPARTAN to estimate utilities for second- and third-line hormone-relapsed metastatic prostate cancer. The company also adjusted the derived utility values to account for population differences between SPARTAN and TA387. The company noted that it did this in line with the method described in the NICE Decision Support Unit's technical support document 12 on the use of health state utility values in decision models. The ERG had concerns with the company's adjusted utility values:\n\nThey were much lower than those used in NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA377) and enzalutamide for hormone-relapsed non-metastatic prostate cancer (TA580). The utility values were 0.658 and 0.612 in TA377 and 0.8 and 0.688 in TA580, for health states reflecting second- and third-line treatments of hormone‑relapsed metastatic prostate cancer.\n\nIt was unclear which line of treatment generated the utility values reported in TA387.\n\nBy applying a 'relative decline ratio', the company assumed that the utility values would decrease by the same relative proportion between first- and second-line treatments for hormone-relapsed metastatic prostate cancer (as in TA387). But the committee considered that this assumption may not be appropriate given the different populations in this appraisal (hormone-relapsed non-metastatic disease) and in TA387 (hormone-relapsed metastatic disease before chemotherapy is indicated).In its base case, the ERG used the utility values from TA377 without adjusting them. The patient experts reiterated the effect of psychological distress (see section\xa03.2) and worry about a treatment's loss of efficacy. The clinical expert was aware that EQ‑5D, measured in SPARTAN, included questions on anxiety and depression and agreed with the company's utility values. The committee agreed that this disease was associated with a significant effect on quality of life. However, it was concerned with the lack of consistency with utility values used in related technology appraisals. Also, the Cancer Drugs Fund clinical lead explained that the ERG's unadjusted utility values better fitted what had been seen in other disease areas with multiple lines of treatment. Therefore, the committee agreed that, on balance, the ERG's utility values had a higher face validity than the company's adjusted utility values. At consultation, the company updated its base case using unadjusted utility values from TA377 for second- and third‑line hormone-relapsed metastatic prostate cancer. The committee concluded that the unadjusted utility values from TA377 were most appropriate for decision making.\n\n# End of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company did not make a case for end of life in its submission. The committee concluded that the end of life criteria were not met for apalutamide in hormone-relapsed non-metastatic prostate cancer.\n\n# Cost-effectiveness estimates\n\n## An acceptable ICER would be in the middle of the range normally considered cost effective, or lower\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The data is immature for overall survival and PFS2 and the appropriate extrapolation model for metastases-free survival was uncertain. The committee also takes into account other factors, and it was aware that NICE has recommended darolutamide plus ADT for this population (see section\xa03.22). Therefore, the committee agreed that an acceptable ICER would be in the middle of the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).\n\n## Apalutamide is cost effective for hormone-relapsed non-metastatic disease\n\nBecause of confidential commercial arrangements for apalutamide and other treatments in the pathway, the cost-effectiveness estimates cannot be reported here. At consultation, the company updated its base case with the committee's preferred assumptions, which were also the ERG's preferred assumptions. These included:\n\nadjusting for the effect of crossover and having a second androgen receptor inhibitor on overall survival and PFS2 (see section\xa03.8)\n\nusing unadjusted utility values for second- and third-line hormone-relapsed metastatic prostate cancer (see section\xa03.18).At consultation, the company also explored scenarios for some of the uncertainties identified by the committee, including:\n\nnot adjusting treatment effect for either crossover or having a second newer androgen receptor inhibitor\n\nadjusting treatment effect for a second newer androgen receptor inhibitor only (and not crossover)\n\nsetting time on treatment as equal to progression-free survival (see section 3.17).The company also presented a probabilistic base-case ICER. It acknowledged that it had chosen not to explore several key uncertainties during consultation. These included exploring methods of adjustment other than the modified RPSFTM, and extrapolating metastases-free survival using a flexible model. The company further increased its discount for apalutamide. The committee considered that the ICER that most closely reflected its preferred assumptions was below the middle of the range of £20,000 to £30,000 per QALY gained. Therefore, apalutamide is recommended as a cost-effective use of NHS resources for treating hormone-relapsed non-metastatic prostate cancer.\n\n# Innovation\n\n## Apalutamide plus ADT is not innovative for high-risk hormone-relapsed non-metastatic prostate cancer\n\nDarolutamide, a new androgen receptor inhibitor that was not available when this appraisal started, is now an option with ADT for treating hormone-relapsed non-metastatic prostate cancer at high risk of developing metastatic disease in the NHS. The recommended dose of darolutamide, an oral treatment, is twice daily; the recommended dose of apalutamide is once daily (as 4\xa0tablets). The committee considered this to be an advantage, but not enough to consider apalutamide plus ADT a step-change in treatment and therefore innovative.\n\n# Equality issues\n\n## The recommendations apply to all people with prostate cancer\n\nThe committee noted that, as in previous NICE technology appraisals of prostate cancer treatments, its recommendations should apply to all people with prostate cancer. It further noted that a person can have a prostate but not identify as a man. Gender reassignment is a protected characteristic under the Equality Act 2010. No other equality issues were raised for hormone-relapsed non-metastatic prostate cancer."}
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https://www.nice.org.uk/guidance/ta740
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Evidence-based recommendations on apalutamide with androgen deprivation therapy for treating high-risk hormone-relapsed non-metastatic prostate cancer in adults.
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32061e9acb884b592249b8735a8338dcccaf4376
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nice
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Apalutamide with androgen deprivation therapy for treating hormone-sensitive metastatic prostate cancer
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Apalutamide with androgen deprivation therapy for treating hormone-sensitive metastatic prostate cancer
Evidence-based recommendations on apalutamide with androgen deprivation therapy for treating hormone-sensitive metastatic prostate cancer in adults.
# Recommendations
Apalutamide plus androgen deprivation therapy (ADT) is recommended as an option for treating hormone-sensitive metastatic prostate cancer in adults, only if:
docetaxel is not suitable
the company provides apalutamide according to the commercial arrangement.
This recommendation is not intended to affect treatment with apalutamide plus ADT that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Hormone-sensitive metastatic prostate cancer is usually treated with docetaxel plus androgen deprivation therapy (ADT), ADT alone or enzalutamide plus ADT. Enzalutamide was not available when this appraisal started.
Clinical trial evidence suggests that, compared with placebo plus ADT, apalutamide plus ADT increases the time until the disease progresses and how long people live.
Apalutamide plus ADT is not cost effective compared with docetaxel. However, compared with ADT, the cost-effectiveness estimates for apalutamide plus ADT are within what NICE considers to be an acceptable use of NHS resources. So, apalutamide plus ADT is recommended for people with hormone-sensitive metastatic prostate cancer only if they cannot have docetaxel.# Information about apalutamide
# Marketing authorisation indication
Apalutamide (Erleada, Janssen) is indicated 'in adult men for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The price for apalutamide is £2,735 per pack of 112 tablets, each containing 60 mg of the active ingredient (excluding VAT; BNF online, March 2021). The company has a commercial arrangement (simple discount patient access scheme). This makes apalutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
# Treatment pathway
## Only 1 newer androgen receptor inhibitor would be used in the prostate cancer treatment pathway
NICE recommends the newer (second-generation) androgen receptor inhibitors enzalutamide plus androgen deprivation therapy (ADT), and darolutamide plus ADT, or abiraterone plus prednisone or prednisolone plus ADT (hereafter abiraterone in combination) for treating hormone‑sensitive metastatic or hormone-relapsed non-metastatic prostate cancer at multiple positions in the treatment pathway:
NICE's technology appraisal guidance on darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer
NICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer
NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated
NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated
NICE's technology appraisal guidance on abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen
NICE's technology appraisal guidance on enzalutamide for metastatic hormone‑relapsed prostate cancer previously treated with a docetaxel‑containing regimen.People have treatment with a second‑generation androgen receptor inhibitor until disease progression, docetaxel for up to 6 cycles, and ADT indefinitely. Apalutamide is another second‑generation androgen receptor inhibitor. The Cancer Drugs Fund clinical lead explained that a person will have only 1 of these drugs in the NHS prostate cancer treatment pathway. The clinical experts confirmed that this is because of the similar way the drugs work, and probable resistance to drugs in the same group when used one after another. For example, if prostate cancer metastasises on apalutamide plus ADT, it would be expected to be resistant to subsequent treatment with enzalutamide plus ADT or abiraterone plus ADT. The Cancer Drugs Fund clinical lead confirmed that NHS England would not commission enzalutamide or abiraterone after apalutamide. The committee concluded that only 1 newer androgen receptor inhibitor would be used in the treatment pathway for prostate cancer.
# Clinical management
## People would value additional treatments for hormone-sensitive metastatic disease
Apalutamide has more than 1 indication for prostate cancer. This appraisal considers apalutamide for treating hormone-sensitive metastatic prostate cancer. Until recently, treatment for hormone-sensitive metastatic prostate cancer included ADT alone, or docetaxel for up to 6 cycles administered as a 1-hour intravenous infusion every 3 weeks, given with ADT and with or without prednisone or prednisolone. People who have had docetaxel plus ADT for hormone-sensitive metastatic disease can have it again if the cancer progresses. NICE now recommends enzalutamide plus ADT for hormone-sensitive metastatic disease. Also, NHS England's interim guidance on treatment options during the COVID-19 pandemic allows use of abiraterone plus prednisone plus ADT but, because of the cost of abiraterone, only for people who cannot tolerate enzalutamide plus ADT. The patient experts explained that people who are diagnosed with metastatic disease may have no or few symptoms and may think that docetaxel worsens quality of life. As a result, some choose to have ADT alone, even though the long-term outcomes may be worse. The patient experts noted that apalutamide plus ADT is likely to be more effective than ADT alone (see section 3.5) and is generally better tolerated than docetaxel plus ADT (see section 3.3). The committee concluded that people with hormone-sensitive metastatic prostate cancer would value additional treatment options.
## Identifying people with hormone-sensitive metastatic disease who cannot have docetaxel involves assessing a person's risks
For people with hormone-sensitive metastatic prostate cancer, the company proposed apalutamide plus ADT as an alternative to ADT alone or docetaxel plus ADT. This included people who should not have docetaxel because of comorbidities, or who choose not to have docetaxel. The company also proposed a comparison of apalutamide plus ADT with ADT alone for people who could not or should not have docetaxel. The committee noted that defining the group for whom docetaxel is unsuitable was complicated. It had done this in the NICE technology appraisal of abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer with input from the Cancer Drugs Fund clinical lead, clinical experts and stakeholders. The committee was aware that NHS England's clinical commissioning policy statement for docetaxel in combination with ADT defines who may not be well enough to have docetaxel. This includes people with a poor overall performance status (World Health Organization performance 3 to 4). The policy also states that docetaxel should be used with caution in people with a WHO performance status of 2 and that there are few absolute contraindications to docetaxel. The Cancer Drugs Fund clinical lead had explained during the appraisal of abiraterone that many factors other than performance status may affect whether a person could have docetaxel. The committee noted that people for whom docetaxel is contraindicated or unsuitable would include:
people for whom docetaxel is contraindicated, as listed in docetaxel's summary of product characteristics and NHS England's clinical commissioning policy statement for docetaxel in combination with ADT
people with poor performance status (WHO or Eastern Cooperative Oncology Group performance status 3 or 4, and possibly status 2 because docetaxel is used with caution in this group)
people with significant comorbidity (for example, cardiovascular, respiratory or liver disease), so prostate cancer is unlikely to be their only life-limiting illness
people with peripheral sensory neuropathy or poor bone marrow function
people with poor cognition or social support leading to a decreased ability to understand treatment options or make a decision.The committee agreed that clinicians should assess the risks and benefits of having docetaxel based on a person's individual risk factors. This should include the advantages and disadvantages of all treatment options, including fewer options for later treatments for people who choose to have apalutamide. The committee appreciated that some people may not be well enough to have docetaxel plus ADT and with or without prednisone or prednisolone, enzalutamide plus ADT, or apalutamide plus ADT, so they would still be offered ADT alone. It concluded that identifying people for whom docetaxel was contraindicated or unsuitable would be based on a clinical framework considering individual patient risk.
# Clinical evidence
## The TITAN results are in line with planned analyses
TITAN was a phase 3, randomised, multicentre trial comparing apalutamide plus ADT (n=525) with placebo plus ADT (n=527) for hormone-sensitive metastatic prostate cancer. The trial population had adenocarcinoma of the prostate that had metastasised but was still sensitive to treatment with hormone therapy. The trial included people with ECOG scores of 0, 1 or 2 and excluded people with severe haematological, hepatic or renal dysfunction. The committee considered that the population in TITAN reflected people with hormone-sensitive prostate cancer in NHS clinical practice reasonably well. TITAN's co-primary endpoints were overall survival and radiographic progression-free survival, that is, the time from randomisation to confirmed evidence of radiographic progressive disease or death from any cause. Secondary endpoints included time to cytotoxic chemotherapy. Exploratory endpoints included progression-free survival on first subsequent treatment (PFS2) and health-related quality of life. The committee was aware that although these were exploratory endpoints, the company used PFS2 and EQ‑5D in its cost-effectiveness modelling. Health-related quality of life was measured using the EQ‑5D‑5L questionnaire, the FACT-P, the Brief Pain Inventory (BPI) and the Brief Pain Inventory Short Form (BPI-SF). The final analysis for radiographic progression-free survival and interim analyses for overall survival and PFS2 were done in November 2018. At this time, most people's cancer had progressed, and the radiographic progression-free survival endpoint had been met. In November 2018, the trial was unblinded and people who had placebo could cross over to have apalutamide plus ADT if their cancer had not progressed. The company did the final analyses of overall survival and PFS2 in September 2020. After disease progression, people could have abiraterone or enzalutamide. The committee was aware that TITAN included people based on whether they could have docetaxel, but only those with an ECOG score of 0 or 1. The company did not present clinical evidence of apalutamide plus ADT's effectiveness compared with ADT alone for people who cannot have docetaxel. The committee concluded that the results were in line with the trial's planned analyses.
## Apalutamide plus ADT is clinically effective compared with placebo plus ADT
In TITAN:
median radiographic progression-free survival for people randomised to apalutamide plus ADT was not reached and for people randomised to placebo plus ADT it was 22.1 months (hazard ratio 0.5, 95% confidence interval 0.4 to 0.6)
median overall survival and median PFS2 for people randomised to apalutamide plus ADT and for people randomised to placebo plus ADT are academic-in-confidence and cannot be reported here
mean change in EQ-5D-5L visual analogue score showed no differences between the apalutamide plus ADT and placebo plus ADT treatment arms for all treatment cycles. For example, mean change at cycle 21 on apalutamide plus ADT was 2.50 and on placebo plus ADT it was 2.04, with a difference of -0.46 (p=0.7678).The company used the hazard ratio for the whole population (that is, people with hormone-sensitive metastatic prostate cancer) to show the effectiveness of apalutamide plus ADT for people whom docetaxel is not suitable. The committee understood that no evidence was available for people who cannot have docetaxel as they were likely excluded from the TITAN trial. It considered whether a subgroup of the trial population could be used as a proxy. For example, the patient expert had explained that people who cannot or should not have docetaxel are often older. The company confirmed that it did have a hazard ratio for a subgroup of older people for the endpoint of time to progression or death, but it did not use this. The hazard ratio and upper boundary of the confidence interval crossed 1.0 (no effect) for people 75 years and older, whereas it did not for people younger than 75 years. However, there was no statistically significant difference for interaction. The committee agreed that there would be several uncertainties in using age as a proxy, including confounding factors and because some younger people cannot have docetaxel. At consultation, the company submitted cost-effectiveness analyses for subgroups it considered to represent people who cannot have docetaxel, but no clinical evidence for the subgroup itself (see section 3.28). The committee concluded that apalutamide plus ADT extended radiographic progression-free survival, overall survival and PFS2 when compared with placebo plus ADT. However, there was no clinical evidence for a subgroup who cannot have docetaxel (see section 3.26).
## The modified RPSFTM is appropriate for decision making, but there is still uncertainty
The results for overall survival and PFS2 (reported as hazard ratios in TITAN) were adjusted to reflect the treatment effect that would be seen in NHS practice. This is because in the trial people randomised to:
placebo plus ADT crossed over to apalutamide plus ADT
apalutamide plus ADT went on to have abiraterone plus ADT or enzalutamide plus ADT.The committee discussed both situations. In TITAN, 208 people (39.5%) randomised to placebo plus ADT crossed over to apalutamide plus ADT. The company explained that this could underestimate the relative benefit of apalutamide plus ADT for overall survival and PFS2. This was because some people progressed or died only after the trial was unblinded (see section 3.4). However, the committee recognised that people with metastatic disease who have ADT alone (as in the placebo plus ADT arm of TITAN) could have abiraterone in combination or enzalutamide plus ADT in the NHS (see section 3.9). This would mean that the trial endpoints may not need to be adjusted. The committee also recognised that people can have only 1 newer androgen receptor inhibitor in the NHS prostate cancer treatment pathway (see section 3.1). Because more people randomised to apalutamide plus ADT had a second newer androgen receptor inhibitor, the trial results may have overestimated the effect of apalutamide plus ADT on PFS2 and overall survival, if having a second newer androgen receptor inhibitor is beneficial. The company considered that the number of people who had a second newer androgen receptor inhibitor is academic-in-confidence and cannot be reported here. The clinical expert explained that having a second newer androgen receptor inhibitor is unlikely to extend life, but might be associated with adverse effects. The committee appreciated that this type of switching might not bias survival estimates, but it was possible that people could have had a better response to the treatment if they had not had a second newer androgen receptor inhibitor. The company considered several different methods for adjusting overall survival and PFS2 results. These included the rank preserving structural failure time model (RPSFTM), iterative parameter estimation (IPE), inverse probability of censoring weights (IPCW) and 2‑stage estimation. The company chose to use a modified version of the RPSFTM (Diels et al. 2019). The company explained that it did not have enough data to estimate the multiple parameters needed for the RPSFTM and IPE methods, and the IPCW method provided counterintuitive and clinically implausible results. The company also said that the 2‑stage method was not viable because of a lack of the data and the need for a 'secondary baseline' before changing to apalutamide plus ADT or having a second newer androgen receptor inhibitor. The committee questioned whether it was necessary to adjust the results because of the likely minimal effect of multiple lines of newer treatments (see section 3.12). It appreciated that the modified RPSFTM appeared to be reasonable but was more like a 2-stage method using aspects of all the adjustment approaches and propensity weighting. It also considered that the IPCW and 2‑stage methods could have been suitable, if appropriately specified. So, at its first meeting the committee asked that the company explore alternative approaches. At consultation the company explained that it did not have time to explore alternative approaches. It reiterated its view that the modified RPSFTM was the most appropriate method. The committee was disappointed that the company chose not to explore alternative approaches. But it noted that the adjusted and unadjusted results were similar, which reduced the risks associated with this uncertainty. It concluded that the modified RPSFTM was acceptable for decision making.
## Using data from COU-AA-302 to estimate the effect of a second newer androgen receptor inhibitor and to adjust for survival causes uncertainty
The company manufactures abiraterone as well as apalutamide, and acknowledged that it can access individual patient data from trials of abiraterone for hormone-relapsed metastatic disease. To estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor in TITAN using the modified RPSFTM, the company used data from another trial, COU‑AA‑302, later in the treatment pathway. COU‑AA‑302 was a randomised trial comparing abiraterone plus prednisone with placebo plus prednisone in people with hormone-relapsed metastatic prostate cancer who had not had cytotoxic chemotherapy. The ERG explained that it could not verify the results of the modified RPSFTM because the company had not provided the requested individual patient data. Although the ERG agreed with using the COU‑AA‑302 data, it noted that the survival benefit of abiraterone may be underestimated. This was because people randomised to placebo plus prednisone in the trial could cross over to have abiraterone plus ADT at unblinding. To address the ERG's concern, the company estimated the survival benefits of abiraterone based on the COU‑AA‑302 trial's interim and final analysis data. This showed that the final analysis data may be affected by crossover from placebo to abiraterone. For the interim data the bias should be small because only 3 people (0.55% of the 542 originally randomised to the placebo plus prednisone arm) had crossed over to abiraterone plus prednisone at this stage. The ERG considered that using the COU-AA-302 interim or final analysis data minimally affected the adjusted hazard ratios for overall survival. It noted that the active treatment in COU-AA-302 had a considerably bigger effect on progression-free survival (used by the company to adjust PFS2) than on overall survival. Therefore, adjusting PFS2 in COU-AA-302 would have a bigger effect on the adjusted hazard ratios and would likely increase the cost-effectiveness estimates. At consultation the company said that progression-free survival in COU‑AA-302 was not affected by crossover from placebo to abiraterone. However, the ERG noted that 17% (93 of 542) of people initially randomised to the placebo plus prednisone arm went on have abiraterone plus prednisone. Because a substantial number of people crossed over to abiraterone, progression-free survival could have been affected by crossover. The company also presented unadjusted results for both crossover and having a second androgen receptor inhibitor, and adjusted results for having a newer androgen receptor inhibitor only. This had a small effect on the results, which the committee noted. It concluded that using COU‑AA‑302 data to estimate the effect of a second newer androgen receptor inhibitor caused uncertainty but was unlikely to affect the results much.
## Adjusting for the survival benefit of having more than 1 newer androgen receptor inhibitor may be unnecessary
The committee noted that COU-AA-302 included only people who had never had a newer androgen receptor inhibitor. So, using this data to adjust for the impact of a second newer androgen receptor inhibitor would 'over adjust' the overall survival of people having a second newer androgen receptor inhibitor in TITAN. This is because it is unlikely that a second newer androgen receptor inhibitor is as effective as the first one. Because more people in the apalutamide plus ADT arm of TITAN had a second newer androgen receptor inhibitor, adjusting for this treatment with COU‑AA‑302 data in this way could bias against apalutamide plus ADT. The committee agreed that using COU-AA-302 data to estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor caused uncertainty (see section 3.7). It noted that using an appropriately specified IPCW or 2‑stage adjustment method applied to TITAN may have avoided the potential bias with estimating the effect of a second newer androgen receptor inhibitor based on data from COU-AA-302. Also, the committee understood that only 1 newer androgen receptor inhibitor would be used in the NHS prostate cancer treatment pathway (see section 3.1). Because they are unlikely to be effective when used again, it may be unnecessary to adjust the TITAN survival estimates. The committee agreed that considering a scenario in which people who had a second newer androgen receptor inhibitor survived longer than if they had followed the NHS treatment pathway could be reasonable. However, the committee also recalled the possibility of adverse events from multiple lines of newer androgen receptor inhibitors. At consultation, the company presented unadjusted results for both crossing over and having a second newer androgen receptor inhibitor, and adjusted results for a second newer androgen receptor inhibitor only. This had only a small effect on the results, which the committee noted. The committee concluded that it was uncertain if adjusting for the survival benefit of having a second newer androgen receptor inhibitor was necessary, but the impact of this on results was likely to be limited.
## How the company adjusts for crossover in TITAN from placebo plus ADT to apalutamide plus ADT may bias results
The committee considered whether the adjusted or the unadjusted hazard ratios for overall survival and PFS2 were more appropriate for decision making. When adjusting for crossover from the placebo plus ADT arm to the apalutamide plus ADT arm the company assumed that people had no treatment after placebo plus ADT. But, in clinical practice, people are likely to be offered a newer androgen receptor inhibitor including abiraterone plus ADT or enzalutamide plus ADT as their next treatment. The committee considered that this part of the company's analysis could have biased against placebo plus ADT. It considered that an analysis that did not adjust survival estimates for crossover could be reasonable, if it was assumed that apalutamide has similar effectiveness to abiraterone and enzalutamide. At consultation, the company highlighted that unblinding rather than progression drove crossover in TITAN, so it considered adjusting to be appropriate. The committee recognised that adjusting for radiographic-free survival could be appropriate when crossover occurs before progression. This crossover may have resulted in people randomised to placebo plus ADT having treatment with a newer androgen receptor inhibitor earlier than they would in clinical practice. The committee was aware that treatment with a newer androgen receptor inhibitor would still be expected at some point in the NHS. Therefore, adjustments that imply no such treatment may be inappropriate. To explore this uncertainty, the company did scenario analyses with and without adjusting for crossover. The committee concluded that it would take these results into account in its decision making.
## Both adjusted and unadjusted hazard ratios for overall survival and PFS2 from TITAN can be considered for decision making
The company adjusted for the effect of crossover and of having a second androgen receptor inhibitor in TITAN. In TITAN, some people randomised to placebo plus ADT crossed over to apalutamide plus ADT. The percentage is academic-in-confidence and cannot be reported here. The company explained that most crossover occurred between the interim and final data cuts (see section 3.4). The committee noted that the percentage was high. This meant that adjusting for crossover would likely influence the size of the reported relative efficacy effect between apalutamide plus ADT and placebo plus ADT. In its base case, the company selected the adjusted hazard ratios for overall survival and PFS2. The ERG agreed it was appropriate to adjust the hazard ratios for overall survival and PFS2. The committee concluded that it would take both adjusted and unadjusted hazard ratios for overall survival and PFS2 into account in its decision making.
## The company's indirect treatment comparison suggests that apalutamide plus ADT offers an advantage and is well tolerated
No trial has compared apalutamide plus ADT with docetaxel plus ADT. So, the company indirectly compared apalutamide plus ADT with docetaxel plus ADT, for endpoints including overall survival, radiographic progression-free survival, PFS2 and safety. The network meta-analysis included TITAN and 3 randomised controlled trials linking docetaxel plus ADT to apalutamide plus ADT through the common comparator of placebo plus ADT (CHAARTED, GETUG-AFU15, STAMPEDE). The ERG was broadly satisfied with the company's approach. The results suggested that people having apalutamide plus ADT survive longer than people having placebo plus ADT and people having docetaxel plus ADT. The committee noted that although the hazard ratio was below 1, which indicates a benefit, the confidence interval included the possibility of no benefit. The results are academic-in-confidence and cannot be presented here. The committee concluded that the company's indirect treatment comparison suggests that apalutamide plus ADT has an advantage over docetaxel plus ADT for efficacy and is well tolerated.
## TITAN is generalisable to NHS clinical practice for people with hormone-sensitive metastatic disease
Unlike in the NHS, people in TITAN, could have additional lines of newer androgen receptor inhibitors, unlike in the NHS. The committee was aware that this may have impacted the treatment effect and caused uncertainty as to what people could have had instead. So, the committee was unclear on the effect of having multiple newer androgen receptor inhibitors on the direction of bias. However, the committee noted that TITAN was a large high-quality trial measuring relevant outcomes. It concluded that TITAN was generalisable to NHS clinical practice.
# Adverse effects
## Adverse effects with apalutamide are tolerable
The clinical experts explained that apalutamide plus ADT is well tolerated. Rash and hypothyroidism have been reported and are manageable. The committee concluded that adverse effects with apalutamide plus ADT are tolerable.
# Economic model
## The model structure is appropriate for decision making
To estimate the cost effectiveness of apalutamide plus ADT compared with placebo plus ADT, the company used a partitioned survival model with health states for progression-free survival, progressed disease and death. After disease progression, people could have up to 3 lines of therapy and their health-related quality of life could decline. The company used PFS2 to inform the probability of moving between the first and second treatments for metastatic disease. The company used mean duration in each health state to assign people to the remaining health states. In the progression-free survival health state, people could be on or off treatment as determined by trial data on time-to-stopping treatment. The company used TITAN (radiographic progression-free survival and overall survival) to estimate efficacy. The committee concluded that the model structure was appropriate for decision making.
# Modelling the TITAN data
## In TITAN, extrapolating radiographic progression-free survival using a Weibull model is uncertain
The company assessed whether the proportional hazards assumption held for radiographic progression-free survival. Based on the log-cumulative hazard plot for radiographic progression-free survival, and a statistical test (Schoenfeld residual testing), it considered that the proportional hazards assumption may be violated. The company, therefore, decided to fit parametric curves to both arms independently. Based on clinical advice, it chose Weibull curves for its base case. The ERG also chose Weibull curves for its base case for both treatments. But the ERG noted that radiographic progression-free survival data for apalutamide plus ADT was highly immature, which is a large driver of the cost-effectiveness results. The ERG also noted that the Weibull models have worse statistical fit (that is, higher Akaike information criterion and Bayesian information criterion scores) than other models. The committee appreciated these measures reflected the model fit, but only to the observed data. Also, expert advice to the ERG suggested that the Weibull models were likely to underestimate the proportion of people who progressed in the ADT arm at 5, 10 and possibly 15 years. Therefore, the ERG suggested that more flexible models may be more appropriate. The committee agreed that, because of the uncertainty with the Weibull model, it would have liked a more flexible model fitted to extrapolate radiographic progression-free survival beyond the duration of TITAN. At consultation, the company declined to explore flexible approaches. It said that these might be more uncertain than standard parametric models, because of their complexity and number of assumptions. It also said that a flexible approach needed a clinical or statistical reason to justify the time point at which the curves flex, which it considered did not exist. The committee concluded that the company's approach to extrapolating radiographic progression-free survival was uncertain, which the committee factored into its decision making.
## In TITAN, extrapolating overall survival using a Weibull model is acceptable for decision making
The trial statisticians for TITAN could not estimate the upper boundary of the confidence interval for median overall survival because not enough deaths had occurred. To reduce uncertainty and provide longer follow up, the company reviewed the literature for alternative sources to inform this outcome. It found 7 published trials with ADT arms which had longer follow up than TITAN, and referred to this as 'historical data'. It generated synthetic patient-level data from the published survival curves for the ADT arms of these studies and combined them. The ERG considered this a good attempt to collect longer follow-up data although it noted that the company included only studies published after 2013. The ERG could not verify the company's work because the company did not share its systematic review. The company assumed a common shape between the ADT arm reflecting pooled data, and the placebo plus ADT arm in TITAN. Based on expert opinion, it chose the Weibull curves in its base case because these provided the most clinically plausible extrapolations. Expert advice to the ERG was that survival at 5, 10 and possibly 15 years in both treatment arms was higher in practice than estimated by the Weibull models. Despite this, the ERG chose the Weibull model for its base case because it gave the most conservative estimates. The ERG suggested that more flexible models may be more appropriate. The committee was aware that people have a treatment until disease progression. It noted that the company's model showed that people with hormone-sensitive metastatic disease had similar post-progression survival if they had apalutamide plus ADT or docetaxel plus ADT or ADT alone. The committee questioned whether this had face validity and biological plausibility, because people had fewer post-progression treatment options if they chose to start with apalutamide plus ADT instead of ADT alone or docetaxel plus ADT. The post-progression survival estimates are academic-in-confidence and cannot be reported here. At consultation, the company found an error made by NICE. The company explained that according to clinical advice, it was both plausible and likely that apalutamide plus ADT would provide a substantial post-progression benefit. However, the company also presented cost-effectiveness results exploring equal post-progression survival between apalutamide plus ADT and its comparators (see section 3.25). The company also explained that it had chosen not to explore flexible survival models (see section 3.15). The committee concluded that, although it would have liked to have seen flexible models explored, the Weibull model was acceptable for decision making.
## In TITAN, extrapolating PFS2 is uncertain because it is based on immature data
The company, having assessed that the proportional hazards assumption holds for PFS2, applied a Weibull model fitted jointly to both treatments in its base case, based on clinical plausibility and consistency (which helps to avoid the issue of curves crossing) with the curves for radiographic progression-free survival (see section 3.15) and overall survival (see section 3.16). The ERG noted that both the Weibull and Gompertz models have the best statistical fits to the observed data. However, the Weibull model likely overestimates PFS2 at 10 and 15 years for people who have apalutamide plus ADT. Also, the ERG stated that the model appears to predict that people spend almost no time on the third-line treatment for metastatic disease. The ERG considered that the Gompertz model was the only clinically relevant alternative, although it is also likely to overestimate long-term survival for people who have apalutamide plus ADT. The ERG noted that, because the PFS2 estimates were immature in TITAN, extrapolating PFS2 assuming proportional hazards was likely to be highly uncertain. For radiographic progression-free survival and overall survival, the ERG suggested that more flexible approaches would be appropriate. The committee concluded that the true estimates of PFS2 after the end of the trial were uncertain because these were based on immature data.
## Treatment effect waning affects the cost-effectiveness results
The company considered that the benefits of apalutamide plus ADT did not wane over time, so it did not apply any treatment effect waning in its base case. It justified this by noting there was no evidence in TITAN that the overall survival curves for both treatments converge over time. The ERG explored treatment effect waning, but considered it unclear from the hazard plots if treatment benefit declined. Because the treatment effect did not wane in abiraterone clinical trials with longer follow up, the clinical experts and the ERG did not expect treatment effect waning with apalutamide. However, a study in advanced prostate cancer (Antonarakis et al. 2016) suggested that resistance to newer androgen receptor inhibitors was likely to develop with time. The ERG noted that resistance to abiraterone or enzalutamide does not necessarily imply that the treatment effect would wane for apalutamide. It considered that there was not enough evidence to assess the best approach to estimate the duration of treatment benefit. The Cancer Drugs Fund clinical lead noted that, in practice, most newer hormonal treatments for prostate cancer lose effectiveness over time. The committee was aware that both the company and the ERG had explored treatment waning in scenarios before technical engagement. The effect on the incremental cost-effectiveness ratio (ICER) was an increase of around £2,000 per quality-adjusted life year (QALY) gained when varying treatment effect waning from 100% to 0% for a duration of 5 years and 10 years. The committee concluded that treatment effect waning affected the cost-effectiveness results.
# Treatment costs
## The costs of apalutamide are appropriately captured in the model
The committee was aware that the company offered apalutamide to the NHS at a discount, which the company increased over the course of the appraisal. The committee was aware that duration of treatment determines cost. People have apalutamide plus ADT until disease progression, or until they can no longer tolerate it or choose to stop. The company took time-to-treatment discontinuation and radiographic progression-free survival from TITAN data cuts that occurred at different times. The company explained that the costs used in the model were informed by the minimum of either time-to-treatment discontinuation, or radiographic progression-free survival curves. The company therefore capped the costs. During the first committee meeting, it noted that this might have underestimated the cost of apalutamide in the model. However, at consultation the company stated that it now believed that the costs of treatment had been fully captured. The company also provided a scenario analysis with time on treatment equal to progression-free survival. The ERG confirmed that it agreed with the company's approach in its base case, because no one with progressed disease should remain on treatment. The ERG considered the company's base case would not underestimate the costs of apalutamide. The committee concluded that the costs of apalutamide were appropriately captured in the company's model.
# Utility values
## The company's utility values are broadly appropriate
The company assumed that health-related quality of life declines over time because simulated people in the model have disease progression and move onto subsequent lines of therapy (see section 3.14). The company's utility value for having first-line treatment for hormone-relapsed metastatic prostate cancer was from TITAN using the EQ-5D-3L. The utility values are considered confidential by the company so cannot be reported here. For second- and third-line treatments for hormone-relapsed metastatic prostate cancer, the company originally used external data from NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA387). This was because a limited number of people completed the EQ-5D-3L questionnaire after developing metastases in TITAN. The company derived the utility values for second- and third-line treatments from the first treatment by applying a 'relative decline ratio'. It did this by estimating the relative decline in utility in TA387 between first- and second-line treatments for metastatic disease, and first- and third-line treatments for metastatic disease. It then applied these ratios to the progressed utility value from TITAN to estimate utilities for second- and third-line hormone-relapsed metastatic prostate cancer. The company also adjusted the derived utility values to account for population differences between TITAN and TA387. The company noted that it did this in line with the method described in the NICE Decision Support Unit's technical support document 12 on the use of health state utility values in decision models. The ERG had concerns with the company's adjusted utility values:
They were much lower than those used in NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA377) and enzalutamide for hormone-relapsed non-metastatic prostate cancer (TA580). The utility values were 0.658 and 0.612 in TA377 and 0.8 and 0.688 in TA580, for health states reflecting second- and third-line treatments of hormone-relapsed metastatic prostate cancer.
It was unclear which line of treatment generated the utility values reported in TA387.
By applying a 'relative decline ratio', the company assumed that the utility values would decrease by the same relative proportion between first- and second-line treatments for hormone-relapsed metastatic prostate cancer (as in TA387). But, the committee considered that this assumption may not be appropriate given the different population in this appraisal (hormone-sensitive metastatic disease) and in TA387 (hormone-relapsed metastatic disease before chemotherapy is indicated).In its base case, the ERG used the utility values from TA377 without adjusting them. The patient experts highlighted the effect of psychological distress and worry about a treatment's loss of efficacy. The clinical expert was aware that EQ‑5D, measured in TITAN, included questions on anxiety and depression and agreed with the company's utility values. The committee agreed that this disease was associated with a significant effect on quality of life. However, it was concerned with the lack of consistency with utility values used in related technology appraisals. Also, the Cancer Drugs Fund clinical lead explained that the ERG's unadjusted utility values better fitted what had been seen in other disease areas with multiple lines of treatment. Therefore, the committee agreed that, on balance, the ERG's utility values had a higher face validity than the company's adjusted utility values. At consultation, the company updated its base case using unadjusted utility values from TA377 for second- and third-line hormone-relapsed metastatic prostate cancer. The committee concluded that the unadjusted utility values from TA377 were most appropriate for decision making.
# Modelling the adverse effects of docetaxel
## The company and ERG's cost estimates are satisfactory
In the original model, the company assumed that the adverse effects of docetaxel occurred throughout the hormone-sensitive metastatic prostate cancer pre-progression health state. At technical engagement before the first committee meeting, the ERG explained that this overestimated the costs of managing adverse effects, and it was more appropriate to apply those costs for the first 6 months. The company agreed that this overestimated the costs but suggested that after 6 months of treatment there would be additional costs associated with the adverse effects of ongoing ADT. Therefore, in its base case, the company applied the costs of managing adverse effects for docetaxel for 6 months and the costs of managing adverse effects for ADT alone thereafter. The ERG's base case reflected the company's assumption. The clinical experts explained that the adverse effects of docetaxel were likely to last for 6 to 12 months. The committee concluded that the company and ERG's cost estimates were satisfactory.
## The committee is satisfied with the ERG's incidence rates for neutropenia and febrile neutropenia
The company's model included grade 3 to 4 neutropenia and febrile neutropenia, which are adverse effects associated with docetaxel. In the hormone-sensitive metastatic pre-progression health state, the rates of these adverse effects were based on an epidemiological study on docetaxel use in the NHS (Patrikidou et al. 2017). These were 36.3% for neutropenia and 18.2% for febrile neutropenia per course of 6 cycles of docetaxel. The company suggested that these rates may be low. The ERG noted that the company's sources of observational data had methodological limitations including no information on patient numbers. In its base case, the ERG used pooled data from 3 docetaxel trials (GETUG-AFU15, STAMPEDE and CHAARTED). It estimated combined rates of 10.6% for febrile neutropenia and 15.4% for neutropenia, at a constant rate over 6 months. STAMPEDE included only people from the UK and Switzerland, and was therefore more likely to represent NHS clinical practice. At consultation, the company also applied the ERG's approach to these incidence rates. The committee concluded that it was satisfied with the company and the ERG's pooled incidence rates for neutropenia and febrile neutropenia.
# End of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company did not make a case for end of life in its submission. The committee concluded that the end of life criteria were not met for apalutamide in hormone-sensitive metastatic prostate cancer.
# Cost-effectiveness estimates
## An acceptable ICER would be lower than the middle of the range normally considered cost effective
The committee recalled its earlier conclusion that the data is immature for overall survival and PFS2 and there is uncertainty about the appropriate extrapolation model for radiographic progression-free survival, overall survival and PFS2. So, the committee agreed that an acceptable ICER would be lower than the middle of the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).
## Apalutamide is not cost effective in the whole population for hormone-sensitive metastatic disease
Because of confidential commercial arrangements for apalutamide and subsequent treatments, the cost-effectiveness estimates cannot be reported here. The committee was satisfied with some of the ERG's preferred assumptions. These included:
not adjusting treatment effect for either crossover or having a second androgen receptor inhibitor on overall survival and PFS2 (see section 3.7)
using unadjusted utility values for second- and third-line metastatic disease (see section 3.20)
using pooled incidence rates for neutropenia (15.4%) and febrile neutropenia (10.6%; see section 3.22)
incremental cost-effectiveness analyses including docetaxel plus ADT, apalutamide plus ADT, and ADT alone.At consultation, the company explored scenarios for some of the uncertainties identified by the committee, including:
not adjusting treatment effect for both crossover and having a second newer androgen receptor inhibitor
adjusting treatment effect for having a second newer androgen receptor inhibitor (and not crossover)
setting time on treatment equal to progression-free survival (see section 3.19)
setting equal post-progression survival between intervention and comparator arms (see section 3.16).The company also presented probabilistic ICERs. The company increased its confidential discount for apalutamide. Based on incremental deterministic ICERs, the committee agreed that the cost-effectiveness estimates for apalutamide plus ADT compared with docetaxel plus ADT were well above the range normally considered a cost-effective use of NHS resources. So, it concluded that apalutamide could not be recommended as a cost-effective use of NHS resources for treating hormone-sensitive metastatic prostate cancer.
## The committee considered a group of people who cannot have docetaxel, but the lack of direct evidence increases uncertainty
The committee considered whether there was a group of people for whom apalutamide plus ADT would be a clinically and cost-effective option. It considered the population who cannot have docetaxel, having discussed how to identify them (see section 3.3). The committee was aware that docetaxel was not a relevant comparator for them or a treatment they would have when their disease became resistant to hormone treatment. The relevant comparator was ADT alone. The committee was aware that it had no direct relevant evidence with which to consider the cost effectiveness of apalutamide plus ADT compared with ADT alone for people who cannot have docetaxel. The committee was aware that TITAN excluded people who would be most likely not to be able to have docetaxel in NHS practice, for example people with an ECOG score of 2 or more (see section 3.4). So, the committee looked at evidence of effectiveness for people who had risk factors, such as age, that would make them more likely to be unsuitable for docetaxel. The committee was aware of data from stakeholders and NHS England documenting the association between older age and decreasing use of docetaxel for hormone-sensitive disease. It was also aware of subgroup analyses from TITAN which showed a hazard ratio for progression or death of 0.65 for people over 75 years compared with hazard ratios of 0.45 and 0.47 for younger age groups. The committee was aware that there was no evidence of treatment-by-age interaction which meant that if there is an interaction, the analysis did not find it.
After consultation, for the committee's third meeting, the company did analyses for groups it considered to represent people who cannot have docetaxel. These included people:
with low volume disease (the company considered chemotherapy to be less effective for this group, but did not provide evidence)
with an ECOG score of 1 (representing a more unwell population than an ECOG score of 0)
-ver 75 years.It also included scenarios:
reducing utility values for all lines of treatment by 10% (to explore utility values reflecting the older more unwell population)
removing chemotherapy during metastatic hormone-relapsed disease (to explore a model in which people do not go on to get docetaxel or chabazite when their disease becomes hormone relapsed).
The committee questioned the relevance of the company's response defining people with low volume disease or people with an ECOG score of 1 as people who cannot or should have docetaxel. The Cancer Drugs Fund clinical lead explained that low volume disease was not a proxy for not being able to have docetaxel. The committee noted that an ECOG score of 1 represented a relatively well population. It recalled that the STAMPEDE trial of docetaxel plus ADT plus prednisone enrolled people with an ECOG score of 0, 1 and 2 and showed that docetaxel was equally effective in people with a score of 0 and a score of 1 and above. Moreover, in the NHS, people with an ECOG score of 1 would likely be offered chemotherapy. The committee concluded that the company's analyses did not reflect a group who could not have docetaxel. Although older people are less likely to be able to have docetaxel, some younger people cannot have docetaxel, and the committee would be unlikely to make age-based recommendations. The committee concluded that, in the absence of evidence directly addressing the population of interest, this increased the uncertainty in the cost effectiveness results. When taking into account the company's increased discount and the uncertainty, the committee considered that the ICER most closely reflecting its preferred assumptions is within a cost-effective use of NHS resources. So, the committee recommended apalutamide plus ADT as an effective use of NHS resources for treating hormone-sensitive metastatic prostate cancer for people who cannot have docetaxel.
# Innovation
## Apalutamide plus ADT is not innovative for hormone-sensitive metastatic prostate cancer
The company considered apalutamide plus ADT to be innovative because it is an oral treatment and requires less monitoring than docetaxel plus ADT. However, the committee noted that enzalutamide, a new oral androgen receptor inhibitor that was not available when this appraisal started, is now an option with ADT for treating hormone-sensitive metastatic prostate cancer in the NHS. It concluded that apalutamide plus ADT was not innovative.
# Equality issues
## The recommendations apply to all people with prostate cancer
The committee noted that, as in previous NICE technology appraisals of prostate cancer treatments, its recommendations should apply to all people with prostate cancer. It further noted that a person can have a prostate but not identify as a man. Gender reassignment is a protected characteristic under the Equality Act 2010. The committee also noted that, in clinical practice, older people are less likely to have docetaxel than younger people. It was aware that although docetaxel is more likely to be contraindicated or unsuitable for older people, age alone will not determine whether a person could or should have docetaxel in clinical practice. The committee was also aware that making recommendations by age to reflect people who cannot have docetaxel could discriminate against younger people for whom docetaxel is contraindicated or unsuitable. The committee concluded that, by considering the cost effectiveness for people who could not have docetaxel (see sections 3.26 to 3.28), it took into account older people in its recommendations.
|
{'Recommendations': 'Apalutamide plus androgen deprivation therapy (ADT) is recommended as an option for treating hormone-sensitive metastatic prostate cancer in adults, only if:\n\ndocetaxel is not suitable\n\nthe company provides apalutamide according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with apalutamide plus ADT that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nHormone-sensitive metastatic prostate cancer is usually treated with docetaxel plus androgen deprivation therapy (ADT), ADT alone or enzalutamide plus ADT. Enzalutamide was not available when this appraisal started.\n\nClinical trial evidence suggests that, compared with placebo plus ADT, apalutamide plus ADT increases the time until the disease progresses and how long people live.\n\nApalutamide plus ADT is not cost effective compared with docetaxel. However, compared with ADT, the cost-effectiveness estimates for apalutamide plus ADT are within what NICE considers to be an acceptable use of NHS resources. So, apalutamide plus ADT is recommended for people with hormone-sensitive metastatic prostate cancer only if they cannot have docetaxel.', 'Information about apalutamide': "# Marketing authorisation indication\n\nApalutamide (Erleada, Janssen) is indicated 'in adult men for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC) in combination with androgen deprivation therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe price for apalutamide is £2,735 per pack of 112\xa0tablets, each containing 60\xa0mg of the active ingredient (excluding VAT; BNF online, March\xa02021). The company has a commercial arrangement (simple discount patient access scheme). This makes apalutamide available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Janssen, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Treatment pathway\n\n## Only 1\xa0newer androgen receptor inhibitor would be used in the prostate cancer treatment pathway\n\nNICE recommends the newer (second-generation) androgen receptor inhibitors enzalutamide plus androgen deprivation therapy (ADT), and darolutamide plus ADT, or abiraterone plus prednisone or prednisolone plus ADT (hereafter abiraterone in combination) for treating hormone‑sensitive metastatic or hormone-relapsed non-metastatic prostate cancer at multiple positions in the treatment pathway:\n\nNICE's technology appraisal guidance on darolutamide with androgen deprivation therapy for treating hormone-relapsed non-metastatic prostate cancer\n\nNICE's technology appraisal guidance on enzalutamide for treating hormone-sensitive metastatic prostate cancer\n\nNICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated\n\nNICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated\n\nNICE's technology appraisal guidance on abiraterone for castration-resistant metastatic prostate cancer previously treated with a docetaxel-containing regimen\n\nNICE's technology appraisal guidance on enzalutamide for metastatic hormone‑relapsed prostate cancer previously treated with a docetaxel‑containing regimen.People have treatment with a second‑generation androgen receptor inhibitor until disease progression, docetaxel for up to 6\xa0cycles, and ADT indefinitely. Apalutamide is another second‑generation androgen receptor inhibitor. The Cancer Drugs Fund clinical lead explained that a person will have only 1 of these drugs in the NHS prostate cancer treatment pathway. The clinical experts confirmed that this is because of the similar way the drugs work, and probable resistance to drugs in the same group when used one after another. For example, if prostate cancer metastasises on apalutamide plus ADT, it would be expected to be resistant to subsequent treatment with enzalutamide plus ADT or abiraterone plus ADT. The Cancer Drugs Fund clinical lead confirmed that NHS England would not commission enzalutamide or abiraterone after apalutamide. The committee concluded that only\xa01 newer androgen receptor inhibitor would be used in the treatment pathway for prostate cancer.\n\n# Clinical management\n\n## People would value additional treatments for hormone-sensitive metastatic disease\n\nApalutamide has more than 1 indication for prostate cancer. This appraisal considers apalutamide for treating hormone-sensitive metastatic prostate cancer. Until recently, treatment for hormone-sensitive metastatic prostate cancer included ADT alone, or docetaxel for up to 6\xa0cycles administered as a 1-hour intravenous infusion every 3\xa0weeks, given with ADT and with or without prednisone or prednisolone. People who have had docetaxel plus ADT for hormone-sensitive metastatic disease can have it again if the cancer progresses. NICE now recommends enzalutamide plus ADT for hormone-sensitive metastatic disease. Also, NHS England's interim guidance on treatment options during the COVID-19 pandemic allows use of abiraterone plus prednisone plus ADT but, because of the cost of abiraterone, only for people who cannot tolerate enzalutamide plus ADT. The patient experts explained that people who are diagnosed with metastatic disease may have no or few symptoms and may think that docetaxel worsens quality of life. As a result, some choose to have ADT alone, even though the long-term outcomes may be worse. The patient experts noted that apalutamide plus ADT is likely to be more effective than ADT alone (see section\xa03.5) and is generally better tolerated than docetaxel plus ADT (see section 3.3). The committee concluded that people with hormone-sensitive metastatic prostate cancer would value additional treatment options.\n\n## Identifying people with hormone-sensitive metastatic disease who cannot have docetaxel involves assessing a person's risks\n\nFor people with hormone-sensitive metastatic prostate cancer, the company proposed apalutamide plus ADT as an alternative to ADT alone or docetaxel plus ADT. This included people who should not have docetaxel because of comorbidities, or who choose not to have docetaxel. The company also proposed a comparison of apalutamide plus ADT with ADT alone for people who could not or should not have docetaxel. The committee noted that defining the group for whom docetaxel is unsuitable was complicated. It had done this in the NICE technology appraisal of abiraterone for treating newly diagnosed high-risk hormone-sensitive metastatic prostate cancer with input from the Cancer Drugs Fund clinical lead, clinical experts and stakeholders. The committee was aware that NHS England's clinical commissioning policy statement for docetaxel in combination with ADT defines who may not be well enough to have docetaxel. This includes people with a poor overall performance status (World Health Organization [WHO] performance 3 to 4). The policy also states that docetaxel should be used with caution in people with a WHO performance status of 2 and that there are few absolute contraindications to docetaxel. The Cancer Drugs Fund clinical lead had explained during the appraisal of abiraterone that many factors other than performance status may affect whether a person could have docetaxel. The committee noted that people for whom docetaxel is contraindicated or unsuitable would include:\n\npeople for whom docetaxel is contraindicated, as listed in docetaxel's summary of product characteristics and NHS England's clinical commissioning policy statement for docetaxel in combination with ADT\n\npeople with poor performance status (WHO or Eastern Cooperative Oncology Group [ECOG] performance status 3 or 4, and possibly status 2 because docetaxel is used with caution in this group)\n\npeople with significant comorbidity (for example, cardiovascular, respiratory or liver disease), so prostate cancer is unlikely to be their only life-limiting illness\n\npeople with peripheral sensory neuropathy or poor bone marrow function\n\npeople with poor cognition or social support leading to a decreased ability to understand treatment options or make a decision.The committee agreed that clinicians should assess the risks and benefits of having docetaxel based on a person's individual risk factors. This should include the advantages and disadvantages of all treatment options, including fewer options for later treatments for people who choose to have apalutamide. The committee appreciated that some people may not be well enough to have docetaxel plus ADT and with or without prednisone or prednisolone, enzalutamide plus ADT, or apalutamide plus ADT, so they would still be offered ADT alone. It concluded that identifying people for whom docetaxel was contraindicated or unsuitable would be based on a clinical framework considering individual patient risk.\n\n# Clinical evidence\n\n## The TITAN results are in line with planned analyses\n\nTITAN was a phase\xa03, randomised, multicentre trial comparing apalutamide plus ADT (n=525) with placebo plus ADT (n=527) for hormone-sensitive metastatic prostate cancer. The trial population had adenocarcinoma of the prostate that had metastasised but was still sensitive to treatment with hormone therapy. The trial included people with ECOG scores of 0, 1 or 2 and excluded people with severe haematological, hepatic or renal dysfunction. The committee considered that the population in TITAN reflected people with hormone-sensitive prostate cancer in NHS clinical practice reasonably well. TITAN's co-primary endpoints were overall survival and radiographic progression-free survival, that is, the time from randomisation to confirmed evidence of radiographic progressive disease or death from any cause. Secondary endpoints included time to cytotoxic chemotherapy. Exploratory endpoints included progression-free survival on first subsequent treatment (PFS2) and health-related quality of life. The committee was aware that although these were exploratory endpoints, the company used PFS2 and EQ‑5D in its cost-effectiveness modelling. Health-related quality of life was measured using the EQ‑5D‑5L questionnaire, the FACT-P, the Brief Pain Inventory (BPI) and the Brief Pain Inventory Short Form (BPI-SF). The final analysis for radiographic progression-free survival and interim analyses for overall survival and PFS2 were done in November 2018. At this time, most people's cancer had progressed, and the radiographic progression-free survival endpoint had been met. In November 2018, the trial was unblinded and people who had placebo could cross over to have apalutamide plus ADT if their cancer had not progressed. The company did the final analyses of overall survival and PFS2 in September 2020. After disease progression, people could have abiraterone or enzalutamide. The committee was aware that TITAN included people based on whether they could have docetaxel, but only those with an ECOG score of 0 or\xa01. The company did not present clinical evidence of apalutamide plus ADT's effectiveness compared with ADT alone for people who cannot have docetaxel. The committee concluded that the results were in line with the trial's planned analyses.\n\n## Apalutamide plus ADT is clinically effective compared with placebo plus ADT\n\nIn TITAN:\n\nmedian radiographic progression-free survival for people randomised to apalutamide plus ADT was not reached and for people randomised to placebo plus ADT it was 22.1\xa0months (hazard ratio 0.5, 95% confidence interval 0.4 to 0.6)\n\nmedian overall survival and median PFS2 for people randomised to apalutamide plus ADT and for people randomised to placebo plus ADT are academic-in-confidence and cannot be reported here\n\nmean change in EQ-5D-5L visual analogue score showed no differences between the apalutamide plus ADT and placebo plus ADT treatment arms for all treatment cycles. For example, mean change at cycle\xa021 on apalutamide plus ADT was 2.50 and on placebo plus ADT it was 2.04, with a difference of -0.46 (p=0.7678).The company used the hazard ratio for the whole population (that is, people with hormone-sensitive metastatic prostate cancer) to show the effectiveness of apalutamide plus ADT for people whom docetaxel is not suitable. The committee understood that no evidence was available for people who cannot have docetaxel as they were likely excluded from the TITAN trial. It considered whether a subgroup of the trial population could be used as a proxy. For example, the patient expert had explained that people who cannot or should not have docetaxel are often older. The company confirmed that it did have a hazard ratio for a subgroup of older people for the endpoint of time to progression or death, but it did not use this. The hazard ratio and upper boundary of the confidence interval crossed 1.0 (no effect) for people 75\xa0years and older, whereas it did not for people younger than 75\xa0years. However, there was no statistically significant difference for interaction. The committee agreed that there would be several uncertainties in using age as a proxy, including confounding factors and because some younger people cannot have docetaxel. At consultation, the company submitted cost-effectiveness analyses for subgroups it considered to represent people who cannot have docetaxel, but no clinical evidence for the subgroup itself (see section 3.28). The committee concluded that apalutamide plus ADT extended radiographic progression-free survival, overall survival and PFS2 when compared with placebo plus ADT. However, there was no clinical evidence for a subgroup who cannot have docetaxel (see section\xa03.26).\n\n## The modified RPSFTM is appropriate for decision making, but there is still uncertainty\n\nThe results for overall survival and PFS2 (reported as hazard ratios in TITAN) were adjusted to reflect the treatment effect that would be seen in NHS practice. This is because in the trial people randomised to:\n\nplacebo plus ADT crossed over to apalutamide plus ADT\n\napalutamide plus ADT went on to have abiraterone plus ADT or enzalutamide plus ADT.The committee discussed both situations. In TITAN, 208\xa0people (39.5%) randomised to placebo plus ADT crossed over to apalutamide plus ADT. The company explained that this could underestimate the relative benefit of apalutamide plus ADT for overall survival and PFS2. This was because some people progressed or died only after the trial was unblinded (see section 3.4). However, the committee recognised that people with metastatic disease who have ADT alone (as in the placebo plus ADT arm of TITAN) could have abiraterone in combination or enzalutamide plus ADT in the NHS (see section\xa03.9). This would mean that the trial endpoints may not need to be adjusted. The committee also recognised that people can have only 1 newer androgen receptor inhibitor in the NHS prostate cancer treatment pathway (see section\xa03.1). Because more people randomised to apalutamide plus ADT had a second newer androgen receptor inhibitor, the trial results may have overestimated the effect of apalutamide plus ADT on PFS2 and overall survival, if having a second newer androgen receptor inhibitor is beneficial. The company considered that the number of people who had a second newer androgen receptor inhibitor is academic-in-confidence and cannot be reported here. The clinical expert explained that having a second newer androgen receptor inhibitor is unlikely to extend life, but might be associated with adverse effects. The committee appreciated that this type of switching might not bias survival estimates, but it was possible that people could have had a better response to the treatment if they had not had a second newer androgen receptor inhibitor. The company considered several different methods for adjusting overall survival and PFS2 results. These included the rank preserving structural failure time model (RPSFTM), iterative parameter estimation (IPE), inverse probability of censoring weights (IPCW) and 2‑stage estimation. The company chose to use a modified version of the RPSFTM (Diels et al. 2019). The company explained that it did not have enough data to estimate the multiple parameters needed for the RPSFTM and IPE methods, and the IPCW method provided counterintuitive and clinically implausible results. The company also said that the 2‑stage method was not viable because of a lack of the data and the need for a 'secondary baseline' before changing to apalutamide plus ADT or having a second newer androgen receptor inhibitor. The committee questioned whether it was necessary to adjust the results because of the likely minimal effect of multiple lines of newer treatments (see section\xa03.12). It appreciated that the modified RPSFTM appeared to be reasonable but was more like a 2-stage method using aspects of all the adjustment approaches and propensity weighting. It also considered that the IPCW and 2‑stage methods could have been suitable, if appropriately specified. So, at its first meeting the committee asked that the company explore alternative approaches. At consultation the company explained that it did not have time to explore alternative approaches. It reiterated its view that the modified RPSFTM was the most appropriate method. The committee was disappointed that the company chose not to explore alternative approaches. But it noted that the adjusted and unadjusted results were similar, which reduced the risks associated with this uncertainty. It concluded that the modified RPSFTM was acceptable for decision making.\n\n## Using data from COU-AA-302 to estimate the effect of a second newer androgen receptor inhibitor and to adjust for survival causes uncertainty\n\nThe company manufactures abiraterone as well as apalutamide, and acknowledged that it can access individual patient data from trials of abiraterone for hormone-relapsed metastatic disease. To estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor in TITAN using the modified RPSFTM, the company used data from another trial, COU‑AA‑302, later in the treatment pathway. COU‑AA‑302 was a randomised trial comparing abiraterone plus prednisone with placebo plus prednisone in people with hormone-relapsed metastatic prostate cancer who had not had cytotoxic chemotherapy. The ERG explained that it could not verify the results of the modified RPSFTM because the company had not provided the requested individual patient data. Although the ERG agreed with using the COU‑AA‑302 data, it noted that the survival benefit of abiraterone may be underestimated. This was because people randomised to placebo plus prednisone in the trial could cross over to have abiraterone plus ADT at unblinding. To address the ERG's concern, the company estimated the survival benefits of abiraterone based on the COU‑AA‑302 trial's interim and final analysis data. This showed that the final analysis data may be affected by crossover from placebo to abiraterone. For the interim data the bias should be small because only 3\xa0people (0.55% of the 542 originally randomised to the placebo plus prednisone arm) had crossed over to abiraterone plus prednisone at this stage. The ERG considered that using the COU-AA-302 interim or final analysis data minimally affected the adjusted hazard ratios for overall survival. It noted that the active treatment in COU-AA-302 had a considerably bigger effect on progression-free survival (used by the company to adjust PFS2) than on overall survival. Therefore, adjusting PFS2 in COU-AA-302 would have a bigger effect on the adjusted hazard ratios and would likely increase the cost-effectiveness estimates. At consultation the company said that progression-free survival in COU‑AA-302 was not affected by crossover from placebo to abiraterone. However, the ERG noted that 17% (93 of 542) of people initially randomised to the placebo plus prednisone arm went on have abiraterone plus prednisone. Because a substantial number of people crossed over to abiraterone, progression-free survival could have been affected by crossover. The company also presented unadjusted results for both crossover and having a second androgen receptor inhibitor, and adjusted results for having a newer androgen receptor inhibitor only. This had a small effect on the results, which the committee noted. It concluded that using COU‑AA‑302 data to estimate the effect of a second newer androgen receptor inhibitor caused uncertainty but was unlikely to affect the results much.\n\n## Adjusting for the survival benefit of having more than 1 newer androgen receptor inhibitor may be unnecessary\n\nThe committee noted that COU-AA-302 included only people who had never had a newer androgen receptor inhibitor. So, using this data to adjust for the impact of a second newer androgen receptor inhibitor would 'over adjust' the overall survival of people having a second newer androgen receptor inhibitor in TITAN. This is because it is unlikely that a second newer androgen receptor inhibitor is as effective as the first one. Because more people in the apalutamide plus ADT arm of TITAN had a second newer androgen receptor inhibitor, adjusting for this treatment with COU‑AA‑302 data in this way could bias against apalutamide plus ADT. The committee agreed that using COU-AA-302 data to estimate and adjust for the survival benefit of a second newer androgen receptor inhibitor caused uncertainty (see section 3.7). It noted that using an appropriately specified IPCW or 2‑stage adjustment method applied to TITAN may have avoided the potential bias with estimating the effect of a second newer androgen receptor inhibitor based on data from COU-AA-302. Also, the committee understood that only 1 newer androgen receptor inhibitor would be used in the NHS prostate cancer treatment pathway (see section 3.1). Because they are unlikely to be effective when used again, it may be unnecessary to adjust the TITAN survival estimates. The committee agreed that considering a scenario in which people who had a second newer androgen receptor inhibitor survived longer than if they had followed the NHS treatment pathway could be reasonable. However, the committee also recalled the possibility of adverse events from multiple lines of newer androgen receptor inhibitors. At consultation, the company presented unadjusted results for both crossing over and having a second newer androgen receptor inhibitor, and adjusted results for a second newer androgen receptor inhibitor only. This had only a small effect on the results, which the committee noted. The committee concluded that it was uncertain if adjusting for the survival benefit of having a second newer androgen receptor inhibitor was necessary, but the impact of this on results was likely to be limited.\n\n## How the company adjusts for crossover in TITAN from placebo plus ADT to apalutamide plus ADT may bias results\n\nThe committee considered whether the adjusted or the unadjusted hazard ratios for overall survival and PFS2 were more appropriate for decision making. When adjusting for crossover from the placebo plus ADT arm to the apalutamide plus ADT arm the company assumed that people had no treatment after placebo plus ADT. But, in clinical practice, people are likely to be offered a newer androgen receptor inhibitor including abiraterone plus ADT or enzalutamide plus ADT as their next treatment. The committee considered that this part of the company's analysis could have biased against placebo plus ADT. It considered that an analysis that did not adjust survival estimates for crossover could be reasonable, if it was assumed that apalutamide has similar effectiveness to abiraterone and enzalutamide. At consultation, the company highlighted that unblinding rather than progression drove crossover in TITAN, so it considered adjusting to be appropriate. The committee recognised that adjusting for radiographic-free survival could be appropriate when crossover occurs before progression. This crossover may have resulted in people randomised to placebo plus ADT having treatment with a newer androgen receptor inhibitor earlier than they would in clinical practice. The committee was aware that treatment with a newer androgen receptor inhibitor would still be expected at some point in the NHS. Therefore, adjustments that imply no such treatment may be inappropriate. To explore this uncertainty, the company did scenario analyses with and without adjusting for crossover. The committee concluded that it would take these results into account in its decision making.\n\n## Both adjusted and unadjusted hazard ratios for overall survival and PFS2 from TITAN can be considered for decision making\n\nThe company adjusted for the effect of crossover and of having a second androgen receptor inhibitor in TITAN. In TITAN, some people randomised to placebo plus ADT crossed over to apalutamide plus ADT. The percentage is academic-in-confidence and cannot be reported here. The company explained that most crossover occurred between the interim and final data cuts (see section\xa03.4). The committee noted that the percentage was high. This meant that adjusting for crossover would likely influence the size of the reported relative efficacy effect between apalutamide plus ADT and placebo plus ADT. In its base case, the company selected the adjusted hazard ratios for overall survival and PFS2. The ERG agreed it was appropriate to adjust the hazard ratios for overall survival and PFS2. The committee concluded that it would take both adjusted and unadjusted hazard ratios for overall survival and PFS2 into account in its decision making.\n\n## The company's indirect treatment comparison suggests that apalutamide plus ADT offers an advantage and is well tolerated\n\nNo trial has compared apalutamide plus ADT with docetaxel plus ADT. So, the company indirectly compared apalutamide plus ADT with docetaxel plus ADT, for endpoints including overall survival, radiographic progression-free survival, PFS2 and safety. The network meta-analysis included TITAN and 3\xa0randomised controlled trials linking docetaxel plus ADT to apalutamide plus ADT through the common comparator of placebo plus ADT (CHAARTED, GETUG-AFU15, STAMPEDE). The ERG was broadly satisfied with the company's approach. The results suggested that people having apalutamide plus ADT survive longer than people having placebo plus ADT and people having docetaxel plus ADT. The committee noted that although the hazard ratio was below\xa01, which indicates a benefit, the confidence interval included the possibility of no benefit. The results are academic-in-confidence and cannot be presented here. The committee concluded that the company's indirect treatment comparison suggests that apalutamide plus ADT has an advantage over docetaxel plus ADT for efficacy and is well tolerated.\n\n## TITAN is generalisable to NHS clinical practice for people with hormone-sensitive metastatic disease\n\nUnlike in the NHS, people in TITAN, could have additional lines of newer androgen receptor inhibitors, unlike in the NHS. The committee was aware that this may have impacted the treatment effect and caused uncertainty as to what people could have had instead. So, the committee was unclear on the effect of having multiple newer androgen receptor inhibitors on the direction of bias. However, the committee noted that TITAN was a large high-quality trial measuring relevant outcomes. It concluded that TITAN was generalisable to NHS clinical practice.\n\n# Adverse effects\n\n## Adverse effects with apalutamide are tolerable\n\nThe clinical experts explained that apalutamide plus ADT is well tolerated. Rash and hypothyroidism have been reported and are manageable. The committee concluded that adverse effects with apalutamide plus ADT are tolerable.\n\n# Economic model\n\n## The model structure is appropriate for decision making\n\nTo estimate the cost effectiveness of apalutamide plus ADT compared with placebo plus ADT, the company used a partitioned survival model with health states for progression-free survival, progressed disease and death. After disease progression, people could have up to 3\xa0lines of therapy and their health-related quality of life could decline. The company used PFS2 to inform the probability of moving between the first and second treatments for metastatic disease. The company used mean duration in each health state to assign people to the remaining health states. In the progression-free survival health state, people could be on or off treatment as determined by trial data on time-to-stopping treatment. The company used TITAN (radiographic progression-free survival and overall survival) to estimate efficacy. The committee concluded that the model structure was appropriate for decision making.\n\n# Modelling the TITAN data\n\n## In TITAN, extrapolating radiographic progression-free survival using a Weibull model is uncertain\n\nThe company assessed whether the proportional hazards assumption held for radiographic progression-free survival. Based on the log-cumulative hazard plot for radiographic progression-free survival, and a statistical test (Schoenfeld residual testing), it considered that the proportional hazards assumption may be violated. The company, therefore, decided to fit parametric curves to both arms independently. Based on clinical advice, it chose Weibull curves for its base case. The ERG also chose Weibull curves for its base case for both treatments. But the ERG noted that radiographic progression-free survival data for apalutamide plus ADT was highly immature, which is a large driver of the cost-effectiveness results. The ERG also noted that the Weibull models have worse statistical fit (that is, higher Akaike information criterion and Bayesian information criterion scores) than other models. The committee appreciated these measures reflected the model fit, but only to the observed data. Also, expert advice to the ERG suggested that the Weibull models were likely to underestimate the proportion of people who progressed in the ADT arm at 5, 10 and possibly 15\xa0years. Therefore, the ERG suggested that more flexible models may be more appropriate. The committee agreed that, because of the uncertainty with the Weibull model, it would have liked a more flexible model fitted to extrapolate radiographic progression-free survival beyond the duration of TITAN. At consultation, the company declined to explore flexible approaches. It said that these might be more uncertain than standard parametric models, because of their complexity and number of assumptions. It also said that a flexible approach needed a clinical or statistical reason to justify the time point at which the curves flex, which it considered did not exist. The committee concluded that the company's approach to extrapolating radiographic progression-free survival was uncertain, which the committee factored into its decision making.\n\n## In TITAN, extrapolating overall survival using a Weibull model is acceptable for decision making\n\nThe trial statisticians for TITAN could not estimate the upper boundary of the confidence interval for median overall survival because not enough deaths had occurred. To reduce uncertainty and provide longer follow up, the company reviewed the literature for alternative sources to inform this outcome. It found 7\xa0published trials with ADT arms which had longer follow up than TITAN, and referred to this as 'historical data'. It generated synthetic patient-level data from the published survival curves for the ADT arms of these studies and combined them. The ERG considered this a good attempt to collect longer follow-up data although it noted that the company included only studies published after 2013. The ERG could not verify the company's work because the company did not share its systematic review. The company assumed a common shape between the ADT arm reflecting pooled data, and the placebo plus ADT arm in TITAN. Based on expert opinion, it chose the Weibull curves in its base case because these provided the most clinically plausible extrapolations. Expert advice to the ERG was that survival at 5, 10 and possibly 15\xa0years in both treatment arms was higher in practice than estimated by the Weibull models. Despite this, the ERG chose the Weibull model for its base case because it gave the most conservative estimates. The ERG suggested that more flexible models may be more appropriate. The committee was aware that people have a treatment until disease progression. It noted that the company's model showed that people with hormone-sensitive metastatic disease had similar post-progression survival if they had apalutamide plus ADT or docetaxel plus ADT or ADT alone. The committee questioned whether this had face validity and biological plausibility, because people had fewer post-progression treatment options if they chose to start with apalutamide plus ADT instead of ADT alone or docetaxel plus ADT. The post-progression survival estimates are academic-in-confidence and cannot be reported here. At consultation, the company found an error made by NICE. The company explained that according to clinical advice, it was both plausible and likely that apalutamide plus ADT would provide a substantial post-progression benefit. However, the company also presented cost-effectiveness results exploring equal post-progression survival between apalutamide plus ADT and its comparators (see section 3.25). The company also explained that it had chosen not to explore flexible survival models (see section 3.15). The committee concluded that, although it would have liked to have seen flexible models explored, the Weibull model was acceptable for decision making.\n\n## In TITAN, extrapolating PFS2 is uncertain because it is based on immature data\n\nThe company, having assessed that the proportional hazards assumption holds for PFS2, applied a Weibull model fitted jointly to both treatments in its base case, based on clinical plausibility and consistency (which helps to avoid the issue of curves crossing) with the curves for radiographic progression-free survival (see section\xa03.15) and overall survival (see section\xa03.16). The ERG noted that both the Weibull and Gompertz models have the best statistical fits to the observed data. However, the Weibull model likely overestimates PFS2 at 10 and 15\xa0years for people who have apalutamide plus ADT. Also, the ERG stated that the model appears to predict that people spend almost no time on the third-line treatment for metastatic disease. The ERG considered that the Gompertz model was the only clinically relevant alternative, although it is also likely to overestimate long-term survival for people who have apalutamide plus ADT. The ERG noted that, because the PFS2 estimates were immature in TITAN, extrapolating PFS2 assuming proportional hazards was likely to be highly uncertain. For radiographic progression-free survival and overall survival, the ERG suggested that more flexible approaches would be appropriate. The committee concluded that the true estimates of PFS2 after the end of the trial were uncertain because these were based on immature data.\n\n## Treatment effect waning affects the cost-effectiveness results\n\nThe company considered that the benefits of apalutamide plus ADT did not wane over time, so it did not apply any treatment effect waning in its base case. It justified this by noting there was no evidence in TITAN that the overall survival curves for both treatments converge over time. The ERG explored treatment effect waning, but considered it unclear from the hazard plots if treatment benefit declined. Because the treatment effect did not wane in abiraterone clinical trials with longer follow up, the clinical experts and the ERG did not expect treatment effect waning with apalutamide. However, a study in advanced prostate cancer (Antonarakis et al. 2016) suggested that resistance to newer androgen receptor inhibitors was likely to develop with time. The ERG noted that resistance to abiraterone or enzalutamide does not necessarily imply that the treatment effect would wane for apalutamide. It considered that there was not enough evidence to assess the best approach to estimate the duration of treatment benefit. The Cancer Drugs Fund clinical lead noted that, in practice, most newer hormonal treatments for prostate cancer lose effectiveness over time. The committee was aware that both the company and the ERG had explored treatment waning in scenarios before technical engagement. The effect on the incremental cost-effectiveness ratio (ICER) was an increase of around £2,000 per quality-adjusted life year (QALY) gained when varying treatment effect waning from 100% to 0% for a duration of 5\xa0years and 10\xa0years. The committee concluded that treatment effect waning affected the cost-effectiveness results.\n\n# Treatment costs\n\n## The costs of apalutamide are appropriately captured in the model\n\nThe committee was aware that the company offered apalutamide to the NHS at a discount, which the company increased over the course of the appraisal. The committee was aware that duration of treatment determines cost. People have apalutamide plus ADT until disease progression, or until they can no longer tolerate it or choose to stop. The company took time-to-treatment discontinuation and radiographic progression-free survival from TITAN data cuts that occurred at different times. The company explained that the costs used in the model were informed by the minimum of either time-to-treatment discontinuation, or radiographic progression-free survival curves. The company therefore capped the costs. During the first committee meeting, it noted that this might have underestimated the cost of apalutamide in the model. However, at consultation the company stated that it now believed that the costs of treatment had been fully captured. The company also provided a scenario analysis with time on treatment equal to progression-free survival. The ERG confirmed that it agreed with the company's approach in its base case, because no one with progressed disease should remain on treatment. The ERG considered the company's base case would not underestimate the costs of apalutamide. The committee concluded that the costs of apalutamide were appropriately captured in the company's model.\n\n# Utility values\n\n## The company's utility values are broadly appropriate\n\nThe company assumed that health-related quality of life declines over time because simulated people in the model have disease progression and move onto subsequent lines of therapy (see section\xa03.14). The company's utility value for having first-line treatment for hormone-relapsed metastatic prostate cancer was from TITAN using the EQ-5D-3L. The utility values are considered confidential by the company so cannot be reported here. For second- and third-line treatments for hormone-relapsed metastatic prostate cancer, the company originally used external data from NICE's technology appraisal guidance on abiraterone for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA387). This was because a limited number of people completed the EQ-5D-3L questionnaire after developing metastases in TITAN. The company derived the utility values for second- and third-line treatments from the first treatment by applying a 'relative decline ratio'. It did this by estimating the relative decline in utility in TA387 between first- and second-line treatments for metastatic disease, and first- and third-line treatments for metastatic disease. It then applied these ratios to the progressed utility value from TITAN to estimate utilities for second- and third-line hormone-relapsed metastatic prostate cancer. The company also adjusted the derived utility values to account for population differences between TITAN and TA387. The company noted that it did this in line with the method described in the NICE Decision Support Unit's technical support document\xa012 on the use of health state utility values in decision models. The ERG had concerns with the company's adjusted utility values:\n\nThey were much lower than those used in NICE's technology appraisal guidance on enzalutamide for treating metastatic hormone-relapsed prostate cancer before chemotherapy is indicated (TA377) and enzalutamide for hormone-relapsed non-metastatic prostate cancer (TA580). The utility values were 0.658 and 0.612 in TA377 and 0.8 and 0.688 in TA580, for health states reflecting second- and third-line treatments of hormone-relapsed metastatic prostate cancer.\n\nIt was unclear which line of treatment generated the utility values reported in TA387.\n\nBy applying a 'relative decline ratio', the company assumed that the utility values would decrease by the same relative proportion between first- and second-line treatments for hormone-relapsed metastatic prostate cancer (as in TA387). But, the committee considered that this assumption may not be appropriate given the different population in this appraisal (hormone-sensitive metastatic disease) and in TA387 (hormone-relapsed metastatic disease before chemotherapy is indicated).In its base case, the ERG used the utility values from TA377 without adjusting them. The patient experts highlighted the effect of psychological distress and worry about a treatment's loss of efficacy. The clinical expert was aware that EQ‑5D, measured in TITAN, included questions on anxiety and depression and agreed with the company's utility values. The committee agreed that this disease was associated with a significant effect on quality of life. However, it was concerned with the lack of consistency with utility values used in related technology appraisals. Also, the Cancer Drugs Fund clinical lead explained that the ERG's unadjusted utility values better fitted what had been seen in other disease areas with multiple lines of treatment. Therefore, the committee agreed that, on balance, the ERG's utility values had a higher face validity than the company's adjusted utility values. At consultation, the company updated its base case using unadjusted utility values from TA377 for second- and third-line hormone-relapsed metastatic prostate cancer. The committee concluded that the unadjusted utility values from TA377 were most appropriate for decision making.\n\n# Modelling the adverse effects of docetaxel\n\n## The company and ERG's cost estimates are satisfactory\n\nIn the original model, the company assumed that the adverse effects of docetaxel occurred throughout the hormone-sensitive metastatic prostate cancer pre-progression health state. At technical engagement before the first committee meeting, the ERG explained that this overestimated the costs of managing adverse effects, and it was more appropriate to apply those costs for the first 6\xa0months. The company agreed that this overestimated the costs but suggested that after 6\xa0months of treatment there would be additional costs associated with the adverse effects of ongoing ADT. Therefore, in its base case, the company applied the costs of managing adverse effects for docetaxel for 6\xa0months and the costs of managing adverse effects for ADT alone thereafter. The ERG's base case reflected the company's assumption. The clinical experts explained that the adverse effects of docetaxel were likely to last for 6\xa0to 12\xa0months. The committee concluded that the company and ERG's cost estimates were satisfactory.\n\n## The committee is satisfied with the ERG's incidence rates for neutropenia and febrile neutropenia\n\nThe company's model included grade\xa03 to 4 neutropenia and febrile neutropenia, which are adverse effects associated with docetaxel. In the hormone-sensitive metastatic pre-progression health state, the rates of these adverse effects were based on an epidemiological study on docetaxel use in the NHS (Patrikidou et al. 2017). These were 36.3% for neutropenia and 18.2% for febrile neutropenia per course of 6\xa0cycles of docetaxel. The company suggested that these rates may be low. The ERG noted that the company's sources of observational data had methodological limitations including no information on patient numbers. In its base case, the ERG used pooled data from 3\xa0docetaxel trials (GETUG-AFU15, STAMPEDE and CHAARTED). It estimated combined rates of 10.6% for febrile neutropenia and 15.4% for neutropenia, at a constant rate over 6\xa0months. STAMPEDE included only people from the UK and Switzerland, and was therefore more likely to represent NHS clinical practice. At consultation, the company also applied the ERG's approach to these incidence rates. The committee concluded that it was satisfied with the company and the ERG's pooled incidence rates for neutropenia and febrile neutropenia.\n\n# End of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The company did not make a case for end of life in its submission. The committee concluded that the end of life criteria were not met for apalutamide in hormone-sensitive metastatic prostate cancer.\n\n# Cost-effectiveness estimates\n\n## An acceptable ICER would be lower than the middle of the range normally considered cost effective\n\nThe committee recalled its earlier conclusion that the data is immature for overall survival and PFS2 and there is uncertainty about the appropriate extrapolation model for radiographic progression-free survival, overall survival and PFS2. So, the committee agreed that an acceptable ICER would be lower than the middle of the range normally considered a cost-effective use of NHS resources (that is, £20,000 to £30,000 per QALY gained).\n\n## Apalutamide is not cost effective in the whole population for hormone-sensitive metastatic disease\n\nBecause of confidential commercial arrangements for apalutamide and subsequent treatments, the cost-effectiveness estimates cannot be reported here. The committee was satisfied with some of the ERG's preferred assumptions. These included:\n\nnot adjusting treatment effect for either crossover or having a second androgen receptor inhibitor on overall survival and PFS2 (see section\xa03.7)\n\nusing unadjusted utility values for second- and third-line metastatic disease (see section\xa03.20)\n\nusing pooled incidence rates for neutropenia (15.4%) and febrile neutropenia (10.6%; see section\xa03.22)\n\nincremental cost-effectiveness analyses including docetaxel plus ADT, apalutamide plus ADT, and ADT alone.At consultation, the company explored scenarios for some of the uncertainties identified by the committee, including:\n\nnot adjusting treatment effect for both crossover and having a second newer androgen receptor inhibitor\n\nadjusting treatment effect for having a second newer androgen receptor inhibitor (and not crossover)\n\nsetting time on treatment equal to progression-free survival (see section 3.19)\n\nsetting equal post-progression survival between intervention and comparator arms (see section\xa03.16).The company also presented probabilistic ICERs. The company increased its confidential discount for apalutamide. Based on incremental deterministic ICERs, the committee agreed that the cost-effectiveness estimates for apalutamide plus ADT compared with docetaxel plus ADT were well above the range normally considered a cost-effective use of NHS resources. So, it concluded that apalutamide could not be recommended as a cost-effective use of NHS resources for treating hormone-sensitive metastatic prostate cancer.\n\n## The committee considered a group of people who cannot have docetaxel, but the lack of direct evidence increases uncertainty\n\nThe committee considered whether there was a group of people for whom apalutamide plus ADT would be a clinically and cost-effective option. It considered the population who cannot have docetaxel, having discussed how to identify them (see section 3.3). The committee was aware that docetaxel was not a relevant comparator for them or a treatment they would have when their disease became resistant to hormone treatment. The relevant comparator was ADT alone. The committee was aware that it had no direct relevant evidence with which to consider the cost effectiveness of apalutamide plus ADT compared with ADT alone for people who cannot have docetaxel. The committee was aware that TITAN excluded people who would be most likely not to be able to have docetaxel in NHS practice, for example people with an ECOG score of 2 or more (see section 3.4). So, the committee looked at evidence of effectiveness for people who had risk factors, such as age, that would make them more likely to be unsuitable for docetaxel. The committee was aware of data from stakeholders and NHS England documenting the association between older age and decreasing use of docetaxel for hormone-sensitive disease. It was also aware of subgroup analyses from TITAN which showed a hazard ratio for progression or death of 0.65 for people over 75 years compared with hazard ratios of 0.45 and 0.47 for younger age groups. The committee was aware that there was no evidence of treatment-by-age interaction which meant that if there is an interaction, the analysis did not find it.\n\nAfter consultation, for the committee's third meeting, the company did analyses for groups it considered to represent people who cannot have docetaxel. These included people:\n\nwith low volume disease (the company considered chemotherapy to be less effective for this group, but did not provide evidence)\n\nwith an ECOG score of 1 (representing a more unwell population than an ECOG score of 0)\n\nover 75\xa0years.It also included scenarios:\n\nreducing utility values for all lines of treatment by 10% (to explore utility values reflecting the older more unwell population)\n\nremoving chemotherapy during metastatic hormone-relapsed disease (to explore a model in which people do not go on to get docetaxel or chabazite when their disease becomes hormone relapsed).\n\nThe committee questioned the relevance of the company's response defining people with low volume disease or people with an ECOG score of 1 as people who cannot or should have docetaxel. The Cancer Drugs Fund clinical lead explained that low volume disease was not a proxy for not being able to have docetaxel. The committee noted that an ECOG score of 1 represented a relatively well population. It recalled that the STAMPEDE trial of docetaxel plus ADT plus prednisone enrolled people with an ECOG score of 0, 1 and 2 and showed that docetaxel was equally effective in people with a score of 0 and a score of 1 and above. Moreover, in the NHS, people with an ECOG score of 1 would likely be offered chemotherapy. The committee concluded that the company's analyses did not reflect a group who could not have docetaxel. Although older people are less likely to be able to have docetaxel, some younger people cannot have docetaxel, and the committee would be unlikely to make age-based recommendations. The committee concluded that, in the absence of evidence directly addressing the population of interest, this increased the uncertainty in the cost effectiveness results. When taking into account the company's increased discount and the uncertainty, the committee considered that the ICER most closely reflecting its preferred assumptions is within a cost-effective use of NHS resources. So, the committee recommended apalutamide plus ADT as an effective use of NHS resources for treating hormone-sensitive metastatic prostate cancer for people who cannot have docetaxel.\n\n# Innovation\n\n## Apalutamide plus ADT is not innovative for hormone-sensitive metastatic prostate cancer\n\nThe company considered apalutamide plus ADT to be innovative because it is an oral treatment and requires less monitoring than docetaxel plus ADT. However, the committee noted that enzalutamide, a new oral androgen receptor inhibitor that was not available when this appraisal started, is now an option with ADT for treating hormone-sensitive metastatic prostate cancer in the NHS. It concluded that apalutamide plus ADT was not innovative.\n\n# Equality issues\n\n## The recommendations apply to all people with prostate cancer\n\nThe committee noted that, as in previous NICE technology appraisals of prostate cancer treatments, its recommendations should apply to all people with prostate cancer. It further noted that a person can have a prostate but not identify as a man. Gender reassignment is a protected characteristic under the Equality Act 2010. The committee also noted that, in clinical practice, older people are less likely to have docetaxel than younger people. It was aware that although docetaxel is more likely to be contraindicated or unsuitable for older people, age alone will not determine whether a person could or should have docetaxel in clinical practice. The committee was also aware that making recommendations by age to reflect people who cannot have docetaxel could discriminate against younger people for whom docetaxel is contraindicated or unsuitable. The committee concluded that, by considering the cost effectiveness for people who could not have docetaxel (see sections\xa03.26 to 3.28), it took into account older people in its recommendations."}
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https://www.nice.org.uk/guidance/ta741
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Evidence-based recommendations on apalutamide with androgen deprivation therapy for treating hormone-sensitive metastatic prostate cancer in adults.
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1751d4070a5c49d5192c0af3d67c24fffb6ae86d
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nice
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Genicular artery embolisation for pain from knee osteoarthritis
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Genicular artery embolisation for pain from knee osteoarthritis
Evidence-based recommendations on genicular artery embolisation for pain from knee osteoarthritis. This involves inserting a tube through an artery in the groin into the genicular artery, and injecting tiny particles through it to block new blood vessels.
# Recommendations
Evidence on the safety of genicular artery embolisation for pain from knee osteoarthritis shows no major safety concerns in the short term. Evidence on its efficacy and long-term safety is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Research should preferably be randomised controlled trials against sham and current best practice. It should report details of patient selection and identify those who would most benefit from this procedure. It should also report details of the technique used, long-term safety, and patient-reported outcomes.
The procedure should only be done by interventional radiologists with specific training in this technique.# The condition, current treatments and procedure
# The condition
Osteoarthritis is characterised by localised loss of cartilage, remodelling of adjacent bone, and associated inflammation. Knees are one of the most affected joints, with pain being a significant symptom.
Angiogenesis may contribute to inflammation, structural damage and pain. This is because the increased vascular network carries inflammatory cells to the synovium and other joint tissues and promotes additional hyperplasia and inflammation in other vessels, leading to bone and cartilage destruction. Angiogenesis also enables the growth of new unmyelinated sensory nerves, which contributes to pain.
# Current treatments
For pain secondary to knee osteoarthritis, various treatments are available including non-pharmacological (such as physiotherapy), pharmacological (such as analgesics and intra-articular steroids) and surgical approaches (such as knee arthroplasty).
Treatment most commonly involves a combination of pharmacological and non-pharmacological interventions. When non-pharmacological and pharmacological interventions do not work or symptoms are severe, surgery may be needed.
# The procedure
This procedure aims to relieve pain by embolising the pathological new vessels while maintaining the larger vascular supply to the bone.
Before the procedure, contrast-enhanced MRI of the knee is done to allow non-invasive assessment of synovial hypervascularity. The procedure is usually done using local anaesthesia with or without sedation. A catheter is passed through an introducer sheath in the femoral artery and then navigated into the genicular arteries supplying the knee to perform lower extremity angiography on the targeted side. Once the abnormal new vessels arising from these arteries are identified, a microcatheter is navigated into them and, under fluoroscopic guidance, tiny embolisation particles are then delivered until the blood flow is stopped.
After the introducer sheath and catheter are removed, haemostasis is achieved with manual compression or a vascular closure device. The patient often goes home the same day. This procedure takes approximately 1 to 2 hours to complete.
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{'Recommendations': 'Evidence on the safety of genicular artery embolisation for pain from knee osteoarthritis shows no major safety concerns in the short term. Evidence on its efficacy and long-term safety is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nResearch should preferably be randomised controlled trials against sham and current best practice. It should report details of patient selection and identify those who would most benefit from this procedure. It should also report details of the technique used, long-term safety, and patient-reported outcomes.\n\nThe procedure should only be done by interventional radiologists with specific training in this technique.', 'The condition, current treatments and procedure': '# The condition\n\nOsteoarthritis is characterised by localised loss of cartilage, remodelling of adjacent bone, and associated inflammation. Knees are one of the most affected joints, with pain being a significant symptom.\n\nAngiogenesis may contribute to inflammation, structural damage and pain. This is because the increased vascular network carries inflammatory cells to the synovium and other joint tissues and promotes additional hyperplasia and inflammation in other vessels, leading to bone and cartilage destruction. Angiogenesis also enables the growth of new unmyelinated sensory nerves, which contributes to pain.\n\n# Current treatments\n\nFor pain secondary to knee osteoarthritis, various treatments are available including non-pharmacological (such as physiotherapy), pharmacological (such as analgesics and intra-articular steroids) and surgical approaches (such as knee arthroplasty).\n\nTreatment most commonly involves a combination of pharmacological and non-pharmacological interventions. When non-pharmacological and pharmacological interventions do not work or symptoms are severe, surgery may be needed.\n\n# The procedure\n\nThis procedure aims to relieve pain by embolising the pathological new vessels while maintaining the larger vascular supply to the bone.\n\nBefore the procedure, contrast-enhanced MRI of the knee is done to allow non-invasive assessment of synovial hypervascularity. The procedure is usually done using local anaesthesia with or without sedation. A catheter is passed through an introducer sheath in the femoral artery and then navigated into the genicular arteries supplying the knee to perform lower extremity angiography on the targeted side. Once the abnormal new vessels arising from these arteries are identified, a microcatheter is navigated into them and, under fluoroscopic guidance, tiny embolisation particles are then delivered until the blood flow is stopped.\n\nAfter the introducer sheath and catheter are removed, haemostasis is achieved with manual compression or a vascular closure device. The patient often goes home the same day. This procedure takes approximately 1\xa0to 2\xa0hours to complete.'}
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https://www.nice.org.uk/guidance/ipg708
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Evidence-based recommendations on genicular artery embolisation for pain from knee osteoarthritis. This involves inserting a tube through an artery in the groin into the genicular artery, and injecting tiny particles through it to block new blood vessels.
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93e0e158a256ffd5ac99670148b0df061b80b0f9
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nice
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Percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access
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Percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access
Evidence-based recommendations on percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access in adults. This involves using radiofrequency energy, or heat and pressure, to join an artery and vein in the forearm to create a fistula for haemodialysis access.
# Recommendations
Evidence on the safety of percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access raises no major safety concerns. However, evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wanting to do percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by a multidisciplinary team including a vascular access surgeon, nephrologist and interventional radiologist.
Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.
NICE encourages further research, preferably randomised controlled trials, into percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access. This should report details of patient selection, particularly about vascular anatomy, technique used, need for training, patency of the fistula and its subsequent ease of use, and quality of life.# The condition, current treatments and procedure
# The condition
Chronic (long-term) haemodialysis is used to treat advanced chronic kidney disease in many people who have renal replacement therapy.
# Current treatments
An arteriovenous fistula is considered the best type of vascular access for haemodialysis. The preferred way of creating such access is to surgically join an artery and vein together in the distal forearm (radiocephalic fistula). However, other anatomical sites may be used. Alternative surgical approaches for vascular access include arteriovenous grafts and placing tunnelled catheters into a large vein. A minimally invasive, percutaneous, endovascular procedure is another way of creating an arteriovenous fistula.
# The procedure
This procedure can be done using different systems, and is usually done in a day-case facility under local anaesthesia, with or without conscious sedation. Using ultrasound or fluoroscopic guidance, 2 small needles are inserted into an artery and a vein in the proximal forearm, that is, the radial, ulnar or brachial artery and adjacent vein. Thin, flexible, specially designed catheters are then advanced and positioned by guidewires in the chosen vessels. The catheters are aligned close to each other (using inbuilt magnets or mechanically, depending on the system). The arterial and venous walls are then fused side to side using heat and pressure, or a small burst of radiofrequency energy released from the catheters. This creates an arteriovenous fistula between the target vessels. The catheters are then removed. High-flow arterial blood passes through the vein and, with time, it arterialises. This allows needles to be inserted into the vein to provide vascular access during haemodialysis.
The exact technique may vary slightly depending on the device used.
|
{'Recommendations': "Evidence on the safety of percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access raises no major safety concerns. However, evidence on its efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wanting to do percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team including a vascular access surgeon, nephrologist and interventional radiologist.\n\nReport any problems with a medical device using the\xa0Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nNICE encourages further research, preferably randomised controlled trials, into percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access. This should report details of patient selection, particularly about vascular anatomy, technique used, need for training, patency of the fistula and its subsequent ease of use, and quality of life.", 'The condition, current treatments and procedure': '# The condition\n\nChronic (long-term) haemodialysis is used to treat advanced chronic kidney disease in many people who have renal replacement therapy.\n\n# Current treatments\n\nAn arteriovenous fistula is considered the best type of vascular access for haemodialysis. The preferred way of creating such access is to surgically join an artery and vein together in the distal forearm (radiocephalic fistula). However, other anatomical sites may be used. Alternative surgical approaches for vascular access include arteriovenous grafts and placing tunnelled catheters into a large vein. A minimally invasive, percutaneous, endovascular procedure is another way of creating an arteriovenous fistula.\n\n# The procedure\n\nThis procedure can be done using different systems, and is usually done in a day-case facility under local anaesthesia, with or without conscious sedation. Using ultrasound or fluoroscopic guidance, 2\xa0small needles are inserted into an artery and a vein in the proximal forearm, that is, the radial, ulnar or brachial artery and adjacent vein. Thin, flexible, specially designed catheters are then advanced and positioned by guidewires in the chosen vessels. The catheters are aligned close to each other (using inbuilt magnets or mechanically, depending on the system). The arterial and venous walls are then fused side to side using heat and pressure, or a small burst of radiofrequency energy released from the catheters. This creates an arteriovenous fistula between the target vessels. The catheters are then removed. High-flow arterial blood passes through the vein and, with time, it arterialises. This allows needles to be inserted into the vein to provide vascular access during haemodialysis.\n\nThe exact technique may vary slightly depending on the device used.'}
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https://www.nice.org.uk/guidance/ipg710
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Evidence-based recommendations on percutaneous endovascular forearm arteriovenous fistula creation for haemodialysis access in adults. This involves using radiofrequency energy, or heat and pressure, to join an artery and vein in the forearm to create a fistula for haemodialysis access.
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5e206d0447df712e2e7dd58658ac60fcc8cf5717
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nice
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Laparoscopic renal denervation for loin pain haematuria syndrome
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Laparoscopic renal denervation for loin pain haematuria syndrome
Evidence-based recommendations on laparoscopic renal denervation for loin pain haematuria syndrome in adults. This involves the stripping away of nerves from the kidney using keyhole surgery to relieve pain.
# Recommendations
Evidence on the safety and efficacy of laparoscopic renal denervation for loin pain haematuria syndrome is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.
Further research should report details of patient selection, technique used and long-term follow-up outcomes.# The condition, current treatments and procedure
# The condition
Loin pain haematuria syndrome (LPHS) causes severe, recurrent flank pain and haematuria (either macroscopic or microscopic). The cause of LPHS is unknown and diagnosis is only made after excluding all other possible renal causes of flank pain and haematuria.
# Current treatments
Initial treatment of LPHS involves prescription of analgesics, up to and including opioids. Other treatments include transcutaneous electrical nerve stimulation, regional nerve blocks and radiofrequency ablation. If these are unsuccessful, surgical intervention can be tried, including open surgical renal denervation, capsulotomy (often done in conjunction with open surgical renal denervation), nephrectomy, and renal autotransplantation.
# The procedure
Laparoscopic renal denervation is a minimally invasive procedure to interrupt the sensorial and sympathetic innervation of the kidney to control pain. The procedure is done under general anaesthesia, using a retroperitoneal approach. Lymphatic and nervous tissue is stripped off the renal artery and vein with subsequent division of all perihilar nervous tissue, with or without mobilisation of the kidney. Laparoscopic renal denervation does not include capsulotomy, which may be included in open surgical renal denervation.
The laparoscopic technique aims to reduce the anaesthetic time and produce a quicker recovery time than open surgery.
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{'Recommendations': 'Evidence on the safety and efficacy of laparoscopic renal denervation for loin pain haematuria syndrome is inadequate in quality and quantity. Therefore, this procedure should only be used in the context of research. Find out what only in research means on the NICE interventional procedures guidance page.\n\nFurther research should report details of patient selection, technique used and long-term follow-up outcomes.', 'The condition, current treatments and procedure': '# The condition\n\nLoin pain haematuria syndrome (LPHS) causes severe, recurrent flank pain and haematuria (either macroscopic or microscopic). The cause of LPHS is unknown and diagnosis is only made after excluding all other possible renal causes of flank pain and haematuria.\n\n# Current treatments\n\nInitial treatment of LPHS involves prescription of analgesics, up to and including opioids. Other treatments include transcutaneous electrical nerve stimulation, regional nerve blocks and radiofrequency ablation. If these are unsuccessful, surgical intervention can be tried, including open surgical renal denervation, capsulotomy (often done in conjunction with open surgical renal denervation), nephrectomy, and renal autotransplantation.\n\n# The procedure\n\nLaparoscopic renal denervation is a minimally invasive procedure to interrupt the sensorial and sympathetic innervation of the kidney to control pain. The procedure is done under general anaesthesia, using a retroperitoneal approach. Lymphatic and nervous tissue is stripped off the renal artery and vein with subsequent division of all perihilar nervous tissue, with or without mobilisation of the kidney. Laparoscopic renal denervation does not include capsulotomy, which may be included in open surgical renal denervation.\n\nThe laparoscopic technique aims to reduce the anaesthetic time and produce a quicker recovery time than open surgery.'}
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https://www.nice.org.uk/guidance/ipg709
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Evidence-based recommendations on laparoscopic renal denervation for loin pain haematuria syndrome in adults. This involves the stripping away of nerves from the kidney using keyhole surgery to relieve pain.
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8e42fb954297d4c44c2f3b90d51ad44247e6ad68
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nice
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Atezolizumab for untreated PD-L1-positive advanced urothelial cancer when cisplatin is unsuitable
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Atezolizumab for untreated PD-L1-positive advanced urothelial cancer when cisplatin is unsuitable
Evidence-based recommendations on atezolizumab (Tecentriq) for untreated PD-L1-positive locally advanced or metastatic urothelial cancer in adults when cisplatin-containing chemotherapy is unsuitable.
# Recommendations
Atezolizumab is recommended, within its marketing authorisation, as an option for untreated locally advanced or metastatic urothelial cancer in adults whose tumours express PD‑L1 at a level of 5% or more and when cisplatin-containing chemotherapy is unsuitable. This is only if the company provides atezolizumab according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for atezolizumab for untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable.
The new evidence includes data from a clinical trial and from people having treatment in the NHS, while this treatment was available in the Cancer Drugs Fund in England. The clinical trial shows that people who have atezolizumab are likely to live longer than those who have platinum-based chemotherapy.
Atezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. So, atezolizumab is recommended.# Information about atezolizumab
# Marketing authorisation indication
Atezolizumab (Tecentriq, Roche) as a monotherapy is indicated for 'the treatment of adult patients with locally advanced or metastatic urothelial cancer who are considered cisplatin ineligible, and whose tumours have a PD‑L1 expression of 5% or more'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £3,807.69 per 1,200‑mg vial (excluding VAT; BNF online, accessed August 2021), which is an annual cost of around £66,000. The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
This review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect efficacy data from the IMvigor 130 study. Data was also collected using the Systemic Anti-Cancer Therapy (SACT) dataset. After entry to the Cancer Drugs Fund the European Medicines Agency (EMA) restricted the marketing authorisation for atezolizumab to people with high levels of PD‑L1. This guidance includes recommendations only for untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable.
The committee was aware that there were remaining areas of uncertainty associated with the analyses presented (see technical report pages 8 to 10) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:
the IMvigor 130 trial treatment estimates were based on a small subgroup of the trial's total population
there were baseline differences between trial arms in IMvigor 130
the overall survival estimates from the SACT dataset and the IMvigor 130 trial differed
no comparison was made between atezolizumab and best supportive care in the company's base case
the approach to modelling the long-term outcomes of overall survival and time to treatment discontinuation.
# The condition and clinical management
## Locally advanced or metastatic urothelial cancer substantially decreases quality of life
Urothelial cancer causes a number of symptoms, including haematuria (blood in the urine), and increased frequency, urgency and pain associated with urination. Surgical treatments such as urostomy can have a substantial impact on quality of life and restrict daily activities. The patient experts explained that chemotherapy is associated with unpleasant side effects such as nausea and has limited effectiveness. In the original appraisal the committee recognised that many people with locally advanced or metastatic urothelial cancer are older and may have comorbidities, which can affect treatment decisions. The committee concluded that locally advanced or metastatic urothelial cancer has a significant impact on quality of life.
## There is an unmet need for effective treatment options
Initial treatment is usually with a cisplatin-containing chemotherapy regimen. However, cisplatin can be damaging to the kidneys, so is not suitable for some people with impaired kidney function or a poor performance status. People for whom cisplatin is unsuitable will usually be offered carboplatin plus gemcitabine. If they are not well enough to tolerate this or they choose not to have it, they will be offered best supportive care. Patient and clinical experts explained that none of the current treatments offer lasting benefit, and the prognosis is poor. The patient experts explained that the disease has a substantial impact on the ability to work and travel, and that the side effects of chemotherapy can have a major negative impact on quality of life. In the committee meeting, the patient experts noted that there have been no new treatments recommended for locally advanced or metastatic urothelial cancer for a number of years. The patient experts also noted that pembrolizumab is no longer recommended for untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable, and so there are limited treatment options for this disease. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced or metastatic urothelial cancer.
## Platinum-based chemotherapy and best supportive care are relevant comparators in untreated disease when cisplatin is unsuitable
The company submitted clinical- and cost-effectiveness analyses comparing atezolizumab with carboplatin plus gemcitabine. Although it was included in the NICE scope, the company did not submit a comparison with best supportive care. It considered that there was not enough data for comparison with best supportive care. In the original appraisal, the committee heard that, in clinical practice, carboplatin plus gemcitabine may not be suitable for a significant proportion of people for whom cisplatin is unsuitable, and this group of people therefore have best supportive care. It understood that because atezolizumab is an immunotherapy with a different side effect profile to carboplatin plus gemcitabine, there may be some people for whom atezolizumab is suitable who would otherwise have best supportive care. For this review, the committee noted that collecting best supportive care data was not part of the managed access agreement. It also acknowledged that there was a lack of evidence in the literature for people who may have best supportive care in the population for whom cisplatin is unsuitable and who have high levels of PD‑L1. The committee concluded that best supportive care was an appropriate comparator for the population with untreated disease for whom cisplatin is unsuitable, but as in the original appraisal, acknowledged the lack of data would make a comparison difficult.
# Stopping treatment
## Most people will stop treatment with atezolizumab when their disease progresses
In the original appraisal the committee concluded that most people with untreated locally advanced or metastatic urothelial cancer would stop treatment with atezolizumab when their disease progresses and a 2‑year stopping rule was not appropriate. The committee did not hear any relevant new evidence and so concluded that its view from the original appraisal had not changed.
# Clinical-effectiveness evidence
## Atezolizumab is more effective than the comparators
In the original appraisal the clinical-effectiveness evidence for atezolizumab came from IMvigor 210, a phase 2 single-arm study. The company did a simulated treatment comparison and network meta-analysis to compare atezolizumab with gemcitabine plus carboplatin. The committee in the original appraisal was concerned that the simulated treatment comparison was not robust and had concerns about the reliability and robustness of the network meta-analysis. To address the committee's concerns from the original appraisal, the company provided the clinical-effectiveness evidence for atezolizumab from IMvigor 130, a phase 3 randomised controlled trial. The trial included 1,213 adults with previously untreated locally advanced or metastatic urothelial cancer, who were in the investigators' judgement eligible to receive platinum-based therapy. Only a subgroup of 93 people, which included people with untreated PD‑L1‑positive (tumour expression of 5% or more) locally advanced or metastatic urothelial cancer and who were ineligible to have treatment with cisplatin, was relevant to this appraisal. This was the result of the restricted EMA marketing authorisation, which stated atezolizumab should only be used in adults with high levels of PD‑L1. The median overall survival was 18.6 months for atezolizumab and 10.0 months for platinum-based chemotherapy. The stratified hazard ratio was 0.50 (95% confidence interval 0.29 to 0.87, p=0.0125), showing atezolizumab was associated with a statistically significant improvement in overall survival compared with platinum-based chemotherapy. The median progression-free survival for atezolizumab was 6.4 months compared with 6.0 months for platinum-based chemotherapy. The stratified hazard ratio was 0.56 (95% CI 0.34 to 0.93, p=0.0235), showing atezolizumab was associated with a statistically significant improvement in progression-free survival compared with platinum-based chemotherapy. The ERG noted that there was uncertainty in the treatment effects as they were based on an interim data analysis of a small subgroup of the trial's total population. Also, the hazard ratio confidence intervals were wide (but did not cross 1). The committee recalled that the small sample size was a result of the restricted marketing authorisation for atezolizumab for people with high levels of PD‑L1. The committee also noted that the survival data was 87% mature. The committee concluded that the data from IMvigor 130 was the most appropriate evidence for decision making.
## The difference in baseline characteristics between trial arms is acceptable
Within the IMvigor 130 subgroup there were baseline differences between trial arms in terms of gender and racial characteristics. The ERG explained that some of the imbalances were likely to bias treatment effects but that the direction and magnitude of the bias were unclear. The committee noted that the gender and racial characteristics may bias in favour of atezolizumab but the Bajorin risk factor and Eastern Cooperative Oncology Group Performance Status scores may bias in favour of platinum-based chemotherapy. The committee concluded that the small sample size and opposing influences meant it was not possible to determine the magnitude of direction of any potential bias and the differences in baseline characteristics were acceptable.
## There are differences between the population in the IMvigor 130 trial and the people eligible to have atezolizumab in the NHS
NHS England also provided data from the SACT dataset. It was collected from 64 people who had atezolizumab through the Cancer Drugs Fund between July 2018 and August 2020. The clinical expert explained that the clinical experience with atezolizumab is positive. The committee noted that the median overall survival in the trial was longer (18.6 months, 95% CI 14.0 to not evaluable) than in the SACT dataset (12.4 months, 95% CI 8.3 to 20.1). However, the 95% confidence intervals overlapped. Both the clinical expert and the lead for the Cancer Drugs Fund explained that people included in the SACT dataset were older and had a poorer performance status, which may have contributed to the differences in the median survival estimates. The clinical expert also noted that there may have been selection bias of good prognostic features for people enrolled in IMvigor 130, who were eligible to have chemotherapy, compared with the SACT dataset in which people were not necessarily able to have chemotherapy. The lead for the Cancer Drugs Fund explained that the COVID‑19 pandemic may have affected people's choice to continue treatment, even if their disease was responding, which would have impacted the SACT dataset. But the IMvigor 130 trial would likely not have been impacted by the COVID‑19 pandemic. The committee concluded that these population differences and impact of the COVID‑19 pandemic likely contributed to the differences in treatment effects between the IMvigor 130 trial and SACT dataset.
# Adverse events
## Atezolizumab is reasonably well tolerated in clinical practice
In the original appraisal the clinical experts explained that, in their experience of using atezolizumab, it is well tolerated and associated with fewer adverse events than chemotherapy. However, the committee in the original appraisal also understood that atezolizumab was associated with some unpleasant and potentially serious adverse events. A clinical expert in this review stated that toxicities are well managed by specialist hospitals in collaboration with other specialities. The committee concluded that atezolizumab is reasonably well tolerated in clinical practice.
# Modelling overall survival and time to treatment discontinuation
## The estimates of overall survival for atezolizumab and platinum-based chemotherapy from each approach to modelling are similar
The company used data from the subgroup of people with untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer, who were ineligible to have treatment with cisplatin. It used the Kaplan–Meier overall survival curve from the clinical trial until 20% of people were at risk and extrapolated the tail using the exponential distribution. The ERG proposed an approach in which it used an exponential parametric function over the whole time period. The ERG explained that it proposed this approach as there was considerable uncertainty with the small sample size in the cisplatin-ineligible, PD‑L1‑positive subgroup from IMvigor 130. This approach resulted in a 5‑year survival of 16%. The clinical expert estimated that it was plausible that between 5% and 30% of people having atezolizumab would be alive at 5 years. In its response to technical engagement, the company updated its approach to use the Kaplan–Meier curve to model the early part of the overall survival curve until 24 (48%) people were at risk, to maintain consistency with the original appraisal. This resulted in a 5‑year survival estimate of 15%. The committee concluded that the company and ERG's approaches were both clinically plausible and estimated similar 5‑year survival estimates and cost-effectiveness results.
## The most plausible estimate for time to treatment discontinuation is less than 5% of people still having treatment at 5 years
Treatment in the platinum-based chemotherapy arm was restricted to 6 cycles, so curve selection had a negligible impact on costs, and the discussion around time to treatment discontinuation curve selection focused on the atezolizumab arm. The company used the Kaplan–Meier time to treatment discontinuation curve for atezolizumab from the clinical trial, until 48% of people were at risk, and extrapolated the tail using the exponential distribution. This resulted in a 5‑year time to treatment discontinuation estimate of 1% for atezolizumab. The clinical experts estimated 5‑year time to treatment discontinuation for atezolizumab would be between 0% and 2%. The committee heard that this approach was clinically plausible, provided a good statistical fit to the data, and was a conservative extrapolation that aligned with the SACT data. The ERG noted that this approach assumed a constant probability of treatment discontinuation over time, whereas this probability decreased in the trial. The ERG explained that using this approach overestimated the probability of treatment discontinuation and underestimated the costs. The ERG preferred to use the Weibull parametric function over the whole time period, resulting in a 5‑year time to treatment discontinuation estimate of 7%. The committee noted that using the Weibull parametric function to extrapolate progression-free survival, the approach proposed by the ERG and accepted by the company in its response to technical engagement, resulted in 5‑year progression-free survival estimates of 5%. Using the ERG's approach to extrapolate time to treatment discontinuation would result in more people having treatment than were progression free, which the committee considered to be implausible. The committee heard that the SACT dataset showed that no one was on treatment after 2 years, but the lead for the Cancer Drugs Fund cautioned that the maximum follow up for the SACT dataset was 25 months. The committee recalled that there is no stopping rule for atezolizumab (see section 3.4). The committee concluded that the most plausible estimate of time to treatment discontinuation would be less than 5% of people having treatment at 5 years to align with the 5‑year progression-free survival estimate and clinical expectations.
# Utility values in the economic model
## The utility values used in the model are appropriate
In the original appraisal, no health-related quality-of-life data was collected in IMvigor 210 and the company used alternative utility values. The committee was concerned that the utility value of 0.71 used for the progressed-disease state was too high and concluded that the most plausible value for post-progression utility was likely to be between 0.5 and 0.71. The company submitted new health-state utility values for the atezolizumab and platinum-based chemotherapy arms, based on the IMvigor 130 trial. The company provided naive utility estimates that did not consider the longitudinal nature of the data. To overcome this, the company used a mixed-effects model that accounted for changes in utility over time as well as correlation among observations within people in the trial to estimate the base-case utilities. In its response to technical engagement, the company updated the selection of the mixed-effects model used to estimate the utility values and explained the updated approach was more robust. The ERG agreed that the updated values were more appropriate and clinically plausible. The company's updated base-case utilities were lower than the naive values also presented by the company and led to higher cost-effectiveness estimates. The committee concluded that the updated base-case utilities were acceptable.
# End of life
## Atezolizumab meets the short life expectancy criterion
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with urothelial cancer was less than 24 months for people having treatment with any standard care. The new evidence from IMvigor 130 also showed that mean overall survival was less than 24 months for people having treatment with UK standard care. The committee concluded that atezolizumab met the short life expectancy criterion.
## Atezolizumab extends life by at least 3 months, and meets the criteria for end of life treatments
The company's economic model also predicted that atezolizumab extended life by at least 3 months, but the exact results are confidential and cannot be reported here. The committee concluded that atezolizumab would extend life by more than 3 months, and therefore met the end of life criteria.
# Cost effectiveness
## The most plausible incremental cost-effectiveness ratios are below £50,000 per quality-adjusted life year
NICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of uncertainty around the incremental cost-effectiveness ratios (ICERs). It states that the committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the level of uncertainty, specifically around the size of the relevant population from IMvigor 130 and the time to treatment discontinuation (see section 3.5 and section 3.10). But it acknowledged that the small sample size was a result of the restricted EMA marketing authorisation and concluded that the most plausible estimate of time to treatment discontinuation would be less than the 5‑year progression-free survival estimate and clinical expectations. For a life-extending treatment at the end of life, the upper limit of the range usually considered to represent a cost-effective use of NHS resources is £50,000 per quality-adjusted life year (QALY) gained. The committee noted that the company's base-case ICER for atezolizumab, including a patient access scheme and corrected by the ERG who found a minor difference in the results estimated by the company, was £32,235 per QALY gained. The committee's preferred assumptions for decision making at the appraisal committee meeting were to use:
any of the approaches for extrapolating overall survival for atezolizumab and platinum-based chemotherapy
less than 5% of people having treatment with atezolizumab at 5 years.Using these preferred assumptions, the plausible ICER was considerably less than £50,000 per QALY gained. The committee recalled the uncertainty in the clinical evidence but noted the survival estimates were reasonably mature. It concluded the cost-effectiveness estimate for atezolizumab suggest it is an acceptable use of NHS resources for a life-extending treatment at the end of life. So, atezolizumab was recommended for routine use in the NHS.
# Equality issues
## The recommendations apply equally to all people with untreated PD-L1-positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable
A patient expert questioned whether there is an equality issue regarding gender. The clinical expert confirmed that women tend to present later so are more likely to have advanced disease and worse cancer-specific mortality. The committee heard from the Cancer Drugs Fund clinical lead that data collected by Public Health England from NHS patients in England showed that more men had taken atezolizumab while it was available in the Cancer Drugs Fund. The committee concluded that its recommendation applies equally, regardless of gender, so this difference is not in itself an equality issue.
# Other factors
No additional benefits that had not been captured in the QALY calculations were identified during the course of the appraisal.
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{'Recommendations': "Atezolizumab is recommended, within its marketing authorisation, as an option for untreated locally advanced or metastatic urothelial cancer in adults whose tumours express PD‑L1 at a level of 5% or more and when cisplatin-containing chemotherapy is unsuitable. This is only if the company provides atezolizumab according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for atezolizumab for untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable.\n\nThe new evidence includes data from a clinical trial and from people having treatment in the NHS, while this treatment was available in the Cancer Drugs Fund in England. The clinical trial shows that people who have atezolizumab are likely to live longer than those who have platinum-based chemotherapy.\n\nAtezolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. So, atezolizumab is recommended.", 'Information about atezolizumab': "# Marketing authorisation indication\n\nAtezolizumab (Tecentriq, Roche) as a monotherapy is indicated for 'the treatment of adult patients with locally advanced or metastatic urothelial cancer who are considered cisplatin ineligible, and whose tumours have a PD‑L1 expression of 5% or more'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £3,807.69 per 1,200‑mg vial (excluding VAT; BNF online, accessed August\xa02021), which is an annual cost of around £66,000. The company has a commercial arrangement. This makes atezolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Roche, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect efficacy data from the IMvigor\xa0130 study. Data was also collected using the Systemic Anti-Cancer Therapy (SACT) dataset. After entry to the Cancer Drugs Fund the European Medicines Agency (EMA) restricted the marketing authorisation for atezolizumab to people with high levels of PD‑L1. This guidance includes recommendations only for untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable.\n\nThe committee was aware that there were remaining areas of uncertainty associated with the analyses presented (see technical report pages\xa08 to\xa010) and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:\n\nthe IMvigor\xa0130 trial treatment estimates were based on a small subgroup of the trial's total population\n\nthere were baseline differences between trial arms in IMvigor\xa0130\n\nthe overall survival estimates from the SACT dataset and the IMvigor\xa0130 trial differed\n\nno comparison was made between atezolizumab and best supportive care in the company's base case\n\nthe approach to modelling the long-term outcomes of overall survival and time to treatment discontinuation.\n\n# The condition and clinical management\n\n## Locally advanced or metastatic urothelial cancer substantially decreases quality of life\n\nUrothelial cancer causes a number of symptoms, including haematuria (blood in the urine), and increased frequency, urgency and pain associated with urination. Surgical treatments such as urostomy can have a substantial impact on quality of life and restrict daily activities. The patient experts explained that chemotherapy is associated with unpleasant side effects such as nausea and has limited effectiveness. In the original appraisal the committee recognised that many people with locally advanced or metastatic urothelial cancer are older and may have comorbidities, which can affect treatment decisions. The committee concluded that locally advanced or metastatic urothelial cancer has a significant impact on quality of life.\n\n## There is an unmet need for effective treatment options\n\nInitial treatment is usually with a cisplatin-containing chemotherapy regimen. However, cisplatin can be damaging to the kidneys, so is not suitable for some people with impaired kidney function or a poor performance status. People for whom cisplatin is unsuitable will usually be offered carboplatin plus gemcitabine. If they are not well enough to tolerate this or they choose not to have it, they will be offered best supportive care. Patient and clinical experts explained that none of the current treatments offer lasting benefit, and the prognosis is poor. The patient experts explained that the disease has a substantial impact on the ability to work and travel, and that the side effects of chemotherapy can have a major negative impact on quality of life. In the committee meeting, the patient experts noted that there have been no new treatments recommended for locally advanced or metastatic urothelial cancer for a number of years. The patient experts also noted that pembrolizumab is no longer recommended for untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable, and so there are limited treatment options for this disease. The committee concluded that there is an unmet need for effective treatment options for people with locally advanced or metastatic urothelial cancer.\n\n## Platinum-based chemotherapy and best supportive care are relevant comparators in untreated disease when cisplatin is unsuitable\n\nThe company submitted clinical- and cost-effectiveness analyses comparing atezolizumab with carboplatin plus gemcitabine. Although it was included in the NICE scope, the company did not submit a comparison with best supportive care. It considered that there was not enough data for comparison with best supportive care. In the original appraisal, the committee heard that, in clinical practice, carboplatin plus gemcitabine may not be suitable for a significant proportion of people for whom cisplatin is unsuitable, and this group of people therefore have best supportive care. It understood that because atezolizumab is an immunotherapy with a different side effect profile to carboplatin plus gemcitabine, there may be some people for whom atezolizumab is suitable who would otherwise have best supportive care. For this review, the committee noted that collecting best supportive care data was not part of the managed access agreement. It also acknowledged that there was a lack of evidence in the literature for people who may have best supportive care in the population for whom cisplatin is unsuitable and who have high levels of PD‑L1. The committee concluded that best supportive care was an appropriate comparator for the population with untreated disease for whom cisplatin is unsuitable, but as in the original appraisal, acknowledged the lack of data would make a comparison difficult.\n\n# Stopping treatment\n\n## Most people will stop treatment with atezolizumab when their disease progresses\n\nIn the original appraisal the committee concluded that most people with untreated locally advanced or metastatic urothelial cancer would stop treatment with atezolizumab when their disease progresses and a 2‑year stopping rule was not appropriate. The committee did not hear any relevant new evidence and so concluded that its view from the original appraisal had not changed.\n\n# Clinical-effectiveness evidence\n\n## Atezolizumab is more effective than the comparators\n\nIn the original appraisal the clinical-effectiveness evidence for atezolizumab came from IMvigor\xa0210, a phase\xa02 single-arm study. The company did a simulated treatment comparison and network meta-analysis to compare atezolizumab with gemcitabine plus carboplatin. The committee in the original appraisal was concerned that the simulated treatment comparison was not robust and had concerns about the reliability and robustness of the network meta-analysis. To address the committee's concerns from the original appraisal, the company provided the clinical-effectiveness evidence for atezolizumab from IMvigor\xa0130, a phase\xa03 randomised controlled trial. The trial included 1,213\xa0adults with previously untreated locally advanced or metastatic urothelial cancer, who were in the investigators' judgement eligible to receive platinum-based therapy. Only a subgroup of 93\xa0people, which included people with untreated PD‑L1‑positive (tumour expression of 5% or more) locally advanced or metastatic urothelial cancer and who were ineligible to have treatment with cisplatin, was relevant to this appraisal. This was the result of the restricted EMA marketing authorisation, which stated atezolizumab should only be used in adults with high levels of PD‑L1. The median overall survival was 18.6\xa0months for atezolizumab and 10.0\xa0months for platinum-based chemotherapy. The stratified hazard ratio was 0.50 (95%\xa0confidence interval [CI] 0.29 to 0.87, p=0.0125), showing atezolizumab was associated with a statistically significant improvement in overall survival compared with platinum-based chemotherapy. The median progression-free survival for atezolizumab was 6.4\xa0months compared with 6.0\xa0months for platinum-based chemotherapy. The stratified hazard ratio was 0.56 (95%\xa0CI 0.34 to 0.93, p=0.0235), showing atezolizumab was associated with a statistically significant improvement in progression-free survival compared with platinum-based chemotherapy. The ERG noted that there was uncertainty in the treatment effects as they were based on an interim data analysis of a small subgroup of the trial's total population. Also, the hazard ratio confidence intervals were wide (but did not cross 1). The committee recalled that the small sample size was a result of the restricted marketing authorisation for atezolizumab for people with high levels of PD‑L1. The committee also noted that the survival data was 87% mature. The committee concluded that the data from IMvigor\xa0130 was the most appropriate evidence for decision making.\n\n## The difference in baseline characteristics between trial arms is acceptable\n\nWithin the IMvigor\xa0130 subgroup there were baseline differences between trial arms in terms of gender and racial characteristics. The ERG explained that some of the imbalances were likely to bias treatment effects but that the direction and magnitude of the bias were unclear. The committee noted that the gender and racial characteristics may bias in favour of atezolizumab but the Bajorin risk factor and Eastern Cooperative Oncology Group Performance Status scores may bias in favour of platinum-based chemotherapy. The committee concluded that the small sample size and opposing influences meant it was not possible to determine the magnitude of direction of any potential bias and the differences in baseline characteristics were acceptable.\n\n## There are differences between the population in the IMvigor\xa0130 trial and the people eligible to have atezolizumab in the NHS\n\nNHS England also provided data from the SACT dataset. It was collected from 64\xa0people who had atezolizumab through the Cancer Drugs Fund between July\xa02018 and August\xa02020. The clinical expert explained that the clinical experience with atezolizumab is positive. The committee noted that the median overall survival in the trial was longer (18.6\xa0months, 95% CI 14.0 to not evaluable) than in the SACT dataset (12.4\xa0months, 95% CI 8.3 to 20.1). However, the 95% confidence intervals overlapped. Both the clinical expert and the lead for the Cancer Drugs Fund explained that people included in the SACT dataset were older and had a poorer performance status, which may have contributed to the differences in the median survival estimates. The clinical expert also noted that there may have been selection bias of good prognostic features for people enrolled in IMvigor\xa0130, who were eligible to have chemotherapy, compared with the SACT dataset in which people were not necessarily able to have chemotherapy. The lead for the Cancer Drugs Fund explained that the COVID‑19 pandemic may have affected people's choice to continue treatment, even if their disease was responding, which would have impacted the SACT dataset. But the IMvigor\xa0130 trial would likely not have been impacted by the COVID‑19 pandemic. The committee concluded that these population differences and impact of the COVID‑19 pandemic likely contributed to the differences in treatment effects between the IMvigor\xa0130 trial and SACT dataset.\n\n# Adverse events\n\n## Atezolizumab is reasonably well tolerated in clinical practice\n\nIn the original appraisal the clinical experts explained that, in their experience of using atezolizumab, it is well tolerated and associated with fewer adverse events than chemotherapy. However, the committee in the original appraisal also understood that atezolizumab was associated with some unpleasant and potentially serious adverse events. A clinical expert in this review stated that toxicities are well managed by specialist hospitals in collaboration with other specialities. The committee concluded that atezolizumab is reasonably well tolerated in clinical practice.\n\n# Modelling overall survival and time to treatment discontinuation\n\n## The estimates of overall survival for atezolizumab and platinum-based chemotherapy from each approach to modelling are similar\n\nThe company used data from the subgroup of people with untreated PD‑L1‑positive locally advanced or metastatic urothelial cancer, who were ineligible to have treatment with cisplatin. It used the Kaplan–Meier overall survival curve from the clinical trial until 20% of people were at risk and extrapolated the tail using the exponential distribution. The ERG proposed an approach in which it used an exponential parametric function over the whole time period. The ERG explained that it proposed this approach as there was considerable uncertainty with the small sample size in the cisplatin-ineligible, PD‑L1‑positive subgroup from IMvigor\xa0130. This approach resulted in a 5‑year survival of 16%. The clinical expert estimated that it was plausible that between 5% and 30% of people having atezolizumab would be alive at 5\xa0years. In its response to technical engagement, the company updated its approach to use the Kaplan–Meier curve to model the early part of the overall survival curve until 24 (48%) people were at risk, to maintain consistency with the original appraisal. This resulted in a 5‑year survival estimate of 15%. The committee concluded that the company and ERG's approaches were both clinically plausible and estimated similar 5‑year survival estimates and cost-effectiveness results.\n\n## The most plausible estimate for time to treatment discontinuation is less than 5% of people still having treatment at 5\xa0years\n\nTreatment in the platinum-based chemotherapy arm was restricted to 6\xa0cycles, so curve selection had a negligible impact on costs, and the discussion around time to treatment discontinuation curve selection focused on the atezolizumab arm. The company used the Kaplan–Meier time to treatment discontinuation curve for atezolizumab from the clinical trial, until 48% of people were at risk, and extrapolated the tail using the exponential distribution. This resulted in a 5‑year time to treatment discontinuation estimate of 1% for atezolizumab. The clinical experts estimated 5‑year time to treatment discontinuation for atezolizumab would be between 0% and 2%. The committee heard that this approach was clinically plausible, provided a good statistical fit to the data, and was a conservative extrapolation that aligned with the SACT data. The ERG noted that this approach assumed a constant probability of treatment discontinuation over time, whereas this probability decreased in the trial. The ERG explained that using this approach overestimated the probability of treatment discontinuation and underestimated the costs. The ERG preferred to use the Weibull parametric function over the whole time period, resulting in a 5‑year time to treatment discontinuation estimate of 7%. The committee noted that using the Weibull parametric function to extrapolate progression-free survival, the approach proposed by the ERG and accepted by the company in its response to technical engagement, resulted in 5‑year progression-free survival estimates of 5%. Using the ERG's approach to extrapolate time to treatment discontinuation would result in more people having treatment than were progression free, which the committee considered to be implausible. The committee heard that the SACT dataset showed that no one was on treatment after 2\xa0years, but the lead for the Cancer Drugs Fund cautioned that the maximum follow\xa0up for the SACT dataset was 25\xa0months. The committee recalled that there is no stopping rule for atezolizumab (see section 3.4). The committee concluded that the most plausible estimate of time to treatment discontinuation would be less than 5% of people having treatment at 5\xa0years to align with the 5‑year progression-free survival estimate and clinical expectations.\n\n# Utility values in the economic model\n\n## The utility values used in the model are appropriate\n\nIn the original appraisal, no health-related quality-of-life data was collected in IMvigor\xa0210 and the company used alternative utility values. The committee was concerned that the utility value of 0.71 used for the progressed-disease state was too high and concluded that the most plausible value for post-progression utility was likely to be between 0.5 and 0.71. The company submitted new health-state utility values for the atezolizumab and platinum-based chemotherapy arms, based on the IMvigor\xa0130 trial. The company provided naive utility estimates that did not consider the longitudinal nature of the data. To overcome this, the company used a mixed-effects model that accounted for changes in utility over time as well as correlation among observations within people in the trial to estimate the base-case utilities. In its response to technical engagement, the company updated the selection of the mixed-effects model used to estimate the utility values and explained the updated approach was more robust. The ERG agreed that the updated values were more appropriate and clinically plausible. The company's updated base-case utilities were lower than the naive values also presented by the company and led to higher cost-effectiveness estimates. The committee concluded that the updated base-case utilities were acceptable.\n\n# End of life\n\n## Atezolizumab meets the short life expectancy criterion\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with urothelial cancer was less than 24\xa0months for people having treatment with any standard care. The new evidence from IMvigor\xa0130 also showed that mean overall survival was less than 24\xa0months for people having treatment with UK standard care. The committee concluded that atezolizumab met the short life expectancy criterion.\n\n## Atezolizumab extends life by at least 3\xa0months, and meets the criteria for end of life treatments\n\nThe company's economic model also predicted that atezolizumab extended life by at least 3\xa0months, but the exact results are confidential and cannot be reported here. The committee concluded that atezolizumab would extend life by more than 3\xa0months, and therefore met the end of life criteria.\n\n# Cost effectiveness\n\n## The most plausible incremental cost-effectiveness ratios are below £50,000 per quality-adjusted life year\n\nNICE's guide to the methods of technology appraisal notes that judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of uncertainty around the incremental cost-effectiveness ratios (ICERs). It states that the committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the level of uncertainty, specifically around the size of the relevant population from IMvigor\xa0130 and the time to treatment discontinuation (see section 3.5 and section 3.10). But it acknowledged that the small sample size was a result of the restricted EMA marketing authorisation and concluded that the most plausible estimate of time to treatment discontinuation would be less than the 5‑year progression-free survival estimate and clinical expectations. For a life-extending treatment at the end of life, the upper limit of the range usually considered to represent a cost-effective use of NHS resources is £50,000 per quality-adjusted life year (QALY) gained. The committee noted that the company's base-case ICER for atezolizumab, including a patient access scheme and corrected by the ERG who found a minor difference in the results estimated by the company, was £32,235 per QALY gained. The committee's preferred assumptions for decision making at the appraisal committee meeting were to use:\n\nany of the approaches for extrapolating overall survival for atezolizumab and platinum-based chemotherapy\n\nless than 5% of people having treatment with atezolizumab at 5\xa0years.Using these preferred assumptions, the plausible ICER was considerably less than £50,000 per QALY gained. The committee recalled the uncertainty in the clinical evidence but noted the survival estimates were reasonably mature. It concluded the cost-effectiveness estimate for atezolizumab suggest it is an acceptable use of NHS resources for a life-extending treatment at the end of life. So, atezolizumab was recommended for routine use in the NHS.\n\n# Equality issues\n\n## The recommendations apply equally to all people with untreated PD-L1-positive locally advanced or metastatic urothelial cancer when cisplatin is unsuitable\n\nA patient expert questioned whether there is an equality issue regarding gender. The clinical expert confirmed that women tend to present later so are more likely to have advanced disease and worse cancer-specific mortality. The committee heard from the Cancer Drugs Fund clinical lead that data collected by Public Health England from NHS patients in England showed that more men had taken atezolizumab while it was available in the Cancer Drugs Fund. The committee concluded that its recommendation applies equally, regardless of gender, so this difference is not in itself an equality issue.\n\n# Other factors\n\nNo additional benefits that had not been captured in the QALY calculations were identified during the course of the appraisal."}
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https://www.nice.org.uk/guidance/ta739
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Evidence-based recommendations on atezolizumab (Tecentriq) for untreated PD-L1-positive locally advanced or metastatic urothelial cancer in adults when cisplatin-containing chemotherapy is unsuitable.
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Looked-after children and young people
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Looked-after children and young people
This guideline covers how organisations, practitioners and carers should work together to deliver high-quality care, stable placements and nurturing relationships for looked-after children and young people. It aims to help these children and young people reach their full potential and have the same opportunities as their peers.
# Context
As of 31 March 2020, there are 80,080 looked-after children and young people in England, with the total number of children being looked after increasing yearly since 2010. Most of the looked-after children are cared for in foster placements (72%), with 14% in connected care, and 13% in residential care, secure units or semi-independent living accommodation. In addition to these, 7% of looked-after children are placed with birth parents.
Although each child or young person will have a unique journey into care, the most common reason for becoming looked after was abuse or neglect (65%). These are considered to be major adverse childhood events (ACEs). These can cause trauma and can lead to long-term damaging effects on children and young people's physical and mental health. Other adverse childhood events experienced by looked-after children and young people include physical abuse (48%), emotional abuse (37%) and sexual abuse (23%). Trauma can also include domestic abuse, serious harm, exposure in the home or community to alcohol, drug misuse or violence. All looked-after children and young people will have experienced trauma in some way.
Every child in care is a unique child with individual strengths and needs. However, the physical, emotional and mental health of some looked-after children and young people will have been compromised by neglect or abuse. The rate of mental health disorders in the general population aged 5 to 15 is 10%. However, for those who are looked after, it is 45%, and 72% for those in residential care. In addition, frequent placement moves can keep looked-after children and young people from receiving the support they need by disrupting treatment plans and access to services. Frequent placement moves are linked to poorer mental health and a lessened sense of belonging. Practitioners and services involved with the child need to work collaboratively to assess and review the child's needs and how these can best be met. Key statutory guidance for promoting the health and wellbeing of looked-after children is available from the Department for Education and the Department of Health and Social Care.
Looked-after children are also at a greater risk of poor educational outcomes. In 2019, 55.9% of looked-after children had a special educational need compared with 14.9% of all children. At key stage 2, 37% of looked-after children and young people reached the expected standard in reading, writing and maths (compared with 65% of those who were not looked after). The higher prevalence of special educational needs, as well as speech, language and communication needs, among looked-after children, in part explains this difference. As of 2018, the rate of permanent exclusions for looked-after children has fallen and is now less than the rate for all children. However, looked-after children and young people continue to be significantly over-represented in the criminal justice system. Around half of the children currently in custody in England and Wales have been in care at some point. Virtual schools oversee the pupil premium grant, which is used by them – or designated to schools – to support looked-after children's education. This and other statutory guidance for the education of looked-after children can be found in the Department for Education's statutory guidance on promoting the education of looked-after and previously looked-after children.
Once a child or young person enters care, a suitable placement will be sought for them. Looked-after children leaving care most commonly return home to their birth parents (29%), but two-thirds of children who return home to birth parents re-enter care within 5 years. However, as of December 2019, although the number of children entering care has been rising year after year, the number of children ceasing to be looked after during the year due to adoption has been falling down to 3,570 from a peak of 5,360 in 2015. This has increased pressures on health and social care providers to continue to provide high-quality care with existing resources. Reductions in adoptions have been partially compensated for with increases in Special Guardianship Orders, which increased from 3,550 to 3,700 in the same period. Statutory support for the transition out of care into adoption, including preparing adopters and arranging contact, is outlined in the Department for Education's statutory guidance on adoption.
From 31 March 2019, the number of young people aged 16 and over leaving care to move into independent living has risen each year from 3,720 in 2015, to 4,560 in 2017, and to 4,680 in 2019. Care leavers as a group also have poorer outcomes on key measures such as housing, health, employment, and continuing in education and training post‑16. For 19- to 21‑year‑olds, 6% were known to be in higher education, 21% were in other education, 25% were in training or employment, and 39% were not in education, employment or training (compared with around 12% of all young people aged 19 to 21 years). Statutory support for care leavers, including providing a personal adviser for all care leavers, can be found in the Department for Education's Children Act 1989 guidance and regulations: transition to adulthood for care leavers (volume 3).
Local authorities have a statutory duty to support looked-after children and young people. Partners cooperate to produce individual care plans covering health, education and placement. In addition, clinical commissioning groups, NHS England and Public Health England have a statutory duty to support local authorities to meet their health needs. The Children Act 1989, Children Act 2004, Care Standards Act 2000, Care Planning, Placement and Case Review Regulations 2010, Children and Social Work Act 2017, Fostering Services Regulations 2011, Children and Adoption Act 2006 and accompanying regulations and statutory guidance provide the legal framework for local authorities, providers of fostering services and children's homes. Other relevant safeguarding legislation and statutory guidance includes the Safeguarding Vulnerable Groups Act 2006, Working Together to Safeguard Children 2018, Children's Act 1989 Guidance and Regulations and Keeping Children Safe in Education 2021.
Despite the gap in health and educational outcomes between looked-after children and young people and the general population outlined above, research suggests that the longer children remain in care, the better they can improve in these areas. And, accounting for their disadvantages, they can do better than children not in care.
The original NICE guideline on looked-after children and young people duplicated existing statutory guidance. This update focuses more on the specific interventions needed to help practitioners improve outcomes for looked-after children and young people, as well as how statutory care is best delivered. It complements existing national statutory guidance, which focuses more on service delivery. It also recognises that looked-after children and young people experience inequality, and these recommendations seek to ensure that their needs are at the centre of any plans being made and are adequately met. This requires special attention and expertise.
The guideline covers support provided to looked-after children and young people and care leavers (from birth to age 25), and their families and carers (including birth parents, connected carers, prospective adoptive parents and special guardians). This includes all who are classed as 'looked-after' under a full or interim local authority care order, whether temporary or long term. For example, it covers looked-after children and young people on remand, those temporarily looked-after under section 20 of the Children Act 1989, and those preparing to leave care. The guideline covers all parts of the care pathway, from entry of looked-after people into the care system, to support provided when moving into permanency and out of care into independent living.
The guideline does not cover children and young people who have moved out of care and are no longer looked after (not including care leavers) – that is, those who have been successfully adopted or reunified with birth parents. It also does not cover those on the edge of care and their families.
The guideline committee wished to acknowledge that the impact of the COVID‑19 pandemic on looked-after children and young people's mental and emotional health and wellbeing, as well as their educational progress, cannot be underestimated.
Although children and young people have been less affected by the virus than adults in terms of infection and mortality rates, the committee raised concerns about lost learning and greater safeguarding risks to this vulnerable group during lockdown. COVID‑19 has disrupted practitioners' relationships with children and families, and the longer-term impact on the voluntary and charitable sector is unknown.
To address the impact on educational progress, the UK government has announced £1 billion of funding for schools (the 'catch-up premium'), which includes millions of pounds specifically for vulnerable and disadvantaged children (including looked-after children) whose education has been most affected. Services, including health and social care services, have also been increasingly delivered remotely using digital technology.
Implementing new ways of working, reconfiguring services to meet evolving social distancing requirements and offering emergency support has resulted in increased cost pressures on local authorities, the healthcare sector and other organisations and agencies involved in the care of looked-after children and young people. The impact of the pandemic on vulnerable groups outside of the care system, such as those experiencing domestic abuse and neglect, and families suffering financially, has also led to more children being referred to children's services who had not previously been known to local authorities and children's social care, leading to a greater impact on the system.# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
Making decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.
This guideline should be read alongside NICE's guideline on children's attachment.
# Diversity
Be aware that many looked-after children and young people are from groups that may face additional disadvantage. Ensure that their needs are met and that they do not face further marginalisation. These groups include those from black, Asian and other minority ethnic groups, Gypsy, Roma and Traveller communities, and those from different religious backgrounds, as well as other groups such as refugees and unaccompanied asylum-seeking children, disabled people with complex needs, autistic children and young people, children and young people with a learning disability or neurodevelopmental disability, lower socioeconomic groups and people who identify as LGBTQ+.
For a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on diversity .
Full details of the evidence and the committee's discussion are in evidence review D: barriers and facilitators for supporting positive relationships among looked-after children and young people.
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# Supporting positive relationships
## Positive relationships in the care network
Ensure that the care network around a looked-after child or young person consists of positive relationships. These are characterised by:
genuine caring – being treated by carers as 'one of their own'
availability – being there when needed
reliability – providing promised support in a timely manner
listening that is engaged and non-judgemental
continuity of relationships
promoting agency and shared decision making that is appropriate to developmental age
providing well-communicated and fair discipline and boundaries
persistence and understanding, to respond to behaviours that challenge and to support positive behaviours
positive role models who offer guidance.
If the looked-after child or young person has speech, language and communication problems (whether or not these have been previously diagnosed), refer them to speech and language therapists, if needed, for assessment and for advice on how to communicate effectively with them.
## Sibling relationships
Consider interventions and support to improve the relationship between siblings in care, including biological siblings who live apart and non-biological siblings who live together (for example, other looked-after children or young people in the placement, and the carer's biological or adopted children). Take into account safeguarding issues and the looked-after child or young person's preferences.
For primary-school-aged children, or those needing greater assistance, ensure that the primary carers are present during interventions to improve relationships between siblings in care. Components of this intervention should include:
structured conversation around relationships and conflict resolution
incentivised cooperation, for example shared activities and outings to encourage prosocial, cooperative behaviour
shared activities with coaching in prosocial skills using life story work.
Consider relationship coaching independently from the carer for adolescent siblings in care.
Offer carers support to help them understand and maintain stable sibling relationships before offering interventions to improve the relationship between siblings in care.
## Relationships with the birth family
Respect the wishes of looked-after children and young people about contact arrangements (where and who with) and take them into account when making plans. Balance them against safeguarding considerations and the risk of repeating trauma.
Provide contact supervisors for contact with birth families if this is necessary for safeguarding, or if it will help support the relationship between the looked-after child or young person and the birth family. Ensure that the looked-after child or young person always has the same contact supervisor if possible.
Contact supervisors should receive training in:
safeguarding the looked-after child or young person, including trauma-informed training in recognising signs of distress (including in babies and in non-verbal children and young people) and how and when to end a session
providing emotional support for the looked-after child or young person, including in transition to and from contact with the birth family
providing support for and feedback to birth parents to help them build positive relationships during contact
knowing when to support, and how to reduce support when necessary
record keeping and sharing information with the broader care team.
Consider the need for more intense contact supervision (in terms of monitoring and feedback provided) between the birth family and looked-after child or young person in the early stages of care placements, with reduced intensity as needs decrease over time.
Provide interpreting services for contact supervisors if the people taking part in contact are non-English speaking. Consider any additional communication support as needed, for example sign language.
Think about using text, email or social media to support contact for looked-after children and young people. Safeguarding plans should also take account of the possibility of ongoing unmonitored online contact and ensure that the time spent in digital or social media contact and the content of these interactions is appropriate.
Consider the contact needs of children placed out of their local area – for example, additional support for the birth family to attend contact centres.
## Relationships with social workers
Support the looked-after child or young person's allocated social worker, to reduce professional turnover. Support could include, for example:
supervision with regular meetings to check on the wellbeing of workers, and reflect on practices that promote positive relationships (see recommendation 1.2.1)
consultation for complex and specialist problems (see recommendation 1.4.3)
trauma-informed training in communication skills to support positive relationships (see also recommendation 1.3.18).
Managers of social workers should use and review ways of working to reduce duplication of effort, increase staff retention and enable more one-to-one time between social workers and looked-after children and young people (for example, by improving administrative support).
Local authorities and partner agencies should collect and review data on staff turnover to assess the impact on looked-after children and young people and the success of existing staff support systems. They should use this data to inform action plans to support greater continuity of practitioners working directly with looked-after people and care leavers.
If possible, social workers should tell looked-after children, young people, care leavers, and primary carers pre-emptively, and in a manner appropriate to developmental age, about upcoming changes in their job that will affect their relationship with the looked-after child or young person. This should include a joint meeting in person between the previous and new social worker and the looked-after child or young person. Recognise the emotional impact of such changes and provide an opportunity to say goodbye.
## Mentoring
Consider programmes (with professional oversight) to support mentoring relationships. For example, by pairing looked-after young people with near peers with care experience to provide positive role models, particularly for looked-after young people with social, emotional and mental wellbeing needs.
## Friendship
To support overnight stays with friends, ensure that safeguarding checks are completed in good time so as not to cause a barrier to relationships.
Consider providing funding to support contact with friends (for example, for travel or activities), particularly for friendships that existed before the looked-after child or young person entered care.
## Placement stability
Provide out-of-hours support services (separate from those provided for carers) for looked-after children and young people to help resolve urgent problems, and tell looked-after children and young people about these options. Services could be provided, for example, through social workers 'on call', voluntary or independent agency helplines or advocacy organisations.
Adopt a proactive approach to identify children and young people who may be likely to present out-of-hours (for example, they may show early warning signs such as skipping school, lying or stealing), for whom out-of-hours support could be planned ahead of time.
Discuss the priorities and needs of carers sensitively and transparently with the looked-after child or young person in a manner appropriate to developmental age. For example, if placements are at risk of breakdown, social workers should facilitate communication between the carers and the looked-after child or young person (and birth parents if relevant) to try to resolve problems.
If a placement changes:
Discuss the reasons for this with the looked-after child or young person in a way they can understand and that is appropriate to their developmental age.
Offer the child or young person emotional support, if possible by a practitioner they have an existing relationship with.
Use ongoing life story work to help them process changes in placement.
Provide the new carer with appropriate health information in good time before the new placement starts (for example, the health plan recommendations, any new health concerns, health contacts and upcoming health appointments).
## Serious behavioural problems
Consider multidimensional treatment foster care for looked-after adolescents with a history of persistent offending behaviour.
For guidance on service design and delivery for learning disabilities and behaviour that challenges, see NICE's guideline on learning disabilities and behaviour that challenges.
## Disorganised attachment
For guidance on attachment difficulties, see the NICE guideline on children's attachment.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting positive relationships .
Full details of the evidence and the committee's discussion are in:
evidence review A: interventions to support care placement stability for looked-after children and young people
evidence review B: barriers and facilitators for supporting care placement stability among looked-after children and young people
evidence review C: interventions to support positive relationships for looked-after children, young people and care leavers
evidence review D: barriers and facilitators for supporting positive relationships among looked-after children and young people
evidence review F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers
evidence review G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.
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# Valuing carers
These recommendations cover support for primary carers, including foster carers, connected carers, key workers in residential care and birth parents (when the looked-after child or young person is placed with the birth parent).
## Supporting and involving carers
Involve and value the carer's input in decision making in the broader care team, and keep carers fully informed about a looked-after child or young person's care plan.
Provide out-of-hours support services for carers to help resolve urgent problems, for example through social workers working 'on call', emergency duty teams or out-of-hours service, voluntary or independent agency helplines, or carer peer support associations.
Ensure that carers log any help sought outside of usual operational hours as part of their routine and urgent reports.
Facilitate peer support for carers at accessible times and places, including online if people may find it difficult to attend a physical meeting.
As part of the care plan, think about the need for planned respite care (or 'support care') for carers.
Ensure that respite (or support) care is used in the looked-after child or young person's best interests and explain this to the looked-after child or young person. For example, make use of short breaks that are fun for the child or young person, such as staying with relatives or extended carer family.
Use a respite (or support care) carer who the child or young person is familiar with if possible, and take into account the skills or training needed to meet the looked-after child or young person's assessed need.
Keep carers fully informed and updated about the support services available to carers and looked-after children and young people in their local authority.
Inform the looked-after child or young person's carers about any interventions used to support the looked-after child or young person, including the purpose of these interventions.
For further guidance on support for adult carers, follow the NICE guideline on supporting adult carers.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting and involving carers .
Full details of the evidence and the committee's discussion are in:
evidence review A: interventions to support care placement stability for looked-after children and young people
evidence review B: barriers and facilitators for supporting care placement stability among looked-after children and young people.
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## Training for carers
Plan training for carers so that it is delivered before it is needed. Think about the need for multiagency involvement in training programmes and ensure that the organisations involved agree the source of funding between them.
Supervising social workers should work with carers to assess the needs of the looked-after child or young person, to inform and tailor training and development needs for the carers.
Provide a schedule of mandatory training for carers, excluding birth parents. Ensure that this training covers:
Therapeutic, trauma-informed parenting (covering attachment-informed, highly supportive and responsive relational care).
Safeguarding procedures.
How to communicate effectively and sensitively (for example, using de-escalation techniques).
Life story work to promote a positive self-identity, which has a consistent, child-focused and planned approach (see the section on life story work for identity and wellbeing).
How to be an educational advocate (this part of the training should be delivered by practitioners from the virtual school).
Identifying problems with, and supporting, good oral health, diet and personal hygiene (particularly among those coming into care).
Encouraging positive relationships and sexual identity (covering issues such as consent, encouraging healthy intimate relationships, 'coming out' and transitioning).
Self-care for carers, preventing burnout and coping with placements ending.
The importance of health assessments, supporting attendance and issues of consent for medical treatment.
Record keeping and sharing the information in the record with the looked-after child or young person in a constructive and positive way, considering the need for confidentiality, and the impact the record may have on the looked-after child or young person. Training can be delivered in person (for example, at home or in community group settings) or virtually.
Provide targeted support and training for birth parents if reunification is a possibility or if the child or young person is to remain in placement with the birth parent. This should be provided through transition planning with family support teams.
Think about providing tailored training for carers if there are specific needs related to race, ethnicity and culture. This could include, for example, understanding and respecting cultural and religious identity (including dietary requirements or preferences), and understanding specific hair and skin care needs.
Provide tailored training for carers if there are specific needs relating to special educational needs, long-term health conditions and disabilities, for example sensory and communication needs. Training could be provided through specialist healthcare teams and voluntary organisations.
Based on the individual needs and developmental age of the looked-after child or young person, consider more intensive training methods for carers to support the delivery of therapeutic, trauma-informed caregiving. These methods should use video feedback, coaching and observation, role play, and follow-up booster sessions and be delivered by trained facilitators.
Ensure that trauma-informed training covers:
understanding behaviour as a form of communication and as a response to trauma
understanding, recognising and processing triggers for trauma responses
understanding attachment and loss.
Ensure that trainers for carers are trauma informed and have a good understanding of attachment issues and therapeutic approaches.
Ensure that new permanent or long-term carers are trained and prepared so that there is continuity of care and support, including therapeutic support if needed, between placements.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on training for carers .
Full details of the evidence and the committee's discussion are in:
evidence review A: interventions to support care placement stability for looked-after children and young people
evidence review B: barriers and facilitators for supporting care placement stability among looked-after children and young people
evidence review C: interventions to support positive relationships for looked-after children, young people and care leavers.
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# Safeguarding
Local authorities should facilitate a multidisciplinary approach to safeguarding looked-after children and young people, recognising that, like other children, looked-after children may need a full safeguarding response despite already being in care. This approach should:
include all relevant agencies in meetings to address safeguarding concerns
facilitate the sharing of data between agencies
seek the views of looked-after children and young people and their carers, to ensure that responses to safeguarding risks are effective and acceptable, for example by coordinating safeguarding responses for siblings in care.
Hold safeguarding meetings to bring together practitioners from multiple agencies involved in the care and support of looked-after children and young people, such as: social care; fostering, residential and connected care; education and the virtual school; healthcare; voluntary agencies; housing services; emergency services; policing; and immigration.
Local authorities should seek specialist support to address safeguarding risks outside the home (contextual safeguarding), exploitation and children missing from care. This practitioner should lead and facilitate safeguarding meetings and build clear lines of accountability. The practitioner could be, for example, a missing person's coordinator or another trauma-informed specialist with knowledge of exploitation and safeguarding issues in the looked-after population.
Assess the safeguarding risk of a looked-after child or young person using data shared across agencies. This could include data on vulnerabilities:
at the individual level (such as those captured by risk-assessment tools)
at the group level (red flags specific to subpopulations such as young girls and boys, trafficked children and unaccompanied asylum-seeking children)
at the community level (gathered from community-level health and mental health data, area deprivation indexes, number of county lines operating in a single area and area-specific missing person reports).
Use training and review meetings to ensure that practitioners and carers working directly with looked-after children and young people are:
able to recognise critical moments for looked-after people; that is, times when they may be more open to change and receiving help
aware of the early signs of, and risk factors for, gang involvement, exploitation and going missing
familiar with how to report concerns.
Promote positive relationships (including broader relationships such as those with carers, siblings and practitioners) as the main way to prevent exploitation and children going missing from care (see recommendation 1.2.1).
Provide tailored support for the looked-after child or young person to prevent exploitation, by addressing issues specific to young girls and boys, trafficked children and unaccompanied asylum-seeking children (for example, addressing issues of self-esteem, domestic abuse, negative relationships and previous exploitation).
Review the case files of looked-after children and young people who have been the subject of safeguarding meetings, to help the safeguarding partnership learn and develop future safeguarding responses (or to inform best practice).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safeguarding .
Full details of the evidence and the committee's discussion are in evidence review G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.
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# Health and wellbeing
## Building expertise about trauma and raising awareness
Ensure that all practitioners working with looked-after children and young people are aware of the impact of trauma (including developmental trauma) and attachment difficulties and appropriate responses to these, to help them build positive relationships and communicate well.
Ensure that practitioners and carers working with unaccompanied asylum-seeking children are aware of the issues that affect this group, including health needs, safeguarding issues, language and culturally sensitive care needs, and the danger of going missing.
Ensure that there is sufficient specialist professional expertise to support, and provide consultation for, looked-after children and young people with more complex needs. This could be provided through more intensive (responsive) trauma-informed training, or by sharing expertise across agencies.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on building expertise about trauma and raising awareness .
Full details of the evidence and the committee's discussion are in:
evidence review C: interventions to support positive relationships for looked-after children, young people and care leavers
evidence review D: barriers and facilitators for supporting positive relationships among looked-after children and young people
evidence review E: interventions and approaches to support practitioners in completing physical and mental health and wellbeing assessments (and act on findings during the care journey) for looked-after children and young people
evidence review G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.
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## Physical and mental health and wellbeing assessments
In line with statutory guidance, when a child or young person enters care, local authorities must ensure that healthcare teams are informed as soon as possible about the legal status of the looked-after child or young person and why they have entered care (within 5 working days, as specified by the Care Planning, Placement and Case Review Regulations 2010). Get consent to share this information from an adult with parental responsibility, or from the looked-after child or young person directly if appropriate.
When a child or young person enters care, social workers should:
Make a formal request for the initial health assessment, giving the reasons that the child or young person is coming into the care system.
Ask for consent from the birth parents (or from another adult with parental responsibility, or from the looked-after young person directly if appropriate) to access and share information from the child health record.
Ask for consent from the birth parents to share their own health information, and ask them to complete a parental health questionnaire to help with this. If the birth mother has agreed to share her health information, ask the relevant hospital about her health during pregnancy. All this information should be available in time for the looked-after child or young person's initial health assessment.
Ensure that statutory review health assessments for a looked-after child or young person are carried out by the same healthcare professional each time, if possible.
Consider the need for confidential and private access to healthcare for looked-after young people, for example if phone use or internet use are restricted because of safeguarding needs, or when seeking out sexual health advice or treatment. For guidance on one-to-one interventions to prevent sexually transmitted infections (STIs) and contraceptive services, see NICE's guidelines on STIs and contraceptive services.
Healthcare professionals should compile a history of the looked-after child or young person's health from the information they hold in the health records and additional information given to healthcare professionals from other teams, to give practitioners and carers a clear sense of their past, present, and likely future physical and mental health needs.
Be aware that care leavers are very likely to request access to their health and social care records. Practitioners should ensure that the language used in the records and the way events are captured are sensitive and empathetic.
Offer a culturally appropriate, registered interpreter to communicate in person with looked-after children and young people for the initial health assessment if language is a barrier to communication. If language remains a barrier to communication, think about the need for a culturally appropriate, registered interpreter to be available in person for subsequent health and social care assessments.
Offer unaccompanied asylum-seeking children tailored initial health assessments that address risks arising from their country of origin and journey to the UK. Include:
diet and nutrition, including nutritional deficiencies such as vitamin D deficiency
gastrointestinal symptoms
-ral health
tuberculosis screening and general immunisation status
sexual health, tailored to the individual (for example, testing for sexually transmitted diseases; and being aware of signs of assault and abuse, including abuse linked to faith and culture such as female genital mutilation and breast flattening). For guidance on one-to-one interventions to prevent sexually transmitted infections (STIs) and under‑18 conceptions, see NICE's guidelines on STIs and contraceptive services
-ther infectious diseases and bloodborne infections, for example HIV and hepatitis testing
sensory issues not previously identified because of lack of screening, for example hearing, vision or mobility problems
an assessment of mental health, with referral to specialist mental health teams if indicated
sleep disturbances.
After looked-after children and young people (including babies) have had their initial health assessment, consider the need for an additional specialist mental and emotional health assessment once the looked-after child or young person has begun to form a relationship with the primary carer. This could be, for example, up to a year or by the first review health assessment.
Healthcare professionals responsible for the care of looked-after children and young people should review whether care recommendations in the health plan have been completed, particularly if the child or young person has been moved out of area, checking with the professionals concerned across agencies.
For guidance on the diagnosis and management of attention deficit hyperactivity disorder (ADHD) in children and young people, see NICE's guideline on ADHD.
For guidance on the recognition, referral and diagnosis of autistic spectrum disorder, see NICE's guideline on autism spectrum disorder in under 19s: recognition, referral and diagnosis.
For guidance on the recognition, assessment and treatment of post-traumatic stress disorder (PTSD), see NICE's guideline on PTSD.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical and mental health and wellbeing assessments .
Full details of the evidence and the committee's discussion are in evidence review E: interventions and approaches to support practitioners in completing physical and mental health and wellbeing assessments (and act on findings during the care journey) for looked-after children and young people.
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## Mental health and child and adolescent mental health services
To avoid delays in care, provide intermediate therapeutic or specialist support for the care network around looked-after children and young people who are on a waiting list for child and adolescent mental health services (CAMHS), for example a specialist outreach team. This should not be used as a replacement for CAMHS.
Offer a range of dedicated CAMHS that are tailored to the needs of looked-after children and young people – for example, making them longer term, more trauma informed and relationship based.
Offer preventive services based on assessed need (see recommendation 1.5.12), with timely delivery to prevent serious mental health problems that need tier 3 or 4 specialist services.
Be aware that children moving placements must not lose their place in the waiting list for CAMHS, as there is a statutory right to not lose a place in a waiting list for a health service.
Provide specialist, trauma-informed mental health and emotional wellbeing support for unaccompanied asylum-seeking children. Take into account cultural sensitivities (for example, the different perspectives of unaccompanied asylum-seeking children about mental health services) and that symptoms of trauma could come to the surface over the long term.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on mental health and child and adolescent mental health services .
Full details of the evidence and the committee's discussion are in:
evidence review F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers
evidence review G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.
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## Life story work for identity and wellbeing
Start life story work as soon as possible after the looked-after child or young person enters care, to support care placement and emotional stability, rather than as an intervention to deliver once placements are stable.
Schedule regular, dedicated times for life story work to help the looked-after child or young person make sense of their journey through the care system and beyond, their significant relationships and their identity.
Ensure that life story work is done in the setting preferred by the looked-after child or young person, and conducted by a named carer or practitioner with whom they have a continuous and close relationship. This named person may change over the period in care.
Include the following in life story work for looked-after children and young people:
the present – identity, strengths and significant relationships
the past – reasons for entering care and for any placement breakdowns, important memories and relationships
the future – building independence, careers, hopes and dreams.
Take a flexible approach to life story work, and tailor it to the developmental age and needs of the looked-after child or young person. The content could include life mapping, pictures, art, narratives, and toys or play.
Compile life story work in 1 place (such as a ring binder) and build on this in each session. Give the child or young person control over who this is shared with and how it is stored. Help them to choose a safe and secure storage option.
Ensure that life story work for looked-after children and young people captures and embraces ethnicity, cultural and religious identity, as well as other personal aspects of identity, for example, sexual identity or disabilities.
Ensure that a social worker oversees the life story work if another carer or practitioner is carrying out the work. For example, the social worker may share background information to support the carer or practitioner carrying out life story work, with the looked-after child or young person's consent.
Think about and plan how to carry out life story work for looked-after children and young people, with sibling groups, in a manner appropriate to developmental age. This may include:
preparing siblings for navigating conversations with older siblings or siblings not in care
deciding whether it is appropriate to deliver life story work sessions in a sibling group or individually
determining whether conversations will include sensitive information.
Ensure that the experience and skillset of the practitioner or carer delivering life story work for looked-after children and young people is sufficient to deliver good quality work, particularly in complex situations.
Explain to the looked-after child or young person's wider support network that life story work is ongoing, so that they can support it as needed. For example, if sensitive or emotional information has been discussed with the child or young person during life story work, schools may need to be informed.
Plan regular reviews of how life story work may affect contact arrangements and the looked-after child or young person's relationship with their birth family. Use information from these reviews to adjust the support provided. This could include, for example, involving birth families in life story work to encourage consistencies in narratives explored, and helping the looked-after child or young person with reframing previous relationships.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on life story work for identity and wellbeing .
Full details of the evidence and the committee's discussion are in evidence review B: barriers and facilitators for supporting care placement stability among looked-after children and young people.
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## Relationships and wellbeing activities
Promote a positive relationship between the primary carer and the looked-after child or young person as the main way to support the social, emotional and mental wellbeing of the looked-after child or young person.
When making safer caring plans, think about a looked-after child or young person's need for:
Physical touch and affection as a part of a healthy relationship with male and female primary carers. Take into account any adverse childhood experiences.
Play, particularly for babies and young children.
Develop the interests of looked-after children and young people to help them develop their identity and to find peer support and new friendships. Do this by helping them to find, and setting aside time, for outings, interest groups and other activities that will help them to build skills. These may include:
-ne-to-one activities accompanied by the primary carer (at least initially) to promote opportunities for listening and positive relationship building (for example, visiting outdoor green spaces such as parks)
funded, supported and facilitated activities (such as school clubs, for example making use of the pupil premium grant as determined in the personal education plan) specifically to address emotional health and wellbeing needs
activities or outings to support identity, for example community support groups, cultural or religious activities, events or festivals
activities to bring together children, carers and practitioners in informal settings, for example group outdoor activities.
For guidance on managing obesity and promoting physical activity, follow NICE's guidelines on preventing obesity, identifying, assessing and managing obesity, weight management and physical activity for children and young people.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on relationships and wellbeing activities .
Full details of the evidence and the committee's discussion are in evidence review G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.
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# Learning and education
## Readiness for starting or changing school
Consider the following to support social competence and emotional stability in looked-after children:
early years education, including playgroups
-ther opportunities to encourage child-led play.
The virtual school should plan bespoke, individual transition support for supporting readiness for school and resilience in looked-after children and young people moving between schools and settings (including those moving out of care to permanency). This includes:
moving from preschool to primary school
moving from primary to secondary school
moving in the middle of a school year
returning to school after an extended absence. Individual transition support for school moves may include structured visits to the school beforehand, school preparation for the carer, meeting the designated teacher, catch-up support and handover between designated teachers (for example, drawing from weekly diaries and life story work).
Think about providing multidisciplinary specialist support for transition between school placements, tailored to the looked-after child or young person's needs and alongside or part of the virtual school and the team around the child – for example, including healthcare professionals in transition support for looked-after people who have health conditions that affect their education.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on readiness for starting or changing school .
Full details of the evidence and the committee's discussion are in evidence review H: interventions to support readiness for school in looked-after children and young people.
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## Support in schools
Inform looked-after children and young people and their carers of:
their rights to educational support and
the purpose of the pupil premium grant for education and how it is distributed by the virtual school.
Schools should ensure that behavioural management policies reflect trauma-informed practices and cover attachment issues.
Schools should ensure that the designated teacher is a consistent advocate for the looked-after child or young person's educational progress.
The designated teacher should:
collaborate with school staff (who the looked-after child or young person is most comfortable with), primary carers and named practitioners in the personal education plan and the education health and care plan
provide timely assessment and ongoing monitoring of learning needs, particularly in times of transition between educational placements
refer for specialist support when needed (for example, educational or clinical psychology), and be aware of the impact of trauma on learning and behaviour
be aware of special educational needs and link up with the special educational needs coordinator
liaise with specialist looked-after children nurse teams if a health problem has been identified that affects education
work to ensure that young people are able to access the most appropriate and inspirational educational opportunities, especially post‑16
have regular one-to-one informal conversations with the looked-after child or young person and their primary carer, at a frequency informed by the looked-after child or young person.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on support in schools .
Full details of the evidence and the committee's discussion are in:
evidence review G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers
evidence review K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.
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## Virtual schools
Ensure that the virtual school includes all of the following:
early years expertise
a special educational needs coordinator
a post‑16 coordinator.
Ensure that the virtual school covers early years provision, incorporating information from nurseries and health visitors (such as the Ages and Stages Questionnaire) and other involved health services. Complete the early years personal education plan and link it to the foundation stage profile if possible.
Ensure that the virtual school special educational needs coordinator is trained in the special educational needs and disability legal framework so they can help looked-after children and young people access all the provision and support that the law entitles them to.
The post‑16 coordinator in the virtual school should help looked-after young people navigate opportunities for training and education (including further and higher education, and apprenticeships) and available funding streams to support these.
Ensure that the expertise in the virtual school reflects the needs and profile of the school-aged population it serves. For example, the population may include unaccompanied asylum-seeking children, trafficked children, children with a history of exploitation, and looked-after children on remand or in secure settings.
Make virtual school heads the key enabler for service collaboration and a link between named specialists in the following:
social workers
independent reviewing officers
school admissions and further or higher education admissions
-ther virtual schools if a looked-after child or young person is placed out of area
designated teachers
school improvement services
designated practitioners working with looked-after children and young people who have a health need, including mental health services or therapeutic services.
Local authorities should simplify and merge meetings about looked-after children and young people if possible. For example, education, health and care plan meetings for looked-after children and young people and personal education plan meetings may benefit from occurring together.
Include healthcare professionals in multiagency review meetings for looked-after children and young people who have additional health needs that affect their education.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on virtual schools .
Full details of the evidence and the committee's discussion are in evidence review K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.
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## Improving educational outcomes
To improve educational outcomes, such as literacy and numeracy, in primary-school-aged looked-after children:
-ffer paired reading
consider individual or small group tutoring (for example, by trained foster carers, trained volunteers or professional tutors).
Ensure that interventions for improving education in secondary-school-aged looked-after young people are regularly evaluated to check they are appropriate for the user and effective as part of the personal education plan.
Assess the language and communication needs of unaccompanied asylum-seeking children:
Offer English language lessons to those who are not fluent in English.
Consider intensive English lessons for those with no previous knowledge of English.
Consider the need for virtual schools to increase specialist education support for unaccompanied asylum-seeking children – for example, by providing designated staff members, and additional English for Speakers of Other Languages (ESOL) support.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on improving educational outcomes .
Full details of the evidence and the committee's discussion are in:
evidence review I: interventions to support learning needs for school-aged looked-after children and young people
evidence review K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.
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## Data collection, sharing and publication in education
The responsible local authorities should collect, publish and monitor information on educational provision for their looked-after children and young people, in particular those missing education (for example, those in schools that do not have a Department for Education number, or those on permanent or fixed-term exclusions). This may include unaccompanied asylum-seeking children and those with a history, or high risk of, exploitation.
Local authorities should agree and share a strategy for reducing the number of looked-after children and young people missing from education.
Local authorities, working with the virtual school, should develop a mechanism to check the spending of the total pupil premium grant, beyond the information recorded in the personal education plan, and evaluate the impact of the spending on the looked after child or young person.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on data collection, sharing and publication in education .
Full details of the evidence and the committee's discussion are in evidence review K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.
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## Further and higher education
Virtual schools should collaborate with universities and colleges to support looked-after young people to access higher or further education. Ways to do this could include:
residential experiences and visits to university or college campuses, mentoring by near peers in higher or further education, and coaching
local opportunities such as university access schemes and college support programmes
encouraging self-identification as a care leaver, once in university or college, to help them access support such as financial bursaries.
Ensure that looked-after young people are aware of the possibility of re-entering education when older (up to age 25) with the financial support of their local authority.
Personal advisers, with the support of the post‑16 coordinator, should help care leavers to understand the funding and support available for re-entering education, as part of the care offer, once they have left care.
Virtual schools should support a looked-after young person's entry into careers and training. Ways to do this could include providing:
careers support and advice
current local opportunities such as work experience placements, apprenticeships and internships (particularly those targeted at looked-after young people and care leavers).
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further and higher education .
Full details of the evidence and the committee's discussion are in evidence review J: interventions to support entry into further or higher education or training in looked-after children and young people.
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# Transition between care placements and to permanent placements
These recommendations cover support for all permanent carers, including long-term foster carers, special guardians, connected carers, adopters, key workers in residential care and reunified birth parents.
## Before transition
When planning transition between care placements, social workers should aim to have a good match between the permanent carers and the looked-after child or young person:
assess the child or young person's case history and care needs, and the carers' strengths, support and training needs (including the length of time needed for training), then
discuss relationship dynamics with the looked-after child or young person and their prospective carers.
During the transition period, support the foster carer and permanent carer relationship. Help to manage foster carer expectations during the planning stage (for example, the need for the permanent carer to be in the foster carer's house at times, using non-judgemental supportive language with new carers and understanding the emotional challenges for the foster carer of 'letting go').
In the planning stage, discuss the need for longer-term contact and longer-term contact arrangements with the current foster carer, for example contact by letter or email or meeting up once the looked-after child or young person has settled in their new placement.
Encourage and help the permanent carer's family and support network, including other children in the home, to be involved when a looked-after child or young person moves into their new placement – for example, by offering a family and friends training day before the placement.
Consider support, by trained staff, for birth parents with substance and alcohol misuse to support reunification. If the support is given, carry it out alongside court processes, such as family drug and alcohol courts.
Think about providing relational, emotional and mental health support for birth parents and families, alongside court processes, to support reunification.
Continue mental health support and support for drug and alcohol abstinence after reunification.
Consider concurrent planning to speed up the transition to permanent placements. If concurrent planning is used, ensure that carers and birth parents are well informed about the risk of late changes to the permanency plan.
For guidance on support for drug and alcohol abstinence and behaviour change, follow NICE's guidance on lifestyle and wellbeing.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on before transition between care placements and to permanent placements .
Full details of the evidence and the committee's discussion are in:
evidence review L: interventions to support looked-after children and young people transitioning out of care to living with adoptive or birth parents or special guardians, or into connected care
evidence review M: barriers to, and facilitators for, supporting looked-after children and young people in transition out of care to living with their adoptive or birth parents or special guardians, or into connected care.
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## During transition
During transition to a new permanent or long-term placement, think about the need for a more integrated experience for looked-after children (including non-verbal children) and young people that takes into account previous significant caregiving relationships. This could be achieved, for example, by creating opportunities for current and new carers to meet, developing positive carer-to-carer relationships and sharing information (such as familiar routines, emotional responses and diet) before the placement move.
When a looked-after child or young person moves between care placements or out of care to permanent placements, ensure that:
contact support takes into account the need for continuity with their existing social network (for example, previous friendships), especially if the care or educational placement is in a new area and
the transition period allows sufficient time for new social connections to form and for coming to terms with the loss of previous relationships.
To ensure that the permanency process is focused on the looked-after child or young person, set aside time for 'checking in' with them. Checking in should consist of careful observation and listening, writing a record of the conversation, and sharing the perspective of the looked-after child or young person to feed into shared decision making about transition arrangements.
In line with statutory guidance, advocacy services must be provided with communication support. The primary carer should also be present during check-ins, particularly for non-verbal children and young people, and children and young people with learning difficulties.
During transition to any new placement, social workers should give prospective carers a profile of the child and their care journey as a history of the care the looked-after child or young person has received. The information can be obtained from the statutory health reports, reports from school and the social worker's assessment.
Give all new carers a history of the looked-after child or young person's care. Create a summary for ease of reading with references to sections that give more detail. Gain consent for information that involves third parties and share only what is directly relevant. Include:
Risk factors for placement instability and long-term physical and emotional health, such as:
family health history
previous exposures to drug or substance use, domestic violence and abuse, or neglect
-ther medical history, including antenatal health problems and antenatal exposure to alcohol or illicit drugs (see recommendation 1.5.4)
significant relationships and previous significant conflicts in these relationships (especially concerning contact)
significant negative events, for example behaviour with potential for harm to others (with context and timeline of previous events)
previous placement moves and reasons for them.
Protective factors to build on, from life story work:
strengths and hopes for the future
significant positive relationships with family members, friends and adults
how behaviours have been successfully supported in previous settings
faith, communities and religion
routines
'things that are enjoyed', such as games, shopping and favourite food
interests, activities and achievements.
For emergency care placements that become long-term placements, review what information the carer has been given about the child or young person, and give them more if needed.
Ensure that there is continuity of the care practitioners who help in the handover of information for new carers, if possible.
Ensure that there is continuity of education (through virtual schools with oversight of a virtual school head) when a looked-after child or young person is placed out of their local authority area. Ensure that the current school provides a handover of information to the new school as part of the personal education plan.
Ensure that there is continuity of healthcare for the looked-after child or young person so that any physical and mental health and wellbeing support can continue in the new placement. This includes making sure that any ongoing referrals and existing specialist care are transferred to healthcare services in the new location, before their move to a new placement.
When supporting adoptive parents or other carers, recognise that they may still be learning to parent. Use non-judgemental language and ensure that they are aware of their rights to receive support.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on during transition between care placements and to permanent placements .
Full details of the evidence and the committee's discussion are in evidence review M: barriers to, and facilitators for, supporting looked-after children and young people in transition out of care to living with their adoptive or birth parents or special guardians, or into connected care.
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## After transition
When social workers give information about a looked-after child or young person's care history to the new carer, they should:
involve the looked-after child or young person, if appropriate and the child or young person is willing, drawing from continuous life story work
think about involving the child or young person in sharing information, after enough time has passed for a relationship of trust to form with the new carer.
Ensure that the looked-after child or young person can keep in contact with their previous carers and friends after the placement move, if the child or young person wants to and would benefit from it.
Agencies should seek feedback from carers and adopters and the child or young person to improve their transition services, after the adoption order is made.
Facilitate peer support for permanent carers – for example, by setting up and moderating social media networks and fun group outings for face-to-face peer support.
Ask experienced volunteer permanent carers to help permanent carers with strategies to manage more specialist problems – for example, when there is emotional distance in the relationship between adoptive parent and child, and with looked-after children and young people who have severe behavioural or mental health problems, or special educational needs.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on after transition between care placements and to permanent placements .
Full details of the evidence and the committee's discussion are in evidence review M: barriers to, and facilitators for, supporting looked-after children and young people in transition out of care to living with their adoptive or birth parents or special guardians, or into connected care.
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# Transition out of care to independence
## Extended care
Encourage and support young people leaving care to stay in their current care placement until at least age 18. Explore the possibility of staying with current carers beyond age 18.
Take into account the increased risk to young people (aged 16 to 17) posed by breakdowns in placement that lead to moves into inappropriate housing. Whenever possible, avoid using unregulated housing, particularly for young people at higher risk of exploitation or risk-taking behaviour. If a move to unregulated housing is planned, thoroughly document the risks and the plans to mitigate these, and review this regularly.
## Needs assessment
Personal advisers, working with social workers, should assess the needs of looked-after young people when transitioning out of care to independence. Take into account:
previous life story work
problem-solving skills and practical skills, including life skills such as financial literacy, budgeting and household management
physical and mental health support and long-term health needs, for example managing treatments and appointments
education, training and employment
financial resources
communication needs
social network (assessing gaps, connectedness, isolation, and both negative and supportive relationships).
Based on the needs assessment, consider providing the following support for care leavers:
Access to health services, including registering with a GP, dentist, optician, sexual health services and therapists (for those with complex healthcare needs), and extending access to CAMHS (to support continuity of care) or alternative emotional and wellbeing services such as online support, face-to-face counselling or group work. If needed, continue services beyond age 18 until care has been transferred to adult services.
Support for gaps in social network.
Life skills training.
Support for pregnancy and parenting.
Job preparation services, job searching and career advice.
Flexible funding to support career development, for example for specialist equipment.
Suitable and ongoing accommodation (through the leaving care team working together with other housing services), for example supported housing.
Provide the following services to give care leavers a safety net:
drop-in services
more frequent meetings with their personal adviser, if the care leaver wants them
facilitated peer support groups.
## Plans and support for care leavers
Tell care leavers and their primary carers:
about the rights of care leavers to statutory support (related to care-leaver status such as child in care and relevant child support) and extended support from age 18 to 25 (including reopening pathway planning and contact with the local authority)
that care leavers can receive the full level of support to re-enter education up to age 25.
Explicitly outline the support available to care leavers in a care offer, and ensure that this can be accessed easily by care leavers up to age 25.
Consider using virtual meetings to help meet the needs of care leavers who are living outside of their responsible authority.
Schedule pathway plan reviews to occur near significant milestones if possible, for example education, training or employment application deadlines.
Explain to care leavers and their primary carers how the pathway plan works, and the care leaver's rights associated with pathway planning – for example, that they can request an additional pathway plan review.
Tell care leavers and their primary carers of the rights of care leavers to advocacy services, to ensure that they receive the statutory provision they are entitled to and that advocacy services are provided in good time to support them with significant milestones.
When developing pathway plans for care leavers, include clear timeframes for actions, and who is responsible for completing the action.
Quality assure and review pathway plans for care leavers to ensure that improvements in outcomes are achieved.
Personal advisers should tell care leavers about services available in their area to support independence. These could include work experience opportunities, apprenticeships and college support.
For further guidance on transition from child to adult services, particularly for those with complex health needs and disabilities, follow NICE's guideline on transition from children's to adults' services for young people using health or social care services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transition out of care to independence .
Full details of the evidence and the committee's discussion are in:
evidence review N: interventions and approaches to support looked-after young people transitioning out of care into independent living
evidence review O: barriers to, and facilitators for, supporting and developing looked-after young people to transition out of care into independent living.
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## Support for care leavers in further and higher education
Consider the need for extended care beyond age 18 for care leavers:
in higher and further education
with special educational needs and disabilities.
Virtual school heads should take into account educational opportunities for care leavers beyond traditional further or higher education when deciding whether to extend support.
For care leavers who move away to college or university, ensure that there is continuity of housing during holidays, with meaningful social support. This support could include 'buddying' systems for peer support, mentoring from older student volunteers on campus, and other social opportunities for care leavers to tackle isolation during the holidays.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on support for care leavers in further and higher education .
Full details of the evidence and the committee's discussion are in:
evidence review N: interventions and approaches to support looked-after young people transitioning out of care into independent living
evidence review O: barriers to, and facilitators for, supporting and developing looked-after young people to transition out of care into independent living.
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## Feedback to improve services
Encourage children and young people in care and care leavers to give feedback about their care placement and the services they receive. This could be done, for example, through children in care councils, care leaver forums and surveys.
When seeking feedback, specifically seek out the views of children and young people who are looked after out of area.
Include feedback in decision making to improve services.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on feedback to improve services .
Full details of the evidence and the committee's discussion are in:
evidence review N: interventions and approaches to support looked-after young people transitioning out of care into independent living
evidence review O: barriers to, and facilitators for, supporting and developing looked-after young people to transition out of care into independent living.
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# Forum for strategic leadership and best practice
Use forums to help communication and bring together expertise and leadership from all agencies providing care for looked-after children and young people, as well as representatives of looked-after children and young people and their carers, and care leavers.
Use forums for looked-after children and young people to highlight examples of exemplary practice, review recent research, align and improve tools used for health and risk assessments, educate practitioners, understand one another's roles and responsibilities (and identify important gaps in provision of services), standardise language (for example, job titles and the names of risk-assessment tools and procedures) and agree a partnership approach to practice.
For a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on forum for strategic leadership and best practice .
Full details of the evidence and the committee's discussion are in evidence review E: interventions and approaches to support practitioners in completing physical and mental health and wellbeing assessments (and act on findings during the care journey) for looked-after children and young people.
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# Terms used in this guideline
This section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local Act Personal Care and Support Jargon Buster.
## Ages and Stages Questionnaire
The Ages and Stages Questionnaire provides developmental and social–emotional screening for children between birth and age 6. It draws on parents' knowledge and is widely used in practice to pinpoint developmental progress and catch developmental delays in young children.
## Attachment
A deep and long-lasting emotional bond between 2 people. For example, it includes the child seeking to be close to their caregiver when they feel upset or threatened, with the caregiver responding sensitively and appropriately to their needs. Attachment disorder is a recognised mental disorder that affects a very small minority of children experiencing attachment problems. Insecure attachment patterns and disorganised attachment are more common and are indicators of possible dysfunction in a child's attachment system that can lead to poor outcomes.
## Carer
The primary carer of the looked-after child or young person – that is, the adult who has primary responsibility for the day-to-day care of the looked-after child or young person.
## Care network
The carers and professionals who support the looked-after child or young person, including, for example, foster carers, social workers, healthcare professionals and educational professionals.
## Concurrent planning
Usually for babies and young children who are likely to need adoption but who have a chance of being reunited with their birth family. In concurrent planning, concurrent carers are approved as both foster and adoptive parents. They act as foster carers while the courts decide whether or not a child can return to their birth family. During this time, the children see their parents regularly in supervised contact centres and the concurrent carers support the birth family's efforts to regain the care for their child.
## Connected carers
Relatives, friends or other people who have a pre-existing relationship with the looked-after child or young person. If a child or young person cannot live with their parents, connected carers can become their approved foster carers. The child formally remains a looked-after child or young person.
## Contact supervisors
The role of a contact supervisor is to unobtrusively observe contact between looked-after children and young people and their parents or other family members during their arranged visits, to ensure that all contact is safe and positive.
## Contextual safeguarding
Seeks to recognise the risks to the child or young person that occur outside the home and respond to these to keep them safe. The risks can include violence and abuse from, for example, the person's neighbourhood or school, or social media.
## Foster carers
Foster carers work alongside a team of practitioners to provide looked-after children and young people with full-time care in the foster carer's home. Foster care may be a temporary arrangement, with children and young people moving on to a permanent placement or returning to their own birth families. Children and young people may also live in long-term foster care placements if a return home is not possible.
## Health plan
Part of each looked-after child and young person's care plan. It is written after the initial and review health assessments. Health needs or concerns are identified and actions are formulated into the health plan to address the health concern. It is incorporated into the child's care plan. The health plan is reviewed after each subsequent health assessment and at the child's looked-after review, or as circumstances change, to ensure that health actions have been completed.
## Initial health assessment
A statutory health assessment for looked-after children and young people that must be completed within 20 working days of coming into care. It must be completed by a doctor who is registered with the General Medical Council and holds a licence to practise.
## Life story work
A social work intervention that aims to help children and young people in care begin to understand and accept their personal history and future. Life story books are often used to give a visual aid and reminder of important events or feelings.
## Multidimensional treatment foster care
Multidimensional treatment foster care (now called Treatment Foster Care Oregon) is a solo foster placement with a specially trained foster family for between 9 and 12 months. It includes intensive support from a multidisciplinary team, with 24‑hour support from the programme supervisor. The intention is to change behaviour through promoting positive role models. During the placement, the young person's behaviour is closely monitored and good behaviour is rewarded. Family therapy is provided for birth parents, and they are taught the same strategies in preparation for reuniting them with their child. Also known as intensive fostering.
## Non-verbal
Not yet able or unable to talk – for example, because they are too young or they have a disability.
## Paired reading
In paired reading, looked-after children read alongside a partner, such as their primary carer. This helps the child practise their spelling, comprehension and pronunciation. Attentive and responsive feedback by the carer throughout helps the child to achieve reading fluency.
## Personal adviser
Local authorities provide personal advisers to care leavers up until they reach the age of 25. The personal adviser ensures that a care leaver is given the correct level of support to achieve independence. They should have a practical knowledge of the issues facing care leavers as they make their transition into adulthood and the legal requirements for support.
## Personal education plan
This is a document describing a course of action to help a looked-after child or young person reach their full academic and life potential. All children in care must have a personal education plan as part of their care plan. It is a legal requirement for every young person in care of statutory school age to have their personal education plan reviewed at least 3 times each academic year.
## Permanency
The conditions that lead to a child or young person experiencing security and continuity in their relationships, particularly those of belonging to a committed family. In a permanency plan, a looked-after child or young person is assessed and prepared for long-term care that meets their needs, and takes into account their wishes and feelings. In a care and placement order, it has been agreed that a child or young person will not return home to their birth family, and parental rights and responsibilities are transferred to another carer, for example an adoptive parent.
## Practitioner
A paid professional providing direct care for looked-after children and young people. Practitioners may include social workers, independent review officers, educational professionals, healthcare professionals and therapists.
## Prosocial
Prosocial behaviour is social behaviour that benefits other people, characterised by actions that show concern for the feelings and welfare of other people – for example, helping, cooperating and sharing.
## Randomised controlled trial
Trials in which participants (or clusters) are randomly allocated to receive either intervention or control. If well implemented, randomisation should ensure that intervention and control groups differ only in their exposure to treatment.
## Safer caring plan
Enables foster carers to consider potentially abusive or risky situations that may arise in the foster home and create a plan to minimise risks.
## Shared decision making
A joint process in which a healthcare professional works together with a person to reach a decision about care. It involves choosing tests and treatments based both on evidence and on the person's individual preferences, beliefs and values. It makes sure the person understands the risks, benefits and possible consequences of different options through discussion and information sharing.
## Special guardians
People or a person appointed by a Special Guardianship Order for children and young people who would benefit from a legally secure placement but cannot live with their birth parents. A birth parent cannot apply to discharge the order unless they have the permission of the court to do so, but the order does not end the legal relationship between the child and the birth parents (as in adoption).
## Staying put
When a foster placement becomes a 'staying put' arrangement, the young person staying put is no longer a looked-after child but is a care leaver. They are therefore entitled to support (for example, a personal adviser) as a care leaver but will remain in the foster home. However, the former foster carer is no longer officially a foster carer for that young adult.
## Support network
This covers carers, professionals, friends, birth family and any other supportive adults who provide formal or informal support to the looked-after child or young person.
## Unaccompanied asylum-seeking children
Children and young people who have left their country of origin without the care or protection of their parents or carers and are seeking asylum in the UK.
## Virtual school
The virtual school champions progress and educational attainment of looked-after children and young people in the local authority. The virtual school is not 'attended' but provides coordination of educational services for looked-after children and young people at a strategic and operational level. Looked-after children and young people within the local authority remain the responsibility of the school at which they are enrolled.# Recommendations for research
The guideline committee has made the following recommendations for research.
# Key recommendations for research
## Interventions to support placement stability in residential care
What interventions are effective in promoting placement stability among looked-after children and young people in residential care?
For a short explanation of why the committee made this recommendation for research, see the rationale section on supporting positive relationships .
Full details of the evidence and the committee's discussion are in evidence review A: interventions to support care placement stability for looked-after children and young people.
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## Interventions to support stability of permanent placements
What interventions are effective in supporting the stability of placements in looked-after children and young people moving out of care to permanency (incorporating the perspectives of looked-after children and permanency carers)?
For a short explanation of why the committee made this recommendation for research, see the rationale section on after transition between care placements and to permanent placements .
Full details of the evidence and the committee's discussion are in evidence review L: interventions to support looked-after children and young people transitioning out of care to living with adoptive or birth parents or special guardians, or into connected care.
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## Supporting mental health of unaccompanied asylum-seeking children
What interventions are effective in supporting the mental health of unaccompanied asylum-seeking children?
For a short explanation of why the committee made this recommendation for research, see the rationale section on mental health and child and adolescent mental health services .
Full details of the evidence and the committee's discussion are in evidence review F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers.
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## Using and safeguarding social media in contact with birth parents
How does social media contribute to contact arrangements for looked-after children and young people, and how can this be safeguarded?
For a short explanation of why the committee made this recommendation for research, see the rationale section on supporting positive relationships .
Full details of the evidence and the committee's discussion are in evidence review D: barriers and facilitators for supporting positive relationships among looked-after children and young people.
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## Mental health support for reunification with birth parents
What is the effectiveness of mental health support for promoting reunification with birth parents?
For a short explanation of why the committee made this recommendation for research, see the rationale section on before transition between care placements and to permanent placements .
Full details of the evidence and the committee's discussion are in evidence review L: interventions to support looked-after children and young people transitioning out of care to living with adoptive or birth parents or special guardians, or into connected care.
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# Other recommendations for research
## Continuing support for the physical and mental health needs of care leavers
What interventions are effective in promoting and continuing to support physical and mental health and wellbeing in care leavers?
For a short explanation of why the committee made this recommendation for research, see the rationale section on transition out of care to independence .
Full details of the evidence and the committee's discussion are in evidence review N: interventions and approaches to support looked-after young people transitioning out of care into independent living.
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## Promoting physical exercise, and a healthy diet and lifestyle
What interventions are effective in promoting physical exercise, and a healthy diet and lifestyle, in looked-after children, young people and care leavers?
For a short explanation of why the committee made this recommendation for research, see the rationale section on relationships and wellbeing activities .
Full details of the evidence and the committee's discussion are in evidence review F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers.
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## Therapeutic interventions for promoting school stability and learning
What therapeutic interventions are effective and cost effective in improving learning outcomes and school attendance and reducing exclusion in educational settings for looked-after children and young people?
For a short explanation of why the committee made this recommendation for research, see the rationale section on improving educational outcomes .
Full details of the evidence and the committee's discussion are in evidence review I: interventions to support learning needs for school-aged looked-after children and young people.
Loading. Please wait.# Rationale and impact
These sections briefly explain why the committee made the recommendations and how they might affect practice.
# Diversity
Recommendation 1.1.1
## Why the committee made the recommendation
The committee noted that children and young people with certain protected characteristics may be over-represented among looked-after children and young people, for example through race or sexuality. They also understood that looked-after children and young people themselves constitute a vulnerable group and therefore certain subgroups of looked-after children and young people may be disadvantaged in multiple ways. Based on their own knowledge and experience, as well as focus group and interview-based evidence, the committee recognised that ensuring these groups are not marginalised, and that their needs are met, may need additional attention and expertise.
## How the recommendation might affect practice
This recommendation is not expected to need significant additional resources. It is the statutory duty of local authorities to ensure that children and young people in their care are not disadvantaged or marginalised as a result of their protected characteristics.
Return to recommendation
# Supporting positive relationships
## Why the committee made the recommendations
Recommendations 1.2.1 and 1.2.2
The committee discussed that supporting positive relationships is often spoken about as an aim of care, but it may be poorly defined in practice. A large amount of evidence from the UK based on interviews and focus groups (qualitative evidence) considered the factors that help to build these relationships. In many cases, the committee observed that looked-after children and young people were not asking for more specific interventions or programmes. On the contrary, they often perceived an excess of practitioners involved with their daily lives. Rather, they wanted genuine caring relationships that reflected core principles outlined in this recommendation.
The committee considered that a common barrier to these relationships lay in the ability of the looked-after child or young person to communicate. They were aware that the prevalence of speech and language problems is higher among children who grow up in disadvantaged homes and experience neglect, which includes many in the care system. Implementing this recommendation could result in more timely referrals to speech and language therapists, if needed.
Recommendations 1.2.3 to 1.2.6
The committee looked at robust study designs (randomised controlled trials) on interventions aimed at enhancing the relationship between siblings in care. The evidence from these showed that the interventions improved the quality of sibling interaction and reduced aggressive behaviour.
The committee considered the main features of the interventions described in these US‑based studies. Carer members of the committee agreed that these activities could have been useful in their own home situations, not just with biological siblings but also non-biological siblings they were living with (biological or adopted children of the carer). However, they noted that harm could result if safeguarding considerations were not taken into account because facilitated sibling relationships may not always be beneficial. Therefore, these interventions were not to be recommended in every case.
The committee noted that the specific evidence-based programmes were drawn from studies in other countries with very different social care contexts. Using the evidence and their own experience, they recommended the features that could be implemented with success in the UK setting. The committee noted that 1 study showed adolescents may benefit from individualised coaching, with time separate from the primary carer to build the sibling relationship, whereas the committee considered primary-school-aged children would benefit from having the primary carer present. For primary school children, this can help to create a non-threatening environment and improve relationships between the siblings and the carer. It can also teach the carer new methods for mediating sibling relationships.
The committee emphasised that training to promote positive sibling relationships should start at the time of placement. However, based on their own experience, the committee agreed that the relationship between siblings needs to be stable before any activity-based interventions could be attempted. This could be achieved by support targeted at helping carers understand and maintain stable sibling relationships – for example, in the home setting with a professional who is trained in mediating strategies.
Recommendations 1.2.7 to 1.2.13
One of the key themes of the interviews and focus groups was the need for those in the care network to form a relationship with the child or young person and with other practitioners within the network and use shared decision making. This is to support the person's capacity to act independently to make their own choices. The committee were keen to highlight this, particularly for contact arrangements, and agreed that the child or young person's ability to choose who to have contact with should be supported. They noted the need to balance this against any safeguarding risks.
The committee reflected on evidence based on interviews and focus groups concerning contact with the birth family and the role of contact supervisors when observed contact is necessary for safeguarding. They also discussed that using contact supervisors can be helpful if the birth family is receptive to support and feedback to improve the quality of contact.
Evidence based on interviews and focus groups in the UK showed that it is important to not overwhelm looked-after children and young people with too many practitioners, and to promote continuity of relationships with practitioners. The committee agreed that retaining the same contact supervisors for a looked-after child or young person, if possible, would help to provide this continuity.
The committee discussed the fact that contact supervisors sometimes share intimate experiences and vulnerable moments with the looked-after child or young person and their birth family. Based on their own experience, the committee considered that if the role of the contact supervisor was more developed, there would be the potential to better support birth family relationships, give greater feedback of information to the care team and have better safeguarding. The committee therefore agreed that more training was needed for contact supervisors to improve the contact experience.
Evidence based on interviews and focus groups showed that contact may need a high level of support at the start of placements. However, this could, in some cases, be hindered by high levels of monitoring, and decreasing levels of support may be needed as time progresses. Therefore, the committee considered that a more cautious approach to contact may be needed in the early stages of care placements, adjusting supervision intensity according to needs over time.
Based on expert testimony, the committee were mindful of unaccompanied asylum-seeking children and those of non-British nationality, so they also stressed that non-English contact supervision needs an interpreter present to make good safeguarding and support possible.
The committee discussed interview- and focus group-based evidence on social-media-based contact. They recognised that such resources could help ongoing relationships much more easily than traditional methods because social media is easily accessible for young people and needs little organisation, but unobserved contact online could pose serious dangers by bypassing safeguarding measures. The committee therefore agreed that safeguarding considerations need to always take into account the possibility of online contact. For example, if social media contact was permitted in cases with moderate safeguarding considerations, it would be important for the content of interactions to be monitored and the amount of time spent communicating managed.
Large amounts of UK-based interview and focus group evidence considered positive relationships and contact arrangements and how these might be supported. However, no themes considered how social media influences contact arrangements or how this might be facilitated by carers and the risks be managed. The committee agreed that research is needed to determine the effectiveness of support mechanisms and interventions to manage the use of social media in care placements, particularly among those at risk of exploitation (see the recommendation for research on using and safeguarding social media in contact with birth parents).
Based on committee experience and knowledge, the committee sought to highlight the extra support that may be needed for children who are placed out of area. Geographical distance may present an obstacle to their ability to remain in contact with family and friends. Support to help overcome this could include financial support to help birth parents pay travel costs and attend contact sessions.
Recommendations 1.2.14 to 1.2.17
Based on UK-based interview and focus group evidence and committee experience, the committee recognised the importance to looked-after children and young people of their relationship with their social worker. The committee agreed that training and support for social workers should include communication skills. This would improve transparency of care and help maintain positive relationships. It would also mean that any information given to the child or young person would be done in a way that they can understand and accept, particularly when a carer transition is approaching.
Based on committee experience and knowledge, and some interview and focus group-based evidence, the committee recognised the need for more support for social workers to prevent burnout, which can lead to greater turnover in staff and loss of continuity for looked-after children and young people. The committee considered factors that could help prevent burnout at work, as well as improving the amount of time available for direct care. These included supervision with regular check-ins and a focus on reflective practice; consultation for complex and specialist problems; and trauma-informed training to promote positive relationships, as well as more practical support to increase the time available for direct one-to-one work.
The committee noted that when social workers are trauma informed, they can make sense and meaning of how the child or young person is behaving in relationships, in the context of their experiences. As the lead professional, they can influence how the network views the child or young person, what language is used and how it will be most helpful to support them in more helpful positive relationships. This is the ripple effect of different levels of trauma training for the network.
Social workers on the committee commented on the increase in workload, lack of funding and an upwards trend in the number of looked-after children and young people. Much work is needed to complete performance indicators and other administrative tasks and this is often prioritised over one-to-one work with young people. Some interview and focus group-based evidence suggested that one-to-one time could be improved by increasing the administrative support for social workers within local authorities. Although recognising that services are often overwhelmed and that resources are limited, the committee agreed that a culture change was also needed that prioritised more time for direct care between social workers and looked-after children and young people. The committee agreed that if managers use and review systems to free up more time for direct care, this could both increase professional retention, and enable more one-to-one time between social workers and looked-after children and young people.
UK intervention and focus group evidence on the impact of professional moves (particularly those of the allocated social worker) on looked-after children and young people supported the committee's own experience that local authorities do not have good systems for monitoring the level of social worker turnover. They agreed that if local authorities could collect and review data on turnover among their frontline staff and reflect on its impact on looked-after children and young people, this would help local authorities assess the success of staff support systems. They could then develop action plans to keep turnover as low as possible.
There was substantial UK-based interview and focus group evidence that looked-after children and young people reacted strongly against the changing of social workers they had built a positive relationship with. The committee discussed the complexity of addressing this issue. Turnover of social workers was frequent as a result of workload, burnout or the need to change work for career progression. Drawing on this evidence and their own experience, the committee noted that these reasons were often not well communicated to looked-after children and young people, and social workers were perceived to simply disappear. The committee agreed this could be ameliorated by informing looked-after children and young people pre-emptively and transparently about changes of social workers, taking care to recognise the emotional impact of such changes and providing an opportunity to say goodbye.
The committee, based on their knowledge and experience, also discussed the problem of the departing social worker and primary carers not giving a consistent message about the reason for leaving. They agreed that this problem could be reduced by informing primary carers in advance about the reasons for professional transitions, particularly if strong relationships had formed.
Recommendation 1.2.18
The committee recognised the potential benefit, both for positive relationships and health and wellbeing, of having a mentor for friendship and guidance, particularly one with care experience. Evidence from robust study designs suggested that older children may be more responsive to coaching and mentoring, particularly those with pre-existing emotional and mental health problems. The committee also noted that professional oversight of safeguarding was important to prevent inappropriate or negative relationships forming, and that a significant mentor–mentee age gap would be advisable.
Recommendations 1.2.19 and 1.2.20
Based on UK-based interview and focus group studies, and their own experience and knowledge, the committee considered the importance of friendship groups to looked-after children and young people. They recognised that looked-after children and young people may rely on these friendships to play a greater supportive role because of the lack of close relationships of other kinds (for example, with the birth family). As a result, the committee were concerned that contact with friends, particularly those from before coming into care, or other placements in care, should be supported if possible.
Based on their own experience and knowledge, the committee were also aware of some of the barriers faced by looked-after children and young people seeking to have 'normal' relationships with peers while in the care system. Sleepovers can be a normal part of such relationships. However, looked-after children and young people can feel stigmatised and exposed if such plans are delayed or prohibited as a result of waiting for safeguarding checks on the family they wish to sleep over with.
Recommendations 1.2.21 to 1.2.25
Many studies, using data from UK-based interviews and focus groups, reported that looked-after children and young people particularly valued care that was available, accessible and reliable. They benefitted from knowing that support was available even out-of-hours for urgent problems. Committee experience also suggested that looked-after children and young people felt the disparity if an out-of-hours call service was available for carers when one was not provided for them. This could lead to a sense of power imbalance and insecurity.
The committee agreed that out-of-hours support should be available for looked-after children and young people. However, they recognised that employing an on-call social worker may need substantial changes to contracts or add expense to already stretched social care budgets. So they agreed that other options might be used to fill this gap. In addition, identifying people at 'higher risk' for presenting out of hours could help with planning out-of-hours service provision.
There was strong UK-based interview and focus group evidence on the importance of shared decision making, including all agendas being laid out transparently to help the looked-after child or young person make their own decisions. For example, the committee discussed occasions when an option for a new placement was 'dressed up' as a great opportunity, when in reality, the young person was being nudged into the placement because of financial pressures, for the local authority, or because the foster carer had decided to end the current placement. The committee agreed that it was better to discuss the reasons for placement breakdown openly, giving emotional support built into ongoing life story work and using accessible and age-appropriate communication.
The committee noted that there was little evidence for interventions to support placement stability in residential care. They therefore made a recommendation for more research on interventions to support placement stability in residential care).
Recommendations 1.2.26 and 1.2.27
Evidence based on robust studies of multidimensional treatment foster care in adolescents largely covered youth offenders referred from the criminal justice system, or populations with significant pre-existing behavioural and conduct disorders. The committee were impressed by the evidence of effectiveness, particularly evidence showing reduced involvement with the criminal system and reduced rates of violent crime and imprisonment across these populations. So, they agreed that this intervention would be suitable for looked-after young people with behavioural issues that are significant and persistent enough to merit regular involvement of the criminal system.
The committee recognised that behaviours that challenge can be a form of communication and may occur as a response to trauma. In addition, behaviours that challenge may be more common in people with learning disabilities - which are themselves more common among looked-after children and young people. The committee therefore agreed to cross-refer to existing relevant NICE guidance.
Recommendation 1.2.28
The committee considered evidence based on robust studies looking at interventions to support development and school-readiness in preschool children. Particularly, they noted evidence on the Attachment and Biobehavioural Catch-up intervention for babies and toddlers, which resulted in improvements in language, attention problems and cognition. The committee looked at the similarity of this intervention to interventions recommended in the NICE guideline on children's attachment. They discussed the overlap between the population in the children's attachment guideline and this guideline. The committee agreed that all looked-after children and young people were at risk of attachment difficulties, and therefore that the evidence base for and recommendations in the children's attachment guideline were also relevant to looked-after children and young people.
## How the recommendations might affect practice
Trauma-informed training may have a limited resource impact because it could be incorporated into existing training for social workers. The committee recognised that existing training has limited capacity for additional material, but they agreed that trauma-informed training was a priority for inclusion. There are freely available resources for trauma-informed training and, although there would be a cost associated with adapting these resources for purpose, these costs are expected to be minimal.
Supervision with regular check-ins to support the social worker is likely to need more personnel time from the social workers and their supervisors. It may also need a culture change that focuses on reflective practice and increasing the amount of direct one-to-one time social workers get with looked-after people. Improving systems to increase professional retention, enable more one-to-one time between social workers and looked-after children and young people, and reduce duplication of effort, could be less costly than purchasing additional social worker time.
Collection and review of data on staff turnover, and development of action plans to address high levels of turnover, are likely to be associated with administrative costs in collating data that is already collected. However, lower levels of staff turnover would allow for better continuity of care and minimise the negative impact of personnel changes on looked-after children and young people, the benefits of which are considered to outweigh the small costs associated with this recommendation.
Providing consultation for complex and specialist problems is likely to need additional personnel time and resources to implement. The committee noted that expertise for this can often be found 'in-house' rather than needing to fund a new role or external training agency, but in some cases an initial investment may be needed to build up expertise within the local authority. Where consultation can be from more advanced social workers or from multiagency professionals in the network, this should not incur significant cost. Consultation provided by specialist agencies and professions may need to be bought in, for example from experts on sexually harmful behaviour.
There are currently limited services specifically aimed at siblings, although there is generally funding already available for shared activities and days out for siblings from local authority leisure budgets. Interventions to promote sibling relationships are potentially costly, but if they could be delivered by trained youth workers rather than graduate-level practitioners, or if existing roles could be adapted to deliver these interventions, this could help contain costs. Similarly, funding to support contact with friends could come from local authority leisure budgets, and there are several activities that are freely available, such as visits to local parks.
Mentoring interventions by peers with experience of the care process would often be carried out on a voluntary basis or through informal peer-to-peer interactions and would not need an increase in resources. Some additional costs may be incurred in providing professional oversight to mentoring programmes, which would need organisation and the processing of, for example, DBS (Disclosure and Barring Service) checks.
Contact supervisors are already a part of the care team, and any additional training needed could be incorporated into existing training, so the recommendation is expected to have a small impact on resource use. Similarly, translation services are already available in NHS settings when needed, so these should not be a substantial extra cost. A child's right of expression is mandated by statutory guidance so expenditures on translation services are justified.
Facilitating online contact, and the additional safeguarding considerations, is not expected to have an impact on current resource use because these contacts are likely to replace other forms of contact that would need similar management.
Resources needed to support the birth family to attend contact centres for children placed outside of their local area are most likely to consist of travel expenses. Although there may be some financial implications as a result of this recommendation, facilitating contact is a statutory duty and so expenditure by local authorities is justified.
Multidimensional treatment foster care is a resource-intensive intervention and will be associated with high implementation and running costs. But when used in adolescents with a history of persistent offending behaviour, these upfront costs are likely to be offset by the lower recurring monthly costs and additional health and social benefits from the intervention compared with usual residential care. A costing analysis comparing these costs of multidimensional treatment foster care with residential care is detailed in evidence review F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers. Additionally, improving the outcomes for adolescents who are offenders will reduce the greater impact on social care and judicial sectors.
Return to recommendations
# Supporting and involving carers
Recommendations 1.3.1 to 1.3.10
## Why the committee made the recommendations
The committee discussed UK-based interview and focus group evidence that carers often feel their input is not valued. They agreed that carers have the most intimate knowledge of the looked-after child or young person, so their perspective and the information they provide are important alongside professional input for decision making by the broader care team.
Studies showed that carers could feel 'left alone' to deal with severe problems on evenings or weekends, and lack of out-of-hours support can make them feel isolated. The committee agreed that out-of-hours support services are important, but recognised that employing an on-call social worker may need substantial changes to contracts and expenses. So, they agreed that various alternatives might be used to fill this gap. For completeness of records and continuation of professional oversight, the committee also agreed that carers should log any help sought outside usual operational hours.
Many UK-based interview and focus group studies looked at the value of peer support, and the committee also heard from experts that peer support could help fill the gaps in support left by overburdened social care systems and social workers. Carers may offer support to each other that is more accessible and available than from practitioners, and such support only needs to be facilitated and moderated to prevent the transfer of misinformation. Creating online spaces for this could be both cheaper and more accessible than hosting in-person groups.
The committee discussed UK-based interview and focus group evidence showing that respite (or support) care was valued. They agreed that it was vitally important to offer carers rest, to prevent burnout and subsequent placement breakdown. They noted that some carers may feel that their caregiving duties prevent them from going on holiday or travelling.
The committee discussed that it is helpful if respite (or support) care is provided by a person the child or young person knows, to prevent the feeling that they are being 'sent away'. This also builds up a network of supportive adults for the child or young person and childcare options for carers. In addition, the respite (or support) care period can be more easily seen as being in the best interests of the looked-after child or young person if it is an enjoyable break for them – for example, through short breaks to stay with relatives.
Based on their own knowledge and experience, and some UK-based interview and focus group data, the committee discussed that planned and proactive offers of respite (or support) care are more effective than respite (or support) care offered reactively in response to crisis, when it may already be too late to prevent placement breakdown. They also discussed the importance of the person who is providing respite (or support) care having the skills needed to support the individual needs of the looked-after child or young person.
The committee looked at UK-based interview and focus group evidence on resource constraints, stretched services, information gaps between carers and practitioners and reactive care (responding to problems as they arise, rather than anticipating). They found that carers were often unaware of the services available for support from their local authority and partner agencies, and therefore felt as though certain services had been kept hidden to save costs. The committee agreed that carers need to be fully informed about the support available before the placement starts. This enables carers to negotiate the support they need, and empowers them to act on a more equal footing with practitioners.
The committee saw UK-based interview and focus group evidence showing that carers (particularly shorter-term foster carers) are often unaware of ongoing interventions for a child placed with them, such as life story or relationship work. They agreed that informing carers about the contents and aims of interventions to support placement stability was in the best interests of the child, and would improve continuity of care with marginal costs.
The committee recognised that there was an additional set of recommendations for carers in the NICE guideline on supporting adult carers, and that these recommendations may be relevant for some carers of older looked-after children and young people.
## How the recommendations might affect practice
Using alternatives to on-call social workers will mitigate the cost of increasing out-of-hours support. A range of possible ways in which out-of-hours support could be offered was included in the recommendation to allow local authorities to use a system that works best for them, both logistically and financially. Some of the options listed would be more affordable, such as the use of volunteer-operated helplines or peer support or advocacy groups. Local foster carer associations may have people working on-call, or provide round the clock access to a peer support network. The use of generic emergency duty teams may also reduce funding pressures.
However, the committee recognised that the availability of alternative options may vary between local authorities. To provide out-of-hours services with social workers 'on call' would need a contract change for social workers, but they agreed this could be done by reallocating existing social worker time from day work to out-of-hours work. This contract change and reallocation would have cost implications, but the committee agreed that having social worker availability for out-of-hours emergencies and urgent problems could allow for problems to be addressed more quickly. This would help to avoid more significant costs and adverse consequences (for example, placement breakdown, self-harm, hospital visits and police being called).
Facilitating accessible peer support for carers is unlikely to have a substantial impact on resources, because most would be peer led and would not need much additional personnel time or physical resources from the local authority. Message boards may need to be moderated to prevent misinformation, but this could save time and resources by helping to resolve issues that would otherwise need the attention of care staff.
Respite (or support) care for carers to prevent placement breakdown is already broadly available in the care system. Costs vary depending on individual needs and local funding streams. The committee recommended the approach to respite (or support) care that should be taken if respite (or support) care is needed, rather than necessarily recommending additional respite (or support) care beyond what is already provided.
Return to recommendations
# Training for carers
Recommendations 1.3.11 to 1.3.20
## Why the committee made the recommendations
Based on their experience and knowledge, the committee recognised that, in practice, training – such as behaviour management training – is often delivered reactively, in response to difficulties that a carer is currently experiencing. This threatens placement stability because the carer may feel underprepared and under-supported to continue the placement. The committee advocated a greater emphasis on forward planning support for carers (before placement) based on the recognised and documented needs of the individual child, and involving other agencies as needed.
The committee discussed evidence, from robustly designed studies, on the effectiveness of parent-training interventions (some of which also included child-training components). This evidence covered a wide range of training programmes. The committee agreed that the evidence broadly supported the benefit of parent-training interventions in tackling child behaviour problems, and in improving the child–carer relationship.
However, they noted that the components of these training interventions may differ. Common components in the interventions studied included teaching and information giving focused on different aspects of parenting theory such as sensitive caregiving, attachment, social interaction learning theory, being trauma informed and broader behavioural management techniques. To support teaching, some interventions used video-feedback techniques, and others used homework or home assignments, role play, coaching, practical activities and follow-up booster sessions.
The committee noted that training can be expensive, and it is likely that different carers would need a different intensity of training. To reduce costs, a mandatory schedule of training could be delivered as a tutorial (perhaps virtually) to all carers. The committee were aware that mandatory training, for example for foster carers, may already be extensive. However, rather than recommending additional capacity to deliver more training, the committee sought to recommend which topics were most important to include in existing training schedules for carers. In addition to these, more intensive methods could be used with carers of looked-after children and young people who have more severe emotional and behavioural problems.
Based on their experience and knowledge, they agreed that how to provide consistent, child-focused and planned life story work to promote positive self-identity, would be an important addition to the mandatory schedule of training for all foster carers.
The committee were not aware of any widely available training for carers on how to be an educational advocate. In their experience, some carers are good at it naturally, but this is not consistent. For example, some may feel a responsibility for providing a home for their child but not see educational advocacy as part of their 'role'. The committee agreed such training is necessary as part of the mandatory training for carers. The importance of involving the primary carer was backed up by UK-based interview and focus group evidence suggesting that looked-after children and young people preferred carer-delivered educational support (as opposed to interventions delivered by other adults or professionals), because of fears of yet more transient practitioners developing a relationship with them and then leaving.
The committee discussed subgroups of carers who may need more individualised training. Using their own experience and knowledge, they considered birth parents in situations in which reunification is a possibility or when the child or young person remains in placement with the birth parent. They recognised that joining mandatory training schedules may not be ideal for birth parents who may have significant personal challenges to overcome and need additional support.
The committee used UK-based interview and focus group studies and their own experience and knowledge to consider other subgroups of carers who may need specialised training. They looked at evidence highlighting the challenges for carers of adapting to a looked-after child or young person's cultural, religious or dietary needs. For example, the committee recognised that certain ethnic groups may have hair and skin care needs that a carer would be expected to support. Likewise, carers of looked-after children and young people with special educational needs, long-term health conditions and disabilities may need specific training.
UK-based interview and focus group evidence and expert testimony both suggested the importance of a knowledge of trauma in those caring for the looked-after population. Based on their experience and knowledge, the committee agreed what trauma-informed training should cover. They recognised that there are multiple levels to this training, from simple awareness of trauma-related issues (for all carers and practitioners working with looked-after children and young people) to training in trauma-responsive care, which may be needed for more specialised carers and practitioners. For effective delivery of training programmes, the committee agreed it was important for trainers themselves to have a good understanding of trauma and attachment disorders as well as the various effective therapeutic approaches.
The committee also discussed evidence on a parent-training intervention for looked-after young people with behaviour that challenges or more severe mental health problems who are moving out of restrictive care and into the community. This showed that it could help maintain their school placement and prevent a return to that care. The committee agreed that, in temporary placements for which training and development needs had been identified and delivered for current carers, new carers in the follow-on or permanent placements would need the same training to provide consistent care. This would help continuity of behaviour management approaches and trauma- and attachment-informed, high-support and high-nurturing relational care. The committee noted that this was particularly true for connected carers, who enter the fostering system quicker than mainstream carers. Often a child or young person is placed with them while assessments are ongoing and there is little time for preparation and training.
## How the recommendations might affect practice
Family support services already offer behavioural management support to birth families, but available training for foster carers and, particularly, other kinds of carers, is more variable.
Training in educational advocacy for carers would be delivered by the virtual school. This could be delivered at low cost, virtually or in person.
Tailored support and training for birth parents if reunification is a possibility should already be available through transition plans with family support teams, and should not incur additional cost.
Cultural or religious needs, or needs related to race or ethnicity may need more tailored training for carers who have no expertise in these areas. Although this may come at some additional cost to time or resources, these looked-after children and young people form a minority of the overall looked-after population. In addition, it is a statutory duty to ensure that looked-after children and young people do not receive poorer care on the basis of race or religion.
Tailored support and training for carers if there are special educational needs and disabilities can be provided through specialist healthcare teams and voluntary organisations (for example, the National Autistic Society and the Independent Provider of Special Education Advice), thereby helping to keep costs down. Trauma-informed training and therapeutic parenting training for all foster carers is part of current practice in some local authorities. The recommendations will reduce variation in practice across the country. Intensive, specialist training given in the home is likely to incur substantial costs in some areas that do not already provide it, but these could be partially offset by preventing placement breakdown. Placement breakdown is associated with significant short-term costs because of increased social care case management work and the need for additional placement arrangements, some of which will be high-cost emergency placements. In addition, placement instability can have long-term consequences, contributing to further disruption of looked-after children and young people's social and emotional relationships, sense of belonging and educational outcomes.
Mandatory training schedules already exist for carers (particularly foster carers) and it is anticipated that trauma-informed training, and other recommended training components, could be incorporated into these sessions without the need for extra training capacity in many cases. For example, the committee noted that there is often already mandatory training on de-escalation that could feasibly be altered or updated to include trauma-informed practice. There are freely available resources for trauma-informed training and other kinds of training. Although there would be a cost associated with adapting these resources for purpose, these costs are expected to be minimal.
Return to recommendations
# Safeguarding
Recommendations 1.4.1 to 1.4.8
## Why the committee made the recommendations
The committee heard from experts about looked-after children who are at risk of criminal exploitation or going missing or are placed out of area. The experts highlighted the importance of multiagency working and appropriate data sharing for safeguarding looked-after children. They gave examples showing how important moments had been missed for sharing information between agencies (for example, policing and social services), and how these missed moments had led to extremely negative outcomes for the looked-after child or young person involved. Although the committee noted that statutory safeguarding procedures exist, they agreed that once a child or young person had become 'looked after', any further safeguarding issues were often dealt with 'in-house' in the care system. Whichever safeguarding system was used, the committee considered the need for it to be as thorough as statutory systems of safeguarding while also addressing additional contextual safeguarding risks. These risks are more commonly an issue among those in care.
The committee discussed ways in which local authorities could facilitate multiagency working and data sharing. They suggested that meetings were needed to bring together practitioners and facilitate information exchange. Based on expert testimony and their own experience, the committee agreed that representatives from education, care, healthcare for looked-after children, and external services could provide vital perspectives on safeguarding looked-after children and young people. Experts told the committee that it was very important to include the views of looked-after children (particularly those with special educational needs or disabilities) and their carers when shaping responses to exploitation and missing children. This supports shared decision making and makes responses effective, accessible and acceptable to looked-after children and young people and their carers.
Based on expert testimony, the committee considered that leadership was needed to organise successful multiagency review meetings, bring practitioners on board and help define clear lines of accountability. The committee considered that leadership in multiagency working would be best provided by a specialist in contextual safeguarding, exploitation and missing children in the looked-after population. If such a practitioner was not readily available, the committee considered that local authorities could build capacity by investing in training a trauma-informed specialist with knowledge of exploitation and safeguarding issues in the looked-after population.
Based on expert testimony, the committee discussed the kinds of data that are most readily available and useful across agencies to inform the safeguarding of looked-after children and young people, and assess the risk of exploitation in any given placement. The committee considered routinely collected indicators at the community level: area deprivation indexes, community-level health and mental health data, number of county lines operating in a single area and missing person reports per 1,000 population (which were considered particularly linked to risk of trafficking).
The committee, in light of their experience and expert testimony, noted that risks and 'red flags' may be different for certain subgroups, such as young girls and boys and unaccompanied asylum-seeking children, as well as the approaches needed to protect from exploitation or going missing. For example, young girls in particular may be at risk of sexual assault, domestic abuse, and attempts through social media and otherwise to coerce and undermine self-esteem.
The committee heard from experts about the need for practitioners and carers working with looked-after children and young people to be able to spot and communicate safeguarding risks. Based on this, the committee discussed the training needs of practitioners working with looked-after children and young people. The committee acknowledged that training is not inexpensive. However, training on the signs of exploitation or abuse, and 'red flags' for going missing, and how to 'flag' or report concerns about these could be included in the regular training schedule for all practitioners working with looked-after children and young people.
The committee discussed how else multiagency working and review meetings could help to re-enforce and educate about 'reachable or critical moments'. That is, moments when looked-after children and young people at risk of criminal exploitation and grooming could be spotted and interventions employed at the earliest possible moment, particularly when looked-after children and young people could be more open to change and receiving support. Experts told the committee that any intervention could constitute a critical moment, for example attending an A&E department.
Likewise, evidence based on UK-based interview and focus group studies and expert testimony about gangs, criminal exploitation and going missing from care strongly suggested that establishing a network of strong, supportive, positive relationships is the primary mechanism to protect looked-after people from these risks.
Experts also suggested to the committee that certain subgroups of looked-after young people may need more tailored care to address issues that increase their risk. These groups include young girls, who may have issues of low self-esteem, and be at risk of targeting on social media; children with a history of trafficking; and unaccompanied asylum-seeking children who have been subject to previous trauma or exploitation. The committee were aware that tailored support for these groups is already offered through well-established organisations such as Abianda.
Based on their experience and knowledge, and on hearing from experts, the committee discussed that safeguarding meetings offer an opportunity to educate and inform health and social care practitioners (for example, by bringing the perspective of emergency services to social workers). The committee were keen that learning opportunities were not lost and that a review of case files could help to spot mistakes or areas in which best practice could improve.
## How the recommendations might affect practice
Tailored support for groups at particular risk from exploitation groups is an important and necessary safeguarding consideration for vulnerable groups. Existing organisations that already focus on these groups can help to supply such support, so this recommendation is unlikely to have a substantial additional resource impact. As well as improving outcomes for these groups, this tailored support may help to avoid future costs associated with negative outcomes, for example legal costs and costs associated with placement breakdown if relationships have deteriorated.
Necessary data are captured in most areas, but the information often needs to be better shared. This is unlikely to need increased resources because the data sharing mechanisms and roles for multidisciplinary teams already exist, and the emphasis of the recommendations is on bringing this work together. Using standardised language for things such as risk assessment tools, processes and personnel titles across agencies and geographical areas is not expected to be resource intensive. It can be achieved over time by greater communication between agencies and local authorities.
Training in risk indicators is unlikely to have a substantial resource impact because it would probably be absorbed into and prioritised in existing staff training. Likewise, training to recognise suitable moments to reach out to the child could be incorporated into existing training for foster carers and social workers.
Return to recommendations
# Building expertise about trauma and raising awareness
Recommendations 1.5.1 to 1.5.3
## Why the committee made the recommendations
The committee considered UK-based evidence from interview and focus group studies and heard from experts about the high prevalence of trauma in looked-after children and young people. Based on this and their own experience and knowledge, the committee agreed that all practitioners working with looked-after children and young people need greater awareness of the impact of trauma, including developmental trauma and attachment difficulties. Such awareness is vital for spotting safeguarding situations. It can also help practitioners working with looked-after children and young people to better understand them and communicate more effectively with them.
UK-based evidence from interview and focus group studies and expert testimony highlighted specific issues faced by unaccompanied asylum-seeking children. The committee agreed that those who were working with unaccompanied asylum-seeking children needed to have additional awareness of the specific risks facing this group and issues that may arise when providing care.
The committee noted that when social workers or other care professionals are trauma informed, they can make sense and meaning of how the child or young person is forming and maintaining relationships, in the context of their experiences. As the lead practitioner, they can influence how the network views the child or young person, what language is used and how it will be most helpful to support them in more helpful positive relationships. This is the ripple effect of different levels of trauma training for the network.
## How the recommendations might affect practice
Additional training on the specific needs of unaccompanied asylum-seeking children, including invited feedback from children that were once cared for in these circumstances, and specialist organisations in the voluntary sector, could be provided as part of existing in-house training. Funding should already be available through general funds that support routine training and activities (for example, team awareness days) for healthcare professionals.
Consultation may be provided from more experienced social workers or from multiagency professionals in the network, so it should not incur cost. However, the committee were aware that such consultation work would mean less time for case work, and therefore would incur some time costs. Consultation provided by specialist agencies and professions may need to be bought in, for example experts on sexually harmful behaviour.
Return to recommendations
# Physical and mental health and wellbeing assessments
Recommendations 1.5.4 to 1.5.16
## Why the committee made the recommendations
There is a statutory requirement for the responsible authority to notify in writing the child or young person's healthcare team (for example, the specialist looked-after children's health team), clinical commissioning group and registered medical practitioner about arrangements for the child or young person's placement. But based on their own experience and knowledge, the committee noted that this was often not sufficiently carried out in practice. That is, the notification is often delayed, or does not give both the looked-after child or young person's legal status and the reason why they have been entered into care.
The committee considered the importance of keeping good health records for looked-after children and young people. This should be a summary for ease of reading, with references to sections that give more detail. Based on some interview and focus group-based evidence and the committee's own experience and knowledge, the committee considered that it was important to obtain a full health record from the birth parents, particularly information about antenatal and postnatal health. They noted that gaining consent for this may be a difficult or lengthy process. So the committee discussed the importance of attempting to gain this consent as soon as possible in the care process, to prevent missing important health information that could be important for directing the plan of care. If social workers supplied relevant information and consent to health teams before the initial health assessment, this could support health teams to make a good health plan. The committee also considered that the request for the initial health assessment should be detailed enough to provide the social care context for the child or young person coming into care.
UK-based interview and focus group studies frequently emphasised that looked-after children and young people and their carers appreciate continuity of care practitioners. The committee discussed the importance of having a continuous healthcare professional who is familiar with the looked-after child or young person, and their medical and social history, to perform routine health assessments. They agreed this is important both to promote a trusting relationship between the child or young person and the medical practitioner and to improve adherence with health plans, and to help the practitioner to spot changes in the health needs of the child or young person to support better care.
Based on their own experience and knowledge, the committee considered the needs of children and young people trying to access confidential healthcare. For example, use of the phone or internet may be restricted, particularly in residential care. The committee recognised that these measures may be in place to support safeguarding, but an unintended consequence could be difficulty or embarrassment when trying to access sexual health advice or treatment.
The committee highlighted that the initial health assessment is an important event for looked-after children and young people because it allows their existing needs to be identified and forms the base of an individualised care plan. The committee were therefore concerned that the initial health assessment should include an accurate and comprehensive review of the person's health history.
Evidence from UK-based interview and focus group studies suggested the need for carers to receive more complete and better-quality information about the child or young person at the start of care, which could include a compilation and summary of health records. The committee noted that work to compile records is done inconsistently across local authorities. The committee considered that compiling good records had the potential to transform the care of looked-after children and young people by facilitating the flow of information between agencies and preventing identified needs and actions in the health plan from becoming lost.
Using some interview and focus group-based studies and their own expertise and knowledge, the committee considered the fact that care leavers very often request access to their health and social care records. Care leavers may do this to help make sense of their own journey through the care system. However, if the language used in the records is depersonalising or judgemental, this can result in significant emotional hurt and offence. The committee therefore agreed that health and social care practitioners should be aware of this risk.
Evidence from UK-based interview and focus group research and from expert testimony strongly supported the need for a culturally appropriate, registered interpreter to communicate in person with looked-after children and young people for the initial health assessment. And, if language remains a barrier to communication, for the same service at subsequent health and social care assessments. However, the committee noted this was particularly important for the first health assessment, which must be thorough and capture all aspects of health needs accurately to provide appropriate support. The committee considered in-person translations to be particularly important because of the difficulty receiving interpretation services over the phone. Unaccompanied asylum-seeking children were especially in need of these services.
Experts highlighted many specific health needs of unaccompanied asylum-seeking children compared with the broader population of looked-after children and young people in the UK. Unaccompanied asylum-seeking children were also frequently found to have problems with their sleep schedule as a result of travelling long distances, often with continuously disturbed sleep. So the committee agreed that tailored initial health assessments should address the additional risks to unaccompanied asylum-seeking children as a result of their country of origin and journey to the UK.
The committee considered mental health screening for children who were entering care. Some evidence (which had a higher risk of bias due to the study design) showed that using an in-depth assessment identified more children needing support and helped with providing early interventions than with the current initial health assessment. The committee agreed that current initial health assessments were often insufficiently detailed to pick up mental health needs and it was important for healthcare professionals to consider the need for a specialist mental and emotional health assessment after the initial health assessment. This is particularly important for babies and children because their mental health needs are often missed. Based on committee experience and knowledge, the committee noted that this second assessment is better carried out once the looked-after child or young person has begun to form a relationship with the primary carer because mental health may improve as a result of a secure attachment relationship.
The committee reflected on less robust evidence (not from randomised controlled trials) showing that auditing systems before and after health assessments improved the uptake of health actions. The committee also considered the problem of actions in the health plan not being followed up or completed (either within a reasonable timeframe or at all). Based on this evidence and their own experience, they agreed it was important that the completion of actions in the health plan be reviewed to ensure the agreed service has been provided. This would need multidisciplinary input because some actions may be undertaken by other agencies.
The committee recognised the higher prevalence of attention deficit hyperactivity disorder, autism and post-traumatic stress disorder among looked-after children and young people. They were aware of existing NICE guidelines on the identification and diagnosis of these conditions and their subsequent management, and agreed to cross-refer to these.
## How the recommendations might affect practice
The initial health assessment is a statutory requirement so there should not be any additional costs to the system, although auditing the health plan may need additional time from the team of health professionals involved. A detailed and well-documented plan can help with timely provision of care, thereby avoiding costs of delay and an overall negative experience for the looked-after child or young person.
Healthcare professionals performing the initial health assessment for unaccompanied asylum-seeking children may need additional training on the specific physical and emotional needs of these children, and on risk factors associated with specific countries of origin or route of travel, and the context of the child's journey. This training, including feedback from children that were once cared for in these circumstances and testimonies from specialist organisations in the voluntary sector, could be provided as part of existing in-house training. Funding should already be available through general funds that support routine training and activities (for example, team awareness days) for healthcare professionals.
Specialised interpretation services incur costs, but a child's right of expression is mandated by statutory guidance so expenditures on such services are justified.
Return to recommendations
# Mental health and child and adolescent mental health services
Recommendations 1.5.17 to 1.5.21
## Why the committee made the recommendations
UK-based evidence from interview and focus group studies frequently highlighted the frustration felt by looked-after children, young people and their carers about delays and waiting lists for mental health support. The committee considered the common problem of delayed support for child and adolescent mental health services (CAMHS), and systems that they had seen in practice to help avoid the delay of therapeutic support for looked-after children and young people. For example, therapeutic social workers, systems for outreach connected to CAMHS (for example, a psychologist or another worker embedded within CAMHS), or a specialist looked-after children and young people team within CAMHS.
However, other evidence, also from interview and focus group studies, highlighted the harm that can be done by introducing a child or young person to a new therapist, only for the therapist to change once CAMHS have taken over care. This can lead to demoralisation and disengagement from mental health interventions. Therefore, the committee agreed that intermediate therapeutic or specialist support should be provided for the care network around looked-after children and young people, rather than to looked-after people themselves. The committee were keen to stress that this intermediate support was only to address the delay, and should not be a replacement for CAMHS itself.
Further interview-based and focus group-based evidence and expert testimony reflected how CAMHS are often inappropriate and not designed for the needs of looked-after children and young people. Traditional techniques such as behavioural-therapy-based interventions are not always suitable for looked-after children and young people, who may need interventions that are more relationship based and trauma informed.
One committee member stated that some CAMHS teams have specialist looked-after children's services, but this is variable across the UK. The committee agreed it was important to encourage prioritised specialist services to be incorporated into CAMHS, to prevent the need for tier 3 or 4 services further down the line.
Based on their own experience, the committee were aware that children and young people could lose their place in the waiting list for CAMHS as a result of moving placements to a new location. This may be more likely to happen to children and young people who most need the attention of CAMHS to help maintain placement stability. Committee members were aware that continuity of CAMHS waiting lists could be maintained by virtual schools co-opting CAMHS or other dedicated services for looked-after children and young people in CAMHS.
Expert testimony highlighted the likelihood that all unaccompanied asylum-seeking children had experienced some form of trauma, as a minimum through the separation from their own parents, and that health and social care practitioners supplying care for this vulnerable population need specialist training. The committee agreed the importance of taking into account the different perspectives of unaccompanied asylum-seeking children in a mental health service setting.
UK-based evidence from interview and focus group studies and expert testimony also reflected the importance of cultural sensitivity and awareness of potential traumatic symptoms in unaccompanied asylum-seeking children. For example, they may have highly stigmatising views of mental health problems, based on previous cultural ideas, and may be reluctant to admit the experience of trauma or problems with mental health.
The committee noted that unaccompanied asylum-seeking children were likely to need a tailored approach to mental health support, but there was insufficient evidence to recommend any specific intervention. Therefore, they made a recommendation for research on supporting mental health of unaccompanied asylum-seeking children.
## How the recommendations might affect practice
Providing dedicated CAMHS services for looked-after children and young people may have substantial resource implications if an expansion of the existing CAMHS services and capacity is needed. However, these dedicated services for looked-after children and young people are mandated by statutory guidance and the recommendations are only reinforcing the statutory provision of these services. Alternative interventions (trauma-informed and those focusing more on relationships) may not necessarily come at greater cost than traditional behavioural approaches. However, tailored approaches would have greater adherence (for example, fewer non-attendances and less disengagement), thereby resulting in greater effectiveness. The committee considered that greater engagement in mental health services at an earlier stage can reduce the risk of more serious mental health problems, avoid the substantial long-term costs and consequences incurred when these issues go unidentified, and reduce the need for the higher tier treatments later down the line (where the greatest pressure on CAMHS services was suggested to be).
Intermediate therapeutic or specialist support for the care network around looked-after children and young people, to reduce waiting times, may need some restructuring of services and additional cost. However, in some parts of the country, existing services could fill this gap – for example, therapeutic social workers, CAMHS outreach systems (for example, a psychologist or another worker embedded within CAMHS), or a specialist looked-after children and young people team within CAMHS.
Return to recommendations
# Life story work for identity and wellbeing
Recommendations 1.5.22 to 1.5.33
## Why the committee made the recommendations
UK-based evidence based on interview and focus group studies showed that forming positive relationships was probably the best possible intervention to prevent placement instability. Life story work has the potential for building relationships (for example, by sharing joint activities). In addition, it is a trauma-focused technique that could help with discussing and negotiating care plans (by outlining felt priorities and experiences). However, evidence showed that life story work was often neglected or poorly completed in practice, was often started late in the care process, and was given little priority or investment. This supported the committee's own experience and knowledge. The committee discussed the importance of standardising life story work and starting it at the earliest opportunity after entry into care. They agreed this could support placement and emotional stability by helping the looked-after child or young person make sense of their journey through care.
Based on UK-based interview and focus group evidence and committee experience, the committee discussed the importance of time for life story work being clearly set aside, with a named practitioner to ensure there is time for it to be completed to a sufficient standard. The relational aspect of this intervention could also be supported by having it conducted by a carer or practitioner that the looked-after child or young person has a close and continuous relationship with. The committee agreed it was important for this work to take place in the context of a safe and continuous relationship, because conversations would be of a personal nature.
The committee discussed the key components of life story work, based on their experience and knowledge. They agreed that this work consists of building a narrative that focuses first on the present identity and strengths before moving onto the past and reasons for entering care, and finally turning thoughts to planning for and building hope towards the future.
Based on committee experience and knowledge, and some interview and focus group evidence, the committee then considered how this may be achieved. Techniques such as life mapping, use of pictures, art, written narratives, toys and play have been used successfully. The committee agreed that these discussions should be compiled in 1 place and built on during regular sessions. They thought that the approach should be flexible according to the needs and response of the looked-after child or young person and should be a shared experience, in a setting preferred by the looked-after child or young person. However, they recognised that compiling life story work in 1 physical place could come with the danger of sensitive information being read by others (for example, peers in residential care).
The committee took into account their own experience and knowledge in considering the role that life story work could play in cultivating a positive self-image and identity – that is, one that embraces the looked-after child or young person's ethnic, cultural or religious differences, as well as sexual identity and disabilities.
The committee stated that the effectiveness of the life story work was closely related to its quality, and agreed that having social worker oversight could help to maintain standards. It would also allow the social worker to provide additional information to support the carer or practitioner carrying out the life story work.
Based on their own experience, the committee considered life story work that involves more people than the practitioner and the looked-after child or young person. For example, sometimes it may be useful to carry out life story work with siblings as a group or pair, because they may have had very different perspectives of shared life events that need to be reconciled. The committee agreed that the need for shared life story work should be carefully planned to ensure it did not destabilise sibling relationships, for example by divulging sensitive information. In addition, particularly for complex situations such as these, it was important for the experience and skillset of the practitioner carrying out the life story work to match the complexity of the care situation. This may need the direct attention of a social worker rather than the primary carer.
Based on their own experience and knowledge, the committee agreed that the network around looked-after children and young people was important to support ongoing life story work. The committee considered it vital that the idea and purpose of life story work and its importance was expressed to the social work team, carers, educational staff, and birth family. Broader social networks can then be engaged in the work when needed. Birth families may need to encourage consistency in narratives explored and reframing previous relationships.
## How the recommendations might affect practice
Life story work is mandated by statutory guidance for all looked-after children and young people with a plan for adoption. It is already current practice and these recommendations can be easily integrated into the process. Although the recommendations may necessitate a higher standard of life story work (for example, with more detail and more time devoted to it) in some cases, the committee agreed that these changes were necessary for the work to be effective and achieve its aims. Training to ensure a consistent approach to life story work could be incorporated into existing training. Social worker oversight for life story work conducted by another practitioner is anticipated to have minimal resource implications because the work is either already being conducted by the social worker or would simply need the social worker to be informed of the content of that work.
Return to recommendations
# Relationships and wellbeing activities
Recommendations 1.5.34 to 1.5.37
## Why the committee made the recommendations
UK-based interview and focus group-based evidence frequently emphasised that positive relationships were the most important aspect of care to looked-after children and young people and care leavers, and that, along with placement stability, they are most linked to social, emotional and mental wellbeing. They discussed that the cornerstone of positive relationships was the relationship with the primary carer. So they agreed that, before recommending specific interventions to support social, emotional and mental wellbeing, the focus of support needs to start with a stable care placement and a strong supportive relationship with the primary carer.
Interview-based and focus group-based evidence showed that some primary carers, for example in residential care or foster care, had concerns about giving physical touch and affection to looked-after children and young people. The committee discussed that physical affection, particularly for younger looked-after children, could be a major source of emotional stability and wellbeing, and yet it may be denied in some cases because of the primary carers' desire to be protected from any form of allegation. They agreed that, in some cases, it may be necessary to proactively promote or encourage appropriate physical affection (for example, through play) and that the need for physical touch and affection as a part of a healthy relationship with the primary carer should be taken into account in safer caring plans.
A variety of evidence reflected the importance of shared activities to help bond relationships with peers, practitioners or carers. The committee considered that peer support could be particularly important among looked-after children and young people because, given the absence of strong family ties, they may place more emotional investment in friendships and other non-conventional relationships (for example, with care practitioners). They agreed that it was important to support the interests and hobbies of looked-after children and young people by setting aside time for outings that would help them invest in these interests, as well as in their close relationships.
The committee considered that looked-after children and young people are more likely to be overweight and obese than standard norms and many come into care with a poor nutritional status. They recognised a gap in good quality research for interventions to help improve diet and exercise, as well as other lifestyle factors such as drug and alcohol use, among looked-after children and young people, and made a recommendation for research on promoting physical exercise, and a healthy diet and lifestyle. In the absence of good quality research to support interventions to improve diet and exercise among looked-after children and young people, the committee cross-referred to existing NICE guidance on physical activity, obesity prevention and weight management in children and young people.
## How the recommendations might affect practice
Facilitating and supporting activities such as school clubs would be unlikely to have a significant resource impact. Funding for group activities may have more substantial resource implications, so these would need to be limited to freely available or inexpensive activities. Some group activities, particularly school clubs, could be prioritised for funding through the pupil premium grant.
Return to recommendations
# Readiness for starting or changing school
Recommendations 1.6.1 to 1.6.3
## Why the committee made the recommendations
The committee considered US-based evidence on therapeutic playgroups for children in kindergarten entering second grade aged 7 to 8. These resulted in improved parent-rated social competence and emotional stability. But this evidence was from a small trial with no long-term follow up. Because of this, and the expense of running therapeutic playgroups, the committee did not recommend them specifically. But they agreed that early years education should include opportunities to improve socialisation, such as early years education in playgroups, as well as other opportunities to encourage child-led play.
The committee considered evidence from robustly designed studies on transition-to-school programmes for looked-after children of primary school age. These programmes resulted in improved early literacy skills, self-regulatory skills, self-competence, and attitudes towards alcohol and antisocial behaviour, as well as days free from internalising symptoms. They also reduced aggressive behaviours. A similar programme for secondary-school-aged children resulted in improved emotional, social and behavioural scores, and reduced substance use.
The committee considered the broadly positive findings for readiness for school interventions, alongside the problems with study quality and assessment of effectiveness. But they highlighted that, particularly for a child returning to school after prolonged absence, the need of a child to cope with the possibility of peers and parents of other children finding out about their 'looked-after' situation could be traumatic, and that this is particularly a risk if the child is receiving special interventions for education. Other evidence from UK-based interview and focus group studies suggested that looked-after children and young people did not necessarily want more professionals or programmes in their lives.
The committee therefore agreed there was a broad benefit of tailored transition support into new school placements. However, they favoured approaches that would help ease the looked-after child or young person into the new school placement but not single them out. The committee also agreed that transition to a new school placement may need input from professionals beyond those in education.
## How the recommendations might affect practice
The resource impact of these recommendations is expected to be low. Early years support should already be provided as a statutory service, so little additional resource expenditure should be needed, other than greater prioritisation of playgroups from existing funds. Transition support and services are also currently supported by the virtual school. Additional interventions to support the transition can be prioritised through the pupil premium grant, which is part of statutory education funding provision for looked-after children and young people.
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# Support in schools
Recommendations 1.6.4 to 1.6.7
## Why the committee made the recommendations
The committee heard from experts that educational resources were available to support looked-after children and young people, but they may not be being spent in the most effective way. The committee agreed that ensuring that looked-after people and their carers know about their rights to educational support (for example, the purpose of the pupil premium grant for education, and how it is distributed), and including special educational provision under the special educational needs and disabilities (SEND) legal framework, would encourage accountability in spending.
The committee discussed the importance of trauma-informed practices for all practitioners working with looked-after people. Based on expert testimony, and on interview and focus group-based evidence describing the needs of looked-after people with trauma, the committee considered that standard behavioural policies in schools may not be adequate or may even be harmful for young people with a history of trauma and disorganised attachment. They agreed that it was important for schools and regulators to understand the impact of behaviour management policies on trauma.
UK-based interview and focus group evidence showed that looked-after children and young people experienced a shortage of adults who have higher expectations and aspirations for their education, as well as positive role models and tailored (individualised) support for education. Based on expert testimony and their own experience, the committee discussed the need for a strong educational advocate for looked-after children and young people. This would be someone who is invested in and supportive of the person's education and is willing and informed enough to fight for the educational provisions that a looked-after child or young person should receive by statutory right (and beyond). The committee agreed that this role is most readily fulfilled by the designated teacher. As well as having a committed educational advocate on the school site, the committee agreed that educational advocacy needs should also come from the primary carer. However, the committee agreed that, in many cases, the foster carer's role in their child's education had not been sufficiently encouraged.
The committee agreed that the role of the designated teacher is carried out with variable quality across the UK. Therefore, the committee felt it important to outline the key principles of practice that this role should include to improve the advocacy relationship with the looked-after child or young person in school settings. They discussed the need for the designated teacher to collaborate with those who have the best information to support and direct the looked-after child or young person's educational path. The committee used their own experience and knowledge to identify personnel as useful partners for this.
The committee used interview and focus group-based evidence and their own experience and knowledge to clarify the role further. They discussed evidence in which carers had identified and organised the diagnosis of educational issues themselves (such as dyslexia). They considered that it would be better for the on-site educational advocate (the designated teacher) to identify and organise such assessments, and in a more timely manner. Therefore, the committee agreed that the designated teacher should ensure ongoing monitoring of learning needs, particularly during placement transition (which can be a time of greater educational and emotional challenges).
The committee also considered that multiagency review meetings, including those from the virtual school and the designated teacher, may need input from professionals beyond those in education. Therefore, they agreed that a designated teacher needs to be sufficiently competent to refer for specialist support if necessary.
The committee emphasised that 1 of the most important roles of the designated teacher (acting as educational advocate) was to 'check in' with the looked-after child or young person regularly, whether or not they have any special educational needs. Check-ins can help to develop a rapport with the looked-after child or young person and build a supportive relationship. Because interview and focus group-based evidence highlighted the importance of maintaining confidentiality about care status whenever possible, especially in school, the committee were keen that these check-ins should not add more stigmatising and formal meetings to the looked-after child or young person's schedule. Rather, the designated teacher could have regular one-to-one informal conversations with them. The committee agreed that the frequency of these conversations should be informed by the looked-after child or young person themselves, because some may favour less intense supervision.
## How the recommendations might affect practice
Advocacy by a named teacher is not anticipated to need significant additional resources because this is already part of the statutory role of the designated teacher. The committee recognised that there are time-resource implications in performing this role to a high standard.
Return to recommendations
# Virtual schools
Recommendations 1.6.8 to 1.6.15
## Why the committee made the recommendations
The committee noted that no consistent model of a virtual school was apparent across the country but that some common features could be identified. As part of this, there was a discussion about the constituent members within a virtual school and the external services that should be linked through the virtual school.
The committee discussed including early years practitioners within the virtual school. Based on expert testimony and their own experience, they noted that early years expertise was not statutory in virtual schools. Smaller numbers of looked-after children in the early years group meant they were often allocated relatively small budgets. The same was true at the other end of the educational age range: early years and over‑16 groups are not well provisioned, with most money devoted to school-aged children and young people.
The committee considered there was a need for early years expertise alongside the virtual school head to provide oversight of interventions to support the early years education of looked-after children, and champion educational services for children during the pivotal younger years. Based on their experience and knowledge, the committee suggested that information to support this role needed to be brought in through collaboration with nurseries and health visitors and using routinely collected data.
Expert testimony highlighted the need for closer working between the virtual school head and the special educational needs (SEN) service. The virtual school team needs to have a breadth and depth of knowledge across social care, education and health and to understand the legislation for each area. Very few social care staff have a working knowledge of the SEN code of practice or the legislation that underpins it. As a result, the committee considered the need for someone with SEN experience in the virtual school, ideally a special educational needs coordinator or someone with SEN specialism or training.
Based on their own expertise, the committee considered that the inclusion of a post‑16 coordinator in the virtual school could help bridge the gap in information for those in care hoping to achieve higher or further education – for example, by helping with the application processes for entrance to college, university or further training (and support while there). Therefore, help was needed to help looked-after young people aspiring to further education to navigate the available support.
The committee recognised that the expertise needed within the virtual school was likely to vary based on the demographics of the population being served. Therefore, they considered the need to take into account the prevalence of groups of special interest in each local authority when expertise for the virtual school is being recruited. They noted that the prevalence of some groups of special interest varied significantly between local authorities.
As a result of expert testimony, the committee recognised that often, virtual school heads had not been properly empowered or used, and their role had not been properly defined. In some cases, the virtual school head may be a peripheral figure, rather than a key leader enacting change in the local authority. Therefore, the committee agreed that, to be able to complete its statutory duties, the virtual school head should be considered the key leader and enabler for the collaboration of educational services for looked-after children and young people.
Expert testimony outlined the range of professionals with a statutory remit to work with, and promote, the needs and wellbeing of children and young people in care and education. These professionals are asked to work together, but the expert noted that this often does not happen sufficiently in practice. In the experience of the expert, a clear bridge is needed between the services, and when this role is taken up by the virtual school, the links work much better. The committee agreed and outlined a list of services for which the virtual school head should act as a 'bridge'.
Based on their expertise and knowledge, the committee noted that simplifying and merging looked-after children review meetings would support multiagency working. For example, merging annual reviews and personal education plan meetings could make it easier for specialists in education and social care to communicate, while also reducing the number of overall meetings that looked-after children and young people need to attend. The committee also considered the importance of including the health perspective in multiagency review meetings when health problems impacted education.
## How the recommendations might affect practice
Every school in the UK is obliged to employ a special educational needs coordinator, so ensuring that one is part of the virtual school team would not incur additional resources. Some virtual schools may not have an existing early years practitioner, so there would be resource implications from adding another staff member to the team. However, it is possible that such expertise could be found, or developed (using training), in existing professionals in the virtual school.
Reviewing meeting structures and condensing them into fewer meetings if possible would not need additional resources because it would reduce the number of meetings being organised and held.
The recommendation for virtual school heads to form a bridge between named specialists in education, social, health and mental healthcare is not anticipated to have a significant resource impact because these roles already exist and would not need an additional staff member at the virtual school.
Return to recommendations
# Improving educational outcomes
Recommendations 1.6.16 to 1.6.19
## Why the committee made the recommendations
The committee considered evidence from robustly designed studies about interventions tested mainly in primary-school-aged children. There was some evidence that tutoring by foster parents or volunteers improved maths and some literacy scores; these were outcomes that the committee considered to be important. However, the evidence base had some problems in quality and the committee noted that some carers may not want to take on the responsibility for tutoring because this can blur the line between the carer and educator roles.
The committee considered that flexibility was important when choosing the tutoring style that best suits the child and the placement. Evidence from studies with weaker designs (non-randomised controlled trial) showed that a paired reading intervention greatly improved reading age over the course of the intervention. Although, again, the evidence was limited, the committee were impressed by the reported size of effect.
The committee considered that paired reading had potential for increasing communication and engagement between foster carers and schools. In addition, it was a simple, cheap and already widely used intervention in primary schools (with parents often encouraged to take part). It showed good evidence of effectiveness, and had historical use, beyond looked-after children. Paired reading was also considered to have a relational aspect, improving quality time spent between carer and child. Older students in primary school could engage in paired reading with younger students, which may also provide an important mentoring role.
The committee discussed tutoring among looked-after young people attending secondary school. They noted that a large amount of money is spent on tutoring, but there is a lack of evidence on its effectiveness for looked-after young people. The committee therefore did not recommend a specific intervention but instead agreed, based on their own experience, that interventions for improving education in secondary-school-aged looked-after children are regularly evaluated.
UK-based evidence from interviews and focus group studies and expert testimony showed the importance that unaccompanied asylum-seeking children placed on educational attainment and learning English. The committee agreed that teaching an unaccompanied asylum-seeking child to speak English fluently was 1 of the first steps to helping them acclimatise to the country, settle with their primary carer, build positive social networks and succeed educationally. Therefore, the committee agreed that English language lessons were important for those who are not fluent, and recommended that intensive lessons be considered for those with no previous knowledge of English.
Likewise, the committee recognised that additional support would be necessary in mainstream educational settings for those who did not speak English fluently. So they agreed that virtual schools should consider increased specialist educational provision for unaccompanied asylum-seeking children.
The committee noted a gap in the evidence base on the use of therapeutic interventions in current practice such as art therapy, play therapy, occupational therapy, music therapy and psychotherapy. The committee highlighted these interventions as being known to have a positive impact on educational, social and emotional outcomes in broader populations of children. They made a recommendation for research on therapeutic interventions for promoting school stability and learning to assess the effectiveness of these interventions on improved learning outcomes, school attendance and exclusion to help address this evidence gap.
## How the recommendations might affect practice
There was no published cost-effectiveness evidence for most of the learning interventions but the resource impact for the recommended interventions is expected to be low. There may be some hidden costs such as carer or volunteer time, training, travel and administrative support.
Paired reading is currently provided to all children in primary schools, so no additional resource is needed. Infrastructure may be needed for extra support or training for foster carers on active reading and to train volunteer paired readers. Virtual schools may be best placed to deliver training in paired reading to foster parents. The only extra costs involved should be for foster carers actually attending training, and costs may be even lower if delivered virtually.
Individual or small group tutoring delivered by trained foster carers or trained volunteers would have a low resource impact, but using professional tutors would have higher cost implications.
These interventions can be prioritised for funding through the pupil premium grant, which is part of statutory education funding provision for looked-after children and young people.
This trauma-informed training for teachers could be incorporated into the existing provision for behavioural management training, so is not anticipated to have a substantial resource impact.
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# Data collection, sharing and publication in education
Recommendations 1.6.20 to 1.6.22
## Why the committee made the recommendations
Evidence from expert testimony highlighted the importance of developing systems of accountability by gathering and sharing data that could help monitor and evaluate services around education for looked-after children and young people. They noted that no data was being collected on the responsibility of local authorities to secure education provision. For example, many looked-after children and young people are not placed on a school roll (defined by having a Department for Education number) by their corporate parent. In addition, there may be a culture of ignoring statutory responsibilities in this area because of lack of oversight, use of unregistered provision, and 'ghost rolls'.
The committee discussed evidence from expert testimony about placement of children in unregistered schools, which results in their data not being captured in national attainment figures. This may create a perverse incentive for local authorities not to secure appropriate provision in order to artificially improve national attainment figures. The committee agreed that local authorities should collect and publish information on the educational provision for looked-after children, with a particular focus on children missing education as well as the strategy for reducing that number.
The committee discussed expert testimony on the lack of accountability for how the pupil premium grant was being spent. Schools and local authorities do not routinely collect data to demonstrate that education funding for looked-after children and young people is being spent within the terms of the grant. This hampers the ability to evaluate the spending of the pupil premium grant to improve outcomes or to ensure that the funds are used directly for the benefit of looked-after children and young people. The committee noted that the Department for Education have acknowledged that they are not able to hold local authorities accountable for either spending of the pupil premium grant or provision of educational placements, because of the lack of available data. Therefore, the committee agreed that the spending of the total pupil premium grant within local authorities needs to be tracked to develop a mechanism of accountability.
## How the recommendations might affect practice
Collecting and publishing information on the educational provision for looked-after children and young people, particularly those who are missing education, and a strategy for reducing the number of these children and young people, and developing a checking mechanism for the spending of the pupil premium grant, is unlikely to have a significant resource impact. Although this data is not currently collected consistently across local authorities, there are existing mechanisms to do so. There are also existing mechanisms for checking local authority spending, so checking educational spending for looked-after children and young people could be incorporated into existing spending checks.
Return to recommendations
# Further and higher education
Recommendations 1.6.23 to 1.6.26
## Why the committee made the recommendations
The committee considered evidence from robustly designed studies on interventions to help looked-after young people aspire to, and be equipped for, higher education. They acknowledged that entry into further or higher education is very different for looked-after children and young people than for the wider population. For example, they have broadly lower expectations of ever attending higher education and may consider this to be something that they are not able to achieve. Interventions need to be tailored accordingly.
Particularly, evidence from a study of individual coaching and group mentoring, with a summer visit and stay at a university campus, showed improvements in several measures of readiness for post-secondary education. Most importantly, there was a considerable improvement in post-secondary participation at 6‑month follow-up in the intervention group.
Based on evidence from robustly designed studies, and some interview and focus group-based evidence, the committee considered that residential experiences, university campus visits, and coaching and mentoring by near peers in higher education could have profoundly beneficial effects on looked-after young people considering higher education. In addition, the committee agreed that university access schemes (offered by several UK universities) can give important support for looked-after young people in navigating the application process and receiving assisted entry to courses. The committee also considered the importance of encouraging people to self-identify as care leavers once they are in university or college because this may give them opportunities to receive additional support. However, they also recognised that care leavers often want to keep their care history private.
Based on their own experience and knowledge, the committee also weighed up the potential harm caused by pushing looked-after young people into higher education when this might not be the best option for them. The evidence did not report whether looked-after young people enrolled in college or higher education thrived or completed their courses. But this is a concern that applies to all young people not just those who are looked after.
The committee also considered that looked-after young people may be more ready to re-enter education when older. They discussed that their personal advisers are well placed to outline the options to do this. However, the young people would benefit from the support of post‑16 coordinators who would have more in-depth knowledge of the funding and support available.
Based on their own experience and knowledge, the committee agreed that support was also important for looked-after young people considering other routes into further education and training. The committee believed careers support and advice, work experience placements, and internships to be useful and available routes into good careers for looked-after young people. Careers support and advice was strongly needed, targeted at looked-after young people because they need an extra level of support and signposting.
## How the recommendations might affect practice
The resource impact of these recommendations to help looked-after young people enter higher or further education or training is expected to be low, although some apparently low-cost interventions funded by local authorities, such as volunteer coaching programmes, are likely to be associated with expenses for travel, management and administration. But the resource impact generally is expected to be small compared with the potential benefits of improved education, employability and independence. In addition, there is a possibility that the UK pupil premium grant may be extended to 16- and 17‑year‑olds in the near future.
It is not possible to make a robust judgement about the potential resource impact to local authorities of recommendations on university access schemes, residential experience and visits on university campus, mentoring by near peers in higher education, and coaching, because uptake is too uncertain to predict. Interventions such as residential experiences and campus visits would be delivered by universities and colleges themselves, although facilitated by the virtual school. Likewise, some interventions may simply involve signposting people to local programmes and schemes that are university, college or third-sector funded, so the resource impact for local authorities would be low.
Return to recommendations
# Before transition between care placements and to permanent placements
Recommendations 1.7.1 to 1.7.9
## Why the committee made the recommendations
Drawing on UK-based evidence from interview and focus group studies indicating it was important to have a good match between carers and the looked-after children and young people, the committee recommended that careful consideration in transition planning should be given to the matching of carers and the looked-after child or young person. In assessing the strengths of the carers, committee members described how they translate the child's needs into what the parenting challenge and task looks like for the carers, and how the carers can best bolster the placement and help meet these needs.
UK-based evidence from interview and focus group studies and expert testimony also highlighted how the relationship between foster carer and adopter could support the move into permanency. Good communication and support can improve this relationship, for example by helping to manage expectations of the foster carer during the planning stage. These measures could help to avoid an adversarial relationship forming between carers, rather than a supportive relationship that allows for a more integrated experience for the looked-after child or young person during transition.
The committee disagreed with perspectives in some of the interview and focus group-based evidence that suggested it was beneficial for the looked-after child or young person to experience the short sharp shock of a foster carer stepping away completely and immediately. Rather, they supported a less traumatic approach that facilitated ongoing communication with current carers if the child or young person wanted this.
The committee looked at interview and focus group-based evidence on facilitating the involvement of the new permanent or long-term carer's extended family. For example, the extended family may help by providing respite (or support) care. The committee agreed that involving family and friends early in the placement was particularly important for helping them to engage with the new family relationship. But they stated that respite (or support) care in the early stages could damage the formation of attachment with the primary carer. Based on their own knowledge and expert testimony, the committee noted that family and friends training days, which are offered through adoption agencies in some local authorities, were helpful.
For birth families involved in substance misuse, the committee considered evidence on 2 interventions to support reunification: recovery coaching and family drug and alcohol courts. This included evidence based on robust study designs, and some weaker forms of evidence (not from randomised controlled trials). Recovery coaching was associated with greater reunification and more stable and long-lasting relationships than services as usual. UK family drug and alcohol courts were associated with improvements in reunification and longevity of reunification compared with ordinary care proceedings. The committee considered that providing independent support for families at the same time as child welfare court processes could support reunification. They agreed that, if reunification had occurred, support needed to continue after reunification to help the permanent placement to last, with clear plans for follow-up. Instead of recommending recovery coaching specifically, the committee recommended substance and alcohol misuse support, by trained staff, with a cross referral to NICE lifestyle and wellbeing guidance (which includes managing substance and alcohol addiction, and behaviour change).
The committee noted that there is evidence for the use of drug and alcohol courts to aid reunification by intervening and providing support for birth parents with drug addiction. However, rates of mental health problems are also high among birth parents who have had a child removed, and these problems may also contribute to the reasons for children going into care. Based on their own experience, the committee also recommended that mental health support continues alongside court processes. The committee made a recommendation for research about the benefit of mental health support to promote reunification.
There was evidence, based on studies with non-randomised designs as well as focus group and interview-based studies, that concurrent planning significantly reduced the likelihood of multiple moves before finding permanency and the time to finding a permanent placement. But evidence also showed 2 particular issues with it. One was that prospective adopters and birth parents found that late changes in the care plan could be particularly distressing for them. And prospective adoptive parents found that the intensive contact arrangements could be taxing for both themselves and the child (in terms of frequency and distance travelled while establishing new routines and building relationships).
The committee discussed concurrent planning as something that was already practised, with success, in certain parts of the UK. However, they considered that carers and birth parents should be well informed of the inherent difficulties of such a strategy and the possibility of late changes to the care plan meaning that adoption or reunification may not occur as anticipated.
## How the recommendations might affect practice
It is not possible to make a robust judgement about the potential resource impact of setting up concurrent planning processes to speed up transition time to permanency, or of carrying out substance and alcohol misuse support alongside court processes, because uptake is too uncertain to predict. However, these processes are already available in some parts of the UK.
Some local authorities already offer family and friends training days through adoption agencies, and there is existing provision for this training, so it is unlikely that extending this to all areas will have large resource implications.
Return to recommendations
# During transition between care placements and to permanent placements
Recommendations 1.7.10 to 1.7.20
## Why the committee made the recommendations
UK-based evidence from interview and focus group studies suggested the need for a more integrated experience for looked-after children and young people that takes into account the significance of previous caregiving relationships. For example, the importance of foster carers for preparing and supporting adoptive parents, focusing on the emotional state of the child or young person during the busy transition out of care, and prospective adoptive carers wanting more information about previous care experiences and health.
The committee agreed that, beyond the benefits for prospective adopters offered by foster carers in terms of sharing information, it was also beneficial for the looked-after child or young person to see positive relationships forming between their current carers and their prospective permanent carers in the period before and after transition.
Based on their own experience and knowledge, and as part of the more integrated experience of transition described above, the committee considered the social network around the looked-after child or young person. They thought that contact arrangements, which may be focused on the birth family, should also take into account whether the looked-after child or young person has other significant relationships with which they would like support to maintain. Such support could help create a more overlapping transition that gives more time for new connections to form and to process the loss of old ones.
Based on interview and focus group evidence about how child-focused the transition period was, the committee agreed it was important to have a practitioner regularly 'check in' with the child or young person to ensure that the transition process was going well for them and to keep the process child-centred. The committee noted that for children not yet able to talk, the primary carer may need to be present and advocacy services may also be needed.
UK-based evidence from interview and focus group studies showed that good clear information before transition was extremely important to new foster carers and prospective adopters. The committee considered the types of information that should be given to a new carer during the process of transition between care placements or out of care, based on their own knowledge and expertise. It was important that this should give new carers a clear sense of the chronology of the care process for the child or young person.
To avoid the information being handed over in an overwhelming quantity, the committee agreed that the information needs to include a clear summary. This will provide the information they need to help carers carry out their nurturing and safeguarding role. They also agreed the importance of briefing the new carer in person, rather than leaving the carer to make sense of the information by themselves. A social care practitioner who has had continuous oversight of the child or young person's history in care would be ideally placed to do this.
The committee considered their own experience and knowledge, and some interview and focus group-based evidence showing the concerns of new carers adopting looked-after children with medical conditions they were not familiar with, and of the need for information about previous placements. The committee discussed what information would be helpful for new carers and prospective adopters, to cover the needs of the new placement, including personal health history. It also included birth family health history; the committee were keen that this was collected for all children entering care, not just during adoption processes. The committee agreed it should also cover behaviour with the potential for significant harm to others (for example, sexual, violent or fire-setting). However, they highlighted it was important for prospective carers to have the context to these events so they could assess them properly.
Based on their experience and knowledge, the committee also stated that this information giving should not simply be a record of negative life events, but that the record should lend equal weight to factors that could support the success of the placement. These include the looked-after child or young person's strengths, hopes for the future, significant positive relationships (with peers and adults), interests and activities, as well as how behaviours had been successfully supported in previous settings. The committee recognised the importance of ongoing life story work to draw out these factors.
The committee also considered the case of emergency foster placements, for which it may not be possible to deliver all information immediately. If it becomes clear these placements will be longer term, the carer may need more information to carry out their nurturing and safeguarding roles. For example, carers often need support to understand why a child or young person is behaving in a certain way in order to respond appropriately. As well as knowing about safeguarding issues, they need to know why children and young people are looked after, which family members pose a risk and why.
There was lot of UK-based evidence from interview and focus group studies showing that children and carers value continuity of care practitioners. The committee agreed that consistency in the practitioners who help in the handover of information for new permanent carers could reduce the sense of instability during transition, and support positive relationships.
Based on expert testimony and their own knowledge, the committee discussed the issue of a continuing education plan when a child or young person is moved outside their local authority area. The committee considered the need for someone who has an overview of the child or young person's educational needs and can help place the child or young person in education that matches their needs. They agreed that this could be assisted by having a transition plan and 'handover' from the old to the new school placement (for example, from 1 designated teacher to another) as part of the personal education plan.
Based on their experience and knowledge, the committee also discussed the need for continuity of healthcare as the looked-after child or young person moves to their new placement. The committee agreed that if regular mental health, physical health or dental support had been provided in the old placement, new referrals local to the new placement need to be in place before the transition, to promote continuity of care.
Expert testimony from an adoptive parent and organisations representing adopters highlighted the importance of language during the transition period. In particular, adoptive parents (who may have no experience of parenting) may feel judged by the child's foster carers. Often, adopters feel this is a highly sensitive time when they do not want to complain or do anything to jeopardise the placement. The committee therefore highlighted the need for transition teams and foster carers to consider these issues and adjust language accordingly.
## How the recommendations might affect practice
Most recommendations are not particularly resource intensive, generally focusing on continuity of healthcare and education, parent and carer training, peer support and the detailed chronology of care process for the individual. Many recommendations focus on ensuring continuity of existing processes, or on processes that are already in place in some areas.
However, extra resources may be needed for those that need more professional time to produce (such as the summarised history of care) or training and preparation for long-term carers.
Giving opportunities for current and new carers to meet before a placement move, and facilitating ongoing communication, should not have substantial resource implications because these can be incorporated into existing transition planning. Similarly, supporting existing social networks to allow time in the transition period for the looked-after child or young person to form new social connections is not expected to be resource intensive because this can be incorporated into existing transition planning.
Return to recommendations
# After transition between care placements and to permanent placements
Recommendations 1.7.21 to 1.7.25
## Why the committee made the recommendations
The committee considered whether it would be useful for the looked-after child or young person to give their own perspective on their journey in care to their prospective carer if the child or young person is willing, drawing from existing life story work. This could aid transparency and help the looked-after child or young person feel in control of their information. However, the committee considered that this may be better occurring once the looked-after child or young person and carer have begun to develop a stronger attachment relationship.
UK-based evidence from interview and focus group studies and expert testimony highlighted the power imbalance perceived by adoptive parents, who may feel unable to complain about the transition process because of fears about jeopardising the placement. The committee considered that although there was little that could be done about this during the transition period (other than making permanency carers aware of their rights to receive support), agencies would benefit from seeking feedback from foster carers and adopters after the permanence order is made, and they could use this to improve the delivery of transition services.
There was very good UK-based interview and focus group evidence, supported by expert testimony, that peer support was useful for adopters and permanent carers. Peer support groups could often give the personalised support and availability that social care teams could not. The committee noted that effective peer support could be achieved in a variety of ways.
The committee noted, based on expert testimony, that there was also the potential for specialised peer support groups to help deal with specific problems in permanency placements. Experienced permanent carers could be linked up with other permanent carers in need of support to provide tailored advice and empathy that may not be covered by the expertise of the support team.
The committee noted that few studies reported long-term placement durability outcomes, including post-permanency outcomes showing that the looked-after child or young person was thriving in their new long-term placement. In addition, there was insufficient evidence on the perspective of adopters and long-term permanency carers about the transition out of care and how this could be improved. The committee therefore made a recommendation for research on interventions to support stability of permanent placements to encourage more evidence in these areas.
## How the recommendations might affect practice
Facilitating accessible peer support for permanent carers (such as adopters) is unlikely to have a substantial impact on resources, because most would be peer led and not need much additional personnel time or physical resources from the local authority. Message boards may need to be moderated to prevent misinformation but, overall, peer support could save time and resources by helping to resolve issues that would otherwise need the attention of care staff, or that, if left without support, could lead to placement instability.
Return to recommendations
# Transition out of care to independence
## Why the committee made the recommendations
Recommendations 1.8.1 and 1.8.2
The committee considered evidence from a study, using less robust research designs (not randomised controlled trials), describing outcomes of participants who had left care at different ages. Those who were still in care placements between the ages of 17 and 23 were less likely to be involved in property crimes (men) or convicted or arrested (women). Those who had left care aged 18 or 19 had worse outcomes for time to arrest and time to first violent offence.
Other UK-based evidence from interview and focus group studies suggested that many care leavers experienced what felt like a cliff edge moving into independence too early. Therefore, the committee recommended that, wherever possible, looked-after young people approaching independence should be encouraged and helped to stay in their current care placement until at least the age of 18.
The committee noted that for some, staying put in their care placements beyond age 18 could be beneficial. However, this was complicated by the fact that carers may be paid less for young people over 18. (Levels of financial support to former foster carers are agreed and specified within each local authority's staying put policy.) In addition, the ability to take on other foster placements may be compromised by allowing an adult who has left care to stay on the premises. Therefore, the committee agreed that the possibility for staying put should be explored with all carers before leaving care, even though this may not be possible in many cases.
Supported by expert testimony, and experience in the committee, the committee considered the danger faced by those whose care placement broke down between the ages of 16 and 17. This may lead to placement in unregulated housing at a young age, when vulnerability and the risk of exploitation may be high. The committee agreed that it was very important to avoid using unregulated housing if at all possible, particularly among those at high risk of exploitation.
Recommendations 1.8.3 to 1.8.5
A needs assessment is already a requirement in pathway planning (beginning at age 15 and completed before age 16). But based on evidence from UK interview and focus group studies reflecting the unmet need of some care leavers after leaving care, the committee agreed that this process needed to be more rigorous and incorporate previous life story work to identify the person's strengths (for example, problem-solving skills and practical skills) and needs.
The committee found that, overall, evidence from studies with robust designs did not suggest that independent living services were ineffective. In the 1 study that looked at providing independent living services that were better than standard care, there were significant improvements across earnings, housing stability and general economic security. There was also some evidence of benefit for various specific aftercare services from evidence based on studies with weaker designs (not randomised controlled trials).
The committee therefore discussed the descriptions of the independent living services in the studies and recommended some core principles of care for supporting looked-after young people moving into independence. The committee sought to link the needs assessment for care leavers to the services provided in the transition out of care to independence.
UK-based evidence based on interview and focus group studies highlighted how care leavers are often lost in the gap between child and adult health services and that they often face a great amount of loneliness and mental strain. This matched the committee's own knowledge and experience. So they agreed that the care leaver's existing mental health, health and dental care needed to be supported by ensuring registration with GP services and access to dental services. In addition, the committee suggested ways of plugging the gap between adult and child services until the transfer to adult services can be completed – for example, by extending access to CAMHS or providing alternative emotional and wellbeing services such as online support, face-to-face counselling or group work.
The committee noted that independent living services described in the evidence reviewed covered several interventions that had components supporting mental health. However, few reported mental health or general health-specific outcomes. Recognising the higher than usual rates of mental illness and health problems among care leavers, the committee recommended that more research was needed on interventions to promote the health and mental health of care leavers (see the recommendation for research on continuing support for the physical and mental health needs of care leavers).
UK-based evidence drawing from interview and focus group studies strongly suggested the benefit of peer groups and support for gaps in social network in helping to combat social isolation. The committee noted that peer support was also a common component of independent living services described in the rest of the reviewed evidence.
Evidence showed the usefulness of and need for various common components of independent living services. For example, ongoing accommodation support is a common component of independent living services and is valued by care leavers. The committee agreed that it was important and emphasised that organising this through the leaving care team working together with other housing services would promote continuity of oversight during the transition out of care.
The committee discussed interview and focus group evidence about the experience of the short sharp shock of independence, and that care leavers were not 'allowed' to make mistakes. For example, care leavers may initially reject support but then regret it. The committee therefore agreed that services that help to provide safety netting should be available for all care leavers to help prevent deterioration in housing stability, connectedness and economic independence. Based on their experience and knowledge, they suggested that the following services could be provided for care leavers without substantial cost to local authorities: drop-in services (for local guidance and signposting), possibility of more frequent meetings with their personal adviser (for individualised guidance and support) and facilitated care leavers peer support groups (to support relationships after care, mentoring, and share ideas and resources).
Recommendations 1.8.6 to 1.8.15
Based on their knowledge and experience, the committee considered that many of the problems young people encounter when transitioning out of care stem from a lack of accountability of local authorities in following and communicating statutory guidance. Care leavers may be unaware of the importance of the pathway plan for agreeing the support they will be given after transition.
Some examples the committee discussed included informing care leavers that if something is in their pathway plan and is signed, it constitutes an agreement that the local authority will provide that service, and that care leavers do not have to sign their pathway plan until they are happy with it and may request a review. The committee agreed the need for practitioners to communicate this.
The committee also agreed that other aspects that need to be communicated included rights to extended support beyond age 18 (for example, support to re-enter education), and rights to advocacy services to improve adherence to statutory requirements, and to take full advantage of rights under statutory law.
The committee considered the need for all of this information about support available to care leavers in their local authorities to be made explicit and easily accessible as outlined in statutory guidelines. They noted that, in practice, care leavers often did not know how to find their care offer and some websites outlining the care offer were not kept up to date.
Based on their own experience and knowledge, the committee considered that virtual meetings could help bridge the gap between care leavers and their personal advisers to help them continue to access support when they had moved out of area.
Based on their own experience, the committee recognised the need for pathway plans to anticipate significant milestones (such as reaching the end of qualifications or training) to help support next steps into greater independence.
The committee discussed the need for local authorities to perform some quality assessment of the pathway plans. Based on their experience and knowledge, they discussed what made a better-quality pathway plan and agreed there was a need for plans to include actions in response to identified need. These actions should clearly identify a timeframe for completion as well as the practitioner responsible for completing the action. The committee also discussed the need for quality assessments to check that the actions were actually completed in the agreed timeframe.
From the committee's experience, the support available to care leavers is likely to differ considerably by area. So they agreed that efforts to raise care leavers' awareness of local opportunities for support in independent living were needed.
## How the recommendations might affect practice
Supporting young people staying in their current placement until at least age 18 is not expected to have significant resource implications. If a foster carer is happy to continue the placement beyond 18, the cost of this (for example, the potential loss of the foster carer to the system) is offset by the benefits of improved outcomes for those who have support for longer beyond their in‑care placement.
The committee acknowledged that avoiding the use of unregulated housing for looked-after young people under 18 would have potential resource implications. However, these resource impacts can be justified on equity grounds, because any reasonable person would not consider the use of unregulated housing to be appropriate for anyone under 18. Therefore, it would be unfair and a social injustice to have looked-after young people endure such living conditions simply because of their looked-after status.
These recommendations should not have substantial additional resource implications because most of them cover care processes that are statutory across the UK, although they are completed with variable quality. For example, many of the possible interventions for preparing care leavers for independent living are currently available across the UK, but with variable access.
Some of the recommended interventions to support care leavers may have resource implications, such as supported housing and increased mental health support to plug the gap between child and adult services. However, the provision of these is already a statutory requirement if based on a good individual needs assessment.
Providing 'safety nets' such as drop-in services for care leavers and peer support groups is expected to be relatively low cost and has large benefits by providing a sense of availability and connectedness. Peer support groups may need administrative staff time, especially to help organise and facilitate meetings, and some monitoring may also be necessary to help prevent misinformation spreading. However, this intervention could save time and resources by helping to resolve issues that would otherwise need the attention of transition teams.
Return to recommendations
# Support for care leavers in further and higher education
Recommendations 1.8.16 to 1.8.18
## Why the committee made the recommendations
Based on their own experience and knowledge, the committee discussed extended educational care. They noted that, for qualifying care leavers, extended support was often offered if the person was in full-time education. However, the definition of what constitutes full-time education may be too narrow for many who would benefit from it. For example, 1 of the committee members raised the example of a care leaver who received a scholarship to train with a sports team, who may not receive the same extended support as someone in university. The committee also considered the high prevalence of those with special educational needs or disabilities among care leavers. Because this group may not progress as quickly in education, the committee agreed that they, especially, may need extended educational support.
Based on their own experience and knowledge, the committee also discussed the issue of university students living away from home and agreed that continuity of housing during holidays was needed for care leavers in college or university to prevent housing instability between terms. This was supported by evidence showing that housing was often cited as the reason for care leavers dropping out of courses in higher and further education.
Based on their experience and knowledge, and evidence showing that isolation may remain a problem even with appropriate housing, the committee agreed that a good level of social support was needed from social care and university teams. Based on evidence showing the benefit of peer support and mentoring interventions, the committee agreed that facilitating a 'buddying system' for peer support, mentoring from older students on campus to tackle isolation during the holidays or providing other social opportunities for care leavers could be beneficial.
## How the recommendations might affect practice
Housing support during university holidays may not cost a substantial amount because many universities already offer the option for care leavers to stay on in their halls of residence in holiday times.
Return to recommendations
# Feedback to improve services
Recommendations 1.8.19 to 1.8.21
## Why the committee made the recommendations
Drawing on UK-based evidence from interview and focus group studies suggesting that shared decision making should be a cornerstone of care provided for looked-after children and young people, the committee discussed the need for a mechanism to incorporate the feedback of looked-after children, young people and care leavers moving into independence back into the services provided. Interview and focus group evidence suggested that children in care councils specifically may facilitate such feedback, although something more focused on care leavers, such as care leavers forums or surveys, was needed to improve services during the transition into independence.
The committee recognised particularly that those who were looked after out of area may be most vulnerable to receiving inadequate statutory support. Therefore, they considered it important that the views of these looked-after children, young people and care leavers were captured and used to improve services.
## How the recommendations might affect practice
These recommendations are not expected to have substantial resource costs, because care leavers may be encouraged to give feedback in numerous ways. Care leaver councils may have more running costs in terms of facilitation and organisation, but the extent to which local authorities will use these councils is uncertain.
Return to recommendations
# Forum for strategic leadership and best practice
Recommendations 1.9.1 and 1.9.2
## Why the committee made the recommendations
Based on evidence from interview, focus group studies, studies with more robust study designs and committee experience and knowledge, the committee considered the benefit of facilitated multiagency working to help systems adapt to local challenges. They were particularly interested in the use of regular broad-system meetings, or forums, for care providers to exchange information and to provide the opportunity to adapt care systems to meet the needs of looked-after children and young people.
The committee considered that 1 of the key components was improving communication between disciplines (for example, health professionals, social care providers and carers) at all levels to ensure that statutory guidance was being adhered to. A forum could also display examples of exemplary practice, review recently published evidence, and align tools used for health and social care assessments. This would help educate leaders, which would enable information to be cascaded down to other professionals. Based on expert testimony, the committee also agreed that these meetings would help standardise the different agencies' use of language, risk-assessment tools, and job titles and roles. The committee agreed that such forums could adapt to situations specific to the local authority – for example, increasing numbers of unaccompanied asylum-seeking children or increasing risks of going missing in care. The committee agreed that risk-assessment tools were useful to determine increased risk of exploitation at the individual level (for example, someone placed out of area is at increased risk), but it needed to be standardised across local authorities and agencies.
## How the recommendations might affect practice
There may be organisation and facilitation costs for starting a forum to bring together agencies and representatives providing care for looked-after children and young people within a local authority. However, these are justified by the benefits of facilitating communication between agencies, providing education, sharing tools and expertise, and giving examples of best practice. Virtual forums may also help to bring costs down.
The committee noted that, in many cases, various boards, groups and councils already exist within local authorities. Partnerships with these could be organised to bring leaders together from several sectors. Some examples of existing relevant boards, groups and councils include: corporate parenting boards; children's safeguarding boards; children's trust boards; health and wellbeing boards; children's care councils; youth councils; foster care liaison groups; and clinical commissioning groups.
Return to recommendations
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{'Context': "As of 31\xa0March\xa02020, there are 80,080\xa0looked-after children and young people in England, with the total number of children being looked after increasing yearly since 2010. Most of the looked-after children are cared for in foster placements (72%), with 14% in connected care, and 13% in residential care, secure units or semi-independent living accommodation. In addition to these, 7% of looked-after children are placed with birth parents.\n\nAlthough each child or young person will have a unique journey into care, the most common reason for becoming looked after was abuse or neglect (65%). These are considered to be major adverse childhood events (ACEs). These can cause trauma and can lead to long-term damaging effects on children and young people's physical and mental health. Other adverse childhood events experienced by looked-after children and young people include physical abuse (48%), emotional abuse (37%) and sexual abuse (23%). Trauma can also include domestic abuse, serious harm, exposure in the home or community to alcohol, drug misuse or violence. All looked-after children and young people will have experienced trauma in some way.\n\nEvery child in care is a unique child with individual strengths and needs. However, the physical, emotional and mental health of some looked-after children and young people will have been compromised by neglect or abuse. The rate of mental health disorders in the general population aged 5\xa0to\xa015 is 10%. However, for those who are looked after, it is 45%, and 72% for those in residential care. In addition, frequent placement moves can keep looked-after children and young people from receiving the support they need by disrupting treatment plans and access to services. Frequent placement moves are linked to poorer mental health and a lessened sense of belonging. Practitioners and services involved with the child need to work collaboratively to assess and review the child's needs and how these can best be met. Key statutory guidance for promoting the health and wellbeing of looked-after children is available from the Department for Education and the Department of Health and Social Care.\n\nLooked-after children are also at a greater risk of poor educational outcomes. In 2019, 55.9% of looked-after children had a special educational need compared with 14.9% of all children. At key stage\xa02, 37% of looked-after children and young people reached the expected standard in reading, writing and maths (compared with 65% of those who were not looked after). The higher prevalence of special educational needs, as well as speech, language and communication needs, among looked-after children, in part explains this difference. As of 2018, the rate of permanent exclusions for looked-after children has fallen and is now less than the rate for all children. However, looked-after children and young people continue to be significantly over-represented in the criminal justice system. Around half of the children currently in custody in England and Wales have been in care at some point. Virtual schools oversee the pupil premium grant, which is used by them – or designated to schools – to support looked-after children's education. This and other statutory guidance for the education of looked-after children can be found in the Department for Education's statutory guidance on promoting the education of looked-after and previously looked-after children.\n\nOnce a child or young person enters care, a suitable placement will be sought for them. Looked-after children leaving care most commonly return home to their birth parents (29%), but two-thirds of children who return home to birth parents re-enter care within 5\xa0years. However, as of December\xa02019, although the number of children entering care has been rising year after year, the number of children ceasing to be looked after during the year due to adoption has been falling down to 3,570 from a peak of 5,360 in 2015. This has increased pressures on health and social care providers to continue to provide high-quality care with existing resources. Reductions in adoptions have been partially compensated for with increases in Special Guardianship Orders, which increased from 3,550 to 3,700 in the same period. Statutory support for the transition out of care into adoption, including preparing adopters and arranging contact, is outlined in the Department for Education's statutory guidance on adoption.\n\nFrom 31\xa0March\xa02019, the number of young people aged 16\xa0and over leaving care to move into independent living has risen each year from 3,720 in 2015, to 4,560 in 2017, and to 4,680 in 2019. Care leavers as a group also have poorer outcomes on key measures such as housing, health, employment, and continuing in education and training post‑16. For 19- to 21‑year‑olds, 6% were known to be in higher education, 21% were in other education, 25% were in training or employment, and 39% were not in education, employment or training (compared with around 12% of all young people aged 19\xa0to 21\xa0years). Statutory support for care leavers, including providing a personal adviser for all care leavers, can be found in the Department for Education's Children Act 1989 guidance and regulations: transition to adulthood for care leavers (volume\xa03).\n\nLocal authorities have a statutory duty to support looked-after children and young people. Partners cooperate to produce individual care plans covering health, education and placement. In addition, clinical commissioning groups, NHS England and Public Health England have a statutory duty to support local authorities to meet their health needs. The Children Act 1989, Children Act 2004, Care Standards Act 2000, Care Planning, Placement and Case Review Regulations 2010, Children and Social Work Act 2017, Fostering Services Regulations 2011, Children and Adoption Act 2006 and accompanying regulations and statutory guidance provide the legal framework for local authorities, providers of fostering services and children's homes. Other relevant safeguarding legislation and statutory guidance includes the Safeguarding Vulnerable Groups Act 2006, Working Together to Safeguard Children 2018, Children's Act 1989 Guidance and Regulations and Keeping Children Safe in Education 2021.\n\nDespite the gap in health and educational outcomes between looked-after children and young people and the general population outlined above, research suggests that the longer children remain in care, the better they can improve in these areas. And, accounting for their disadvantages, they can do better than children not in care.\n\nThe original NICE guideline on looked-after children and young people duplicated existing statutory guidance. This update focuses more on the specific interventions needed to help practitioners improve outcomes for looked-after children and young people, as well as how statutory care is best delivered. It complements existing national statutory guidance, which focuses more on service delivery. It also recognises that looked-after children and young people experience inequality, and these recommendations seek to ensure that their needs are at the centre of any plans being made and are adequately met. This requires special attention and expertise.\n\nThe guideline covers support provided to looked-after children and young people and care leavers (from birth to age\xa025), and their families and carers (including birth parents, connected carers, prospective adoptive parents and special guardians). This includes all who are classed as 'looked-after' under a full or interim local authority care order, whether temporary or long term. For example, it covers looked-after children and young people on remand, those temporarily looked-after under section\xa020 of the Children Act 1989, and those preparing to leave care. The guideline covers all parts of the care pathway, from entry of looked-after people into the care system, to support provided when moving into permanency and out of care into independent living.\n\nThe guideline does not cover children and young people who have moved out of care and are no longer looked after (not including care leavers) – that is, those who have been successfully adopted or reunified with birth parents. It also does not cover those on the edge of care and their families.\n\nThe guideline committee wished to acknowledge that the impact of the COVID‑19 pandemic on looked-after children and young people's mental and emotional health and wellbeing, as well as their educational progress, cannot be underestimated.\n\nAlthough children and young people have been less affected by the virus than adults in terms of infection and mortality rates, the committee raised concerns about lost learning and greater safeguarding risks to this vulnerable group during lockdown. COVID‑19 has disrupted practitioners' relationships with children and families, and the longer-term impact on the voluntary and charitable sector is unknown.\n\nTo address the impact on educational progress, the UK government has announced £1\xa0billion of funding for schools (the 'catch-up premium'), which includes millions of pounds specifically for vulnerable and disadvantaged children (including looked-after children) whose education has been most affected. Services, including health and social care services, have also been increasingly delivered remotely using digital technology.\n\nImplementing new ways of working, reconfiguring services to meet evolving social distancing requirements and offering emergency support has resulted in increased cost pressures on local authorities, the healthcare sector and other organisations and agencies involved in the care of looked-after children and young people. The impact of the pandemic on vulnerable groups outside of the care system, such as those experiencing domestic abuse and neglect, and families suffering financially, has also led to more children being referred to children's services who had not previously been known to local authorities and children's social care, leading to a greater impact on the system.", 'Recommendations': "People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.\n\nMaking decisions using NICE guidelines explains how we use words to show the strength (or certainty) of our recommendations, and has information about prescribing medicines (including off-label use), professional guidelines, standards and laws (including on consent and mental capacity), and safeguarding.\n\nThis guideline should be read alongside NICE's guideline on children's attachment.\n\n# Diversity\n\nBe aware that many looked-after children and young people are from groups that may face additional disadvantage. Ensure that their needs are met and that they do not face further marginalisation. These groups include those from black, Asian and other minority ethnic groups, Gypsy, Roma and Traveller communities, and those from different religious backgrounds, as well as other groups such as refugees and unaccompanied asylum-seeking children, disabled people with complex needs, autistic children and young people, children and young people with a learning disability or neurodevelopmental disability, lower socioeconomic groups and people who identify as LGBTQ+.\n\nFor a short explanation of why the committee made this recommendation and how it might affect practice, see the rationale and impact section on diversity\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: barriers and facilitators for supporting positive relationships among looked-after children and young people.\n\nLoading. Please wait.\n\n# Supporting positive relationships\n\n## Positive relationships in the care network\n\nEnsure that the care network around a looked-after child or young person consists of positive relationships. These are characterised by:\n\ngenuine caring – being treated by carers as 'one of their own'\n\navailability – being there when needed\n\nreliability – providing promised support in a timely manner\n\nlistening that is engaged and non-judgemental\n\ncontinuity of relationships\n\npromoting agency and shared decision making that is appropriate to developmental age\n\nproviding well-communicated and fair discipline and boundaries\n\npersistence and understanding, to respond to behaviours that challenge and to support positive behaviours\n\npositive role models who offer guidance.\n\nIf the looked-after child or young person has speech, language and communication problems (whether or not these have been previously diagnosed), refer them to speech and language therapists, if needed, for assessment and for advice on how to communicate effectively with them.\n\n## Sibling relationships\n\nConsider interventions and support to improve the relationship between siblings in care, including biological siblings who live apart and non-biological siblings who live together (for example, other looked-after children or young people in the placement, and the carer's biological or adopted children). Take into account safeguarding issues and the looked-after child or young person's preferences.\n\nFor primary-school-aged children, or those needing greater assistance, ensure that the primary carers are present during interventions to improve relationships between siblings in care. Components of this intervention should include:\n\nstructured conversation around relationships and conflict resolution\n\nincentivised cooperation, for example shared activities and outings to encourage prosocial, cooperative behaviour\n\nshared activities with coaching in prosocial skills using life story work.\n\nConsider relationship coaching independently from the carer for adolescent siblings in care.\n\nOffer carers support to help them understand and maintain stable sibling relationships before offering interventions to improve the relationship between siblings in care.\n\n## Relationships with the birth family\n\nRespect the wishes of looked-after children and young people about contact arrangements (where and who with) and take them into account when making plans. Balance them against safeguarding considerations and the risk of repeating trauma.\n\nProvide contact supervisors for contact with birth families if this is necessary for safeguarding, or if it will help support the relationship between the looked-after child or young person and the birth family. Ensure that the looked-after child or young person always has the same contact supervisor if possible.\n\nContact supervisors should receive training in:\n\nsafeguarding the looked-after child or young person, including trauma-informed training in recognising signs of distress (including in babies and in non-verbal children and young people) and how and when to end a session\n\nproviding emotional support for the looked-after child or young person, including in transition to and from contact with the birth family\n\nproviding support for and feedback to birth parents to help them build positive relationships during contact\n\nknowing when to support, and how to reduce support when necessary\n\nrecord keeping and sharing information with the broader care team.\n\nConsider the need for more intense contact supervision (in terms of monitoring and feedback provided) between the birth family and looked-after child or young person in the early stages of care placements, with reduced intensity as needs decrease over time.\n\nProvide interpreting services for contact supervisors if the people taking part in contact are non-English speaking. Consider any additional communication support as needed, for example sign language.\n\nThink about using text, email or social media to support contact for looked-after children and young people. Safeguarding plans should also take account of the possibility of ongoing unmonitored online contact and ensure that the time spent in digital or social media contact and the content of these interactions is appropriate.\n\nConsider the contact needs of children placed out of their local area – for example, additional support for the birth family to attend contact centres.\n\n## Relationships with social workers\n\nSupport the looked-after child or young person's allocated social worker, to reduce professional turnover. Support could include, for example:\n\nsupervision with regular meetings to check on the wellbeing of workers, and reflect on practices that promote positive relationships (see recommendation 1.2.1)\n\nconsultation for complex and specialist problems (see recommendation 1.4.3)\n\ntrauma-informed training in communication skills to support positive relationships (see also recommendation 1.3.18).\n\nManagers of social workers should use and review ways of working to reduce duplication of effort, increase staff retention and enable more one-to-one time between social workers and looked-after children and young people (for example, by improving administrative support).\n\nLocal authorities and partner agencies should collect and review data on staff turnover to assess the impact on looked-after children and young people and the success of existing staff support systems. They should use this data to inform action plans to support greater continuity of practitioners working directly with looked-after people and care leavers.\n\nIf possible, social workers should tell looked-after children, young people, care leavers, and primary carers pre-emptively, and in a manner appropriate to developmental age, about upcoming changes in their job that will affect their relationship with the looked-after child or young person. This should include a joint meeting in person between the previous and new social worker and the looked-after child or young person. Recognise the emotional impact of such changes and provide an opportunity to say goodbye.\n\n## Mentoring\n\nConsider programmes (with professional oversight) to support mentoring relationships. For example, by pairing looked-after young people with near peers with care experience to provide positive role models, particularly for looked-after young people with social, emotional and mental wellbeing needs.\n\n## Friendship\n\nTo support overnight stays with friends, ensure that safeguarding checks are completed in good time so as not to cause a barrier to relationships.\n\nConsider providing funding to support contact with friends (for example, for travel or activities), particularly for friendships that existed before the looked-after child or young person entered care.\n\n## Placement stability\n\nProvide out-of-hours support services (separate from those provided for carers) for looked-after children and young people to help resolve urgent problems, and tell looked-after children and young people about these options. Services could be provided, for example, through social workers 'on call', voluntary or independent agency helplines or advocacy organisations.\n\nAdopt a proactive approach to identify children and young people who may be likely to present out-of-hours (for example, they may show early warning signs such as skipping school, lying or stealing), for whom out-of-hours support could be planned ahead of time.\n\nDiscuss the priorities and needs of carers sensitively and transparently with the looked-after child or young person in a manner appropriate to developmental age. For example, if placements are at risk of breakdown, social workers should facilitate communication between the carers and the looked-after child or young person (and birth parents if relevant) to try to resolve problems.\n\nIf a placement changes:\n\nDiscuss the reasons for this with the looked-after child or young person in a way they can understand and that is appropriate to their developmental age.\n\nOffer the child or young person emotional support, if possible by a practitioner they have an existing relationship with.\n\nUse ongoing life story work to help them process changes in placement.\n\nProvide the new carer with appropriate health information in good time before the new placement starts (for example, the health plan recommendations, any new health concerns, health contacts and upcoming health appointments).\n\n## Serious behavioural problems\n\nConsider multidimensional treatment foster care for looked-after adolescents with a history of persistent offending behaviour.\n\nFor guidance on service design and delivery for learning disabilities and behaviour that challenges, see NICE's guideline on learning disabilities and behaviour that challenges.\n\n## Disorganised attachment\n\nFor guidance on attachment difficulties, see the NICE guideline on children's attachment.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting positive relationships\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to support care placement stability for looked-after children and young people\n\nevidence review\xa0B: barriers and facilitators for supporting care placement stability among looked-after children and young people\n\nevidence review\xa0C: interventions to support positive relationships for looked-after children, young people and care leavers\n\nevidence review\xa0D: barriers and facilitators for supporting positive relationships among looked-after children and young people\n\nevidence review\xa0F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers\n\nevidence review\xa0G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.\n\nLoading. Please wait.\n\n# Valuing carers\n\nThese recommendations cover support for primary carers, including foster carers, connected carers, key workers in residential care and birth parents (when the looked-after child or young person is placed with the birth parent).\n\n## Supporting and involving carers\n\nInvolve and value the carer's input in decision making in the broader care team, and keep carers fully informed about a looked-after child or young person's care plan.\n\nProvide out-of-hours support services for carers to help resolve urgent problems, for example through social workers working 'on call', emergency duty teams or out-of-hours service, voluntary or independent agency helplines, or carer peer support associations.\n\nEnsure that carers log any help sought outside of usual operational hours as part of their routine and urgent reports.\n\nFacilitate peer support for carers at accessible times and places, including online if people may find it difficult to attend a physical meeting.\n\nAs part of the care plan, think about the need for planned respite care (or 'support care') for carers.\n\nEnsure that respite (or support) care is used in the looked-after child or young person's best interests and explain this to the looked-after child or young person. For example, make use of short breaks that are fun for the child or young person, such as staying with relatives or extended carer family.\n\nUse a respite (or support care) carer who the child or young person is familiar with if possible, and take into account the skills or training needed to meet the looked-after child or young person's assessed need.\n\nKeep carers fully informed and updated about the support services available to carers and looked-after children and young people in their local authority.\n\nInform the looked-after child or young person's carers about any interventions used to support the looked-after child or young person, including the purpose of these interventions.\n\nFor further guidance on support for adult carers, follow the NICE guideline on supporting adult carers.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on supporting and involving carers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to support care placement stability for looked-after children and young people\n\nevidence review\xa0B: barriers and facilitators for supporting care placement stability among looked-after children and young people.\n\nLoading. Please wait.\n\n## Training for carers\n\nPlan training for carers so that it is delivered before it is needed. Think about the need for multiagency involvement in training programmes and ensure that the organisations involved agree the source of funding between them.\n\nSupervising social workers should work with carers to assess the needs of the looked-after child or young person, to inform and tailor training and development needs for the carers.\n\nProvide a schedule of mandatory training for carers, excluding birth parents. Ensure that this training covers:\n\nTherapeutic, trauma-informed parenting (covering attachment-informed, highly supportive and responsive relational care).\n\nSafeguarding procedures.\n\nHow to communicate effectively and sensitively (for example, using de-escalation techniques).\n\nLife story work to promote a positive self-identity, which has a consistent, child-focused and planned approach (see the section on life story work for identity and wellbeing).\n\nHow to be an educational advocate (this part of the training should be delivered by practitioners from the virtual school).\n\nIdentifying problems with, and supporting, good oral health, diet and personal hygiene (particularly among those coming into care).\n\nEncouraging positive relationships and sexual identity (covering issues such as consent, encouraging healthy intimate relationships, 'coming out' and transitioning).\n\nSelf-care for carers, preventing burnout and coping with placements ending.\n\nThe importance of health assessments, supporting attendance and issues of consent for medical treatment.\n\nRecord keeping and sharing the information in the record with the looked-after child or young person in a constructive and positive way, considering the need for confidentiality, and the impact the record may have on the looked-after child or young person. Training can be delivered in person (for example, at home or in community group settings) or virtually.\n\nProvide targeted support and training for birth parents if reunification is a possibility or if the child or young person is to remain in placement with the birth parent. This should be provided through transition planning with family support teams.\n\nThink about providing tailored training for carers if there are specific needs related to race, ethnicity and culture. This could include, for example, understanding and respecting cultural and religious identity (including dietary requirements or preferences), and understanding specific hair and skin care needs.\n\nProvide tailored training for carers if there are specific needs relating to special educational needs, long-term health conditions and disabilities, for example sensory and communication needs. Training could be provided through specialist healthcare teams and voluntary organisations.\n\nBased on the individual needs and developmental age of the looked-after child or young person, consider more intensive training methods for carers to support the delivery of therapeutic, trauma-informed caregiving. These methods should use video feedback, coaching and observation, role play, and follow-up booster sessions and be delivered by trained facilitators.\n\nEnsure that trauma-informed training covers:\n\nunderstanding behaviour as a form of communication and as a response to trauma\n\nunderstanding, recognising and processing triggers for trauma responses\n\nunderstanding attachment and loss.\n\nEnsure that trainers for carers are trauma informed and have a good understanding of attachment issues and therapeutic approaches.\n\nEnsure that new permanent or long-term carers are trained and prepared so that there is continuity of care and support, including therapeutic support if needed, between placements.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on training for carers\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0A: interventions to support care placement stability for looked-after children and young people\n\nevidence review\xa0B: barriers and facilitators for supporting care placement stability among looked-after children and young people\n\nevidence review\xa0C: interventions to support positive relationships for looked-after children, young people and care leavers.\n\nLoading. Please wait.\n\n# Safeguarding\n\nLocal authorities should facilitate a multidisciplinary approach to safeguarding looked-after children and young people, recognising that, like other children, looked-after children may need a full safeguarding response despite already being in care. This approach should:\n\ninclude all relevant agencies in meetings to address safeguarding concerns\n\nfacilitate the sharing of data between agencies\n\nseek the views of looked-after children and young people and their carers, to ensure that responses to safeguarding risks are effective and acceptable, for example by coordinating safeguarding responses for siblings in care.\n\nHold safeguarding meetings to bring together practitioners from multiple agencies involved in the care and support of looked-after children and young people, such as: social care; fostering, residential and connected care; education and the virtual school; healthcare; voluntary agencies; housing services; emergency services; policing; and immigration.\n\nLocal authorities should seek specialist support to address safeguarding risks outside the home (contextual safeguarding), exploitation and children missing from care. This practitioner should lead and facilitate safeguarding meetings and build clear lines of accountability. The practitioner could be, for example, a missing person's coordinator or another trauma-informed specialist with knowledge of exploitation and safeguarding issues in the looked-after population.\n\nAssess the safeguarding risk of a looked-after child or young person using data shared across agencies. This could include data on vulnerabilities:\n\nat the individual level (such as those captured by risk-assessment tools)\n\nat the group level (red flags specific to subpopulations such as young girls and boys, trafficked children and unaccompanied asylum-seeking children)\n\nat the community level (gathered from community-level health and mental health data, area deprivation indexes, number of county lines operating in a single area and area-specific missing person reports).\n\nUse training and review meetings to ensure that practitioners and carers working directly with looked-after children and young people are:\n\nable to recognise critical moments for looked-after people; that is, times when they may be more open to change and receiving help\n\naware of the early signs of, and risk factors for, gang involvement, exploitation and going missing\n\nfamiliar with how to report concerns.\n\nPromote positive relationships (including broader relationships such as those with carers, siblings and practitioners) as the main way to prevent exploitation and children going missing from care (see recommendation\xa01.2.1).\n\nProvide tailored support for the looked-after child or young person to prevent exploitation, by addressing issues specific to young girls and boys, trafficked children and unaccompanied asylum-seeking children (for example, addressing issues of self-esteem, domestic abuse, negative relationships and previous exploitation).\n\nReview the case files of looked-after children and young people who have been the subject of safeguarding meetings, to help the safeguarding partnership learn and develop future safeguarding responses (or to inform best practice).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on safeguarding\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.\n\nLoading. Please wait.\n\n# Health and wellbeing\n\n## Building expertise about trauma and raising awareness\n\nEnsure that all practitioners working with looked-after children and young people are aware of the impact of trauma (including developmental trauma) and attachment difficulties and appropriate responses to these, to help them build positive relationships and communicate well.\n\nEnsure that practitioners and carers working with unaccompanied asylum-seeking children are aware of the issues that affect this group, including health needs, safeguarding issues, language and culturally sensitive care needs, and the danger of going missing.\n\nEnsure that there is sufficient specialist professional expertise to support, and provide consultation for, looked-after children and young people with more complex needs. This could be provided through more intensive (responsive) trauma-informed training, or by sharing expertise across agencies.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on building expertise about trauma and raising awareness\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0C: interventions to support positive relationships for looked-after children, young people and care leavers\n\nevidence review\xa0D: barriers and facilitators for supporting positive relationships among looked-after children and young people\n\nevidence review\xa0E: interventions and approaches to support practitioners in completing physical and mental health and wellbeing assessments (and act on findings during the care journey) for looked-after children and young people\n\nevidence review\xa0G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.\n\nLoading. Please wait.\n\n## Physical and mental health and wellbeing assessments\n\nIn line with statutory guidance, when a child or young person enters care, local authorities must ensure that healthcare teams are informed as soon as possible about the legal status of the looked-after child or young person and why they have entered care (within 5\xa0working days, as specified by the Care Planning, Placement and Case Review Regulations 2010). Get consent to share this information from an adult with parental responsibility, or from the looked-after child or young person directly if appropriate.\n\nWhen a child or young person enters care, social workers should:\n\nMake a formal request for the initial health assessment, giving the reasons that the child or young person is coming into the care system.\n\nAsk for consent from the birth parents (or from another adult with parental responsibility, or from the looked-after young person directly if appropriate) to access and share information from the child health record.\n\nAsk for consent from the birth parents to share their own health information, and ask them to complete a parental health questionnaire to help with this. If the birth mother has agreed to share her health information, ask the relevant hospital about her health during pregnancy. All this information should be available in time for the looked-after child or young person's initial health assessment.\n\nEnsure that statutory review health assessments for a looked-after child or young person are carried out by the same healthcare professional each time, if possible.\n\nConsider the need for confidential and private access to healthcare for looked-after young people, for example if phone use or internet use are restricted because of safeguarding needs, or when seeking out sexual health advice or treatment. For guidance on one-to-one interventions to prevent sexually transmitted infections (STIs) and contraceptive services, see NICE's guidelines on STIs and contraceptive services.\n\nHealthcare professionals should compile a history of the looked-after child or young person's health from the information they hold in the health records and additional information given to healthcare professionals from other teams, to give practitioners and carers a clear sense of their past, present, and likely future physical and mental health needs.\n\nBe aware that care leavers are very likely to request access to their health and social care records. Practitioners should ensure that the language used in the records and the way events are captured are sensitive and empathetic.\n\nOffer a culturally appropriate, registered interpreter to communicate in person with looked-after children and young people for the initial health assessment if language is a barrier to communication. If language remains a barrier to communication, think about the need for a culturally appropriate, registered interpreter to be available in person for subsequent health and social care assessments.\n\nOffer unaccompanied asylum-seeking children tailored initial health assessments that address risks arising from their country of origin and journey to the UK. Include:\n\ndiet and nutrition, including nutritional deficiencies such as vitamin\xa0D deficiency\n\ngastrointestinal symptoms\n\noral health\n\ntuberculosis screening and general immunisation status\n\nsexual health, tailored to the individual (for example, testing for sexually transmitted diseases; and being aware of signs of assault and abuse, including abuse linked to faith and culture such as female genital mutilation and breast flattening). For guidance on one-to-one interventions to prevent sexually transmitted infections (STIs) and under‑18 conceptions, see NICE's guidelines on STIs and contraceptive services\n\nother infectious diseases and bloodborne infections, for example HIV and hepatitis testing\n\nsensory issues not previously identified because of lack of screening, for example hearing, vision or mobility problems\n\nan assessment of mental health, with referral to specialist mental health teams if indicated\n\nsleep disturbances.\n\nAfter looked-after children and young people (including babies) have had their initial health assessment, consider the need for an additional specialist mental and emotional health assessment once the looked-after child or young person has begun to form a relationship with the primary carer. This could be, for example, up to a year or by the first review health assessment.\n\nHealthcare professionals responsible for the care of looked-after children and young people should review whether care recommendations in the health plan have been completed, particularly if the child or young person has been moved out of area, checking with the professionals concerned across agencies.\n\nFor guidance on the diagnosis and management of attention deficit hyperactivity disorder (ADHD) in children and young people, see NICE's guideline on ADHD.\n\nFor guidance on the recognition, referral and diagnosis of autistic spectrum disorder, see NICE's guideline on autism spectrum disorder in under\xa019s: recognition, referral and diagnosis.\n\nFor guidance on the recognition, assessment and treatment of post-traumatic stress disorder (PTSD), see NICE's guideline on PTSD.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on physical and mental health and wellbeing assessments\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: interventions and approaches to support practitioners in completing physical and mental health and wellbeing assessments (and act on findings during the care journey) for looked-after children and young people.\n\nLoading. Please wait.\n\n## Mental health and child and adolescent mental health services\n\nTo avoid delays in care, provide intermediate therapeutic or specialist support for the care network around looked-after children and young people who are on a waiting list for child and adolescent mental health services (CAMHS), for example a specialist outreach team. This should not be used as a replacement for CAMHS.\n\nOffer a range of dedicated CAMHS that are tailored to the needs of looked-after children and young people – for example, making them longer term, more trauma informed and relationship based.\n\nOffer preventive services based on assessed need (see recommendation 1.5.12), with timely delivery to prevent serious mental health problems that need tier\xa03 or\xa04 specialist services.\n\nBe aware that children moving placements must not lose their place in the waiting list for CAMHS, as there is a statutory right to not lose a place in a waiting list for a health service.\n\nProvide specialist, trauma-informed mental health and emotional wellbeing support for unaccompanied asylum-seeking children. Take into account cultural sensitivities (for example, the different perspectives of unaccompanied asylum-seeking children about mental health services) and that symptoms of trauma could come to the surface over the long term.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on mental health and child and adolescent mental health services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers\n\nevidence review\xa0G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.\n\nLoading. Please wait.\n\n## Life story work for identity and wellbeing\n\nStart life story work as soon as possible after the looked-after child or young person enters care, to support care placement and emotional stability, rather than as an intervention to deliver once placements are stable.\n\nSchedule regular, dedicated times for life story work to help the looked-after child or young person make sense of their journey through the care system and beyond, their significant relationships and their identity.\n\nEnsure that life story work is done in the setting preferred by the looked-after child or young person, and conducted by a named carer or practitioner with whom they have a continuous and close relationship. This named person may change over the period in care.\n\nInclude the following in life story work for looked-after children and young people:\n\nthe present – identity, strengths and significant relationships\n\nthe past – reasons for entering care and for any placement breakdowns, important memories and relationships\n\nthe future – building independence, careers, hopes and dreams.\n\nTake a flexible approach to life story work, and tailor it to the developmental age and needs of the looked-after child or young person. The content could include life mapping, pictures, art, narratives, and toys or play.\n\nCompile life story work in 1\xa0place (such as a ring binder) and build on this in each session. Give the child or young person control over who this is shared with and how it is stored. Help them to choose a safe and secure storage option.\n\nEnsure that life story work for looked-after children and young people captures and embraces ethnicity, cultural and religious identity, as well as other personal aspects of identity, for example, sexual identity or disabilities.\n\nEnsure that a social worker oversees the life story work if another carer or practitioner is carrying out the work. For example, the social worker may share background information to support the carer or practitioner carrying out life story work, with the looked-after child or young person's consent.\n\nThink about and plan how to carry out life story work for looked-after children and young people, with sibling groups, in a manner appropriate to developmental age. This may include:\n\npreparing siblings for navigating conversations with older siblings or siblings not in care\n\ndeciding whether it is appropriate to deliver life story work sessions in a sibling group or individually\n\ndetermining whether conversations will include sensitive information.\n\nEnsure that the experience and skillset of the practitioner or carer delivering life story work for looked-after children and young people is sufficient to deliver good quality work, particularly in complex situations.\n\nExplain to the looked-after child or young person's wider support network that life story work is ongoing, so that they can support it as needed. For example, if sensitive or emotional information has been discussed with the child or young person during life story work, schools may need to be informed.\n\nPlan regular reviews of how life story work may affect contact arrangements and the looked-after child or young person's relationship with their birth family. Use information from these reviews to adjust the support provided. This could include, for example, involving birth families in life story work to encourage consistencies in narratives explored, and helping the looked-after child or young person with reframing previous relationships.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on life story work for identity and wellbeing\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0B: barriers and facilitators for supporting care placement stability among looked-after children and young people.\n\nLoading. Please wait.\n\n## Relationships and wellbeing activities\n\nPromote a positive relationship between the primary carer and the looked-after child or young person as the main way to support the social, emotional and mental wellbeing of the looked-after child or young person.\n\nWhen making safer caring plans, think about a looked-after child or young person's need for:\n\nPhysical touch and affection as a part of a healthy relationship with male and female primary carers. Take into account any adverse childhood experiences.\n\nPlay, particularly for babies and young children.\n\nDevelop the interests of looked-after children and young people to help them develop their identity and to find peer support and new friendships. Do this by helping them to find, and setting aside time, for outings, interest groups and other activities that will help them to build skills. These may include:\n\none-to-one activities accompanied by the primary carer (at least initially) to promote opportunities for listening and positive relationship building (for example, visiting outdoor green spaces such as parks)\n\nfunded, supported and facilitated activities (such as school clubs, for example making use of the pupil premium grant as determined in the personal education plan) specifically to address emotional health and wellbeing needs\n\nactivities or outings to support identity, for example community support groups, cultural or religious activities, events or festivals\n\nactivities to bring together children, carers and practitioners in informal settings, for example group outdoor activities.\n\nFor guidance on managing obesity and promoting physical activity, follow NICE's guidelines on preventing obesity, identifying, assessing and managing obesity, weight management and physical activity for children and young people.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on relationships and wellbeing activities\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers.\n\nLoading. Please wait.\n\n# Learning and education\n\n## Readiness for starting or changing school\n\nConsider the following to support social competence and emotional stability in looked-after children:\n\nearly years education, including playgroups\n\nother opportunities to encourage child-led play.\n\nThe virtual school should plan bespoke, individual transition support for supporting readiness for school and resilience in looked-after children and young people moving between schools and settings (including those moving out of care to permanency). This includes:\n\nmoving from preschool to primary school\n\nmoving from primary to secondary school\n\nmoving in the middle of a school year\n\nreturning to school after an extended absence. Individual transition support for school moves may include structured visits to the school beforehand, school preparation for the carer, meeting the designated teacher, catch-up support and handover between designated teachers (for example, drawing from weekly diaries and life story work).\n\nThink about providing multidisciplinary specialist support for transition between school placements, tailored to the looked-after child or young person's needs and alongside or part of the virtual school and the team around the child – for example, including healthcare professionals in transition support for looked-after people who have health conditions that affect their education.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on readiness for starting or changing school\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0H: interventions to support readiness for school in looked-after children and young people.\n\nLoading. Please wait.\n\n## Support in schools\n\nInform looked-after children and young people and their carers of:\n\ntheir rights to educational support and\n\nthe purpose of the pupil premium grant for education and how it is distributed by the virtual school.\n\nSchools should ensure that behavioural management policies reflect trauma-informed practices and cover attachment issues.\n\nSchools should ensure that the designated teacher is a consistent advocate for the looked-after child or young person's educational progress.\n\nThe designated teacher should:\n\ncollaborate with school staff (who the looked-after child or young person is most comfortable with), primary carers and named practitioners in the personal education plan and the education health and care plan\n\nprovide timely assessment and ongoing monitoring of learning needs, particularly in times of transition between educational placements\n\nrefer for specialist support when needed (for example, educational or clinical psychology), and be aware of the impact of trauma on learning and behaviour\n\nbe aware of special educational needs and link up with the special educational needs coordinator\n\nliaise with specialist looked-after children nurse teams if a health problem has been identified that affects education\n\nwork to ensure that young people are able to access the most appropriate and inspirational educational opportunities, especially post‑16\n\nhave regular one-to-one informal conversations with the looked-after child or young person and their primary carer, at a frequency informed by the looked-after child or young person.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on support in schools\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0G: barriers and facilitators for promoting physical, mental and emotional health and wellbeing of looked-after children and young people and care leavers\n\nevidence review K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.\n\nLoading. Please wait.\n\n## Virtual schools\n\nEnsure that the virtual school includes all of the following:\n\nearly years expertise\n\na special educational needs coordinator\n\na post‑16 coordinator.\n\nEnsure that the virtual school covers early years provision, incorporating information from nurseries and health visitors (such as the Ages and Stages Questionnaire) and other involved health services. Complete the early years personal education plan and link it to the foundation stage profile if possible.\n\nEnsure that the virtual school special educational needs coordinator is trained in the special educational needs and disability legal framework so they can help looked-after children and young people access all the provision and support that the law entitles them to.\n\nThe post‑16 coordinator in the virtual school should help looked-after young people navigate opportunities for training and education (including further and higher education, and apprenticeships) and available funding streams to support these.\n\nEnsure that the expertise in the virtual school reflects the needs and profile of the school-aged population it serves. For example, the population may include unaccompanied asylum-seeking children, trafficked children, children with a history of exploitation, and looked-after children on remand or in secure settings.\n\nMake virtual school heads the key enabler for service collaboration and a link between named specialists in the following:\n\nsocial workers\n\nindependent reviewing officers\n\nschool admissions and further or higher education admissions\n\nother virtual schools if a looked-after child or young person is placed out of area\n\ndesignated teachers\n\nschool improvement services\n\ndesignated practitioners working with looked-after children and young people who have a health need, including mental health services or therapeutic services.\n\nLocal authorities should simplify and merge meetings about looked-after children and young people if possible. For example, education, health and care plan meetings for looked-after children and young people and personal education plan meetings may benefit from occurring together.\n\nInclude healthcare professionals in multiagency review meetings for looked-after children and young people who have additional health needs that affect their education.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on virtual schools\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.\n\nLoading. Please wait.\n\n## Improving educational outcomes\n\nTo improve educational outcomes, such as literacy and numeracy, in primary-school-aged looked-after children:\n\noffer paired reading\n\nconsider individual or small group tutoring (for example, by trained foster carers, trained volunteers or professional tutors).\n\nEnsure that interventions for improving education in secondary-school-aged looked-after young people are regularly evaluated to check they are appropriate for the user and effective as part of the personal education plan.\n\nAssess the language and communication needs of unaccompanied asylum-seeking children:\n\nOffer English language lessons to those who are not fluent in English.\n\nConsider intensive English lessons for those with no previous knowledge of English.\n\nConsider the need for virtual schools to increase specialist education support for unaccompanied asylum-seeking children – for example, by providing designated staff members, and additional English for Speakers of Other Languages (ESOL) support.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on improving educational outcomes\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review I: interventions to support learning needs for school-aged looked-after children and young people\n\nevidence review K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.\n\nLoading. Please wait.\n\n## Data collection, sharing and publication in education\n\nThe responsible local authorities should collect, publish and monitor information on educational provision for their looked-after children and young people, in particular those missing education (for example, those in schools that do not have a Department for Education number, or those on permanent or fixed-term exclusions). This may include unaccompanied asylum-seeking children and those with a history, or high risk of, exploitation.\n\nLocal authorities should agree and share a strategy for reducing the number of looked-after children and young people missing from education.\n\nLocal authorities, working with the virtual school, should develop a mechanism to check the spending of the total pupil premium grant, beyond the information recorded in the personal education plan, and evaluate the impact of the spending on the looked after child or young person.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on data collection, sharing and publication in education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0K: barriers to, and facilitators for, supporting learning needs of looked-after children and young people.\n\nLoading. Please wait.\n\n## Further and higher education\n\nVirtual schools should collaborate with universities and colleges to support looked-after young people to access higher or further education. Ways to do this could include:\n\nresidential experiences and visits to university or college campuses, mentoring by near peers in higher or further education, and coaching\n\nlocal opportunities such as university access schemes and college support programmes\n\nencouraging self-identification as a care leaver, once in university or college, to help them access support such as financial bursaries.\n\nEnsure that looked-after young people are aware of the possibility of re-entering education when older (up to age\xa025) with the financial support of their local authority.\n\nPersonal advisers, with the support of the post‑16 coordinator, should help care leavers to understand the funding and support available for re-entering education, as part of the care offer, once they have left care.\n\nVirtual schools should support a looked-after young person's entry into careers and training. Ways to do this could include providing:\n\ncareers support and advice\n\ncurrent local opportunities such as work experience placements, apprenticeships and internships (particularly those targeted at looked-after young people and care leavers).\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on further and higher education\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0J: interventions to support entry into further or higher education or training in looked-after children and young people.\n\nLoading. Please wait.\n\n# Transition between care placements and to permanent placements\n\nThese recommendations cover support for all permanent carers, including long-term foster carers, special guardians, connected carers, adopters, key workers in residential care and reunified birth parents.\n\n## Before transition\n\nWhen planning transition between care placements, social workers should aim to have a good match between the permanent carers and the looked-after child or young person:\n\nassess the child or young person's case history and care needs, and the carers' strengths, support and training needs (including the length of time needed for training), then\n\ndiscuss relationship dynamics with the looked-after child or young person and their prospective carers.\n\nDuring the transition period, support the foster carer and permanent carer relationship. Help to manage foster carer expectations during the planning stage (for example, the need for the permanent carer to be in the foster carer's house at times, using non-judgemental supportive language with new carers and understanding the emotional challenges for the foster carer of 'letting go').\n\nIn the planning stage, discuss the need for longer-term contact and longer-term contact arrangements with the current foster carer, for example contact by letter or email or meeting up once the looked-after child or young person has settled in their new placement.\n\nEncourage and help the permanent carer's family and support network, including other children in the home, to be involved when a looked-after child or young person moves into their new placement – for example, by offering a family and friends training day before the placement.\n\nConsider support, by trained staff, for birth parents with substance and alcohol misuse to support reunification. If the support is given, carry it out alongside court processes, such as family drug and alcohol courts.\n\nThink about providing relational, emotional and mental health support for birth parents and families, alongside court processes, to support reunification.\n\nContinue mental health support and support for drug and alcohol abstinence after reunification.\n\nConsider concurrent planning to speed up the transition to permanent placements. If concurrent planning is used, ensure that carers and birth parents are well informed about the risk of late changes to the permanency plan.\n\nFor guidance on support for drug and alcohol abstinence and behaviour change, follow NICE's guidance on lifestyle and wellbeing.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on before transition between care placements and to permanent placements\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review\xa0L: interventions to support looked-after children and young people transitioning out of care to living with adoptive or birth parents or special guardians, or into connected care\n\nevidence review\xa0M: barriers to, and facilitators for, supporting looked-after children and young people in transition out of care to living with their adoptive or birth parents or special guardians, or into connected care.\n\nLoading. Please wait.\n\n## During transition\n\nDuring transition to a new permanent or long-term placement, think about the need for a more integrated experience for looked-after children (including non-verbal children) and young people that takes into account previous significant caregiving relationships. This could be achieved, for example, by creating opportunities for current and new carers to meet, developing positive carer-to-carer relationships and sharing information (such as familiar routines, emotional responses and diet) before the placement move.\n\nWhen a looked-after child or young person moves between care placements or out of care to permanent placements, ensure that:\n\ncontact support takes into account the need for continuity with their existing social network (for example, previous friendships), especially if the care or educational placement is in a new area and\n\nthe transition period allows sufficient time for new social connections to form and for coming to terms with the loss of previous relationships.\n\nTo ensure that the permanency process is focused on the looked-after child or young person, set aside time for 'checking in' with them. Checking in should consist of careful observation and listening, writing a record of the conversation, and sharing the perspective of the looked-after child or young person to feed into shared decision making about transition arrangements.\n\nIn line with statutory guidance, advocacy services must be provided with communication support. The primary carer should also be present during check-ins, particularly for non-verbal children and young people, and children and young people with learning difficulties.\n\nDuring transition to any new placement, social workers should give prospective carers a profile of the child and their care journey as a history of the care the looked-after child or young person has received. The information can be obtained from the statutory health reports, reports from school and the social worker's assessment.\n\nGive all new carers a history of the looked-after child or young person's care. Create a summary for ease of reading with references to sections that give more detail. Gain consent for information that involves third parties and share only what is directly relevant. Include:\n\nRisk factors for placement instability and long-term physical and emotional health, such as:\n\n\n\nfamily health history\n\nprevious exposures to drug or substance use, domestic violence and abuse, or neglect\n\nother medical history, including antenatal health problems and antenatal exposure to alcohol or illicit drugs (see recommendation 1.5.4)\n\nsignificant relationships and previous significant conflicts in these relationships (especially concerning contact)\n\nsignificant negative events, for example behaviour with potential for harm to others (with context and timeline of previous events)\n\nprevious placement moves and reasons for them.\n\n\n\nProtective factors to build on, from life story work:\n\n\n\nstrengths and hopes for the future\n\nsignificant positive relationships with family members, friends and adults\n\nhow behaviours have been successfully supported in previous settings\n\nfaith, communities and religion\n\nroutines\n\n'things that are enjoyed', such as games, shopping and favourite food\n\ninterests, activities and achievements.\n\n\n\nFor emergency care placements that become long-term placements, review what information the carer has been given about the child or young person, and give them more if needed.\n\nEnsure that there is continuity of the care practitioners who help in the handover of information for new carers, if possible.\n\nEnsure that there is continuity of education (through virtual schools with oversight of a virtual school head) when a looked-after child or young person is placed out of their local authority area. Ensure that the current school provides a handover of information to the new school as part of the personal education plan.\n\nEnsure that there is continuity of healthcare for the looked-after child or young person so that any physical and mental health and wellbeing support can continue in the new placement. This includes making sure that any ongoing referrals and existing specialist care are transferred to healthcare services in the new location, before their move to a new placement.\n\nWhen supporting adoptive parents or other carers, recognise that they may still be learning to parent. Use non-judgemental language and ensure that they are aware of their rights to receive support.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on during transition between care placements and to permanent placements\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: barriers to, and facilitators for, supporting looked-after children and young people in transition out of care to living with their adoptive or birth parents or special guardians, or into connected care.\n\nLoading. Please wait.\n\n## After transition\n\nWhen social workers give information about a looked-after child or young person's care history to the new carer, they should:\n\ninvolve the looked-after child or young person, if appropriate and the child or young person is willing, drawing from continuous life story work\n\nthink about involving the child or young person in sharing information, after enough time has passed for a relationship of trust to form with the new carer.\n\nEnsure that the looked-after child or young person can keep in contact with their previous carers and friends after the placement move, if the child or young person wants to and would benefit from it.\n\nAgencies should seek feedback from carers and adopters and the child or young person to improve their transition services, after the adoption order is made.\n\nFacilitate peer support for permanent carers – for example, by setting up and moderating social media networks and fun group outings for face-to-face peer support.\n\nAsk experienced volunteer permanent carers to help permanent carers with strategies to manage more specialist problems – for example, when there is emotional distance in the relationship between adoptive parent and child, and with looked-after children and young people who have severe behavioural or mental health problems, or special educational needs.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on after transition between care placements and to permanent placements\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0M: barriers to, and facilitators for, supporting looked-after children and young people in transition out of care to living with their adoptive or birth parents or special guardians, or into connected care.\n\nLoading. Please wait.\n\n# Transition out of care to independence\n\n## Extended care\n\nEncourage and support young people leaving care to stay in their current care placement until at least age\xa018. Explore the possibility of staying with current carers beyond age\xa018.\n\nTake into account the increased risk to young people (aged\xa016 to\xa017) posed by breakdowns in placement that lead to moves into inappropriate housing. Whenever possible, avoid using unregulated housing, particularly for young people at higher risk of exploitation or risk-taking behaviour. If a move to unregulated housing is planned, thoroughly document the risks and the plans to mitigate these, and review this regularly.\n\n## Needs assessment\n\nPersonal advisers, working with social workers, should assess the needs of looked-after young people when transitioning out of care to independence. Take into account:\n\nprevious life story work\n\nproblem-solving skills and practical skills, including life skills such as financial literacy, budgeting and household management\n\nphysical and mental health support and long-term health needs, for example managing treatments and appointments\n\neducation, training and employment\n\nfinancial resources\n\ncommunication needs\n\nsocial network (assessing gaps, connectedness, isolation, and both negative and supportive relationships).\n\nBased on the needs assessment, consider providing the following support for care leavers:\n\nAccess to health services, including registering with a GP, dentist, optician, sexual health services and therapists (for those with complex healthcare needs), and extending access to CAMHS (to support continuity of care) or alternative emotional and wellbeing services such as online support, face-to-face counselling or group work. If needed, continue services beyond\xa0age 18 until care has been transferred to adult services.\n\nSupport for gaps in social network.\n\nLife skills training.\n\nSupport for pregnancy and parenting.\n\nJob preparation services, job searching and career advice.\n\nFlexible funding to support career development, for example for specialist equipment.\n\nSuitable and ongoing accommodation (through the leaving care team working together with other housing services), for example supported housing.\n\nProvide the following services to give care leavers a safety net:\n\ndrop-in services\n\nmore frequent meetings with their personal adviser, if the care leaver wants them\n\nfacilitated peer support groups.\n\n## Plans and support for care leavers\n\nTell care leavers and their primary carers:\n\nabout the rights of care leavers to statutory support (related to care-leaver status such as child in care and relevant child support) and extended support from age\xa018 to\xa025 (including reopening pathway planning and contact with the local authority)\n\nthat care leavers can receive the full level of support to re-enter education up to age\xa025.\n\nExplicitly outline the support available to care leavers in a care offer, and ensure that this can be accessed easily by care leavers up to age\xa025.\n\nConsider using virtual meetings to help meet the needs of care leavers who are living outside of their responsible authority.\n\nSchedule pathway plan reviews to occur near significant milestones if possible, for example education, training or employment application deadlines.\n\nExplain to care leavers and their primary carers how the pathway plan works, and the care leaver's rights associated with pathway planning – for example, that they can request an additional pathway plan review.\n\nTell care leavers and their primary carers of the rights of care leavers to advocacy services, to ensure that they receive the statutory provision they are entitled to and that advocacy services are provided in good time to support them with significant milestones.\n\nWhen developing pathway plans for care leavers, include clear timeframes for actions, and who is responsible for completing the action.\n\nQuality assure and review pathway plans for care leavers to ensure that improvements in outcomes are achieved.\n\nPersonal advisers should tell care leavers about services available in their area to support independence. These could include work experience opportunities, apprenticeships and college support.\n\nFor further guidance on transition from child to adult services, particularly for those with complex health needs and disabilities, follow NICE's guideline on transition from children's to adults' services for young people using health or social care services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on transition out of care to independence\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review N: interventions and approaches to support looked-after young people transitioning out of care into independent living\n\nevidence review O: barriers to, and facilitators for, supporting and developing looked-after young people to transition out of care into independent living.\n\nLoading. Please wait.\n\n## Support for care leavers in further and higher education\n\nConsider the need for extended care beyond age\xa018 for care leavers:\n\nin higher and further education\n\nwith special educational needs and disabilities.\n\nVirtual school heads should take into account educational opportunities for care leavers beyond traditional further or higher education when deciding whether to extend support.\n\nFor care leavers who move away to college or university, ensure that there is continuity of housing during holidays, with meaningful social support. This support could include 'buddying' systems for peer support, mentoring from older student volunteers on campus, and other social opportunities for care leavers to tackle isolation during the holidays.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on support for care leavers in further and higher education\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review N: interventions and approaches to support looked-after young people transitioning out of care into independent living\n\nevidence review O: barriers to, and facilitators for, supporting and developing looked-after young people to transition out of care into independent living.\n\nLoading. Please wait.\n\n## Feedback to improve services\n\nEncourage children and young people in care and care leavers to give feedback about their care placement and the services they receive. This could be done, for example, through children in care councils, care leaver forums and surveys.\n\nWhen seeking feedback, specifically seek out the views of children and young people who are looked after out of area.\n\nInclude feedback in decision making to improve services.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on feedback to improve services\xa0.\n\nFull details of the evidence and the committee's discussion are in:\n\nevidence review N: interventions and approaches to support looked-after young people transitioning out of care into independent living\n\nevidence review O: barriers to, and facilitators for, supporting and developing looked-after young people to transition out of care into independent living.\n\nLoading. Please wait.\n\n# Forum for strategic leadership and best practice\n\nUse forums to help communication and bring together expertise and leadership from all agencies providing care for looked-after children and young people, as well as representatives of looked-after children and young people and their carers, and care leavers.\n\nUse forums for looked-after children and young people to highlight examples of exemplary practice, review recent research, align and improve tools used for health and risk assessments, educate practitioners, understand one another's roles and responsibilities (and identify important gaps in provision of services), standardise language (for example, job titles and the names of risk-assessment tools and procedures) and agree a partnership approach to practice.\n\nFor a short explanation of why the committee made these recommendations and how they might affect practice, see the rationale and impact section on forum for strategic leadership and best practice\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0E: interventions and approaches to support practitioners in completing physical and mental health and wellbeing assessments (and act on findings during the care journey) for looked-after children and young people.\n\nLoading. Please wait.\n\n# Terms used in this guideline\n\nThis section defines terms that have been used in a particular way for this guideline. For other definitions see the NICE glossary and the Think Local Act Personal Care and Support Jargon Buster.\n\n## Ages and Stages Questionnaire\n\nThe Ages and Stages Questionnaire provides developmental and social–emotional screening for children between birth and age\xa06. It draws on parents' knowledge and is widely used in practice to pinpoint developmental progress and catch developmental delays in young children.\n\n## Attachment\n\nA deep and long-lasting emotional bond between 2\xa0people. For example, it includes the child seeking to be close to their caregiver when they feel upset or threatened, with the caregiver responding sensitively and appropriately to their needs. Attachment disorder is a recognised mental disorder that affects a very small minority of children experiencing attachment problems. Insecure attachment patterns and disorganised attachment are more common and are indicators of possible dysfunction in a child's attachment system that can lead to poor outcomes.\n\n## Carer\n\nThe primary carer of the looked-after child or young person – that is, the adult who has primary responsibility for the day-to-day care of the looked-after child or young person.\n\n## Care network\n\nThe carers and professionals who support the looked-after child or young person, including, for example, foster carers, social workers, healthcare professionals and educational professionals.\n\n## Concurrent planning\n\nUsually for babies and young children who are likely to need adoption but who have a chance of being reunited with their birth family. In concurrent planning, concurrent carers are approved as both foster and adoptive parents. They act as foster carers while the courts decide whether or not a child can return to their birth family. During this time, the children see their parents regularly in supervised contact centres and the concurrent carers support the birth family's efforts to regain the care for their child.\n\n## Connected carers\n\nRelatives, friends or other people who have a pre-existing relationship with the looked-after child or young person. If a child or young person cannot live with their parents, connected carers can become their approved foster carers. The child formally remains a looked-after child or young person.\n\n## Contact supervisors\n\nThe role of a contact supervisor is to unobtrusively observe contact between looked-after children and young people and their parents or other family members during their arranged visits, to ensure that all contact is safe and positive.\n\n## Contextual safeguarding\n\nSeeks to recognise the risks to the child or young person that occur outside the home and respond to these to keep them safe. The risks can include violence and abuse from, for example, the person's neighbourhood or school, or social media.\n\n## Foster carers\n\nFoster carers work alongside a team of practitioners to provide looked-after children and young people with full-time care in the foster carer's home. Foster care may be a temporary arrangement, with children and young people moving on to a permanent placement or returning to their own birth families. Children and young people may also live in long-term foster care placements if a return home is not possible.\n\n## Health plan\n\nPart of each looked-after child and young person's care plan. It is written after the initial and review health assessments. Health needs or concerns are identified and actions are formulated into the health plan to address the health concern. It is incorporated into the child's care plan. The health plan is reviewed after each subsequent health assessment and at the child's looked-after review, or as circumstances change, to ensure that health actions have been completed.\n\n## Initial health assessment\n\nA statutory health assessment for looked-after children and young people that must be completed within 20\xa0working days of coming into care. It must be completed by a doctor who is registered with the General Medical Council and holds a licence to practise.\n\n## Life story work\n\nA social work intervention that aims to help children and young people in care begin to understand and accept their personal history and future. Life story books are often used to give a visual aid and reminder of important events or feelings.\n\n## Multidimensional treatment foster care\n\nMultidimensional treatment foster care (now called Treatment Foster Care Oregon) is a solo foster placement with a specially trained foster family for between 9\xa0and 12\xa0months. It includes intensive support from a multidisciplinary team, with 24‑hour support from the programme supervisor. The intention is to change behaviour through promoting positive role models. During the placement, the young person's behaviour is closely monitored and good behaviour is rewarded. Family therapy is provided for birth parents, and they are taught the same strategies in preparation for reuniting them with their child. Also known as intensive fostering.\n\n## Non-verbal\n\nNot yet able or unable to talk – for example, because they are too young or they have a disability.\n\n## Paired reading\n\nIn paired reading, looked-after children read alongside a partner, such as their primary carer. This helps the child practise their spelling, comprehension and pronunciation. Attentive and responsive feedback by the carer throughout helps the child to achieve reading fluency.\n\n## Personal adviser\n\nLocal authorities provide personal advisers to care leavers up until they reach the age of\xa025. The personal adviser ensures that a care leaver is given the correct level of support to achieve independence. They should have a practical knowledge of the issues facing care leavers as they make their transition into adulthood and the legal requirements for support.\n\n## Personal education plan\n\nThis is a document describing a course of action to help a looked-after child or young person reach their full academic and life potential. All children in care must have a personal education plan as part of their care plan. It is a legal requirement for every young person in care of statutory school age to have their personal education plan reviewed at least 3\xa0times each academic year.\n\n## Permanency\n\nThe conditions that lead to a child or young person experiencing security and continuity in their relationships, particularly those of belonging to a committed family. In a permanency plan, a looked-after child or young person is assessed and prepared for long-term care that meets their needs, and takes into account their wishes and feelings. In a care and placement order, it has been agreed that a child or young person will not return home to their birth family, and parental rights and responsibilities are transferred to another carer, for example an adoptive parent.\n\n## Practitioner\n\nA paid professional providing direct care for looked-after children and young people. Practitioners may include social workers, independent review officers, educational professionals, healthcare professionals and therapists.\n\n## Prosocial\n\nProsocial behaviour is social behaviour that benefits other people, characterised by actions that show concern for the feelings and welfare of other people – for example, helping, cooperating and sharing.\n\n## Randomised controlled trial\n\nTrials in which participants (or clusters) are randomly allocated to receive either intervention or control. If well implemented, randomisation should ensure that intervention and control groups differ only in their exposure to treatment.\n\n## Safer caring plan\n\nEnables foster carers to consider potentially abusive or risky situations that may arise in the foster home and create a plan to minimise risks.\n\n## Shared decision making\n\nA joint process in which a healthcare professional works together with a person to reach a decision about care. It involves choosing tests and treatments based both on evidence and on the person's individual preferences, beliefs and values. It makes sure the person understands the risks, benefits and possible consequences of different options through discussion and information sharing.\n\n## Special guardians\n\nPeople or a person appointed by a Special Guardianship Order for children and young people who would benefit from a legally secure placement but cannot live with their birth parents. A birth parent cannot apply to discharge the order unless they have the permission of the court to do so, but the order does not end the legal relationship between the child and the birth parents (as in adoption).\n\n## Staying put\n\nWhen a foster placement becomes a 'staying put' arrangement, the young person staying put is no longer a looked-after child but is a care leaver. They are therefore entitled to support (for example, a personal adviser) as a care leaver but will remain in the foster home. However, the former foster carer is no longer officially a foster carer for that young adult.\n\n## Support network\n\nThis covers carers, professionals, friends, birth family and any other supportive adults who provide formal or informal support to the looked-after child or young person.\n\n## Unaccompanied asylum-seeking children\n\nChildren and young people who have left their country of origin without the care or protection of their parents or carers and are seeking asylum in the UK.\n\n## Virtual school\n\nThe virtual school champions progress and educational attainment of looked-after children and young people in the local authority. The virtual school is not 'attended' but provides coordination of educational services for looked-after children and young people at a strategic and operational level. Looked-after children and young people within the local authority remain the responsibility of the school at which they are enrolled.", 'Recommendations for research': "The guideline committee has made the following recommendations for research.\n\n# Key recommendations for research\n\n## Interventions to support placement stability in residential care\n\nWhat interventions are effective in promoting placement stability among looked-after children and young people in residential care?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on supporting positive relationships\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0A: interventions to support care placement stability for looked-after children and young people.\n\nLoading. Please wait.\n\n## Interventions to support stability of permanent placements\n\nWhat interventions are effective in supporting the stability of placements in looked-after children and young people moving out of care to permanency (incorporating the perspectives of looked-after children and permanency carers)?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on after transition between care placements and to permanent placements\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: interventions to support looked-after children and young people transitioning out of care to living with adoptive or birth parents or special guardians, or into connected care.\n\nLoading. Please wait.\n\n## Supporting mental health of unaccompanied asylum-seeking children\n\nWhat interventions are effective in supporting the mental health of unaccompanied asylum-seeking children?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on mental health and child and adolescent mental health services\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers.\n\nLoading. Please wait.\n\n## Using and safeguarding social media in contact with birth parents\n\nHow does social media contribute to contact arrangements for looked-after children and young people, and how can this be safeguarded?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on supporting positive relationships\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0D: barriers and facilitators for supporting positive relationships among looked-after children and young people.\n\nLoading. Please wait.\n\n## Mental health support for reunification with birth parents\n\nWhat is the effectiveness of mental health support for promoting reunification with birth parents?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on before transition between care placements and to permanent placements\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0L: interventions to support looked-after children and young people transitioning out of care to living with adoptive or birth parents or special guardians, or into connected care.\n\nLoading. Please wait.\n\n# Other recommendations for research\n\n## Continuing support for the physical and mental health needs of care leavers\n\nWhat interventions are effective in promoting and continuing to support physical and mental health and wellbeing in care leavers?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on transition out of care to independence\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0N: interventions and approaches to support looked-after young people transitioning out of care into independent living.\n\nLoading. Please wait.\n\n## Promoting physical exercise, and a healthy diet and lifestyle\n\nWhat interventions are effective in promoting physical exercise, and a healthy diet and lifestyle, in looked-after children, young people and care leavers?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on relationships and wellbeing activities\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers.\n\nLoading. Please wait.\n\n## Therapeutic interventions for promoting school stability and learning\n\nWhat therapeutic interventions are effective and cost effective in improving learning outcomes and school attendance and reducing exclusion in educational settings for looked-after children and young people?\n\nFor a short explanation of why the committee made this recommendation for research, see the rationale section on improving educational outcomes\xa0.\n\nFull details of the evidence and the committee's discussion are in evidence review\xa0I: interventions to support learning needs for school-aged looked-after children and young people.\n\nLoading. Please wait.", 'Rationale and impact': "These sections briefly explain why the committee made the recommendations and how they might affect practice.\n\n# Diversity\n\nRecommendation 1.1.1\n\n## Why the committee made the recommendation\n\nThe committee noted that children and young people with certain protected characteristics may be over-represented among looked-after children and young people, for example through race or sexuality. They also understood that looked-after children and young people themselves constitute a vulnerable group and therefore certain subgroups of looked-after children and young people may be disadvantaged in multiple ways. Based on their own knowledge and experience, as well as focus group and interview-based evidence, the committee recognised that ensuring these groups are not marginalised, and that their needs are met, may need additional attention and expertise.\n\n## How the recommendation might affect practice\n\nThis recommendation is not expected to need significant additional resources. It is the statutory duty of local authorities to ensure that children and young people in their care are not disadvantaged or marginalised as a result of their protected characteristics.\n\nReturn to recommendation\n\n# Supporting positive relationships\n\n## Why the committee made the recommendations\n\nRecommendations 1.2.1 and 1.2.2\n\nThe committee discussed that supporting positive relationships is often spoken about as an aim of care, but it may be poorly defined in practice. A large amount of evidence from the UK based on interviews and focus groups (qualitative evidence) considered the factors that help to build these relationships. In many cases, the committee observed that looked-after children and young people were not asking for more specific interventions or programmes. On the contrary, they often perceived an excess of practitioners involved with their daily lives. Rather, they wanted genuine caring relationships that reflected core principles outlined in this recommendation.\n\nThe committee considered that a common barrier to these relationships lay in the ability of the looked-after child or young person to communicate. They were aware that the prevalence of speech and language problems is higher among children who grow up in disadvantaged homes and experience neglect, which includes many in the care system. Implementing this recommendation could result in more timely referrals to speech and language therapists, if needed.\n\nRecommendations 1.2.3 to 1.2.6\n\nThe committee looked at robust study designs (randomised controlled trials) on interventions aimed at enhancing the relationship between siblings in care. The evidence from these showed that the interventions improved the quality of sibling interaction and reduced aggressive behaviour.\n\nThe committee considered the main features of the interventions described in these US‑based studies. Carer members of the committee agreed that these activities could have been useful in their own home situations, not just with biological siblings but also non-biological siblings they were living with (biological or adopted children of the carer). However, they noted that harm could result if safeguarding considerations were not taken into account because facilitated sibling relationships may not always be beneficial. Therefore, these interventions were not to be recommended in every case.\n\nThe committee noted that the specific evidence-based programmes were drawn from studies in other countries with very different social care contexts. Using the evidence and their own experience, they recommended the features that could be implemented with success in the UK setting. The committee noted that 1\xa0study showed adolescents may benefit from individualised coaching, with time separate from the primary carer to build the sibling relationship, whereas the committee considered primary-school-aged children would benefit from having the primary carer present. For primary school children, this can help to create a non-threatening environment and improve relationships between the siblings and the carer. It can also teach the carer new methods for mediating sibling relationships.\n\nThe committee emphasised that training to promote positive sibling relationships should start at the time of placement. However, based on their own experience, the committee agreed that the relationship between siblings needs to be stable before any activity-based interventions could be attempted. This could be achieved by support targeted at helping carers understand and maintain stable sibling relationships – for example, in the home setting with a professional who is trained in mediating strategies.\n\nRecommendations 1.2.7 to 1.2.13\n\nOne of the key themes of the interviews and focus groups was the need for those in the care network to form a relationship with the child or young person and with other practitioners within the network and use shared decision making. This is to support the person's capacity to act independently to make their own choices. The committee were keen to highlight this, particularly for contact arrangements, and agreed that the child or young person's ability to choose who to have contact with should be supported. They noted the need to balance this against any safeguarding risks.\n\nThe committee reflected on evidence based on interviews and focus groups concerning contact with the birth family and the role of contact supervisors when observed contact is necessary for safeguarding. They also discussed that using contact supervisors can be helpful if the birth family is receptive to support and feedback to improve the quality of contact.\n\nEvidence based on interviews and focus groups in the UK showed that it is important to not overwhelm looked-after children and young people with too many practitioners, and to promote continuity of relationships with practitioners. The committee agreed that retaining the same contact supervisors for a looked-after child or young person, if possible, would help to provide this continuity.\n\nThe committee discussed the fact that contact supervisors sometimes share intimate experiences and vulnerable moments with the looked-after child or young person and their birth family. Based on their own experience, the committee considered that if the role of the contact supervisor was more developed, there would be the potential to better support birth family relationships, give greater feedback of information to the care team and have better safeguarding. The committee therefore agreed that more training was needed for contact supervisors to improve the contact experience.\n\nEvidence based on interviews and focus groups showed that contact may need a high level of support at the start of placements. However, this could, in some cases, be hindered by high levels of monitoring, and decreasing levels of support may be needed as time progresses. Therefore, the committee considered that a more cautious approach to contact may be needed in the early stages of care placements, adjusting supervision intensity according to needs over time.\n\nBased on expert testimony, the committee were mindful of unaccompanied asylum-seeking children and those of non-British nationality, so they also stressed that non-English contact supervision needs an interpreter present to make good safeguarding and support possible.\n\nThe committee discussed interview- and focus group-based evidence on social-media-based contact. They recognised that such resources could help ongoing relationships much more easily than traditional methods because social media is easily accessible for young people and needs little organisation, but unobserved contact online could pose serious dangers by bypassing safeguarding measures. The committee therefore agreed that safeguarding considerations need to always take into account the possibility of online contact. For example, if social media contact was permitted in cases with moderate safeguarding considerations, it would be important for the content of interactions to be monitored and the amount of time spent communicating managed.\n\nLarge amounts of UK-based interview and focus group evidence considered positive relationships and contact arrangements and how these might be supported. However, no themes considered how social media influences contact arrangements or how this might be facilitated by carers and the risks be managed. The committee agreed that research is needed to determine the effectiveness of support mechanisms and interventions to manage the use of social media in care placements, particularly among those at risk of exploitation (see the recommendation for research on using and safeguarding social media in contact with birth parents).\n\nBased on committee experience and knowledge, the committee sought to highlight the extra support that may be needed for children who are placed out of area. Geographical distance may present an obstacle to their ability to remain in contact with family and friends. Support to help overcome this could include financial support to help birth parents pay travel costs and attend contact sessions.\n\nRecommendations 1.2.14 to 1.2.17\n\nBased on UK-based interview and focus group evidence and committee experience, the committee recognised the importance to looked-after children and young people of their relationship with their social worker. The committee agreed that training and support for social workers should include communication skills. This would improve transparency of care and help maintain positive relationships. It would also mean that any information given to the child or young person would be done in a way that they can understand and accept, particularly when a carer transition is approaching.\n\nBased on committee experience and knowledge, and some interview and focus group-based evidence, the committee recognised the need for more support for social workers to prevent burnout, which can lead to greater turnover in staff and loss of continuity for looked-after children and young people. The committee considered factors that could help prevent burnout at work, as well as improving the amount of time available for direct care. These included supervision with regular check-ins and a focus on reflective practice; consultation for complex and specialist problems; and trauma-informed training to promote positive relationships, as well as more practical support to increase the time available for direct one-to-one work.\n\nThe committee noted that when social workers are trauma informed, they can make sense and meaning of how the child or young person is behaving in relationships, in the context of their experiences. As the lead professional, they can influence how the network views the child or young person, what language is used and how it will be most helpful to support them in more helpful positive relationships. This is the ripple effect of different levels of trauma training for the network.\n\nSocial workers on the committee commented on the increase in workload, lack of funding and an upwards trend in the number of looked-after children and young people. Much work is needed to complete performance indicators and other administrative tasks and this is often prioritised over one-to-one work with young people. Some interview and focus group-based evidence suggested that one-to-one time could be improved by increasing the administrative support for social workers within local authorities. Although recognising that services are often overwhelmed and that resources are limited, the committee agreed that a culture change was also needed that prioritised more time for direct care between social workers and looked-after children and young people. The committee agreed that if managers use and review systems to free up more time for direct care, this could both increase professional retention, and enable more one-to-one time between social workers and looked-after children and young people.\n\nUK intervention and focus group evidence on the impact of professional moves (particularly those of the allocated social worker) on looked-after children and young people supported the committee's own experience that local authorities do not have good systems for monitoring the level of social worker turnover. They agreed that if local authorities could collect and review data on turnover among their frontline staff and reflect on its impact on looked-after children and young people, this would help local authorities assess the success of staff support systems. They could then develop action plans to keep turnover as low as possible.\n\nThere was substantial UK-based interview and focus group evidence that looked-after children and young people reacted strongly against the changing of social workers they had built a positive relationship with. The committee discussed the complexity of addressing this issue. Turnover of social workers was frequent as a result of workload, burnout or the need to change work for career progression. Drawing on this evidence and their own experience, the committee noted that these reasons were often not well communicated to looked-after children and young people, and social workers were perceived to simply disappear. The committee agreed this could be ameliorated by informing looked-after children and young people pre-emptively and transparently about changes of social workers, taking care to recognise the emotional impact of such changes and providing an opportunity to say goodbye.\n\nThe committee, based on their knowledge and experience, also discussed the problem of the departing social worker and primary carers not giving a consistent message about the reason for leaving. They agreed that this problem could be reduced by informing primary carers in advance about the reasons for professional transitions, particularly if strong relationships had formed.\n\nRecommendation 1.2.18\n\nThe committee recognised the potential benefit, both for positive relationships and health and wellbeing, of having a mentor for friendship and guidance, particularly one with care experience. Evidence from robust study designs suggested that older children may be more responsive to coaching and mentoring, particularly those with pre-existing emotional and mental health problems. The committee also noted that professional oversight of safeguarding was important to prevent inappropriate or negative relationships forming, and that a significant mentor–mentee age gap would be advisable.\n\nRecommendations 1.2.19 and 1.2.20\n\nBased on UK-based interview and focus group studies, and their own experience and knowledge, the committee considered the importance of friendship groups to looked-after children and young people. They recognised that looked-after children and young people may rely on these friendships to play a greater supportive role because of the lack of close relationships of other kinds (for example, with the birth family). As a result, the committee were concerned that contact with friends, particularly those from before coming into care, or other placements in care, should be supported if possible.\n\nBased on their own experience and knowledge, the committee were also aware of some of the barriers faced by looked-after children and young people seeking to have 'normal' relationships with peers while in the care system. Sleepovers can be a normal part of such relationships. However, looked-after children and young people can feel stigmatised and exposed if such plans are delayed or prohibited as a result of waiting for safeguarding checks on the family they wish to sleep over with.\n\nRecommendations 1.2.21 to 1.2.25\n\nMany studies, using data from UK-based interviews and focus groups, reported that looked-after children and young people particularly valued care that was available, accessible and reliable. They benefitted from knowing that support was available even out-of-hours for urgent problems. Committee experience also suggested that looked-after children and young people felt the disparity if an out-of-hours call service was available for carers when one was not provided for them. This could lead to a sense of power imbalance and insecurity.\n\nThe committee agreed that out-of-hours support should be available for looked-after children and young people. However, they recognised that employing an on-call social worker may need substantial changes to contracts or add expense to already stretched social care budgets. So they agreed that other options might be used to fill this gap. In addition, identifying people at 'higher risk' for presenting out of hours could help with planning out-of-hours service provision.\n\nThere was strong UK-based interview and focus group evidence on the importance of shared decision making, including all agendas being laid out transparently to help the looked-after child or young person make their own decisions. For example, the committee discussed occasions when an option for a new placement was 'dressed up' as a great opportunity, when in reality, the young person was being nudged into the placement because of financial pressures, for the local authority, or because the foster carer had decided to end the current placement. The committee agreed that it was better to discuss the reasons for placement breakdown openly, giving emotional support built into ongoing life story work and using accessible and age-appropriate communication.\n\nThe committee noted that there was little evidence for interventions to support placement stability in residential care. They therefore made a recommendation for more research on interventions to support placement stability in residential care).\n\nRecommendations 1.2.26 and 1.2.27\n\nEvidence based on robust studies of multidimensional treatment foster care in adolescents largely covered youth offenders referred from the criminal justice system, or populations with significant pre-existing behavioural and conduct disorders. The committee were impressed by the evidence of effectiveness, particularly evidence showing reduced involvement with the criminal system and reduced rates of violent crime and imprisonment across these populations. So, they agreed that this intervention would be suitable for looked-after young people with behavioural issues that are significant and persistent enough to merit regular involvement of the criminal system.\n\nThe committee recognised that behaviours that challenge can be a form of communication and may occur as a response to trauma. In addition, behaviours that challenge may be more common in people with learning disabilities - which are themselves more common among looked-after children and young people. The committee therefore agreed to cross-refer to existing relevant NICE guidance.\n\nRecommendation 1.2.28\n\nThe committee considered evidence based on robust studies looking at interventions to support development and school-readiness in preschool children. Particularly, they noted evidence on the Attachment and Biobehavioural Catch-up intervention for babies and toddlers, which resulted in improvements in language, attention problems and cognition. The committee looked at the similarity of this intervention to interventions recommended in the NICE guideline on children's attachment. They discussed the overlap between the population in the children's attachment guideline and this guideline. The committee agreed that all looked-after children and young people were at risk of attachment difficulties, and therefore that the evidence base for and recommendations in the children's attachment guideline were also relevant to looked-after children and young people.\n\n## How the recommendations might affect practice\n\nTrauma-informed training may have a limited resource impact because it could be incorporated into existing training for social workers. The committee recognised that existing training has limited capacity for additional material, but they agreed that trauma-informed training was a priority for inclusion. There are freely available resources for trauma-informed training and, although there would be a cost associated with adapting these resources for purpose, these costs are expected to be minimal.\n\nSupervision with regular check-ins to support the social worker is likely to need more personnel time from the social workers and their supervisors. It may also need a culture change that focuses on reflective practice and increasing the amount of direct one-to-one time social workers get with looked-after people. Improving systems to increase professional retention, enable more one-to-one time between social workers and looked-after children and young people, and reduce duplication of effort, could be less costly than purchasing additional social worker time.\n\nCollection and review of data on staff turnover, and development of action plans to address high levels of turnover, are likely to be associated with administrative costs in collating data that is already collected. However, lower levels of staff turnover would allow for better continuity of care and minimise the negative impact of personnel changes on looked-after children and young people, the benefits of which are considered to outweigh the small costs associated with this recommendation.\n\nProviding consultation for complex and specialist problems is likely to need additional personnel time and resources to implement. The committee noted that expertise for this can often be found 'in-house' rather than needing to fund a new role or external training agency, but in some cases an initial investment may be needed to build up expertise within the local authority. Where consultation can be from more advanced social workers or from multiagency professionals in the network, this should not incur significant cost. Consultation provided by specialist agencies and professions may need to be bought in, for example from experts on sexually harmful behaviour.\n\nThere are currently limited services specifically aimed at siblings, although there is generally funding already available for shared activities and days out for siblings from local authority leisure budgets. Interventions to promote sibling relationships are potentially costly, but if they could be delivered by trained youth workers rather than graduate-level practitioners, or if existing roles could be adapted to deliver these interventions, this could help contain costs. Similarly, funding to support contact with friends could come from local authority leisure budgets, and there are several activities that are freely available, such as visits to local parks.\n\nMentoring interventions by peers with experience of the care process would often be carried out on a voluntary basis or through informal peer-to-peer interactions and would not need an increase in resources. Some additional costs may be incurred in providing professional oversight to mentoring programmes, which would need organisation and the processing of, for example, DBS (Disclosure and Barring Service) checks.\n\nContact supervisors are already a part of the care team, and any additional training needed could be incorporated into existing training, so the recommendation is expected to have a small impact on resource use. Similarly, translation services are already available in NHS settings when needed, so these should not be a substantial extra cost. A child's right of expression is mandated by statutory guidance so expenditures on translation services are justified.\n\nFacilitating online contact, and the additional safeguarding considerations, is not expected to have an impact on current resource use because these contacts are likely to replace other forms of contact that would need similar management.\n\nResources needed to support the birth family to attend contact centres for children placed outside of their local area are most likely to consist of travel expenses. Although there may be some financial implications as a result of this recommendation, facilitating contact is a statutory duty and so expenditure by local authorities is justified.\n\nMultidimensional treatment foster care is a resource-intensive intervention and will be associated with high implementation and running costs. But when used in adolescents with a history of persistent offending behaviour, these upfront costs are likely to be offset by the lower recurring monthly costs and additional health and social benefits from the intervention compared with usual residential care. A costing analysis comparing these costs of multidimensional treatment foster care with residential care is detailed in evidence review\xa0F: interventions to promote physical, mental, and emotional health and wellbeing of looked-after children, young people and care leavers. Additionally, improving the outcomes for adolescents who are offenders will reduce the greater impact on social care and judicial sectors.\n\nReturn to recommendations\n\n# Supporting and involving carers\n\nRecommendations 1.3.1 to 1.3.10\n\n## Why the committee made the recommendations\n\nThe committee discussed UK-based interview and focus group evidence that carers often feel their input is not valued. They agreed that carers have the most intimate knowledge of the looked-after child or young person, so their perspective and the information they provide are important alongside professional input for decision making by the broader care team.\n\nStudies showed that carers could feel 'left alone' to deal with severe problems on evenings or weekends, and lack of out-of-hours support can make them feel isolated. The committee agreed that out-of-hours support services are important, but recognised that employing an on-call social worker may need substantial changes to contracts and expenses. So, they agreed that various alternatives might be used to fill this gap. For completeness of records and continuation of professional oversight, the committee also agreed that carers should log any help sought outside usual operational hours.\n\nMany UK-based interview and focus group studies looked at the value of peer support, and the committee also heard from experts that peer support could help fill the gaps in support left by overburdened social care systems and social workers. Carers may offer support to each other that is more accessible and available than from practitioners, and such support only needs to be facilitated and moderated to prevent the transfer of misinformation. Creating online spaces for this could be both cheaper and more accessible than hosting in-person groups.\n\nThe committee discussed UK-based interview and focus group evidence showing that respite (or support) care was valued. They agreed that it was vitally important to offer carers rest, to prevent burnout and subsequent placement breakdown. They noted that some carers may feel that their caregiving duties prevent them from going on holiday or travelling.\n\nThe committee discussed that it is helpful if respite (or support) care is provided by a person the child or young person knows, to prevent the feeling that they are being 'sent away'. This also builds up a network of supportive adults for the child or young person and childcare options for carers. In addition, the respite (or support) care period can be more easily seen as being in the best interests of the looked-after child or young person if it is an enjoyable break for them – for example, through short breaks to stay with relatives.\n\nBased on their own knowledge and experience, and some UK-based interview and focus group data, the committee discussed that planned and proactive offers of respite (or support) care are more effective than respite (or support) care offered reactively in response to crisis, when it may already be too late to prevent placement breakdown. They also discussed the importance of the person who is providing respite (or support) care having the skills needed to support the individual needs of the looked-after child or young person.\n\nThe committee looked at UK-based interview and focus group evidence on resource constraints, stretched services, information gaps between carers and practitioners and reactive care (responding to problems as they arise, rather than anticipating). They found that carers were often unaware of the services available for support from their local authority and partner agencies, and therefore felt as though certain services had been kept hidden to save costs. The committee agreed that carers need to be fully informed about the support available before the placement starts. This enables carers to negotiate the support they need, and empowers them to act on a more equal footing with practitioners.\n\nThe committee saw UK-based interview and focus group evidence showing that carers (particularly shorter-term foster carers) are often unaware of ongoing interventions for a child placed with them, such as life story or relationship work. They agreed that informing carers about the contents and aims of interventions to support placement stability was in the best interests of the child, and would improve continuity of care with marginal costs.\n\nThe committee recognised that there was an additional set of recommendations for carers in the NICE guideline on supporting adult carers, and that these recommendations may be relevant for some carers of older looked-after children and young people.\n\n## How the recommendations might affect practice\n\nUsing alternatives to on-call social workers will mitigate the cost of increasing out-of-hours support. A range of possible ways in which out-of-hours support could be offered was included in the recommendation to allow local authorities to use a system that works best for them, both logistically and financially. Some of the options listed would be more affordable, such as the use of volunteer-operated helplines or peer support or advocacy groups. Local foster carer associations may have people working on-call, or provide round the clock access to a peer support network. The use of generic emergency duty teams may also reduce funding pressures.\n\nHowever, the committee recognised that the availability of alternative options may vary between local authorities. To provide out-of-hours services with social workers 'on call' would need a contract change for social workers, but they agreed this could be done by reallocating existing social worker time from day work to out-of-hours work. This contract change and reallocation would have cost implications, but the committee agreed that having social worker availability for out-of-hours emergencies and urgent problems could allow for problems to be addressed more quickly. This would help to avoid more significant costs and adverse consequences (for example, placement breakdown, self-harm, hospital visits and police being called).\n\nFacilitating accessible peer support for carers is unlikely to have a substantial impact on resources, because most would be peer led and would not need much additional personnel time or physical resources from the local authority. Message boards may need to be moderated to prevent misinformation, but this could save time and resources by helping to resolve issues that would otherwise need the attention of care staff.\n\nRespite (or support) care for carers to prevent placement breakdown is already broadly available in the care system. Costs vary depending on individual needs and local funding streams. The committee recommended the approach to respite (or support) care that should be taken if respite (or support) care is needed, rather than necessarily recommending additional respite (or support) care beyond what is already provided.\n\nReturn to recommendations\n\n# Training for carers\n\nRecommendations 1.3.11 to 1.3.20\n\n## Why the committee made the recommendations\n\nBased on their experience and knowledge, the committee recognised that, in practice, training – such as behaviour management training – is often delivered reactively, in response to difficulties that a carer is currently experiencing. This threatens placement stability because the carer may feel underprepared and under-supported to continue the placement. The committee advocated a greater emphasis on forward planning support for carers (before placement) based on the recognised and documented needs of the individual child, and involving other agencies as needed.\n\nThe committee discussed evidence, from robustly designed studies, on the effectiveness of parent-training interventions (some of which also included child-training components). This evidence covered a wide range of training programmes. The committee agreed that the evidence broadly supported the benefit of parent-training interventions in tackling child behaviour problems, and in improving the child–carer relationship.\n\nHowever, they noted that the components of these training interventions may differ. Common components in the interventions studied included teaching and information giving focused on different aspects of parenting theory such as sensitive caregiving, attachment, social interaction learning theory, being trauma informed and broader behavioural management techniques. To support teaching, some interventions used video-feedback techniques, and others used homework or home assignments, role play, coaching, practical activities and follow-up booster sessions.\n\nThe committee noted that training can be expensive, and it is likely that different carers would need a different intensity of training. To reduce costs, a mandatory schedule of training could be delivered as a tutorial (perhaps virtually) to all carers. The committee were aware that mandatory training, for example for foster carers, may already be extensive. However, rather than recommending additional capacity to deliver more training, the committee sought to recommend which topics were most important to include in existing training schedules for carers. In addition to these, more intensive methods could be used with carers of looked-after children and young people who have more severe emotional and behavioural problems.\n\nBased on their experience and knowledge, they agreed that how to provide consistent, child-focused and planned life story work to promote positive self-identity, would be an important addition to the mandatory schedule of training for all foster carers.\n\nThe committee were not aware of any widely available training for carers on how to be an educational advocate. In their experience, some carers are good at it naturally, but this is not consistent. For example, some may feel a responsibility for providing a home for their child but not see educational advocacy as part of their 'role'. The committee agreed such training is necessary as part of the mandatory training for carers. The importance of involving the primary carer was backed up by UK-based interview and focus group evidence suggesting that looked-after children and young people preferred carer-delivered educational support (as opposed to interventions delivered by other adults or professionals), because of fears of yet more transient practitioners developing a relationship with them and then leaving.\n\nThe committee discussed subgroups of carers who may need more individualised training. Using their own experience and knowledge, they considered birth parents in situations in which reunification is a possibility or when the child or young person remains in placement with the birth parent. They recognised that joining mandatory training schedules may not be ideal for birth parents who may have significant personal challenges to overcome and need additional support.\n\nThe committee used UK-based interview and focus group studies and their own experience and knowledge to consider other subgroups of carers who may need specialised training. They looked at evidence highlighting the challenges for carers of adapting to a looked-after child or young person's cultural, religious or dietary needs. For example, the committee recognised that certain ethnic groups may have hair and skin care needs that a carer would be expected to support. Likewise, carers of looked-after children and young people with special educational needs, long-term health conditions and disabilities may need specific training.\n\nUK-based interview and focus group evidence and expert testimony both suggested the importance of a knowledge of trauma in those caring for the looked-after population. Based on their experience and knowledge, the committee agreed what trauma-informed training should cover. They recognised that there are multiple levels to this training, from simple awareness of trauma-related issues (for all carers and practitioners working with looked-after children and young people) to training in trauma-responsive care, which may be needed for more specialised carers and practitioners. For effective delivery of training programmes, the committee agreed it was important for trainers themselves to have a good understanding of trauma and attachment disorders as well as the various effective therapeutic approaches.\n\nThe committee also discussed evidence on a parent-training intervention for looked-after young people with behaviour that challenges or more severe mental health problems who are moving out of restrictive care and into the community. This showed that it could help maintain their school placement and prevent a return to that care. The committee agreed that, in temporary placements for which training and development needs had been identified and delivered for current carers, new carers in the follow-on or permanent placements would need the same training to provide consistent care. This would help continuity of behaviour management approaches and trauma- and attachment-informed, high-support and high-nurturing relational care. The committee noted that this was particularly true for connected carers, who enter the fostering system quicker than mainstream carers. Often a child or young person is placed with them while assessments are ongoing and there is little time for preparation and training.\n\n## How the recommendations might affect practice\n\nFamily support services already offer behavioural management support to birth families, but available training for foster carers and, particularly, other kinds of carers, is more variable.\n\nTraining in educational advocacy for carers would be delivered by the virtual school. This could be delivered at low cost, virtually or in person.\n\nTailored support and training for birth parents if reunification is a possibility should already be available through transition plans with family support teams, and should not incur additional cost.\n\nCultural or religious needs, or needs related to race or ethnicity may need more tailored training for carers who have no expertise in these areas. Although this may come at some additional cost to time or resources, these looked-after children and young people form a minority of the overall looked-after population. In addition, it is a statutory duty to ensure that looked-after children and young people do not receive poorer care on the basis of race or religion.\n\nTailored support and training for carers if there are special educational needs and disabilities can be provided through specialist healthcare teams and voluntary organisations (for example, the National Autistic Society and the Independent Provider of Special Education Advice), thereby helping to keep costs down. Trauma-informed training and therapeutic parenting training for all foster carers is part of current practice in some local authorities. The recommendations will reduce variation in practice across the country. Intensive, specialist training given in the home is likely to incur substantial costs in some areas that do not already provide it, but these could be partially offset by preventing placement breakdown. Placement breakdown is associated with significant short-term costs because of increased social care case management work and the need for additional placement arrangements, some of which will be high-cost emergency placements. In addition, placement instability can have long-term consequences, contributing to further disruption of looked-after children and young people's social and emotional relationships, sense of belonging and educational outcomes.\n\nMandatory training schedules already exist for carers (particularly foster carers) and it is anticipated that trauma-informed training, and other recommended training components, could be incorporated into these sessions without the need for extra training capacity in many cases. For example, the committee noted that there is often already mandatory training on de-escalation that could feasibly be altered or updated to include trauma-informed practice. There are freely available resources for trauma-informed training and other kinds of training. Although there would be a cost associated with adapting these resources for purpose, these costs are expected to be minimal.\n\nReturn to recommendations\n\n# Safeguarding\n\nRecommendations 1.4.1 to 1.4.8\n\n## Why the committee made the recommendations\n\nThe committee heard from experts about looked-after children who are at risk of criminal exploitation or going missing or are placed out of area. The experts highlighted the importance of multiagency working and appropriate data sharing for safeguarding looked-after children. They gave examples showing how important moments had been missed for sharing information between agencies (for example, policing and social services), and how these missed moments had led to extremely negative outcomes for the looked-after child or young person involved. Although the committee noted that statutory safeguarding procedures exist, they agreed that once a child or young person had become 'looked after', any further safeguarding issues were often dealt with 'in-house' in the care system. Whichever safeguarding system was used, the committee considered the need for it to be as thorough as statutory systems of safeguarding while also addressing additional contextual safeguarding risks. These risks are more commonly an issue among those in care.\n\nThe committee discussed ways in which local authorities could facilitate multiagency working and data sharing. They suggested that meetings were needed to bring together practitioners and facilitate information exchange. Based on expert testimony and their own experience, the committee agreed that representatives from education, care, healthcare for looked-after children, and external services could provide vital perspectives on safeguarding looked-after children and young people. Experts told the committee that it was very important to include the views of looked-after children (particularly those with special educational needs or disabilities) and their carers when shaping responses to exploitation and missing children. This supports shared decision making and makes responses effective, accessible and acceptable to looked-after children and young people and their carers.\n\nBased on expert testimony, the committee considered that leadership was needed to organise successful multiagency review meetings, bring practitioners on board and help define clear lines of accountability. The committee considered that leadership in multiagency working would be best provided by a specialist in contextual safeguarding, exploitation and missing children in the looked-after population. If such a practitioner was not readily available, the committee considered that local authorities could build capacity by investing in training a trauma-informed specialist with knowledge of exploitation and safeguarding issues in the looked-after population.\n\nBased on expert testimony, the committee discussed the kinds of data that are most readily available and useful across agencies to inform the safeguarding of looked-after children and young people, and assess the risk of exploitation in any given placement. The committee considered routinely collected indicators at the community level: area deprivation indexes, community-level health and mental health data, number of county lines operating in a single area and missing person reports per 1,000\xa0population (which were considered particularly linked to risk of trafficking).\n\nThe committee, in light of their experience and expert testimony, noted that risks and 'red flags' may be different for certain subgroups, such as young girls and boys and unaccompanied asylum-seeking children, as well as the approaches needed to protect from exploitation or going missing. For example, young girls in particular may be at risk of sexual assault, domestic abuse, and attempts through social media and otherwise to coerce and undermine self-esteem.\n\nThe committee heard from experts about the need for practitioners and carers working with looked-after children and young people to be able to spot and communicate safeguarding risks. Based on this, the committee discussed the training needs of practitioners working with looked-after children and young people. The committee acknowledged that training is not inexpensive. However, training on the signs of exploitation or abuse, and 'red flags' for going missing, and how to 'flag' or report concerns about these could be included in the regular training schedule for all practitioners working with looked-after children and young people.\n\nThe committee discussed how else multiagency working and review meetings could help to re-enforce and educate about 'reachable or critical moments'. That is, moments when looked-after children and young people at risk of criminal exploitation and grooming could be spotted and interventions employed at the earliest possible moment, particularly when looked-after children and young people could be more open to change and receiving support. Experts told the committee that any intervention could constitute a critical moment, for example attending an A&E department.\n\nLikewise, evidence based on UK-based interview and focus group studies and expert testimony about gangs, criminal exploitation and going missing from care strongly suggested that establishing a network of strong, supportive, positive relationships is the primary mechanism to protect looked-after people from these risks.\n\nExperts also suggested to the committee that certain subgroups of looked-after young people may need more tailored care to address issues that increase their risk. These groups include young girls, who may have issues of low self-esteem, and be at risk of targeting on social media; children with a history of trafficking; and unaccompanied asylum-seeking children who have been subject to previous trauma or exploitation. The committee were aware that tailored support for these groups is already offered through well-established organisations such as Abianda.\n\nBased on their experience and knowledge, and on hearing from experts, the committee discussed that safeguarding meetings offer an opportunity to educate and inform health and social care practitioners (for example, by bringing the perspective of emergency services to social workers). The committee were keen that learning opportunities were not lost and that a review of case files could help to spot mistakes or areas in which best practice could improve.\n\n## How the recommendations might affect practice\n\nTailored support for groups at particular risk from exploitation groups is an important and necessary safeguarding consideration for vulnerable groups. Existing organisations that already focus on these groups can help to supply such support, so this recommendation is unlikely to have a substantial additional resource impact. As well as improving outcomes for these groups, this tailored support may help to avoid future costs associated with negative outcomes, for example legal costs and costs associated with placement breakdown if relationships have deteriorated.\n\nNecessary data are captured in most areas, but the information often needs to be better shared. This is unlikely to need increased resources because the data sharing mechanisms and roles for multidisciplinary teams already exist, and the emphasis of the recommendations is on bringing this work together. Using standardised language for things such as risk assessment tools, processes and personnel titles across agencies and geographical areas is not expected to be resource intensive. It can be achieved over time by greater communication between agencies and local authorities.\n\nTraining in risk indicators is unlikely to have a substantial resource impact because it would probably be absorbed into and prioritised in existing staff training. Likewise, training to recognise suitable moments to reach out to the child could be incorporated into existing training for foster carers and social workers.\n\nReturn to recommendations\n\n# Building expertise about trauma and raising awareness\n\nRecommendations 1.5.1 to 1.5.3\n\n## Why the committee made the recommendations\n\nThe committee considered UK-based evidence from interview and focus group studies and heard from experts about the high prevalence of trauma in looked-after children and young people. Based on this and their own experience and knowledge, the committee agreed that all practitioners working with looked-after children and young people need greater awareness of the impact of trauma, including developmental trauma and attachment difficulties. Such awareness is vital for spotting safeguarding situations. It can also help practitioners working with looked-after children and young people to better understand them and communicate more effectively with them.\n\nUK-based evidence from interview and focus group studies and expert testimony highlighted specific issues faced by unaccompanied asylum-seeking children. The committee agreed that those who were working with unaccompanied asylum-seeking children needed to have additional awareness of the specific risks facing this group and issues that may arise when providing care.\n\nThe committee noted that when social workers or other care professionals are trauma informed, they can make sense and meaning of how the child or young person is forming and maintaining relationships, in the context of their experiences. As the lead practitioner, they can influence how the network views the child or young person, what language is used and how it will be most helpful to support them in more helpful positive relationships. This is the ripple effect of different levels of trauma training for the network.\n\n## How the recommendations might affect practice\n\nAdditional training on the specific needs of unaccompanied asylum-seeking children, including invited feedback from children that were once cared for in these circumstances, and specialist organisations in the voluntary sector, could be provided as part of existing in-house training. Funding should already be available through general funds that support routine training and activities (for example, team awareness days) for healthcare professionals.\n\nConsultation may be provided from more experienced social workers or from multiagency professionals in the network, so it should not incur cost. However, the committee were aware that such consultation work would mean less time for case work, and therefore would incur some time costs. Consultation provided by specialist agencies and professions may need to be bought in, for example experts on sexually harmful behaviour.\n\nReturn to recommendations\n\n# Physical and mental health and wellbeing assessments\n\nRecommendations 1.5.4 to 1.5.16\n\n## Why the committee made the recommendations\n\nThere is a statutory requirement for the responsible authority to notify in writing the child or young person's healthcare team (for example, the specialist looked-after children's health team), clinical commissioning group and registered medical practitioner about arrangements for the child or young person's placement. But based on their own experience and knowledge, the committee noted that this was often not sufficiently carried out in practice. That is, the notification is often delayed, or does not give both the looked-after child or young person's legal status and the reason why they have been entered into care.\n\nThe committee considered the importance of keeping good health records for looked-after children and young people. This should be a summary for ease of reading, with references to sections that give more detail. Based on some interview and focus group-based evidence and the committee's own experience and knowledge, the committee considered that it was important to obtain a full health record from the birth parents, particularly information about antenatal and postnatal health. They noted that gaining consent for this may be a difficult or lengthy process. So the committee discussed the importance of attempting to gain this consent as soon as possible in the care process, to prevent missing important health information that could be important for directing the plan of care. If social workers supplied relevant information and consent to health teams before the initial health assessment, this could support health teams to make a good health plan. The committee also considered that the request for the initial health assessment should be detailed enough to provide the social care context for the child or young person coming into care.\n\nUK-based interview and focus group studies frequently emphasised that looked-after children and young people and their carers appreciate continuity of care practitioners. The committee discussed the importance of having a continuous healthcare professional who is familiar with the looked-after child or young person, and their medical and social history, to perform routine health assessments. They agreed this is important both to promote a trusting relationship between the child or young person and the medical practitioner and to improve adherence with health plans, and to help the practitioner to spot changes in the health needs of the child or young person to support better care.\n\nBased on their own experience and knowledge, the committee considered the needs of children and young people trying to access confidential healthcare. For example, use of the phone or internet may be restricted, particularly in residential care. The committee recognised that these measures may be in place to support safeguarding, but an unintended consequence could be difficulty or embarrassment when trying to access sexual health advice or treatment.\n\nThe committee highlighted that the initial health assessment is an important event for looked-after children and young people because it allows their existing needs to be identified and forms the base of an individualised care plan. The committee were therefore concerned that the initial health assessment should include an accurate and comprehensive review of the person's health history.\n\nEvidence from UK-based interview and focus group studies suggested the need for carers to receive more complete and better-quality information about the child or young person at the start of care, which could include a compilation and summary of health records. The committee noted that work to compile records is done inconsistently across local authorities. The committee considered that compiling good records had the potential to transform the care of looked-after children and young people by facilitating the flow of information between agencies and preventing identified needs and actions in the health plan from becoming lost.\n\nUsing some interview and focus group-based studies and their own expertise and knowledge, the committee considered the fact that care leavers very often request access to their health and social care records. Care leavers may do this to help make sense of their own journey through the care system. However, if the language used in the records is depersonalising or judgemental, this can result in significant emotional hurt and offence. The committee therefore agreed that health and social care practitioners should be aware of this risk.\n\nEvidence from UK-based interview and focus group research and from expert testimony strongly supported the need for a culturally appropriate, registered interpreter to communicate in person with looked-after children and young people for the initial health assessment. And, if language remains a barrier to communication, for the same service at subsequent health and social care assessments. However, the committee noted this was particularly important for the first health assessment, which must be thorough and capture all aspects of health needs accurately to provide appropriate support. The committee considered in-person translations to be particularly important because of the difficulty receiving interpretation services over the phone. Unaccompanied asylum-seeking children were especially in need of these services.\n\nExperts highlighted many specific health needs of unaccompanied asylum-seeking children compared with the broader population of looked-after children and young people in the UK. Unaccompanied asylum-seeking children were also frequently found to have problems with their sleep schedule as a result of travelling long distances, often with continuously disturbed sleep. So the committee agreed that tailored initial health assessments should address the additional risks to unaccompanied asylum-seeking children as a result of their country of origin and journey to the UK.\n\nThe committee considered mental health screening for children who were entering care. Some evidence (which had a higher risk of bias due to the study design) showed that using an in-depth assessment identified more children needing support and helped with providing early interventions than with the current initial health assessment. The committee agreed that current initial health assessments were often insufficiently detailed to pick up mental health needs and it was important for healthcare professionals to consider the need for a specialist mental and emotional health assessment after the initial health assessment. This is particularly important for babies and children because their mental health needs are often missed. Based on committee experience and knowledge, the committee noted that this second assessment is better carried out once the looked-after child or young person has begun to form a relationship with the primary carer because mental health may improve as a result of a secure attachment relationship.\n\nThe committee reflected on less robust evidence (not from randomised controlled trials) showing that auditing systems before and after health assessments improved the uptake of health actions. The committee also considered the problem of actions in the health plan not being followed up or completed (either within a reasonable timeframe or at all). Based on this evidence and their own experience, they agreed it was important that the completion of actions in the health plan be reviewed to ensure the agreed service has been provided. This would need multidisciplinary input because some actions may be undertaken by other agencies.\n\nThe committee recognised the higher prevalence of attention deficit hyperactivity disorder, autism and post-traumatic stress disorder among looked-after children and young people. They were aware of existing NICE guidelines on the identification and diagnosis of these conditions and their subsequent management, and agreed to cross-refer to these.\n\n## How the recommendations might affect practice\n\nThe initial health assessment is a statutory requirement so there should not be any additional costs to the system, although auditing the health plan may need additional time from the team of health professionals involved. A detailed and well-documented plan can help with timely provision of care, thereby avoiding costs of delay and an overall negative experience for the looked-after child or young person.\n\nHealthcare professionals performing the initial health assessment for unaccompanied asylum-seeking children may need additional training on the specific physical and emotional needs of these children, and on risk factors associated with specific countries of origin or route of travel, and the context of the child's journey. This training, including feedback from children that were once cared for in these circumstances and testimonies from specialist organisations in the voluntary sector, could be provided as part of existing in-house training. Funding should already be available through general funds that support routine training and activities (for example, team awareness days) for healthcare professionals.\n\nSpecialised interpretation services incur costs, but a child's right of expression is mandated by statutory guidance so expenditures on such services are justified.\n\nReturn to recommendations\n\n# Mental health and child and adolescent mental health services\n\nRecommendations 1.5.17 to 1.5.21\n\n## Why the committee made the recommendations\n\nUK-based evidence from interview and focus group studies frequently highlighted the frustration felt by looked-after children, young people and their carers about delays and waiting lists for mental health support. The committee considered the common problem of delayed support for child and adolescent mental health services (CAMHS), and systems that they had seen in practice to help avoid the delay of therapeutic support for looked-after children and young people. For example, therapeutic social workers, systems for outreach connected to CAMHS (for example, a psychologist or another worker embedded within CAMHS), or a specialist looked-after children and young people team within CAMHS.\n\nHowever, other evidence, also from interview and focus group studies, highlighted the harm that can be done by introducing a child or young person to a new therapist, only for the therapist to change once CAMHS have taken over care. This can lead to demoralisation and disengagement from mental health interventions. Therefore, the committee agreed that intermediate therapeutic or specialist support should be provided for the care network around looked-after children and young people, rather than to looked-after people themselves. The committee were keen to stress that this intermediate support was only to address the delay, and should not be a replacement for CAMHS itself.\n\nFurther interview-based and focus group-based evidence and expert testimony reflected how CAMHS are often inappropriate and not designed for the needs of looked-after children and young people. Traditional techniques such as behavioural-therapy-based interventions are not always suitable for looked-after children and young people, who may need interventions that are more relationship based and trauma informed.\n\nOne committee member stated that some CAMHS teams have specialist looked-after children's services, but this is variable across the UK. The committee agreed it was important to encourage prioritised specialist services to be incorporated into CAMHS, to prevent the need for tier\xa03 or\xa04 services further down the line.\n\nBased on their own experience, the committee were aware that children and young people could lose their place in the waiting list for CAMHS as a result of moving placements to a new location. This may be more likely to happen to children and young people who most need the attention of CAMHS to help maintain placement stability. Committee members were aware that continuity of CAMHS waiting lists could be maintained by virtual schools co-opting CAMHS or other dedicated services for looked-after children and young people in CAMHS.\n\nExpert testimony highlighted the likelihood that all unaccompanied asylum-seeking children had experienced some form of trauma, as a minimum through the separation from their own parents, and that health and social care practitioners supplying care for this vulnerable population need specialist training. The committee agreed the importance of taking into account the different perspectives of unaccompanied asylum-seeking children in a mental health service setting.\n\nUK-based evidence from interview and focus group studies and expert testimony also reflected the importance of cultural sensitivity and awareness of potential traumatic symptoms in unaccompanied asylum-seeking children. For example, they may have highly stigmatising views of mental health problems, based on previous cultural ideas, and may be reluctant to admit the experience of trauma or problems with mental health.\n\nThe committee noted that unaccompanied asylum-seeking children were likely to need a tailored approach to mental health support, but there was insufficient evidence to recommend any specific intervention. Therefore, they made a recommendation for research on supporting mental health of unaccompanied asylum-seeking children.\n\n## How the recommendations might affect practice\n\nProviding dedicated CAMHS services for looked-after children and young people may have substantial resource implications if an expansion of the existing CAMHS services and capacity is needed. However, these dedicated services for looked-after children and young people are mandated by statutory guidance and the recommendations are only reinforcing the statutory provision of these services. Alternative interventions (trauma-informed and those focusing more on relationships) may not necessarily come at greater cost than traditional behavioural approaches. However, tailored approaches would have greater adherence (for example, fewer non-attendances and less disengagement), thereby resulting in greater effectiveness. The committee considered that greater engagement in mental health services at an earlier stage can reduce the risk of more serious mental health problems, avoid the substantial long-term costs and consequences incurred when these issues go unidentified, and reduce the need for the higher tier treatments later down the line (where the greatest pressure on CAMHS services was suggested to be).\n\nIntermediate therapeutic or specialist support for the care network around looked-after children and young people, to reduce waiting times, may need some restructuring of services and additional cost. However, in some parts of the country, existing services could fill this gap – for example, therapeutic social workers, CAMHS outreach systems (for example, a psychologist or another worker embedded within CAMHS), or a specialist looked-after children and young people team within CAMHS.\n\nReturn to recommendations\n\n# Life story work for identity and wellbeing\n\nRecommendations 1.5.22 to 1.5.33\n\n## Why the committee made the recommendations\n\nUK-based evidence based on interview and focus group studies showed that forming positive relationships was probably the best possible intervention to prevent placement instability. Life story work has the potential for building relationships (for example, by sharing joint activities). In addition, it is a trauma-focused technique that could help with discussing and negotiating care plans (by outlining felt priorities and experiences). However, evidence showed that life story work was often neglected or poorly completed in practice, was often started late in the care process, and was given little priority or investment. This supported the committee's own experience and knowledge. The committee discussed the importance of standardising life story work and starting it at the earliest opportunity after entry into care. They agreed this could support placement and emotional stability by helping the looked-after child or young person make sense of their journey through care.\n\nBased on UK-based interview and focus group evidence and committee experience, the committee discussed the importance of time for life story work being clearly set aside, with a named practitioner to ensure there is time for it to be completed to a sufficient standard. The relational aspect of this intervention could also be supported by having it conducted by a carer or practitioner that the looked-after child or young person has a close and continuous relationship with. The committee agreed it was important for this work to take place in the context of a safe and continuous relationship, because conversations would be of a personal nature.\n\nThe committee discussed the key components of life story work, based on their experience and knowledge. They agreed that this work consists of building a narrative that focuses first on the present identity and strengths before moving onto the past and reasons for entering care, and finally turning thoughts to planning for and building hope towards the future.\n\nBased on committee experience and knowledge, and some interview and focus group evidence, the committee then considered how this may be achieved. Techniques such as life mapping, use of pictures, art, written narratives, toys and play have been used successfully. The committee agreed that these discussions should be compiled in 1\xa0place and built on during regular sessions. They thought that the approach should be flexible according to the needs and response of the looked-after child or young person and should be a shared experience, in a setting preferred by the looked-after child or young person. However, they recognised that compiling life story work in 1\xa0physical place could come with the danger of sensitive information being read by others (for example, peers in residential care).\n\nThe committee took into account their own experience and knowledge in considering the role that life story work could play in cultivating a positive self-image and identity – that is, one that embraces the looked-after child or young person's ethnic, cultural or religious differences, as well as sexual identity and disabilities.\n\nThe committee stated that the effectiveness of the life story work was closely related to its quality, and agreed that having social worker oversight could help to maintain standards. It would also allow the social worker to provide additional information to support the carer or practitioner carrying out the life story work.\n\nBased on their own experience, the committee considered life story work that involves more people than the practitioner and the looked-after child or young person. For example, sometimes it may be useful to carry out life story work with siblings as a group or pair, because they may have had very different perspectives of shared life events that need to be reconciled. The committee agreed that the need for shared life story work should be carefully planned to ensure it did not destabilise sibling relationships, for example by divulging sensitive information. In addition, particularly for complex situations such as these, it was important for the experience and skillset of the practitioner carrying out the life story work to match the complexity of the care situation. This may need the direct attention of a social worker rather than the primary carer.\n\nBased on their own experience and knowledge, the committee agreed that the network around looked-after children and young people was important to support ongoing life story work. The committee considered it vital that the idea and purpose of life story work and its importance was expressed to the social work team, carers, educational staff, and birth family. Broader social networks can then be engaged in the work when needed. Birth families may need to encourage consistency in narratives explored and reframing previous relationships.\n\n## How the recommendations might affect practice\n\nLife story work is mandated by statutory guidance for all looked-after children and young people with a plan for adoption. It is already current practice and these recommendations can be easily integrated into the process. Although the recommendations may necessitate a higher standard of life story work (for example, with more detail and more time devoted to it) in some cases, the committee agreed that these changes were necessary for the work to be effective and achieve its aims. Training to ensure a consistent approach to life story work could be incorporated into existing training. Social worker oversight for life story work conducted by another practitioner is anticipated to have minimal resource implications because the work is either already being conducted by the social worker or would simply need the social worker to be informed of the content of that work.\n\nReturn to recommendations\n\n# Relationships and wellbeing activities\n\nRecommendations 1.5.34 to 1.5.37\n\n## Why the committee made the recommendations\n\nUK-based interview and focus group-based evidence frequently emphasised that positive relationships were the most important aspect of care to looked-after children and young people and care leavers, and that, along with placement stability, they are most linked to social, emotional and mental wellbeing. They discussed that the cornerstone of positive relationships was the relationship with the primary carer. So they agreed that, before recommending specific interventions to support social, emotional and mental wellbeing, the focus of support needs to start with a stable care placement and a strong supportive relationship with the primary carer.\n\nInterview-based and focus group-based evidence showed that some primary carers, for example in residential care or foster care, had concerns about giving physical touch and affection to looked-after children and young people. The committee discussed that physical affection, particularly for younger looked-after children, could be a major source of emotional stability and wellbeing, and yet it may be denied in some cases because of the primary carers' desire to be protected from any form of allegation. They agreed that, in some cases, it may be necessary to proactively promote or encourage appropriate physical affection (for example, through play) and that the need for physical touch and affection as a part of a healthy relationship with the primary carer should be taken into account in safer caring plans.\n\nA variety of evidence reflected the importance of shared activities to help bond relationships with peers, practitioners or carers. The committee considered that peer support could be particularly important among looked-after children and young people because, given the absence of strong family ties, they may place more emotional investment in friendships and other non-conventional relationships (for example, with care practitioners). They agreed that it was important to support the interests and hobbies of looked-after children and young people by setting aside time for outings that would help them invest in these interests, as well as in their close relationships.\n\nThe committee considered that looked-after children and young people are more likely to be overweight and obese than standard norms and many come into care with a poor nutritional status. They recognised a gap in good quality research for interventions to help improve diet and exercise, as well as other lifestyle factors such as drug and alcohol use, among looked-after children and young people, and made a recommendation for research on promoting physical exercise, and a healthy diet and lifestyle. In the absence of good quality research to support interventions to improve diet and exercise among looked-after children and young people, the committee cross-referred to existing NICE guidance on physical activity, obesity prevention and weight management in children and young people.\n\n## How the recommendations might affect practice\n\nFacilitating and supporting activities such as school clubs would be unlikely to have a significant resource impact. Funding for group activities may have more substantial resource implications, so these would need to be limited to freely available or inexpensive activities. Some group activities, particularly school clubs, could be prioritised for funding through the pupil premium grant.\n\nReturn to recommendations\n\n# Readiness for starting or changing school\n\nRecommendations 1.6.1 to 1.6.3\n\n## Why the committee made the recommendations\n\nThe committee considered US-based evidence on therapeutic playgroups for children in kindergarten entering second grade aged\xa07\xa0to\xa08. These resulted in improved parent-rated social competence and emotional stability. But this evidence was from a small trial with no long-term follow up. Because of this, and the expense of running therapeutic playgroups, the committee did not recommend them specifically. But they agreed that early years education should include opportunities to improve socialisation, such as early years education in playgroups, as well as other opportunities to encourage child-led play.\n\nThe committee considered evidence from robustly designed studies on transition-to-school programmes for looked-after children of primary school age. These programmes resulted in improved early literacy skills, self-regulatory skills, self-competence, and attitudes towards alcohol and antisocial behaviour, as well as days free from internalising symptoms. They also reduced aggressive behaviours. A similar programme for secondary-school-aged children resulted in improved emotional, social and behavioural scores, and reduced substance use.\n\nThe committee considered the broadly positive findings for readiness for school interventions, alongside the problems with study quality and assessment of effectiveness. But they highlighted that, particularly for a child returning to school after prolonged absence, the need of a child to cope with the possibility of peers and parents of other children finding out about their 'looked-after' situation could be traumatic, and that this is particularly a risk if the child is receiving special interventions for education. Other evidence from UK-based interview and focus group studies suggested that looked-after children and young people did not necessarily want more professionals or programmes in their lives.\n\nThe committee therefore agreed there was a broad benefit of tailored transition support into new school placements. However, they favoured approaches that would help ease the looked-after child or young person into the new school placement but not single them out. The committee also agreed that transition to a new school placement may need input from professionals beyond those in education.\n\n## How the recommendations might affect practice\n\nThe resource impact of these recommendations is expected to be low. Early years support should already be provided as a statutory service, so little additional resource expenditure should be needed, other than greater prioritisation of playgroups from existing funds. Transition support and services are also currently supported by the virtual school. Additional interventions to support the transition can be prioritised through the pupil premium grant, which is part of statutory education funding provision for looked-after children and young people.\n\nReturn to recommendations\n\n# Support in schools\n\nRecommendations 1.6.4 to 1.6.7\n\n## Why the committee made the recommendations\n\nThe committee heard from experts that educational resources were available to support looked-after children and young people, but they may not be being spent in the most effective way. The committee agreed that ensuring that looked-after people and their carers know about their rights to educational support (for example, the purpose of the pupil premium grant for education, and how it is distributed), and including special educational provision under the special educational needs and disabilities (SEND) legal framework, would encourage accountability in spending.\n\nThe committee discussed the importance of trauma-informed practices for all practitioners working with looked-after people. Based on expert testimony, and on interview and focus group-based evidence describing the needs of looked-after people with trauma, the committee considered that standard behavioural policies in schools may not be adequate or may even be harmful for young people with a history of trauma and disorganised attachment. They agreed that it was important for schools and regulators to understand the impact of behaviour management policies on trauma.\n\nUK-based interview and focus group evidence showed that looked-after children and young people experienced a shortage of adults who have higher expectations and aspirations for their education, as well as positive role models and tailored (individualised) support for education. Based on expert testimony and their own experience, the committee discussed the need for a strong educational advocate for looked-after children and young people. This would be someone who is invested in and supportive of the person's education and is willing and informed enough to fight for the educational provisions that a looked-after child or young person should receive by statutory right (and beyond). The committee agreed that this role is most readily fulfilled by the designated teacher. As well as having a committed educational advocate on the school site, the committee agreed that educational advocacy needs should also come from the primary carer. However, the committee agreed that, in many cases, the foster carer's role in their child's education had not been sufficiently encouraged.\n\nThe committee agreed that the role of the designated teacher is carried out with variable quality across the UK. Therefore, the committee felt it important to outline the key principles of practice that this role should include to improve the advocacy relationship with the looked-after child or young person in school settings. They discussed the need for the designated teacher to collaborate with those who have the best information to support and direct the looked-after child or young person's educational path. The committee used their own experience and knowledge to identify personnel as useful partners for this.\n\nThe committee used interview and focus group-based evidence and their own experience and knowledge to clarify the role further. They discussed evidence in which carers had identified and organised the diagnosis of educational issues themselves (such as dyslexia). They considered that it would be better for the on-site educational advocate (the designated teacher) to identify and organise such assessments, and in a more timely manner. Therefore, the committee agreed that the designated teacher should ensure ongoing monitoring of learning needs, particularly during placement transition (which can be a time of greater educational and emotional challenges).\n\nThe committee also considered that multiagency review meetings, including those from the virtual school and the designated teacher, may need input from professionals beyond those in education. Therefore, they agreed that a designated teacher needs to be sufficiently competent to refer for specialist support if necessary.\n\nThe committee emphasised that 1\xa0of the most important roles of the designated teacher (acting as educational advocate) was to 'check in' with the looked-after child or young person regularly, whether or not they have any special educational needs. Check-ins can help to develop a rapport with the looked-after child or young person and build a supportive relationship. Because interview and focus group-based evidence highlighted the importance of maintaining confidentiality about care status whenever possible, especially in school, the committee were keen that these check-ins should not add more stigmatising and formal meetings to the looked-after child or young person's schedule. Rather, the designated teacher could have regular one-to-one informal conversations with them. The committee agreed that the frequency of these conversations should be informed by the looked-after child or young person themselves, because some may favour less intense supervision.\n\n## How the recommendations might affect practice\n\nAdvocacy by a named teacher is not anticipated to need significant additional resources because this is already part of the statutory role of the designated teacher. The committee recognised that there are time-resource implications in performing this role to a high standard.\n\nReturn to recommendations\n\n# Virtual schools\n\nRecommendations 1.6.8 to 1.6.15\n\n## Why the committee made the recommendations\n\nThe committee noted that no consistent model of a virtual school was apparent across the country but that some common features could be identified. As part of this, there was a discussion about the constituent members within a virtual school and the external services that should be linked through the virtual school.\n\nThe committee discussed including early years practitioners within the virtual school. Based on expert testimony and their own experience, they noted that early years expertise was not statutory in virtual schools. Smaller numbers of looked-after children in the early years group meant they were often allocated relatively small budgets. The same was true at the other end of the educational age range: early years and over‑16 groups are not well provisioned, with most money devoted to school-aged children and young people.\n\nThe committee considered there was a need for early years expertise alongside the virtual school head to provide oversight of interventions to support the early years education of looked-after children, and champion educational services for children during the pivotal younger years. Based on their experience and knowledge, the committee suggested that information to support this role needed to be brought in through collaboration with nurseries and health visitors and using routinely collected data.\n\nExpert testimony highlighted the need for closer working between the virtual school head and the special educational needs (SEN) service. The virtual school team needs to have a breadth and depth of knowledge across social care, education and health and to understand the legislation for each area. Very few social care staff have a working knowledge of the SEN code of practice or the legislation that underpins it. As a result, the committee considered the need for someone with SEN experience in the virtual school, ideally a special educational needs coordinator or someone with SEN specialism or training.\n\nBased on their own expertise, the committee considered that the inclusion of a post‑16 coordinator in the virtual school could help bridge the gap in information for those in care hoping to achieve higher or further education – for example, by helping with the application processes for entrance to college, university or further training (and support while there). Therefore, help was needed to help looked-after young people aspiring to further education to navigate the available support.\n\nThe committee recognised that the expertise needed within the virtual school was likely to vary based on the demographics of the population being served. Therefore, they considered the need to take into account the prevalence of groups of special interest in each local authority when expertise for the virtual school is being recruited. They noted that the prevalence of some groups of special interest varied significantly between local authorities.\n\nAs a result of expert testimony, the committee recognised that often, virtual school heads had not been properly empowered or used, and their role had not been properly defined. In some cases, the virtual school head may be a peripheral figure, rather than a key leader enacting change in the local authority. Therefore, the committee agreed that, to be able to complete its statutory duties, the virtual school head should be considered the key leader and enabler for the collaboration of educational services for looked-after children and young people.\n\nExpert testimony outlined the range of professionals with a statutory remit to work with, and promote, the needs and wellbeing of children and young people in care and education. These professionals are asked to work together, but the expert noted that this often does not happen sufficiently in practice. In the experience of the expert, a clear bridge is needed between the services, and when this role is taken up by the virtual school, the links work much better. The committee agreed and outlined a list of services for which the virtual school head should act as a 'bridge'.\n\nBased on their expertise and knowledge, the committee noted that simplifying and merging looked-after children review meetings would support multiagency working. For example, merging annual reviews and personal education plan meetings could make it easier for specialists in education and social care to communicate, while also reducing the number of overall meetings that looked-after children and young people need to attend. The committee also considered the importance of including the health perspective in multiagency review meetings when health problems impacted education.\n\n## How the recommendations might affect practice\n\nEvery school in the UK is obliged to employ a special educational needs coordinator, so ensuring that one is part of the virtual school team would not incur additional resources. Some virtual schools may not have an existing early years practitioner, so there would be resource implications from adding another staff member to the team. However, it is possible that such expertise could be found, or developed (using training), in existing professionals in the virtual school.\n\nReviewing meeting structures and condensing them into fewer meetings if possible would not need additional resources because it would reduce the number of meetings being organised and held.\n\nThe recommendation for virtual school heads to form a bridge between named specialists in education, social, health and mental healthcare is not anticipated to have a significant resource impact because these roles already exist and would not need an additional staff member at the virtual school.\n\nReturn to recommendations\n\n# Improving educational outcomes\n\nRecommendations 1.6.16 to 1.6.19\n\n## Why the committee made the recommendations\n\nThe committee considered evidence from robustly designed studies about interventions tested mainly in primary-school-aged children. There was some evidence that tutoring by foster parents or volunteers improved maths and some literacy scores; these were outcomes that the committee considered to be important. However, the evidence base had some problems in quality and the committee noted that some carers may not want to take on the responsibility for tutoring because this can blur the line between the carer and educator roles.\n\nThe committee considered that flexibility was important when choosing the tutoring style that best suits the child and the placement. Evidence from studies with weaker designs (non-randomised controlled trial) showed that a paired reading intervention greatly improved reading age over the course of the intervention. Although, again, the evidence was limited, the committee were impressed by the reported size of effect.\n\nThe committee considered that paired reading had potential for increasing communication and engagement between foster carers and schools. In addition, it was a simple, cheap and already widely used intervention in primary schools (with parents often encouraged to take part). It showed good evidence of effectiveness, and had historical use, beyond looked-after children. Paired reading was also considered to have a relational aspect, improving quality time spent between carer and child. Older students in primary school could engage in paired reading with younger students, which may also provide an important mentoring role.\n\nThe committee discussed tutoring among looked-after young people attending secondary school. They noted that a large amount of money is spent on tutoring, but there is a lack of evidence on its effectiveness for looked-after young people. The committee therefore did not recommend a specific intervention but instead agreed, based on their own experience, that interventions for improving education in secondary-school-aged looked-after children are regularly evaluated.\n\nUK-based evidence from interviews and focus group studies and expert testimony showed the importance that unaccompanied asylum-seeking children placed on educational attainment and learning English. The committee agreed that teaching an unaccompanied asylum-seeking child to speak English fluently was 1\xa0of the first steps to helping them acclimatise to the country, settle with their primary carer, build positive social networks and succeed educationally. Therefore, the committee agreed that English language lessons were important for those who are not fluent, and recommended that intensive lessons be considered for those with no previous knowledge of English.\n\nLikewise, the committee recognised that additional support would be necessary in mainstream educational settings for those who did not speak English fluently. So they agreed that virtual schools should consider increased specialist educational provision for unaccompanied asylum-seeking children.\n\nThe committee noted a gap in the evidence base on the use of therapeutic interventions in current practice such as art therapy, play therapy, occupational therapy, music therapy and psychotherapy. The committee highlighted these interventions as being known to have a positive impact on educational, social and emotional outcomes in broader populations of children. They made a recommendation for research on therapeutic interventions for promoting school stability and learning to assess the effectiveness of these interventions on improved learning outcomes, school attendance and exclusion to help address this evidence gap.\n\n## How the recommendations might affect practice\n\nThere was no published cost-effectiveness evidence for most of the learning interventions but the resource impact for the recommended interventions is expected to be low. There may be some hidden costs such as carer or volunteer time, training, travel and administrative support.\n\nPaired reading is currently provided to all children in primary schools, so no additional resource is needed. Infrastructure may be needed for extra support or training for foster carers on active reading and to train volunteer paired readers. Virtual schools may be best placed to deliver training in paired reading to foster parents. The only extra costs involved should be for foster carers actually attending training, and costs may be even lower if delivered virtually.\n\nIndividual or small group tutoring delivered by trained foster carers or trained volunteers would have a low resource impact, but using professional tutors would have higher cost implications.\n\nThese interventions can be prioritised for funding through the pupil premium grant, which is part of statutory education funding provision for looked-after children and young people.\n\nThis trauma-informed training for teachers could be incorporated into the existing provision for behavioural management training, so is not anticipated to have a substantial resource impact.\n\nReturn to recommendations\n\n# Data collection, sharing and publication in education\n\nRecommendations 1.6.20 to 1.6.22\n\n## Why the committee made the recommendations\n\nEvidence from expert testimony highlighted the importance of developing systems of accountability by gathering and sharing data that could help monitor and evaluate services around education for looked-after children and young people. They noted that no data was being collected on the responsibility of local authorities to secure education provision. For example, many looked-after children and young people are not placed on a school roll (defined by having a Department for Education number) by their corporate parent. In addition, there may be a culture of ignoring statutory responsibilities in this area because of lack of oversight, use of unregistered provision, and 'ghost rolls'.\n\nThe committee discussed evidence from expert testimony about placement of children in unregistered schools, which results in their data not being captured in national attainment figures. This may create a perverse incentive for local authorities not to secure appropriate provision in order to artificially improve national attainment figures. The committee agreed that local authorities should collect and publish information on the educational provision for looked-after children, with a particular focus on children missing education as well as the strategy for reducing that number.\n\nThe committee discussed expert testimony on the lack of accountability for how the pupil premium grant was being spent. Schools and local authorities do not routinely collect data to demonstrate that education funding for looked-after children and young people is being spent within the terms of the grant. This hampers the ability to evaluate the spending of the pupil premium grant to improve outcomes or to ensure that the funds are used directly for the benefit of looked-after children and young people. The committee noted that the Department for Education have acknowledged that they are not able to hold local authorities accountable for either spending of the pupil premium grant or provision of educational placements, because of the lack of available data. Therefore, the committee agreed that the spending of the total pupil premium grant within local authorities needs to be tracked to develop a mechanism of accountability.\n\n## How the recommendations might affect practice\n\nCollecting and publishing information on the educational provision for looked-after children and young people, particularly those who are missing education, and a strategy for reducing the number of these children and young people, and developing a checking mechanism for the spending of the pupil premium grant, is unlikely to have a significant resource impact. Although this data is not currently collected consistently across local authorities, there are existing mechanisms to do so. There are also existing mechanisms for checking local authority spending, so checking educational spending for looked-after children and young people could be incorporated into existing spending checks.\n\nReturn to recommendations\n\n# Further and higher education\n\nRecommendations 1.6.23 to 1.6.26\n\n## Why the committee made the recommendations\n\nThe committee considered evidence from robustly designed studies on interventions to help looked-after young people aspire to, and be equipped for, higher education. They acknowledged that entry into further or higher education is very different for looked-after children and young people than for the wider population. For example, they have broadly lower expectations of ever attending higher education and may consider this to be something that they are not able to achieve. Interventions need to be tailored accordingly.\n\nParticularly, evidence from a study of individual coaching and group mentoring, with a summer visit and stay at a university campus, showed improvements in several measures of readiness for post-secondary education. Most importantly, there was a considerable improvement in post-secondary participation at 6‑month follow-up in the intervention group.\n\nBased on evidence from robustly designed studies, and some interview and focus group-based evidence, the committee considered that residential experiences, university campus visits, and coaching and mentoring by near peers in higher education could have profoundly beneficial effects on looked-after young people considering higher education. In addition, the committee agreed that university access schemes (offered by several UK universities) can give important support for looked-after young people in navigating the application process and receiving assisted entry to courses. The committee also considered the importance of encouraging people to self-identify as care leavers once they are in university or college because this may give them opportunities to receive additional support. However, they also recognised that care leavers often want to keep their care history private.\n\nBased on their own experience and knowledge, the committee also weighed up the potential harm caused by pushing looked-after young people into higher education when this might not be the best option for them. The evidence did not report whether looked-after young people enrolled in college or higher education thrived or completed their courses. But this is a concern that applies to all young people not just those who are looked after.\n\nThe committee also considered that looked-after young people may be more ready to re-enter education when older. They discussed that their personal advisers are well placed to outline the options to do this. However, the young people would benefit from the support of post‑16 coordinators who would have more in-depth knowledge of the funding and support available.\n\nBased on their own experience and knowledge, the committee agreed that support was also important for looked-after young people considering other routes into further education and training. The committee believed careers support and advice, work experience placements, and internships to be useful and available routes into good careers for looked-after young people. Careers support and advice was strongly needed, targeted at looked-after young people because they need an extra level of support and signposting.\n\n## How the recommendations might affect practice\n\nThe resource impact of these recommendations to help looked-after young people enter higher or further education or training is expected to be low, although some apparently low-cost interventions funded by local authorities, such as volunteer coaching programmes, are likely to be associated with expenses for travel, management and administration. But the resource impact generally is expected to be small compared with the potential benefits of improved education, employability and independence. In addition, there is a possibility that the UK pupil premium grant may be extended to 16- and 17‑year‑olds in the near future.\n\nIt is not possible to make a robust judgement about the potential resource impact to local authorities of recommendations on university access schemes, residential experience and visits on university campus, mentoring by near peers in higher education, and coaching, because uptake is too uncertain to predict. Interventions such as residential experiences and campus visits would be delivered by universities and colleges themselves, although facilitated by the virtual school. Likewise, some interventions may simply involve signposting people to local programmes and schemes that are university, college or third-sector funded, so the resource impact for local authorities would be low.\n\nReturn to recommendations\n\n# Before transition between care placements and to permanent placements\n\nRecommendations 1.7.1 to 1.7.9\n\n## Why the committee made the recommendations\n\nDrawing on UK-based evidence from interview and focus group studies indicating it was important to have a good match between carers and the looked-after children and young people, the committee recommended that careful consideration in transition planning should be given to the matching of carers and the looked-after child or young person. In assessing the strengths of the carers, committee members described how they translate the child's needs into what the parenting challenge and task looks like for the carers, and how the carers can best bolster the placement and help meet these needs.\n\nUK-based evidence from interview and focus group studies and expert testimony also highlighted how the relationship between foster carer and adopter could support the move into permanency. Good communication and support can improve this relationship, for example by helping to manage expectations of the foster carer during the planning stage. These measures could help to avoid an adversarial relationship forming between carers, rather than a supportive relationship that allows for a more integrated experience for the looked-after child or young person during transition.\n\nThe committee disagreed with perspectives in some of the interview and focus group-based evidence that suggested it was beneficial for the looked-after child or young person to experience the short sharp shock of a foster carer stepping away completely and immediately. Rather, they supported a less traumatic approach that facilitated ongoing communication with current carers if the child or young person wanted this.\n\nThe committee looked at interview and focus group-based evidence on facilitating the involvement of the new permanent or long-term carer's extended family. For example, the extended family may help by providing respite (or support) care. The committee agreed that involving family and friends early in the placement was particularly important for helping them to engage with the new family relationship. But they stated that respite (or support) care in the early stages could damage the formation of attachment with the primary carer. Based on their own knowledge and expert testimony, the committee noted that family and friends training days, which are offered through adoption agencies in some local authorities, were helpful.\n\nFor birth families involved in substance misuse, the committee considered evidence on 2\xa0interventions to support reunification: recovery coaching and family drug and alcohol courts. This included evidence based on robust study designs, and some weaker forms of evidence (not from randomised controlled trials). Recovery coaching was associated with greater reunification and more stable and long-lasting relationships than services as usual. UK family drug and alcohol courts were associated with improvements in reunification and longevity of reunification compared with ordinary care proceedings. The committee considered that providing independent support for families at the same time as child welfare court processes could support reunification. They agreed that, if reunification had occurred, support needed to continue after reunification to help the permanent placement to last, with clear plans for follow-up. Instead of recommending recovery coaching specifically, the committee recommended substance and alcohol misuse support, by trained staff, with a cross referral to NICE lifestyle and wellbeing guidance (which includes managing substance and alcohol addiction, and behaviour change).\n\nThe committee noted that there is evidence for the use of drug and alcohol courts to aid reunification by intervening and providing support for birth parents with drug addiction. However, rates of mental health problems are also high among birth parents who have had a child removed, and these problems may also contribute to the reasons for children going into care. Based on their own experience, the committee also recommended that mental health support continues alongside court processes. The committee made a recommendation for research about the benefit of mental health support to promote reunification.\n\nThere was evidence, based on studies with non-randomised designs as well as focus group and interview-based studies, that concurrent planning significantly reduced the likelihood of multiple moves before finding permanency and the time to finding a permanent placement. But evidence also showed 2\xa0particular issues with it. One was that prospective adopters and birth parents found that late changes in the care plan could be particularly distressing for them. And prospective adoptive parents found that the intensive contact arrangements could be taxing for both themselves and the child (in terms of frequency and distance travelled while establishing new routines and building relationships).\n\nThe committee discussed concurrent planning as something that was already practised, with success, in certain parts of the UK. However, they considered that carers and birth parents should be well informed of the inherent difficulties of such a strategy and the possibility of late changes to the care plan meaning that adoption or reunification may not occur as anticipated.\n\n## How the recommendations might affect practice\n\nIt is not possible to make a robust judgement about the potential resource impact of setting up concurrent planning processes to speed up transition time to permanency, or of carrying out substance and alcohol misuse support alongside court processes, because uptake is too uncertain to predict. However, these processes are already available in some parts of the UK.\n\nSome local authorities already offer family and friends training days through adoption agencies, and there is existing provision for this training, so it is unlikely that extending this to all areas will have large resource implications.\n\nReturn to recommendations\n\n# During transition between care placements and to permanent placements\n\nRecommendations 1.7.10 to 1.7.20\n\n## Why the committee made the recommendations\n\nUK-based evidence from interview and focus group studies suggested the need for a more integrated experience for looked-after children and young people that takes into account the significance of previous caregiving relationships. For example, the importance of foster carers for preparing and supporting adoptive parents, focusing on the emotional state of the child or young person during the busy transition out of care, and prospective adoptive carers wanting more information about previous care experiences and health.\n\nThe committee agreed that, beyond the benefits for prospective adopters offered by foster carers in terms of sharing information, it was also beneficial for the looked-after child or young person to see positive relationships forming between their current carers and their prospective permanent carers in the period before and after transition.\n\nBased on their own experience and knowledge, and as part of the more integrated experience of transition described above, the committee considered the social network around the looked-after child or young person. They thought that contact arrangements, which may be focused on the birth family, should also take into account whether the looked-after child or young person has other significant relationships with which they would like support to maintain. Such support could help create a more overlapping transition that gives more time for new connections to form and to process the loss of old ones.\n\nBased on interview and focus group evidence about how child-focused the transition period was, the committee agreed it was important to have a practitioner regularly 'check in' with the child or young person to ensure that the transition process was going well for them and to keep the process child-centred. The committee noted that for children not yet able to talk, the primary carer may need to be present and advocacy services may also be needed.\n\nUK-based evidence from interview and focus group studies showed that good clear information before transition was extremely important to new foster carers and prospective adopters. The committee considered the types of information that should be given to a new carer during the process of transition between care placements or out of care, based on their own knowledge and expertise. It was important that this should give new carers a clear sense of the chronology of the care process for the child or young person.\n\nTo avoid the information being handed over in an overwhelming quantity, the committee agreed that the information needs to include a clear summary. This will provide the information they need to help carers carry out their nurturing and safeguarding role. They also agreed the importance of briefing the new carer in person, rather than leaving the carer to make sense of the information by themselves. A social care practitioner who has had continuous oversight of the child or young person's history in care would be ideally placed to do this.\n\nThe committee considered their own experience and knowledge, and some interview and focus group-based evidence showing the concerns of new carers adopting looked-after children with medical conditions they were not familiar with, and of the need for information about previous placements. The committee discussed what information would be helpful for new carers and prospective adopters, to cover the needs of the new placement, including personal health history. It also included birth family health history; the committee were keen that this was collected for all children entering care, not just during adoption processes. The committee agreed it should also cover behaviour with the potential for significant harm to others (for example, sexual, violent or fire-setting). However, they highlighted it was important for prospective carers to have the context to these events so they could assess them properly.\n\nBased on their experience and knowledge, the committee also stated that this information giving should not simply be a record of negative life events, but that the record should lend equal weight to factors that could support the success of the placement. These include the looked-after child or young person's strengths, hopes for the future, significant positive relationships (with peers and adults), interests and activities, as well as how behaviours had been successfully supported in previous settings. The committee recognised the importance of ongoing life story work to draw out these factors.\n\nThe committee also considered the case of emergency foster placements, for which it may not be possible to deliver all information immediately. If it becomes clear these placements will be longer term, the carer may need more information to carry out their nurturing and safeguarding roles. For example, carers often need support to understand why a child or young person is behaving in a certain way in order to respond appropriately. As well as knowing about safeguarding issues, they need to know why children and young people are looked after, which family members pose a risk and why.\n\nThere was lot of UK-based evidence from interview and focus group studies showing that children and carers value continuity of care practitioners. The committee agreed that consistency in the practitioners who help in the handover of information for new permanent carers could reduce the sense of instability during transition, and support positive relationships.\n\nBased on expert testimony and their own knowledge, the committee discussed the issue of a continuing education plan when a child or young person is moved outside their local authority area. The committee considered the need for someone who has an overview of the child or young person's educational needs and can help place the child or young person in education that matches their needs. They agreed that this could be assisted by having a transition plan and 'handover' from the old to the new school placement (for example, from 1\xa0designated teacher to another) as part of the personal education plan.\n\nBased on their experience and knowledge, the committee also discussed the need for continuity of healthcare as the looked-after child or young person moves to their new placement. The committee agreed that if regular mental health, physical health or dental support had been provided in the old placement, new referrals local to the new placement need to be in place before the transition, to promote continuity of care.\n\nExpert testimony from an adoptive parent and organisations representing adopters highlighted the importance of language during the transition period. In particular, adoptive parents (who may have no experience of parenting) may feel judged by the child's foster carers. Often, adopters feel this is a highly sensitive time when they do not want to complain or do anything to jeopardise the placement. The committee therefore highlighted the need for transition teams and foster carers to consider these issues and adjust language accordingly.\n\n## How the recommendations might affect practice\n\nMost recommendations are not particularly resource intensive, generally focusing on continuity of healthcare and education, parent and carer training, peer support and the detailed chronology of care process for the individual. Many recommendations focus on ensuring continuity of existing processes, or on processes that are already in place in some areas.\n\nHowever, extra resources may be needed for those that need more professional time to produce (such as the summarised history of care) or training and preparation for long-term carers.\n\nGiving opportunities for current and new carers to meet before a placement move, and facilitating ongoing communication, should not have substantial resource implications because these can be incorporated into existing transition planning. Similarly, supporting existing social networks to allow time in the transition period for the looked-after child or young person to form new social connections is not expected to be resource intensive because this can be incorporated into existing transition planning.\n\nReturn to recommendations\n\n# After transition between care placements and to permanent placements\n\nRecommendations 1.7.21 to 1.7.25\n\n## Why the committee made the recommendations\n\nThe committee considered whether it would be useful for the looked-after child or young person to give their own perspective on their journey in care to their prospective carer if the child or young person is willing, drawing from existing life story work. This could aid transparency and help the looked-after child or young person feel in control of their information. However, the committee considered that this may be better occurring once the looked-after child or young person and carer have begun to develop a stronger attachment relationship.\n\nUK-based evidence from interview and focus group studies and expert testimony highlighted the power imbalance perceived by adoptive parents, who may feel unable to complain about the transition process because of fears about jeopardising the placement. The committee considered that although there was little that could be done about this during the transition period (other than making permanency carers aware of their rights to receive support), agencies would benefit from seeking feedback from foster carers and adopters after the permanence order is made, and they could use this to improve the delivery of transition services.\n\nThere was very good UK-based interview and focus group evidence, supported by expert testimony, that peer support was useful for adopters and permanent carers. Peer support groups could often give the personalised support and availability that social care teams could not. The committee noted that effective peer support could be achieved in a variety of ways.\n\nThe committee noted, based on expert testimony, that there was also the potential for specialised peer support groups to help deal with specific problems in permanency placements. Experienced permanent carers could be linked up with other permanent carers in need of support to provide tailored advice and empathy that may not be covered by the expertise of the support team.\n\nThe committee noted that few studies reported long-term placement durability outcomes, including post-permanency outcomes showing that the looked-after child or young person was thriving in their new long-term placement. In addition, there was insufficient evidence on the perspective of adopters and long-term permanency carers about the transition out of care and how this could be improved. The committee therefore made a recommendation for research on interventions to support stability of permanent placements to encourage more evidence in these areas.\n\n## How the recommendations might affect practice\n\nFacilitating accessible peer support for permanent carers (such as adopters) is unlikely to have a substantial impact on resources, because most would be peer led and not need much additional personnel time or physical resources from the local authority. Message boards may need to be moderated to prevent misinformation but, overall, peer support could save time and resources by helping to resolve issues that would otherwise need the attention of care staff, or that, if left without support, could lead to placement instability.\n\nReturn to recommendations\n\n# Transition out of care to independence\n\n## Why the committee made the recommendations\n\nRecommendations 1.8.1 and 1.8.2\n\nThe committee considered evidence from a study, using less robust research designs (not randomised controlled trials), describing outcomes of participants who had left care at different ages. Those who were still in care placements between the ages of\xa017 and\xa023 were less likely to be involved in property crimes (men) or convicted or arrested (women). Those who had left care aged\xa018 or\xa019 had worse outcomes for time to arrest and time to first violent offence.\n\nOther UK-based evidence from interview and focus group studies suggested that many care leavers experienced what felt like a cliff edge moving into independence too early. Therefore, the committee recommended that, wherever possible, looked-after young people approaching independence should be encouraged and helped to stay in their current care placement until at least the age of\xa018.\n\nThe committee noted that for some, staying put in their care placements beyond age\xa018 could be beneficial. However, this was complicated by the fact that carers may be paid less for young people over\xa018. (Levels of financial support to former foster carers are agreed and specified within each local authority's staying put policy.) In addition, the ability to take on other foster placements may be compromised by allowing an adult who has left care to stay on the premises. Therefore, the committee agreed that the possibility for staying put should be explored with all carers before leaving care, even though this may not be possible in many cases.\n\nSupported by expert testimony, and experience in the committee, the committee considered the danger faced by those whose care placement broke down between the ages of\xa016 and\xa017. This may lead to placement in unregulated housing at a young age, when vulnerability and the risk of exploitation may be high. The committee agreed that it was very important to avoid using unregulated housing if at all possible, particularly among those at high risk of exploitation.\n\nRecommendations 1.8.3 to 1.8.5\n\nA needs assessment is already a requirement in pathway planning (beginning at age\xa015 and completed before age\xa016). But based on evidence from UK interview and focus group studies reflecting the unmet need of some care leavers after leaving care, the committee agreed that this process needed to be more rigorous and incorporate previous life story work to identify the person's strengths (for example, problem-solving skills and practical skills) and needs.\n\nThe committee found that, overall, evidence from studies with robust designs did not suggest that independent living services were ineffective. In the 1\xa0study that looked at providing independent living services that were better than standard care, there were significant improvements across earnings, housing stability and general economic security. There was also some evidence of benefit for various specific aftercare services from evidence based on studies with weaker designs (not randomised controlled trials).\n\nThe committee therefore discussed the descriptions of the independent living services in the studies and recommended some core principles of care for supporting looked-after young people moving into independence. The committee sought to link the needs assessment for care leavers to the services provided in the transition out of care to independence.\n\nUK-based evidence based on interview and focus group studies highlighted how care leavers are often lost in the gap between child and adult health services and that they often face a great amount of loneliness and mental strain. This matched the committee's own knowledge and experience. So they agreed that the care leaver's existing mental health, health and dental care needed to be supported by ensuring registration with GP services and access to dental services. In addition, the committee suggested ways of plugging the gap between adult and child services until the transfer to adult services can be completed – for example, by extending access to CAMHS or providing alternative emotional and wellbeing services such as online support, face-to-face counselling or group work.\n\nThe committee noted that independent living services described in the evidence reviewed covered several interventions that had components supporting mental health. However, few reported mental health or general health-specific outcomes. Recognising the higher than usual rates of mental illness and health problems among care leavers, the committee recommended that more research was needed on interventions to promote the health and mental health of care leavers (see the recommendation for research on continuing support for the physical and mental health needs of care leavers).\n\nUK-based evidence drawing from interview and focus group studies strongly suggested the benefit of peer groups and support for gaps in social network in helping to combat social isolation. The committee noted that peer support was also a common component of independent living services described in the rest of the reviewed evidence.\n\nEvidence showed the usefulness of and need for various common components of independent living services. For example, ongoing accommodation support is a common component of independent living services and is valued by care leavers. The committee agreed that it was important and emphasised that organising this through the leaving care team working together with other housing services would promote continuity of oversight during the transition out of care.\n\nThe committee discussed interview and focus group evidence about the experience of the short sharp shock of independence, and that care leavers were not 'allowed' to make mistakes. For example, care leavers may initially reject support but then regret it. The committee therefore agreed that services that help to provide safety netting should be available for all care leavers to help prevent deterioration in housing stability, connectedness and economic independence. Based on their experience and knowledge, they suggested that the following services could be provided for care leavers without substantial cost to local authorities: drop-in services (for local guidance and signposting), possibility of more frequent meetings with their personal adviser (for individualised guidance and support) and facilitated care leavers peer support groups (to support relationships after care, mentoring, and share ideas and resources).\n\nRecommendations 1.8.6 to 1.8.15\n\nBased on their knowledge and experience, the committee considered that many of the problems young people encounter when transitioning out of care stem from a lack of accountability of local authorities in following and communicating statutory guidance. Care leavers may be unaware of the importance of the pathway plan for agreeing the support they will be given after transition.\n\nSome examples the committee discussed included informing care leavers that if something is in their pathway plan and is signed, it constitutes an agreement that the local authority will provide that service, and that care leavers do not have to sign their pathway plan until they are happy with it and may request a review. The committee agreed the need for practitioners to communicate this.\n\nThe committee also agreed that other aspects that need to be communicated included rights to extended support beyond age\xa018 (for example, support to re-enter education), and rights to advocacy services to improve adherence to statutory requirements, and to take full advantage of rights under statutory law.\n\nThe committee considered the need for all of this information about support available to care leavers in their local authorities to be made explicit and easily accessible as outlined in statutory guidelines. They noted that, in practice, care leavers often did not know how to find their care offer and some websites outlining the care offer were not kept up to date.\n\nBased on their own experience and knowledge, the committee considered that virtual meetings could help bridge the gap between care leavers and their personal advisers to help them continue to access support when they had moved out of area.\n\nBased on their own experience, the committee recognised the need for pathway plans to anticipate significant milestones (such as reaching the end of qualifications or training) to help support next steps into greater independence.\n\nThe committee discussed the need for local authorities to perform some quality assessment of the pathway plans. Based on their experience and knowledge, they discussed what made a better-quality pathway plan and agreed there was a need for plans to include actions in response to identified need. These actions should clearly identify a timeframe for completion as well as the practitioner responsible for completing the action. The committee also discussed the need for quality assessments to check that the actions were actually completed in the agreed timeframe.\n\nFrom the committee's experience, the support available to care leavers is likely to differ considerably by area. So they agreed that efforts to raise care leavers' awareness of local opportunities for support in independent living were needed.\n\n## How the recommendations might affect practice\n\nSupporting young people staying in their current placement until at least age\xa018 is not expected to have significant resource implications. If a foster carer is happy to continue the placement beyond\xa018, the cost of this (for example, the potential loss of the foster carer to the system) is offset by the benefits of improved outcomes for those who have support for longer beyond their in‑care placement.\n\nThe committee acknowledged that avoiding the use of unregulated housing for looked-after young people under\xa018 would have potential resource implications. However, these resource impacts can be justified on equity grounds, because any reasonable person would not consider the use of unregulated housing to be appropriate for anyone under\xa018. Therefore, it would be unfair and a social injustice to have looked-after young people endure such living conditions simply because of their looked-after status.\n\nThese recommendations should not have substantial additional resource implications because most of them cover care processes that are statutory across the UK, although they are completed with variable quality. For example, many of the possible interventions for preparing care leavers for independent living are currently available across the UK, but with variable access.\n\nSome of the recommended interventions to support care leavers may have resource implications, such as supported housing and increased mental health support to plug the gap between child and adult services. However, the provision of these is already a statutory requirement if based on a good individual needs assessment.\n\nProviding 'safety nets' such as drop-in services for care leavers and peer support groups is expected to be relatively low cost and has large benefits by providing a sense of availability and connectedness. Peer support groups may need administrative staff time, especially to help organise and facilitate meetings, and some monitoring may also be necessary to help prevent misinformation spreading. However, this intervention could save time and resources by helping to resolve issues that would otherwise need the attention of transition teams.\n\nReturn to recommendations\n\n# Support for care leavers in further and higher education\n\nRecommendations 1.8.16 to 1.8.18\n\n## Why the committee made the recommendations\n\nBased on their own experience and knowledge, the committee discussed extended educational care. They noted that, for qualifying care leavers, extended support was often offered if the person was in full-time education. However, the definition of what constitutes full-time education may be too narrow for many who would benefit from it. For example, 1\xa0of the committee members raised the example of a care leaver who received a scholarship to train with a sports team, who may not receive the same extended support as someone in university. The committee also considered the high prevalence of those with special educational needs or disabilities among care leavers. Because this group may not progress as quickly in education, the committee agreed that they, especially, may need extended educational support.\n\nBased on their own experience and knowledge, the committee also discussed the issue of university students living away from home and agreed that continuity of housing during holidays was needed for care leavers in college or university to prevent housing instability between terms. This was supported by evidence showing that housing was often cited as the reason for care leavers dropping out of courses in higher and further education.\n\nBased on their experience and knowledge, and evidence showing that isolation may remain a problem even with appropriate housing, the committee agreed that a good level of social support was needed from social care and university teams. Based on evidence showing the benefit of peer support and mentoring interventions, the committee agreed that facilitating a 'buddying system' for peer support, mentoring from older students on campus to tackle isolation during the holidays or providing other social opportunities for care leavers could be beneficial.\n\n## How the recommendations might affect practice\n\nHousing support during university holidays may not cost a substantial amount because many universities already offer the option for care leavers to stay on in their halls of residence in holiday times.\n\nReturn to recommendations\n\n# Feedback to improve services\n\nRecommendations 1.8.19 to 1.8.21\n\n## Why the committee made the recommendations\n\nDrawing on UK-based evidence from interview and focus group studies suggesting that shared decision making should be a cornerstone of care provided for looked-after children and young people, the committee discussed the need for a mechanism to incorporate the feedback of looked-after children, young people and care leavers moving into independence back into the services provided. Interview and focus group evidence suggested that children in care councils specifically may facilitate such feedback, although something more focused on care leavers, such as care leavers forums or surveys, was needed to improve services during the transition into independence.\n\nThe committee recognised particularly that those who were looked after out of area may be most vulnerable to receiving inadequate statutory support. Therefore, they considered it important that the views of these looked-after children, young people and care leavers were captured and used to improve services.\n\n## How the recommendations might affect practice\n\nThese recommendations are not expected to have substantial resource costs, because care leavers may be encouraged to give feedback in numerous ways. Care leaver councils may have more running costs in terms of facilitation and organisation, but the extent to which local authorities will use these councils is uncertain.\n\nReturn to recommendations\n\n# Forum for strategic leadership and best practice\n\nRecommendations 1.9.1 and 1.9.2\n\n## Why the committee made the recommendations\n\nBased on evidence from interview, focus group studies, studies with more robust study designs and committee experience and knowledge, the committee considered the benefit of facilitated multiagency working to help systems adapt to local challenges. They were particularly interested in the use of regular broad-system meetings, or forums, for care providers to exchange information and to provide the opportunity to adapt care systems to meet the needs of looked-after children and young people.\n\nThe committee considered that 1\xa0of the key components was improving communication between disciplines (for example, health professionals, social care providers and carers) at all levels to ensure that statutory guidance was being adhered to. A forum could also display examples of exemplary practice, review recently published evidence, and align tools used for health and social care assessments. This would help educate leaders, which would enable information to be cascaded down to other professionals. Based on expert testimony, the committee also agreed that these meetings would help standardise the different agencies' use of language, risk-assessment tools, and job titles and roles. The committee agreed that such forums could adapt to situations specific to the local authority – for example, increasing numbers of unaccompanied asylum-seeking children or increasing risks of going missing in care. The committee agreed that risk-assessment tools were useful to determine increased risk of exploitation at the individual level (for example, someone placed out of area is at increased risk), but it needed to be standardised across local authorities and agencies.\n\n## How the recommendations might affect practice\n\nThere may be organisation and facilitation costs for starting a forum to bring together agencies and representatives providing care for looked-after children and young people within a local authority. However, these are justified by the benefits of facilitating communication between agencies, providing education, sharing tools and expertise, and giving examples of best practice. Virtual forums may also help to bring costs down.\n\nThe committee noted that, in many cases, various boards, groups and councils already exist within local authorities. Partnerships with these could be organised to bring leaders together from several sectors. Some examples of existing relevant boards, groups and councils include: corporate parenting boards; children's safeguarding boards; children's trust boards; health and wellbeing boards; children's care councils; youth councils; foster care liaison groups; and clinical commissioning groups.\n\nReturn to recommendations"}
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https://www.nice.org.uk/guidance/ng205
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This guideline covers how organisations, practitioners and carers should work together to deliver high-quality care, stable placements and nurturing relationships for looked-after children and young people. It aims to help these children and young people reach their full potential and have the same opportunities as their peers.
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091c1edefc17c3fa340ea39684cbf5b471715302
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nice
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Berotralstat for preventing recurrent attacks of hereditary angioedema
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Berotralstat for preventing recurrent attacks of hereditary angioedema
Evidence-based recommendations on berotralstat (Orladeyo) for preventing recurrent attacks of hereditary angioedema in people 12 years and older.
# Recommendations
Berotralstat is recommended as an option for preventing recurrent attacks of hereditary angioedema in people 12 years and older, only if:
they have at least 2 attacks per month, and
it is stopped if the number of attacks per month does not reduce by at least 50% after 3 months.It is only recommended if the company provides berotralstat according to the commercial arrangement.
This recommendation is not intended to affect treatment with berotralstat that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician and the young person and the young person's parents or carers.
Why the committee made these recommendations
There are not many effective treatments available for preventing recurrent attacks of hereditary angioedema. Clinical trial evidence suggests that berotralstat is effective at reducing the number of attacks per month compared with placebo.
Despite some uncertainty in the clinical evidence, berotralstat is considered cost effective for people who have at least 2 attacks per month, and if they stop having berotralstat if it has not reduced attacks enough after 3 months. So, it is recommended for these people.# Information about berotralstat
# Marketing authorisation indication
Berotralstat (Orladeyo, BioCryst) is indicated for 'routine prevention of recurrent attacks of hereditary angioedema (HAE) in adult and adolescent patients aged 12 years and older'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of berotralstat is £10,205 for a 28-pack of 150 mg capsules (company submission), which equates to an annual cost of £133,120.60. The company has a commercial arrangement. This makes berotralstat available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by BioCryst, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# New treatment option
## There is an unmet need for effective treatment options for preventing recurrent attacks of hereditary angioedema
Hereditary angioedema is a rare genetic disorder. It affects approximately 1 per 10,000 to 50,000 people, and usually develops in the first 10 to 20 years of life. It is a relapsing condition that causes unpredictable and recurrent attacks of swelling. This is usually in the mouth, gut or airway, but it can affect multiple places in the body at once. It often leads to difficulty breathing and severe pain. The patient experts explained that acute attacks of hereditary angioedema are difficult to predict and can vary in severity from mild to life threatening. Attacks can significantly affect the quality of life of people with this condition, as well as that of their family members and carers. The patient and clinical experts explained that attacks can be triggered by anxiety and stress; for example, exams, surgery or dental treatment, as well as positive life events such as weddings and holidays. The clinical experts highlighted that usually attacks are treated as they happen. They advised that the aim of prophylactic treatment is to reduce the rate and severity of attacks and allow people to live an attack-free life. There are currently no effective licensed oral prophylactic treatments. Current oral long-term prophylactic treatment includes attenuated androgens, usually danazol. These are prescribed early in the treatment pathway but often have side effects and limited effectiveness. Also, access to androgens is often limited because of supply issues (see section 3.2). The clinical experts explained that long-term prophylactic treatment with injectable lanadelumab or C1 esterase inhibitors (C1‑INH) is only available in England for a very small number of people who have 2 or more clinically significant attacks per week as per NHS England's commissioning policy. The patient and clinical experts also highlighted that there are limited prophylactic treatment options for people with difficult intravenous access and needle phobia. The committee recognised that hereditary angioedema can be a severe and debilitating condition. It acknowledged the lack of effective prophylactic treatment options available to people with this condition. The committee concluded that there is an unmet need for effective treatment options for preventing recurrent attacks of hereditary angioedema.
# Treatment pathway and comparators
## Berotralstat is recommended whether or not people have had androgens before
The company originally positioned berotralstat for people with at least 2 angioedema attacks per month who have used androgens before, or if androgens are unsuitable. To align with its proposed positioning for berotralstat, in the economic model the company used data on the subgroup of patients in APeX‑2 (the main source of clinical evidence; see section 3.4 and section 3.5) who had at least 2 attacks per month and who had used androgens before. This population is narrower than that specified in the marketing authorisation and NICE scope. It is also narrower than the intention to treat population of APeX‑2 (n=80 in the intention to treat population compared with n=35 in the company's proposed positioning subgroup). The intention to treat population in APeX‑2 also includes patients who had fewer than 2 attacks per month, and those who had not used androgens before. The clinical experts explained that specifying 2 or more attacks a month is reasonable. This is because people having less frequent attacks may not want to take regular or preventative treatments to avoid attacks. However, they stated that supply of androgens in the NHS is inconsistent. They explained that access to androgens varies, is based on local arrangements, and people are unable to get them from local pharmacies. One expert highlighted that the Department of Health and Social Care's advice to clinicians is to not prescribe androgens to people who have not had them before. The committee heard that people under 18 cannot have androgens, but people under 18 are included in the marketing authorisation for berotralstat. It was concerned that positioning berotralstat after androgens may prevent some people from accessing berotralstat. Consultation comments highlighted that the term 'unsuitable for androgens' in the company's proposed positioning wording should apply to people under 18. During consultation, the company agreed that it is suboptimal to deny access to berotralstat because of androgen supply shortages and updated its proposed positioning wording to include 'unavailability of androgens'. However, the committee remained concerned that this may still inadvertently prevent some people from accessing berotralstat. So it based its decision making on a larger subgroup (see section 3.7), which included some people who had not had androgens before. Since the cost-effectiveness estimates for this subgroup are within the range normally considered cost effective, berotralstat is recommended whether or not people have had androgens before (see section 3.16).
## Standard care is an appropriate comparator at the company's proposed positioning of berotralstat
The company submission compared prophylactic berotralstat with no prophylactic treatment. In both groups people had treatment if they had an attack. The company described this as standard care. Standard care treatments include C1-INHs, icatibant and conestat alfa. The ERG noted that this was narrower than the comparators specified in NICE's final scope for this appraisal. But the ERG's clinical expert agreed with the company's description of how hereditary angioedema is currently treated in the UK. The committee concluded that standard care is an appropriate comparator at the company's proposed positioning of berotralstat.
# Clinical effectiveness
## The clinical evidence for berotralstat is from APeX-2, a phase 3, randomised, placebo-controlled trial
The clinical-effectiveness evidence for berotralstat is from APeX‑2. This is a 3-part, phase 3, randomised, double-blind, placebo-controlled trial in people 12 years or older with type 1 or type 2 hereditary angioedema. Part 1 of APeX‑2 compared berotralstat 150 mg (n=40) with placebo (n=40) over a follow-up period of 6 months. People had standard care if they had an attack during the trial period in both the berotralstat and placebo arms (see section 3.3). The placebo arm of APeX‑2 informed the clinical evidence for the standard care arm used in the economic model. Berotralstat 110 mg was also included in APeX‑2 but was not considered relevant to this appraisal because this dose will not be licensed or marketed in the UK. The committee was aware of the small sample size of the trial, particularly for the trial data relevant to the company's proposed positioning (see section 3.2). However, it acknowledged that doing a robust trial in hereditary angioedema is difficult because of the rarity of the disease.
## Clinical evidence suggests berotralstat is more effective than placebo in reducing attack rate, but its effect on attack severity is not known
Results from the intention to treat population of APeX‑2 show a statistically significant reduction in mean monthly attack rates of 44% with berotralstat compared with placebo. Similar results were observed for the subgroup of patients from APeX‑2 who had 2 or more attacks at baseline. The patient experts explained that a prophylactic treatment that reduces attack rate could potentially be life changing for people with this condition. However, they explained that although the reduction in attack rate is a clinically important outcome for people with hereditary angioedema, the reduction in attack severity would be equally important. They noted that if a treatment did not reduce attack rate, but reduced attack severity, they would still value the option to have that treatment. They further highlighted that the hospitalisation of people with hereditary angioedema is often because of attack severity rather than attack rate. The company and the ERG stated that the location of the attack (such as the limbs or the airway) and duration of attack were used as a proxy for attack severity in the model. The company explained that the direct measure of attack severity in the trial was subjective and did not show that berotralstat reduced attack severity more than placebo. This was despite the proxy measures showing that berotralstat reduced severity. So this subjective measure was not considered credible enough to be included as an outcome in the analysis. The committee recognised that it is important to consider evidence on attack severity as well as attack rate when assessing the clinical effectiveness of berotralstat. The committee was dissatisfied that direct data on severity from APeX‑2 was not presented and applied in the model but accepted that there are limitations with this data. It concluded that the clinical evidence suggests berotralstat is more effective than placebo in reducing attack rate, but its effect on attack severity is not known.
# Economic model
## The company's model structure is acceptable for decision making
The company submitted a cohort-level Markov model with 2 health states: alive and dead. The alive health state was split into 2 substates: attack free or attack. The time spent in each of these substates was determined by treatment-specific attack rates from APeX‑2. The model used percentage reductions from baseline attack rates in the berotralstat and placebo arms of APeX‑2, applied to the baseline attack rates specified in the model. People in the attack substate incur the costs of an acute attack and lower health benefits compared with those in the attack-free substate. The ERG advised that the model structure is generally acceptable and similar to a previous appraisal in this disease area (see NICE's technology appraisal guidance on lanadelumab). In the berotralstat arm of the model, the company applied a treatment continuation rule. This rule states that people can only continue taking berotralstat if they have a reduction in attack rate of at least 50% compared with baseline by 3 months. However, the committee noted that there was no continuation rule in APeX‑2 or the marketing authorisation. It was concerned with the choice of a 50% or more reduction in attack rate from baseline as the cut-off point to continue treatment beyond 3 months. The company stated that this 50% or more cut-off point was based on people having 2 or more attacks per month. It noted that applying this cut-off point results in a reduction of at least 1 attack per month. The patient experts explained that if people had fewer attacks but did not reach the threshold of a 50% reduction, they would likely want to continue treatment anyway. Also, even if the number of attacks did not decrease, but the severity did, they would consider it beneficial to continue treatment. The committee noted the importance of the patient experts' comments, and was concerned that it would be difficult to implement the continuation rule in clinical practice. In response to consultation, the company highlighted that a continuation rule is already being used in clinical practice through the early access to medicines scheme for berotralstat. It noted that continuation rules are in place for other treatments for hereditary angioedema through NHS England's commissioning policy on C1‑INHs. Comments from consultees, including patient organisations, also supported applying the continuation rule in clinical practice. They suggested that clear guidance on stopping if the response to berotralstat is not good enough should be provided and that a 50% reduction in attacks is reasonable. Clinical advice to the ERG also supported the continuation rule. However, the ERG highlighted that the early access to medicines scheme for berotralstat and NHS England's commissioning policy for use of C1‑INHs do not strictly define the percentage reduction in attack rate. The committee was satisfied that it was appropriate to include a continuation rule in the economic model. It concluded that the model structure is acceptable for decision making.
## Analysis from the larger subgroup is appropriate for decision making
To align with its proposed positioning for berotralstat, the company's model inputs were based on data from a subgroup of APeX‑2 with a small number of patients (n=35, 17 patients who had berotralstat and 18 who had standard care; see section 3.2). The ERG highlighted its concerns with using clinical evidence for attack rate reductions based on a small sample size. It suggested that analysis using the intention to treat population would provide this evidence for a larger number of people. This would also reduce uncertainty in the cost-effectiveness analysis. In response to technical engagement, the company considered using the intention to treat population from APeX‑2 to inform its economic model. But because this included people who would not have berotralstat in UK clinical practice, it suggested that this would undermine the cost-effectiveness evidence used for decision making. Instead, it provided a scenario analysis using clinical evidence from a larger subgroup (n=57) of people with at least 2 attacks per month who may not have used androgens before. The ERG agreed with using this larger subgroup because it included more people than the company's proposed positioning subgroup. At the second meeting, the ERG also highlighted that the company's updated positioning (see section 3.2) may include more people who have not had androgens before. This made using data from the larger subgroup more relevant. The committee recalled its concerns about the company's positioning (see section 3.2). It concluded that the larger subgroup including those who may not have used androgens before is more appropriate for decision making.
## Applying the placebo effect consistently across treatment arms when extrapolating attack rate is appropriate
The company's original model used observed data from APeX‑2 to inform treatment-specific baseline attack rates. It used the monthly percentage reduction in attack rates from baseline to 12 months for the berotralstat arm, and to 6 months for the standard care arm. To extrapolate the long-term percentage reduction in attack rate in each treatment arm beyond the specified periods, it used the last observed percentage reduction carried forward over the remaining time horizon of the model. The ERG raised several concerns with the company's original base-case analysis:
It relied on treatment-arm specific baseline attack rates, rather than adjusting these to be equal between arms.
Percentage reductions in attack rate for people who met the company's criteria to continue treatment at 3 months (see section 3.6; n=8) were calculated from the average baseline attack rate of the wider subgroup (including people who met the criteria and those who did not; n=17), rather than only using the baseline attack rate of people who met the criteria.
Using the last observation carried forward approach does not recognise the observed variation in monthly attack rates compared with baseline. This may potentially exaggerate the expected difference in attack rate between the berotralstat and standard care arms over the duration of the model (particularly given the small patient numbers). The company noted the ERG's comments and provided a revised base case at the first committee meeting, which included:
a pooled baseline attack rate between the berotralstat and standard care arms
a separate baseline attack rate for people who met the company's criteria to continue treatment with berotralstat
an average reduction in attack rate (using data from months 4 to 12) applied from month 12 onwards for the berotralstat arm. This was relative to the baseline attack rate for people who met the criteria to continue treatment with berotralstat. The committee noted that in its revised base case the company assumed a 0% reduction in attack rate for the standard care arm to be carried forward beyond 6 months in the model. This was different from the ERG's suggested approach to carry forward the average attack rate reduction between months 0 and 6. The ERG explained that the company's approach only removed the placebo effect from the standard care arm. But it suggested that some placebo effect is also likely in the berotralstat arm as well. The committee suggested it may be more appropriate to adjust the average percentage reduction in attack rate in the berotralstat arm carried forward beyond the observed trial period, using the size of placebo effect seen in the standard care arm. In response to consultation, the company provided an updated model using APeX‑2 data up to 24 months for the berotralstat arm. For the berotralstat arm, the updated model used an average attack rate carried forward from month 24 onwards. For the standard care arm, the reduction in attack rate was tapered to the baseline attack rate from months 6 to 12. This is to account for the placebo effect observed in the placebo arm of APeX‑2. The baseline attack rate is then carried forward from month 12 onwards. The ERG provided additional scenarios using different methods for extrapolating attack rate reduction for the standard care and berotralstat arms, including accounting for a placebo effect in the berotralstat arm. The committee considered the company's approach inconsistent and likely to favour the treatment effect in the berotralstat arm. It preferred the ERG's scenario in which the placebo effect is accounted for in both the standard care arm and berotralstat arm from month 7, with the placebo effect applied to the average berotralstat attack rate reduction beyond the trial observed period. It concluded that the extrapolation of attack rate reduction that applies the placebo effect consistently across treatment arms is more appropriate.
## Treatment-arm specific costs for managing acute attacks taken directly from APeX-2 are appropriate for decision making
The company's model took treatment-arm specific costs for managing acute attacks from APeX‑2. This resulted in the estimated costs per attack being lower in the berotralstat arm than in the standard care arm. This was because of a reduced need for multiple administrations of treatments to manage acute attacks. However, the ERG's clinical expert suggested that there was no plausible reason for berotralstat to consistently affect the cost of treating attacks. Because of the small sample size of the company's proposed positioning subgroup (see section 3.2), the ERG advised that it would be more appropriate to use equal acute attack treatment costs between the berotralstat and standard care arms, based on the intention to treat population. In response to technical engagement, the company highlighted that use of acute treatments in the berotralstat and standard care arms of APeX‑2 was consistent between its proposed positioning subgroup, the intention to treat population and the larger subgroup. Clinical advice to the company suggested that a reduced need for multiple treatments for acute attacks in the berotralstat arm was because of reduced attack severity. During technical engagement, the clinical experts highlighted that prophylactic treatment would likely reduce both the rate and severity of attacks, resulting in lower costs per acute attack overall. They explained that the number of people who need a second dose of treatment to manage acute attacks would reduce if berotralstat reduces attack severity. The committee considered that alternative published data sources may provide information about the use of treatments for acute attacks. However, it concluded that treatment-arm specific costs for managing acute attacks taken directly from APeX‑2 were appropriate for decision making.
# Health-related quality of life
## Analysis using utility values that reflect attack severity as well as attack rate reduction would have been preferable
The company used utility values from Nordenfelt et al. (2014), a Swedish registry study that included EQ‑5D‑5L values for both the attack-free and attack substates. The ERG highlighted that EQ‑5D data was collected in APeX‑2. It considered that this should have been explored further, particularly in the APeX‑2 intention to treat population given the small sample size of the company's proposed positioning subgroup (see section 3.2) and the continuation rule (see section 3.6). During technical engagement, the company explained that using the EQ‑5D data from APeX‑2 resulted in implausible utility values for the attack-free health state because they were higher than those of the general UK population. The clinical experts explained that the effect of an attack on quality of life is more likely to be influenced by personal factors and severity of attacks, rather than prior treatment with androgens or attack rate. They advised that quality of life is better for those in the berotralstat arm compared with the standard care arm when attack free. The ERG also highlighted that the utility values from Nordenfelt et al. were based on a larger sample size and that the attack utility data was collected systematically. In contrast, in APeX‑2, the quality-of-life data collection may not have coincided with an attack. The committee was concerned that using utility values directly from APeX‑2 may not adequately capture the effect of attacks on health‑related quality of life and does not reflect the effect of attack severity. But it noted that the latter was likely to apply to the utility values from Nordenfelt et al. too. The ERG explained that the duration of attack, which is used as a proxy for attack severity, is captured in the quality-adjusted life year (QALY) calculation. But it noted that there was not much difference in the duration of attack between the different treatment arms in APeX‑2. The committee concluded that analysis using utility values that reflect attack severity as well as attack rate reduction would have been preferable.
## It is not appropriate to include health-related quality of life effects for carers in the base case
The company's original model included a caregiver disutility based on a time trade off study that reflected how anxiety and the need to provide care affect caregivers' health-related quality of life. This was applied in the model for all the time spent caring for a person with an attack in the alive health state. The ERG explained that applying a single carer disutility for every attack and for every person may be too simplistic. It noted that it is unlikely that all attacks will affect carers to the same extent. It also had concerns with how large the carer disutility is, but this figure is considered confidential by the company and cannot be reported here. It suggested that this was too large when compared with the range identified in the NICE's decision support unit review of other technology appraisals (0.01 to 0.173 per year). Following technical engagement, the company revised its base case by applying carer disutility to 52% of attacks based on a burden of illness study. The patient experts explained the effect hereditary angioedema attacks have on carers, and the level of anxiety associated with caring for a family member with hereditary angioedema. The committee heard that, despite a reduction in attack rate, the level of anxiety remains, although often to a lesser extent for both patients and carers. The committee was aware that NICE's guide to the methods of technology appraisal states that the perspective on outcomes should be 'all direct health effects, whether for patients or, when relevant, carers'. However, it noted that although many diseases and conditions may adversely affect carers, few technology appraisals model this. For example, carer disutility was not included in a previous appraisal in this disease area (see NICE's technology appraisal guidance on lanadelumab). It considered that there was no clear evidence to suggest that the utility gains for carers associated with berotralstat use would be substantially greater than those with displaced treatments. It concluded that it was not appropriate to include health-related quality of life effects for carers in the base case.
# Cost-effectiveness estimates
## Berotralstat is cost effective compared with standard care
The committee considered the cost effectiveness for berotralstat compared with standard care using its preferred assumptions, that is:
using the larger subgroup to inform the clinical and cost-effectiveness evidence (see section 3.7)
using a continuation rule in the economic model (see section 3.6)
applying the placebo effect consistently across treatment arms when extrapolating attack rate reduction (see section 3.8)
not applying carer disutility to ongoing attacks (see section 3.11)
treatment-arm specific costs for managing acute attacks taken directly from APeX‑2 (see section 3.9). The analyses took into account the updated confidential commercial arrangement for berotralstat and the confidential Commercial Medicines Unit prices for treatments used for acute attacks. It agreed that the most plausible incremental cost-effectiveness ratio (ICER) was within the range NICE normally considers an acceptable use of NHS resources, that is £20,000 to £30,000 per QALY gained. The exact figure cannot be reported because of the confidential prices for the treatments used for acute attacks. The committee concluded that berotralstat is a cost-effective use of NHS resources compared with standard care.
# End of life
## Berotralstat does not meet the criteria to be considered a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that berotralstat is a long-term prophylactic treatment and that the company did not make a case for berotralstat to be considered a life-extending treatment. The committee concluded that berotralstat does not meet the criteria to be considered a life-extending treatment at the end of life.
# Innovation
## Berotralstat is an innovative prophylactic treatment for recurrent attacks of hereditary angioedema
The committee considered berotralstat to be innovative because it would be the first licensed oral prophylactic treatment option for people with recurrent attacks of hereditary angioedema. This would mean people would have access to medicine that is more convenient than injectables. The patient and clinical experts explained the importance of reducing attack rate and people being attack free. They highlighted the potential for berotralstat to improve unpredictable and recurrent attacks of swelling and overall quality of life of people with this condition. The committee noted that berotralstat was granted early access to medicines scheme status. This gives people with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorisation or when there is a clear unmet medical need. The committee concluded that berotralstat is an innovative prophylactic treatment for recurrent attacks of hereditary angioedema, but all relevant benefits are reflected in the cost-effectiveness estimates.
# Equality considerations
## There are no equalities issues relevant to the recommendation
No equalities issues were raised during scoping and technical engagement. The committee considered the implications of the company's positioning for berotralstat (see section 3.2), including any equality considerations. No additional equality issues were raised. The committee concluded that there were no equalities issues relevant to the recommendation.
# Conclusion
## Berotralstat is recommended for preventing recurrent attacks of hereditary angioedema
Berotralstat is clinically effective at reducing attack rate compared with placebo. The committee took into account all commercial discounts for berotralstat and standard care treatments and agreed that the most plausible ICER was within the range NICE normally considers to be a cost-effective use of NHS resources. So, it concluded that berotralstat is recommended for preventing recurrent attacks of hereditary angioedema for people 12 years and older. But it is recommended only if they have at least 2 attacks per month, and it is stopped if the number of attacks per month does not reduce by at least 50% after 3 months.
|
{'Recommendations': "Berotralstat is recommended as an option for preventing recurrent attacks of hereditary angioedema in people 12\xa0years and older, only if:\n\nthey have at least 2\xa0attacks per month, and\n\nit is stopped if the number of attacks per month does not reduce by at least 50% after 3\xa0months.It is only recommended if the company provides berotralstat according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with berotralstat that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. For young people, this decision should be made jointly by the clinician and the young person and the young person's parents or carers.\n\nWhy the committee made these recommendations\n\nThere are not many effective treatments available for preventing recurrent attacks of hereditary angioedema. Clinical trial evidence suggests that berotralstat is effective at reducing the number of attacks per month compared with placebo.\n\nDespite some uncertainty in the clinical evidence, berotralstat is considered cost effective for people who have at least 2\xa0attacks per month, and if they stop having berotralstat if it has not reduced attacks enough after 3\xa0months. So, it is recommended for these people.", 'Information about berotralstat': "# Marketing authorisation indication\n\nBerotralstat (Orladeyo, BioCryst) is indicated for 'routine prevention of recurrent attacks of hereditary angioedema (HAE) in adult and adolescent patients aged 12\xa0years and older'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of berotralstat is £10,205 for a 28-pack of 150\xa0mg capsules (company submission), which equates to an annual cost of £133,120.60. The company has a commercial arrangement. This makes berotralstat available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by BioCryst, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# New treatment option\n\n## There is an unmet need for effective treatment options for preventing recurrent attacks of hereditary angioedema\n\nHereditary angioedema is a rare genetic disorder. It affects approximately 1 per 10,000 to 50,000 people, and usually develops in the first 10 to 20\xa0years of life. It is a relapsing condition that causes unpredictable and recurrent attacks of swelling. This is usually in the mouth, gut or airway, but it can affect multiple places in the body at once. It often leads to difficulty breathing and severe pain. The patient experts explained that acute attacks of hereditary angioedema are difficult to predict and can vary in severity from mild to life threatening. Attacks can significantly affect the quality of life of people with this condition, as well as that of their family members and carers. The patient and clinical experts explained that attacks can be triggered by anxiety and stress; for example, exams, surgery or dental treatment, as well as positive life events such as weddings and holidays. The clinical experts highlighted that usually attacks are treated as they happen. They advised that the aim of prophylactic treatment is to reduce the rate and severity of attacks and allow people to live an attack-free life. There are currently no effective licensed oral prophylactic treatments. Current oral long-term prophylactic treatment includes attenuated androgens, usually danazol. These are prescribed early in the treatment pathway but often have side effects and limited effectiveness. Also, access to androgens is often limited because of supply issues (see section 3.2). The clinical experts explained that long-term prophylactic treatment with injectable lanadelumab or C1 esterase inhibitors (C1‑INH) is only available in England for a very small number of people who have 2 or more clinically significant attacks per week as per NHS England's commissioning policy. The patient and clinical experts also highlighted that there are limited prophylactic treatment options for people with difficult intravenous access and needle phobia. The committee recognised that hereditary angioedema can be a severe and debilitating condition. It acknowledged the lack of effective prophylactic treatment options available to people with this condition. The committee concluded that there is an unmet need for effective treatment options for preventing recurrent attacks of hereditary angioedema.\n\n# Treatment pathway and comparators\n\n## Berotralstat is recommended whether or not people have had androgens before\n\nThe company originally positioned berotralstat for people with at least 2\xa0angioedema attacks per month who have used androgens before, or if androgens are unsuitable. To align with its proposed positioning for berotralstat, in the economic model the company used data on the subgroup of patients in APeX‑2 (the main source of clinical evidence; see section 3.4 and section 3.5) who had at least 2\xa0attacks per month and who had used androgens before. This population is narrower than that specified in the marketing authorisation and NICE scope. It is also narrower than the intention to treat population of APeX‑2 (n=80 in the intention to treat population compared with n=35 in the company's proposed positioning subgroup). The intention to treat population in APeX‑2 also includes patients who had fewer than 2\xa0attacks per month, and those who had not used androgens before. The clinical experts explained that specifying 2 or more attacks a month is reasonable. This is because people having less frequent attacks may not want to take regular or preventative treatments to avoid attacks. However, they stated that supply of androgens in the NHS is inconsistent. They explained that access to androgens varies, is based on local arrangements, and people are unable to get them from local pharmacies. One expert highlighted that the Department of Health and Social Care's advice to clinicians is to not prescribe androgens to people who have not had them before. The committee heard that people under\xa018 cannot have androgens, but people under\xa018 are included in the marketing authorisation for berotralstat. It was concerned that positioning berotralstat after androgens may prevent some people from accessing berotralstat. Consultation comments highlighted that the term 'unsuitable for androgens' in the company's proposed positioning wording should apply to people under\xa018. During consultation, the company agreed that it is suboptimal to deny access to berotralstat because of androgen supply shortages and updated its proposed positioning wording to include 'unavailability of androgens'. However, the committee remained concerned that this may still inadvertently prevent some people from accessing berotralstat. So it based its decision making on a larger subgroup (see section 3.7), which included some people who had not had androgens before. Since the cost-effectiveness estimates for this subgroup are within the range normally considered cost effective, berotralstat is recommended whether or not people have had androgens before (see section 3.16).\n\n## Standard care is an appropriate comparator at the company's proposed positioning of berotralstat\n\nThe company submission compared prophylactic berotralstat with no prophylactic treatment. In both groups people had treatment if they had an attack. The company described this as standard care. Standard care treatments include C1-INHs, icatibant and conestat alfa. The ERG noted that this was narrower than the comparators specified in NICE's final scope for this appraisal. But the ERG's clinical expert agreed with the company's description of how hereditary angioedema is currently treated in the UK. The committee concluded that standard care is an appropriate comparator at the company's proposed positioning of berotralstat.\n\n# Clinical effectiveness\n\n## The clinical evidence for berotralstat is from APeX-2, a phase 3, randomised, placebo-controlled trial\n\nThe clinical-effectiveness evidence for berotralstat is from APeX‑2. This is a 3-part, phase\xa03, randomised, double-blind, placebo-controlled trial in people 12\xa0years or older with type 1 or type\xa02 hereditary angioedema. Part 1 of APeX‑2 compared berotralstat 150\xa0mg (n=40) with placebo (n=40) over a follow-up period of 6\xa0months. People had standard care if they had an attack during the trial period in both the berotralstat and placebo arms (see section 3.3). The placebo arm of APeX‑2 informed the clinical evidence for the standard care arm used in the economic model. Berotralstat 110\xa0mg was also included in APeX‑2 but was not considered relevant to this appraisal because this dose will not be licensed or marketed in the UK. The committee was aware of the small sample size of the trial, particularly for the trial data relevant to the company's proposed positioning (see section 3.2). However, it acknowledged that doing a robust trial in hereditary angioedema is difficult because of the rarity of the disease.\n\n## Clinical evidence suggests berotralstat is more effective than placebo in reducing attack rate, but its effect on attack severity is not known\n\nResults from the intention to treat population of APeX‑2 show a statistically significant reduction in mean monthly attack rates of 44% with berotralstat compared with placebo. Similar results were observed for the subgroup of patients from APeX‑2 who had 2 or more attacks at baseline. The patient experts explained that a prophylactic treatment that reduces attack rate could potentially be life changing for people with this condition. However, they explained that although the reduction in attack rate is a clinically important outcome for people with hereditary angioedema, the reduction in attack severity would be equally important. They noted that if a treatment did not reduce attack rate, but reduced attack severity, they would still value the option to have that treatment. They further highlighted that the hospitalisation of people with hereditary angioedema is often because of attack severity rather than attack rate. The company and the ERG stated that the location of the attack (such as the limbs or the airway) and duration of attack were used as a proxy for attack severity in the model. The company explained that the direct measure of attack severity in the trial was subjective and did not show that berotralstat reduced attack severity more than placebo. This was despite the proxy measures showing that berotralstat reduced severity. So this subjective measure was not considered credible enough to be included as an outcome in the analysis. The committee recognised that it is important to consider evidence on attack severity as well as attack rate when assessing the clinical effectiveness of berotralstat. The committee was dissatisfied that direct data on severity from APeX‑2 was not presented and applied in the model but accepted that there are limitations with this data. It concluded that the clinical evidence suggests berotralstat is more effective than placebo in reducing attack rate, but its effect on attack severity is not known.\n\n# Economic model\n\n## The company's model structure is acceptable for decision making\n\nThe company submitted a cohort-level Markov model with 2\xa0health states: alive and dead. The alive health state was split into 2\xa0substates: attack free or attack. The time spent in each of these substates was determined by treatment-specific attack rates from APeX‑2. The model used percentage reductions from baseline attack rates in the berotralstat and placebo arms of APeX‑2, applied to the baseline attack rates specified in the model. People in the attack substate incur the costs of an acute attack and lower health benefits compared with those in the attack-free substate. The ERG advised that the model structure is generally acceptable and similar to a previous appraisal in this disease area (see NICE's technology appraisal guidance on lanadelumab). In the berotralstat arm of the model, the company applied a treatment continuation rule. This rule states that people can only continue taking berotralstat if they have a reduction in attack rate of at least 50% compared with baseline by 3\xa0months. However, the committee noted that there was no continuation rule in APeX‑2 or the marketing authorisation. It was concerned with the choice of a 50% or more reduction in attack rate from baseline as the cut-off point to continue treatment beyond 3\xa0months. The company stated that this 50% or more cut-off point was based on people having 2 or more attacks per month. It noted that applying this cut-off point results in a reduction of at least 1\xa0attack per month. The patient experts explained that if people had fewer attacks but did not reach the threshold of a 50% reduction, they would likely want to continue treatment anyway. Also, even if the number of attacks did not decrease, but the severity did, they would consider it beneficial to continue treatment. The committee noted the importance of the patient experts' comments, and was concerned that it would be difficult to implement the continuation rule in clinical practice. In response to consultation, the company highlighted that a continuation rule is already being used in clinical practice through the early access to medicines scheme for berotralstat. It noted that continuation rules are in place for other treatments for hereditary angioedema through NHS England's commissioning policy on C1‑INHs. Comments from consultees, including patient organisations, also supported applying the continuation rule in clinical practice. They suggested that clear guidance on stopping if the response to berotralstat is not good enough should be provided and that a 50% reduction in attacks is reasonable. Clinical advice to the ERG also supported the continuation rule. However, the ERG highlighted that the early access to medicines scheme for berotralstat and NHS England's commissioning policy for use of C1‑INHs do not strictly define the percentage reduction in attack rate. The committee was satisfied that it was appropriate to include a continuation rule in the economic model. It concluded that the model structure is acceptable for decision making.\n\n## Analysis from the larger subgroup is appropriate for decision making\n\nTo align with its proposed positioning for berotralstat, the company's model inputs were based on data from a subgroup of APeX‑2 with a small number of patients (n=35, 17\xa0patients who had berotralstat and 18 who had standard care; see section 3.2). The ERG highlighted its concerns with using clinical evidence for attack rate reductions based on a small sample size. It suggested that analysis using the intention to treat population would provide this evidence for a larger number of people. This would also reduce uncertainty in the cost-effectiveness analysis. In response to technical engagement, the company considered using the intention to treat population from APeX‑2 to inform its economic model. But because this included people who would not have berotralstat in UK clinical practice, it suggested that this would undermine the cost-effectiveness evidence used for decision making. Instead, it provided a scenario analysis using clinical evidence from a larger subgroup (n=57) of people with at least 2\xa0attacks per month who may not have used androgens before. The ERG agreed with using this larger subgroup because it included more people than the company's proposed positioning subgroup. At the second meeting, the ERG also highlighted that the company's updated positioning (see section 3.2) may include more people who have not had androgens before. This made using data from the larger subgroup more relevant. The committee recalled its concerns about the company's positioning (see section 3.2). It concluded that the larger subgroup including those who may not have used androgens before is more appropriate for decision making.\n\n## Applying the placebo effect consistently across treatment arms when extrapolating attack rate is appropriate\n\nThe company's original model used observed data from APeX‑2 to inform treatment-specific baseline attack rates. It used the monthly percentage reduction in attack rates from baseline to 12\xa0months for the berotralstat arm, and to 6\xa0months for the standard care arm. To extrapolate the long-term percentage reduction in attack rate in each treatment arm beyond the specified periods, it used the last observed percentage reduction carried forward over the remaining time horizon of the model. The ERG raised several concerns with the company's original base-case analysis:\n\nIt relied on treatment-arm specific baseline attack rates, rather than adjusting these to be equal between arms.\n\nPercentage reductions in attack rate for people who met the company's criteria to continue treatment at 3\xa0months (see section 3.6; n=8) were calculated from the average baseline attack rate of the wider subgroup (including people who met the criteria and those who did not; n=17), rather than only using the baseline attack rate of people who met the criteria.\n\nUsing the last observation carried forward approach does not recognise the observed variation in monthly attack rates compared with baseline. This may potentially exaggerate the expected difference in attack rate between the berotralstat and standard care arms over the duration of the model (particularly given the small patient numbers). The company noted the ERG's comments and provided a revised base case at the first committee meeting, which included:\n\na pooled baseline attack rate between the berotralstat and standard care arms\n\na separate baseline attack rate for people who met the company's criteria to continue treatment with berotralstat\n\nan average reduction in attack rate (using data from months\xa04 to 12) applied from month\xa012 onwards for the berotralstat arm. This was relative to the baseline attack rate for people who met the criteria to continue treatment with berotralstat. The committee noted that in its revised base case the company assumed a 0% reduction in attack rate for the standard care arm to be carried forward beyond 6\xa0months in the model. This was different from the ERG's suggested approach to carry forward the average attack rate reduction between months\xa00 and 6. The ERG explained that the company's approach only removed the placebo effect from the standard care arm. But it suggested that some placebo effect is also likely in the berotralstat arm as well. The committee suggested it may be more appropriate to adjust the average percentage reduction in attack rate in the berotralstat arm carried forward beyond the observed trial period, using the size of placebo effect seen in the standard care arm. In response to consultation, the company provided an updated model using APeX‑2 data up to 24\xa0months for the berotralstat arm. For the berotralstat arm, the updated model used an average attack rate carried forward from month\xa024 onwards. For the standard care arm, the reduction in attack rate was tapered to the baseline attack rate from months\xa06 to 12. This is to account for the placebo effect observed in the placebo arm of APeX‑2. The baseline attack rate is then carried forward from month\xa012 onwards. The ERG provided additional scenarios using different methods for extrapolating attack rate reduction for the standard care and berotralstat arms, including accounting for a placebo effect in the berotralstat arm. The committee considered the company's approach inconsistent and likely to favour the treatment effect in the berotralstat arm. It preferred the ERG's scenario in which the placebo effect is accounted for in both the standard care arm and berotralstat arm from month\xa07, with the placebo effect applied to the average berotralstat attack rate reduction beyond the trial observed period. It concluded that the extrapolation of attack rate reduction that applies the placebo effect consistently across treatment arms is more appropriate.\n\n## Treatment-arm specific costs for managing acute attacks taken directly from APeX-2 are appropriate for decision making\n\nThe company's model took treatment-arm specific costs for managing acute attacks from APeX‑2. This resulted in the estimated costs per attack being lower in the berotralstat arm than in the standard care arm. This was because of a reduced need for multiple administrations of treatments to manage acute attacks. However, the ERG's clinical expert suggested that there was no plausible reason for berotralstat to consistently affect the cost of treating attacks. Because of the small sample size of the company's proposed positioning subgroup (see section 3.2), the ERG advised that it would be more appropriate to use equal acute attack treatment costs between the berotralstat and standard care arms, based on the intention to treat population. In response to technical engagement, the company highlighted that use of acute treatments in the berotralstat and standard care arms of APeX‑2 was consistent between its proposed positioning subgroup, the intention to treat population and the larger subgroup. Clinical advice to the company suggested that a reduced need for multiple treatments for acute attacks in the berotralstat arm was because of reduced attack severity. During technical engagement, the clinical experts highlighted that prophylactic treatment would likely reduce both the rate and severity of attacks, resulting in lower costs per acute attack overall. They explained that the number of people who need a second dose of treatment to manage acute attacks would reduce if berotralstat reduces attack severity. The committee considered that alternative published data sources may provide information about the use of treatments for acute attacks. However, it concluded that treatment-arm specific costs for managing acute attacks taken directly from APeX‑2 were appropriate for decision making.\n\n# Health-related quality of life\n\n## Analysis using utility values that reflect attack severity as well as attack rate reduction would have been preferable\n\nThe company used utility values from Nordenfelt et al. (2014), a Swedish registry study that included EQ‑5D‑5L values for both the attack-free and attack substates. The ERG highlighted that EQ‑5D data was collected in APeX‑2. It considered that this should have been explored further, particularly in the APeX‑2 intention to treat population given the small sample size of the company's proposed positioning subgroup (see section 3.2) and the continuation rule (see section 3.6). During technical engagement, the company explained that using the EQ‑5D data from APeX‑2 resulted in implausible utility values for the attack-free health state because they were higher than those of the general UK population. The clinical experts explained that the effect of an attack on quality of life is more likely to be influenced by personal factors and severity of attacks, rather than prior treatment with androgens or attack rate. They advised that quality of life is better for those in the berotralstat arm compared with the standard care arm when attack free. The ERG also highlighted that the utility values from Nordenfelt et al. were based on a larger sample size and that the attack utility data was collected systematically. In contrast, in APeX‑2, the quality-of-life data collection may not have coincided with an attack. The committee was concerned that using utility values directly from APeX‑2 may not adequately capture the effect of attacks on health‑related quality of life and does not reflect the effect of attack severity. But it noted that the latter was likely to apply to the utility values from Nordenfelt et al. too. The ERG explained that the duration of attack, which is used as a proxy for attack severity, is captured in the quality-adjusted life year (QALY) calculation. But it noted that there was not much difference in the duration of attack between the different treatment arms in APeX‑2. The committee concluded that analysis using utility values that reflect attack severity as well as attack rate reduction would have been preferable.\n\n## It is not appropriate to include health-related quality of life effects for carers in the base case\n\nThe company's original model included a caregiver disutility based on a time trade off study that reflected how anxiety and the need to provide care affect caregivers' health-related quality of life. This was applied in the model for all the time spent caring for a person with an attack in the alive health state. The ERG explained that applying a single carer disutility for every attack and for every person may be too simplistic. It noted that it is unlikely that all attacks will affect carers to the same extent. It also had concerns with how large the carer disutility is, but this figure is considered confidential by the company and cannot be reported here. It suggested that this was too large when compared with the range identified in the NICE's decision support unit review of other technology appraisals (0.01 to 0.173 per year). Following technical engagement, the company revised its base case by applying carer disutility to 52% of attacks based on a burden of illness study. The patient experts explained the effect hereditary angioedema attacks have on carers, and the level of anxiety associated with caring for a family member with hereditary angioedema. The committee heard that, despite a reduction in attack rate, the level of anxiety remains, although often to a lesser extent for both patients and carers. The committee was aware that NICE's guide to the methods of technology appraisal states that the perspective on outcomes should be 'all direct health effects, whether for patients or, when relevant, carers'. However, it noted that although many diseases and conditions may adversely affect carers, few technology appraisals model this. For example, carer disutility was not included in a previous appraisal in this disease area (see NICE's technology appraisal guidance on lanadelumab). It considered that there was no clear evidence to suggest that the utility gains for carers associated with berotralstat use would be substantially greater than those with displaced treatments. It concluded that it was not appropriate to include health-related quality of life effects for carers in the base case.\n\n# Cost-effectiveness estimates\n\n## Berotralstat is cost effective compared with standard care\n\nThe committee considered the cost effectiveness for berotralstat compared with standard care using its preferred assumptions, that is:\n\nusing the larger subgroup to inform the clinical and cost-effectiveness evidence (see section 3.7)\n\nusing a continuation rule in the economic model (see section 3.6)\n\napplying the placebo effect consistently across treatment arms when extrapolating attack rate reduction (see section 3.8)\n\nnot applying carer disutility to ongoing attacks (see section 3.11)\n\ntreatment-arm specific costs for managing acute attacks taken directly from APeX‑2 (see section 3.9). The analyses took into account the updated confidential commercial arrangement for berotralstat and the confidential Commercial Medicines Unit prices for treatments used for acute attacks. It agreed that the most plausible incremental cost-effectiveness ratio (ICER) was within the range NICE normally considers an acceptable use of NHS resources, that is £20,000 to £30,000 per QALY gained. The exact figure cannot be reported because of the confidential prices for the treatments used for acute attacks. The committee concluded that berotralstat is a cost-effective use of NHS resources compared with standard care.\n\n# End of life\n\n## Berotralstat does not meet the criteria to be considered a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It noted that berotralstat is a long-term prophylactic treatment and that the company did not make a case for berotralstat to be considered a life-extending treatment. The committee concluded that berotralstat does not meet the criteria to be considered a life-extending treatment at the end of life.\n\n# Innovation\n\n## Berotralstat is an innovative prophylactic treatment for recurrent attacks of hereditary angioedema\n\nThe committee considered berotralstat to be innovative because it would be the first licensed oral prophylactic treatment option for people with recurrent attacks of hereditary angioedema. This would mean people would have access to medicine that is more convenient than injectables. The patient and clinical experts explained the importance of reducing attack rate and people being attack free. They highlighted the potential for berotralstat to improve unpredictable and recurrent attacks of swelling and overall quality of life of people with this condition. The committee noted that berotralstat was granted early access to medicines scheme status. This gives people with life threatening or seriously debilitating conditions access to medicines that do not yet have a marketing authorisation or when there is a clear unmet medical need. The committee concluded that berotralstat is an innovative prophylactic treatment for recurrent attacks of hereditary angioedema, but all relevant benefits are reflected in the cost-effectiveness estimates.\n\n# Equality considerations\n\n## There are no equalities issues relevant to the recommendation\n\nNo equalities issues were raised during scoping and technical engagement. The committee considered the implications of the company's positioning for berotralstat (see section 3.2), including any equality considerations. No additional equality issues were raised. The committee concluded that there were no equalities issues relevant to the recommendation.\n\n# Conclusion\n\n## Berotralstat is recommended for preventing recurrent attacks of hereditary angioedema\n\nBerotralstat is clinically effective at reducing attack rate compared with placebo. The committee took into account all commercial discounts for berotralstat and standard care treatments and agreed that the most plausible ICER was within the range NICE normally considers to be a cost-effective use of NHS resources. So, it concluded that berotralstat is recommended for preventing recurrent attacks of hereditary angioedema for people 12\xa0years and older. But it is recommended only if they have at least 2\xa0attacks per month, and it is stopped if the number of attacks per month does not reduce by at least 50% after 3\xa0months."}
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https://www.nice.org.uk/guidance/ta738
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Evidence-based recommendations on berotralstat (Orladeyo) for preventing recurrent attacks of hereditary angioedema in people 12 years and older.
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5ea4ffa23ccca6fc6c793901e8a8c0710264c3b8
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nice
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Nivolumab for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based chemotherapy
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Nivolumab for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based chemotherapy
Evidence-based recommendations on nivolumab (Opdivo) for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based chemotherapy in adults.
# Recommendations
Nivolumab is recommended as an option for treating recurrent or metastatic squamous cell carcinoma of the head and neck in adults whose disease has progressed on platinum‑based chemotherapy, only if:
the disease has progressed within 6 months of having chemotherapy and
the company provides it according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for nivolumab for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum‑based chemotherapy.
The new evidence includes data from 1 clinical trial and from people having treatment in the NHS, while this treatment was available in the Cancer Drugs Fund in England. The new evidence shows that people who have nivolumab are likely to live up to 9 months longer than those who have other treatments. But it is unclear how well nivolumab works compared with docetaxel, which is the most relevant comparator.
Nivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. Despite the uncertainty in the clinical evidence, the cost-effectiveness estimates are likely to be within the range NICE considers an acceptable use of NHS resources. So, nivolumab is recommended.# Information about nivolumab
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol—Myers Squibb) as monotherapy is indicated for 'the treatment of recurrent or metastatic squamous cell cancer of the head and neck in adults progressing on or after platinum‑based therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £439 per 40‑mg vial, £1,097 per 100‑mg vial and £2,633 per 240‑mg vial (excluding VAT; BNF online and company submission). The company has a commercial access agreement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Bristol—Myers Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
This guidance review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate 141 study. Data was also collected using the Systemic Anti-Cancer Therapy (SACT) dataset.
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, page 8), and took these into account in its decision making. The committee discussed the following issues, which were outstanding after consultation:
the generalisability of the trial population to NHS clinical practice
the cost effectiveness in PD‑L1 subgroups
the choice of parametric models to predict overall survival
the choice of parametric models to predict time-to-treatment discontinuation
the 2‑year stopping rule and the continued duration of treatment benefit if nivolumab is stopped at 2 years
the choice of utility values
if nivolumab meets the life-extending element of NICE's end of life criteria.
# The condition and clinical management
## Squamous cell carcinoma of the head and neck is a debilitating condition with an unmet need for effective treatment options
Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) that has progressed during or after platinum‑based chemotherapy has a poor prognosis. The patient experts described SCCHN as a debilitating condition with multiple distressing symptoms such as disfigurement, a dry and sore mouth, weight loss and decreased appetite. They explained that the disease affects all aspects of life including mental wellbeing, social functioning, mobility and work. The clinical expert explained that people have limited treatment options and their disease is generally considered incurable at this stage. Existing treatments are taxane‑based chemotherapies such as docetaxel or paclitaxel, which can cause serious adverse reactions, and more recently pembrolizumab and cetuximab have become available (for more about comparators, see section 3.2). The patient experts stated that the outlook is poor for patients with recurrent or metastatic SCCHN that has relapsed on or after platinum‑based chemotherapy. The committee noted that improved quality of life both during and after treatment is most important to this patient group, as is extending life. The committee concluded that there is an unmet need for effective treatment options for people with recurrent or metastatic SCCHN that has progressed on or after platinum‑based chemotherapy.
## Docetaxel is the most appropriate comparator for people fit enough to have it
The committee noted that the treatment pathway for recurrent or metastatic SCCHN had changed since the publication of the original appraisal of nivolumab. This is because cetuximab combination therapy and pembrolizumab monotherapy have been recommended for treating recurrent or metastatic SCCHN (see NICE's technology appraisal guidance on cetuximab for treating recurrent or metastatic squamous cell cancer of the head and neck and pembrolizumab for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma). Although no changes are permitted to the scope in a Cancer Drugs Fund review, the committee noted that there are potential implications for using nivolumab to treat SCCHN that has progressed within 6 months of platinum‑based chemotherapy. It was aware that pembrolizumab is recommended by NICE for untreated metastatic or unresectable recurrent SCCHN in adults whose tumours express PD‑L1 with a combined positive score of 1 or more. The clinical lead for the Cancer Drugs Fund explained that pembrolizumab is administered every 3 or 6 weeks, whereas nivolumab is administered every 2 weeks. Therefore, when both drugs are indicated, pembrolizumab would be more likely to be chosen. They also explained that there are people whose PD‑L1 status cannot be determined because of issues accessing tissue or assays not working, and these people would likely get nivolumab because they are not eligible for pembrolizumab. The committee considered that, in NHS clinical practice, this could result in a large proportion of people having nivolumab when they have tumours with a PD‑L1 score of less than 1 or indeterminate. This could be different to the proportion of those tumours seen in the clinical trial population. At the time of the original appraisal of nivolumab, treatment options in clinical practice in England included taxane‑based chemotherapies (such as docetaxel and paclitaxel) or methotrexate. In the original appraisal, the clinical experts agreed that although there was no evidence of difference in efficacy between docetaxel and paclitaxel, docetaxel would be the standard single‑agent chemotherapy used for recurrent or metastatic SCCHN that progressed during or after platinum‑based therapy in the NHS (most often prescribed as a 3‑weekly treatment regimen). They agreed that the use of paclitaxel in clinical practice is limited. They also stated that methotrexate is normally only offered to people with a poor performance status who are not fit enough to have a taxane, or as subsequent therapy for people who have had a single‑agent taxane. The committee concluded in the original appraisal that docetaxel would be the most appropriate comparator for people fit enough to have it. For this review, the committee concluded that docetaxel was still the most appropriate comparator for its decision making.
# Clinical effectiveness
## Both the intention-to-treat population and docetaxel subgroup from CheckMate 141 should inform decision making
The clinical-effectiveness evidence for nivolumab came from 1 randomised controlled trial (CheckMate 141) that compared nivolumab with the investigator's choice of therapy. Patients randomised to the investigator‑choice arm had 1 of 3 possible weekly therapies (docetaxel , methotrexate and cetuximab ). In the original appraisal, the committee concluded that excluding paclitaxel from the trial and including cetuximab, a drug not used in clinical practice at that time and therefore not included in the NICE scope, introduced uncertainty about the relevance of CheckMate 141 to UK clinical practice. The committee also concluded, based on the opinion of the clinical experts, that it was valid to assume that docetaxel and paclitaxel were equivalent. But it was not persuaded by the company's assumption that docetaxel is equivalent to methotrexate. For this guidance review, the clinical expert acknowledged that the trial took place in several countries where standard care differs from NHS clinical practice. They suggested that the investigator‑choice arm of the trial was an appropriate data source comparison even though cetuximab was not standard care in NHS clinical practice at the time of the original appraisal and methotrexate is only offered to people with poor performance status and may be less effective. The clinical lead for the Cancer Drugs Fund stated that people in the trial (who had an Eastern Cooperative Oncology Group performance status of 0 or 1) would have been fit enough to have docetaxel in NHS clinical practice, and therefore the investigator‑choice arm would not be a relevant comparator. The committee noted that the company had presented results for an analysis comparing nivolumab and docetaxel in patients who would have docetaxel (referred to as the 'docetaxel subgroup') in CheckMate 141. The company highlighted that the trial was not powered to detect differences between nivolumab and docetaxel alone and therefore any results had to be treated with caution. The committee acknowledged that this was not a prespecified subgroup analysis and such a comparison was less robust than using the intention-to-treat population, because of the smaller sample size. It acknowledged that use of the intention-to-treat population may underestimate docetaxel's effectiveness because it includes other treatments that are less effective than docetaxel. The committee concluded that the intention-to-treat trial population is the most appropriate data source for this guidance review, as in the original appraisal, but the docetaxel subgroup analysis should also be considered.
## The clinical benefit of nivolumab compared with docetaxel alone is not clear
For this guidance review, the company provided an additional 37 months of follow-up data (up to October 2019) from Checkmate 141. The results for the intention-to-treat population showed that people who had nivolumab lived longer than people who had the investigator‑choice treatment (median overall survival for nivolumab was 7.7 months, 95% confidence interval 5.7 to 8.7 months; investigator's choice was 5.1 months, 95% CI 4.0 to 6.2 months; hazard ratio 0.69, 95% CI 0.55 to 0.86). The clinical lead for the Cancer Drugs Fund referred to an amendment update of the clinical protocol for CheckMate 141, which meant that people in the investigator‑choice arm could have had nivolumab in the extension phase of the trial. In response to consultation, the company provided the number of people who switched to nivolumab in both the intention-to-treat and docetaxel subgroup population (the exact number of people is confidential so cannot be reported here). The ERG explained that the effect of switching to nivolumab in the comparator arm is unclear, but the percentage of people who switched was low and therefore unlikely to have led to substantial bias. The committee acknowledged that the effect of treatment switching was unknown but agreed that it was unlikely to have had a large effect on the results. The company provided results for the docetaxel subgroup that showed a numerical survival benefit for nivolumab compared with docetaxel, but this was not statistically significant (the exact data are confidential and cannot be reported here). The committee acknowledged that there was uncertainty about the results from the docetaxel subgroup because of the small number of people in the subgroup analysis, and in NHS clinical practice not all patients would have docetaxel. However, it agreed that the subgroup analysis was informative for decision making (for more about this decision, see section 3.3). It concluded, based on the evidence that had been presented, that it was uncertain whether nivolumab was clinically effective compared with docetaxel alone.
## There is evidence of nivolumab's benefit for tumours with a PD-L1 score of 1% or higher, but at a lower PD-L1 score the benefit is not clear
In the original appraisal, the committee concluded that there was evidence of nivolumab's benefit for tumours expressing 1% or more PD‑L1 protein, but at lower expression levels the benefit was not clear. For this guidance review, the company provided subgroup analyses based on the latest available data (up to 15 October 2019) for PD‑L1 of 1% and above and PD‑L1 of less than 1% subgroups in the intention-to-treat population of CheckMate 141. For the subgroup with a PD‑L1 score of 1% and above, the median overall-survival gain was 3.6 months with nivolumab compared with investigator‑choice treatment (hazard ratio 0.54, 95% CI 0.39 to 0.76). For the less than 1% PD‑L1 group, the median overall-survival gain was 1 month (hazard ratio 0.74, 95% CI 0.50 to 1.10). The clinical expert explained that in clinical practice the availability of PD‑L1 testing varies across the NHS in England, and that PD‑L1 scores might not be available for all people at the time when treatment is started. The clinical lead for the Cancer Drugs Fund advised that testing for PD‑L1 status should now be routine for people with recurrent or metastatic SCCHN. Some people do not get testing because of issues with accessing tissue, or they do not get a score because of assays not working. The clinical expert suggested that the PD‑L1 score may not be as good a predictor of treatment outcome as previously thought. The committee noted that PD‑L1 testing in SCCHN would become routine in the NHS now that pembrolizumab is recommended for treating SCCHN in adults whose tumours express 1% or more PD‑L1. It acknowledged that there was uncertainty about the results from the subgroup analyses based on PD‑L1 expression because of the small number of people in the subgroup analysis. However, it considered that it was important to explore them because of NICE's recommendation for using pembrolizumab to treat tumours with a PD‑L1 score of 1 or higher, meaning that nivolumab is likely to be used more often to treat SCCHN with a low or indeterminate PD‑L1 score than in the CheckMate 141 population (for more about comparators at different PD‑L1 scores, see section 3.2). The committee concluded that there was evidence that nivolumab is clinically beneficial for tumours with a PD‑L1 score of 1% and above but the benefit for those with a low PD‑L1 score was less certain.
## Clinical experience with nivolumab in the Cancer Drugs Fund reflects the trial results
As well as new data from CheckMate 141, data from the SACT Dataset was available for this review. Data was collected from 506 people who had nivolumab through the Cancer Drugs Fund between October 2017 and June 2019. The clinical expert explained that clinical experience with nivolumab is positive, and outcomes reflect what was seen in the clinical trials. The 1‑year overall survival was similar between the nivolumab arm of the intention-to-treat population in CheckMate 141 and the SACT data (CheckMate 141 data 33.4%, 95% CI 27.5 to 39.5; SACT data 34%, 95% CI 29% to 38%). The median overall survival in CheckMate 141 was longer (7.7 months, 95% CI 5.7 to 8.7 months) than in the SACT data (6.5 months, 95% CI 5.6 to 7.6 months). However, the 95% confidence intervals overlapped. The time-to-treatment discontinuation in the SACT data was 3.0 months (95% CI 2.7 to 3.3 months), which is longer than in CheckMate 141 (results are confidential and cannot be reported). The committee noted that the SACT data had a median follow up of 5.9 months compared with a minimum follow up of 48.2 months in the trial.
# Modelling overall survival and time-to-treatment discontinuation
## The company's piecewise model is appropriate to extrapolate overall survival, but fully parametric models may also be plausible
In the original appraisal, the committee accepted that a piecewise model was appropriate for estimating overall survival in the intention-to-treat population. The model used Kaplan–Meier data followed by a lognormal distribution, but the time point from which to extrapolate was uncertain. For this guidance review, the company used data from the intention-to-treat population of the trial. It extrapolated from 96 weeks in line with the median follow up of the trial. This resulted in a 5‑year survival of 5.7% and a 10‑year survival of 2.6%. The clinical expert estimated that it was plausible that between 1% and 5% of people having nivolumab will be alive at 5 years, and that few people survive up to 10 years. In its response to technical engagement, the company used the same extrapolation method for the docetaxel subgroup. In response to consultation, it presented evidence of the goodness of fit for this method to the docetaxel subgroup data, and also explored fully parametric methods. The ERG agreed that the company's piecewise method was appropriate to extrapolate overall survival using both the intention-to-treat and docetaxel subgroup data. The committee noted that the company's fully parametric models, in particular the lognormal, could also be plausible and may be useful for decision making. It concluded that the company's piecewise model was appropriate to extrapolate overall survival using both the intention-to-treat and docetaxel subgroup data.
## The company's and the ERG's extrapolation methods for time-to-treatment discontinuation for the docetaxel subgroup are both plausible
In the original appraisal, using the intention-to-treat population, the committee concluded that none of the parametric distributions fitted the time-to-treatment discontinuation data well. It preferred the generalised gamma distribution for both arms in the model for this population. In this guidance review, the company presented an alternative approach using different distributions for the 2 treatment arms. It used the 2‑spline normal distribution for the nivolumab arm, because it had a better statistical and visual fit to the data than the generalised gamma distribution. The method used for the investigator‑choice arm is confidential and cannot be reported here. In its response to technical engagement, the company used the same extrapolation method for the docetaxel subgroup. The ERG preferred using the generalised gamma distribution for both arms, as in the original appraisal and in line with the NICE Decision Support Unit's technical support document 14. The ERG advised that, when the stopping rule was removed (for more about the stopping rule, see section 3.9), using the company's preferred extrapolation for time-to-treatment discontinuation resulted in overall survival falling below time-to-treatment discontinuation, which is implausible. Therefore, the ERG advised that the generalised gamma distribution should be used to extrapolate time-to-treatment discontinuation for both arms in all scenarios in which the stopping rule was removed. The committee noted that real-world treatment discontinuation data was available from the SACT cohort, in which the time-to-treatment discontinuation was generally longer than in CheckMate 141. The committee considered this would result in a higher incremental cost-effectiveness ratio (ICER). In response to consultation, the ERG explained that using different distributions in the 2 arms might introduce bias. Therefore, it preferred to use the generalised gamma distribution to estimate time-to-treatment discontinuation for both treatment arms in the docetaxel subgroup. The committee concluded that both the company's and the ERG's extrapolations for time-to-treatment discontinuation for the docetaxel subgroup were plausible, and it would consider both. It also concluded that the time-to-treatment discontinuation in the SACT cohort was informative.
# Stopping rule and continued treatment effect
## Analyses without a stopping rule are more appropriate for decision making
In the original appraisal, the committee concluded that analyses without a nivolumab stopping rule are more appropriate for decision making than analyses that included a stopping rule. The 2‑year stopping rule was only accepted in the context of the Cancer Drugs Fund. In this guidance review, the patient experts and the clinical expert agreed that people might be disappointed if treatment was beneficial but was stopped at 2 years. The clinical expert confirmed that people who can tolerate and benefit from treatment should be able to have it until their disease progresses, or they have intolerable side effects or choose to stop. People who stopped nivolumab after 2 years but whose disease has not progressed would be offered platinum‑based chemotherapy. The clinical expert explained that people who are alive 5 years after treatment started are considered 'cured' from the disease. In response to consultation, the company provided an updated base case that included a 5‑year stopping rule. It explained that the 5‑year stopping rule was based on clinical expert opinion that people are considered 'cured' at 5 years. It explained that extrapolated data from the trial resulted in 1% of people remaining on treatment at 5 years. The committee considered there to be no clinical evidence that nivolumab can be curative and questioned whether the low numbers on treatment at 5 years reflects real life. The ERG explained that having low numbers of people on treatment at 5 years is not a plausible reason to include a stopping rule. The committee noted that there was no stopping rule included in the trial, and that some people were still taking nivolumab after 2 years. It acknowledged that a stopping rule had been accepted in previous appraisals for nivolumab and other similar drugs, whether or not it was included in the trial. However, in this instance, the committee concluded that a stopping rule was not appropriate, as stated in the original appraisal that recommended nivolumab for use only in the Cancer Drugs Fund.
## Continued treatment benefit up to 5 years is plausible
In the original appraisal, the committee concluded that it was plausible that the treatment benefit of nivolumab continued for 5 years after treatment started. For this guidance review, the company provided a smoothed hazard-rates plot for overall survival for the intention-to-treat population for nivolumab and investigator‑choice treatment. The plot suggested that the hazard rates seemed to meet at around 5 years. This indicates that there was no difference in the treatment effect of the 2 arms at 5 years. In response to consultation, the company provided an updated plot, suggesting the hazard rates did not converge at 5 years. However, the ERG concluded that the rates do converge at 5 years and included treatment waning at 5 years after the start of treatment in its base-case analysis. In CheckMate 141, people in the investigator‑choice arm could have had nivolumab during the extension phase of the trial (for more about this trial, see section 3.4). The committee acknowledged that this crossover could decrease the apparent relative effectiveness of nivolumab compared with investigator's choice. But the percentage of people who switched to nivolumab was low, so any bias is not likely to be substantial. It concluded that it was plausible that nivolumab's treatment effect matches that of standard care at 5 years after treatment started.
# Utility values in the economic model
## The most appropriate utility values lie between the treatment-dependent and the treatment-independent estimates
In the original appraisal, the committee agreed that the most appropriate utility estimates would lie between the treatment-dependent utilities and the treatment-independent utilities. The clinical expert explained that the effect on quality of life was similar for the different treatment options available for recurrent and metastatic SCCHN. The patient experts and the clinical expert confirmed that people's quality of life diminishes during the last months of life. In response to consultation, the company updated its base case to use a different set of utility estimates. These utility values varied depending on whether somebody was on or off treatment, progression-free or had progressed disease, and whether they were having nivolumab or investigator‑choice treatment. The committee noted the company's utility values were derived from surveys done during the trial. However, about one-third of people in the intervention arm and half of people in the investigator‑choice arm did not complete the survey, so there is a large amount of missing data. The clinical lead for the Cancer Drugs Fund noted that some of the utilities applied in the company's updated approach were implausible. For example, people in the investigator‑choice arm who were progression-free and having treatment had a higher utility value compared with those who were progression-free and off treatment. The exact utility values are confidential and cannot be reported here. The committee agreed that the company's updated utility model generated implausible values, and it therefore preferred the models used in the original appraisal. The ERG advised that using the company's treatment-dependent utility model meant that utility benefits associated with nivolumab continue for the rest of a person's life. The company attempted to resolve this life-long benefit by including time-to-death disutilities, but the ERG stated this is not a reasonable approach. The ERG preferred to use treatment-independent utility values in its base case. The committee noted that, in the trial, people could continue having nivolumab after they progressed if the investigator thought they were still benefiting. If people were perceived not to be benefiting, they would stop taking nivolumab. Therefore, the committee considered it is not reasonable to assume an ongoing utility benefit after people had stopped treatment. The treatment-independent utilities are based solely on progression state, whereas the treatment-dependent utilities assume nivolumab has a benefit that continues for the rest of a person's life. Therefore, the committee considered that treatment-dependent utilities were likely to lead to better outcomes and lower ICERs. It concluded that the most appropriate utility values are between the treatment-dependent and the treatment-independent estimates and are likely to be closer to the treatment-independent values.
# End of life
## Life expectancy for people with recurrent or metastatic SCCHN is less than 24 months
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with SCCHN that has progressed within 6 months of having platinum‑based chemotherapy was less than 24 months. The committee did not hear any evidence to change this conclusion. Therefore, it concluded that nivolumab met the short life-expectancy criterion.
## Nivolumab meets the life-extending element of the end-of-life criteria
In the latest data available for CheckMate 141, the median overall survival for the intention-to-treat population for nivolumab was 7.7 months (95% confidence interval 5.7 to 8.7 months) compared with 5.1 months (95% confidence interval 4.0 to 6.2 months) for investigator's choice. The model predicted a mean survival benefit for nivolumab of between 6.8 and 9.2 months in this population. The median overall-survival results for the docetaxel subgroup are confidential and cannot be reported here. When the docetaxel subgroup data were used in the company's base-case model, the mean overall-survival benefit for nivolumab was estimated to be less than when intention-to-treat data were used (the exact values are confidential and cannot be reported here). Although the clinical effectiveness of nivolumab was uncertain in the docetaxel subgroup (for more about this subgroup, see section 3.4), the committee concluded that nivolumab offered a survival benefit of more than 3 months compared with docetaxel. This is regardless of whether the investigator‑choice or docetaxel subgroup data was used in the model. In CheckMate 141, nivolumab also increased the median overall survival by more than 3 months in people whose tumours had a PD‑L1 score of 1% or above (for more about this trial, see section 3.5). In people whose tumours had a PD‑L1 score of less than 1% the increase in median survival was only 1 month, and this was not statistically significant. In response to consultation, the company provided updated overall-survival modelling using a variety of extrapolation methods for PD‑L1 with a combined positive score of less than 1%. The model estimated a mean overall-survival benefit of greater than 6 months for the subgroup with PD‑L1 less than 1%. The committee concluded although there is uncertainty about the PD‑L1 less than 1% subgroup, the life-extending element was met in that subgroup. Therefore, nivolumab meets the life-extending element of the end of life criteria.
# Cost effectiveness
## The company's base case does not reflect the committee's preferred assumptions
The committee agreed it would have preferred the company's base case to:
include treatment-dependent and treatment-independent utility values, with committee preference towards treatment-independent utilities (for more about these utility values, see section 3.11)
assume no treatment benefit for nivolumab 5 years after the start of treatment, and
exclude the stopping rule.
In response to consultation, the company did not provide a scenario that included all of the committee's preferred assumptions. The committee concluded the intention-to-treat population is the most appropriate data source, but agreed that the company's analyses using the docetaxel subgroup data and by PD‑L1 status were of interest and would be considered in its decision making. Because of the uncertainty, an acceptable ICER for nivolumab compared with docetaxel using the intention-to-treat population is toward the lower end of the range normally considered a cost-effective use of NHS resources.
## Nivolumab's cost effectiveness is highly uncertain
NICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for special consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty in the docetaxel subgroup and PD‑L1 subgroups, specifically about the clinical effectiveness (for more about docetaxel and the PD‑L1 scores, see section 3.4 and section 3.5). There is also uncertainty around the most appropriate utility values (for more about the utility values, see section 3.11).
## The maximum acceptable ICER is substantially below £50,000 per QALY gained
Because the conditions of a life-extending treatment at the end of life had been met, the committee considered the maximum acceptable ICER in the context of applying a QALY weight of 1.7 to the range of ICERs normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). Because of the uncertainties about docetaxel efficacy being underestimated in the intention-to-treat population (see for more about the docetaxel subgroup, see section 3.3), clinical effectiveness in PD‑L1 subgroups (for more about the PD‑L1 scores, see section 3.5), different overall-survival extrapolations increasing the ICER (for more about these survival extrapolations, see section 3.7), and time-to-treatment discontinuation based on SACT data increasing the ICER (for more about this data, see section 3.8), the committee decided that the maximum acceptable ICER would be substantially below £50,000 per QALY gained.
## Nivolumab is likely to be a cost-effective use of NHS resources
The company's base-case assumptions differed from the committee's preferred assumptions. The company's base case after consultation included a lifetime treatment benefit of nivolumab, its revised treatment-dependent utilities and a 5‑year stopping rule. Also, the time-to-treatment discontinuation was extrapolated using different distributions in the 2 arms. The committee agreed that the most likely ICER for nivolumab compared with docetaxel, based on its preferred assumptions and using treatment-dependent and treatment-independent utilities, would be substantially below £50,000 per QALY gained. Taking into account the updated commercial arrangement, the ICER was within the range that could be considered a cost-effective use of NHS resources when the stopping rule was removed, a 5‑year treatment waning effect was applied, and time-to-treatment discontinuation was extrapolated using the generalised gamma distribution in the 2 arms (for more about these extrapolations, see section 3.8). When the treatment-independent utility values were applied instead of the treatment-dependent utilities in the same scenario the ICER increased but it still remained within the range that could be considered cost effective. It concluded that incorporating the company's updated commercial arrangement meant that its preferred ICERs were in the range that could be considered cost effective, even though some uncertainties remained. So, nivolumab is recommended for routine use in the NHS.
# Equality issues
## The recommendations apply equally to all people with SCCHN
A patient expert questioned whether age is an equality issue in this appraisal. The clinical expert confirmed that there is no age limit for treatment with nivolumab. The committee heard from the Cancer Drugs Fund clinical lead that data collected by Public Health England from NHS patients in England showed that many older patients had taken nivolumab while it was available in the Cancer Drugs Fund. The committee concluded that there was no relevant equality issue.
# Other factors
The company did not highlight any additional benefits that had not been captured in the QALY calculations.
# Conclusion
## Nivolumab is recommended for routine commissioning
The committee recommended nivolumab, within its marketing authorisation, for recurrent or metastatic SCCHN after platinum‑based chemotherapy in adults. In the original appraisal, the committee concluded that docetaxel was the most relevant comparator, and that assuming clinical equivalence between some of the comparators was uncertain. This meant that using investigator‑choice data from the intention-to-treat population to model all comparators would likely underestimate the effectiveness of docetaxel. In this guidance review, the committee acknowledged the uncertainty surrounding the intention-to-treat population with regard to the docetaxel comparator. Based on the ICERs for nivolumab compared with docetaxel, the committee concluded that the cost-effectiveness estimates were unlikely to exceed its acceptable maximum even though some uncertainties remained. Therefore, nivolumab is recommended.
|
{'Recommendations': "Nivolumab is recommended as an option for treating recurrent or metastatic squamous cell carcinoma of the head and neck in adults whose disease has progressed on platinum‑based chemotherapy, only if:\n\nthe disease has progressed within 6\xa0months of having chemotherapy and\n\nthe company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for nivolumab for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum‑based chemotherapy.\n\nThe new evidence includes data from 1\xa0clinical trial and from people having treatment in the NHS, while this treatment was available in the Cancer Drugs Fund in England. The new evidence shows that people who have nivolumab are likely to live up to 9\xa0months longer than those who have other treatments. But it is unclear how well nivolumab works compared with docetaxel, which is the most relevant comparator.\n\nNivolumab meets NICE's criteria to be considered a life-extending treatment at the end of life. Despite the uncertainty in the clinical evidence, the cost-effectiveness estimates are likely to be within the range NICE considers an acceptable use of NHS resources. So, nivolumab is recommended.", 'Information about nivolumab': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol—Myers Squibb) as monotherapy is indicated for 'the treatment of recurrent or metastatic squamous cell cancer of the head and neck in adults progressing on or after platinum‑based therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £439 per 40‑mg vial, £1,097 per 100‑mg vial and £2,633 per 240‑mg vial (excluding VAT; BNF online [accessed June\xa02021] and company submission). The company has a commercial access agreement. This makes nivolumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol—Myers Squibb, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThis guidance review looks at data collected in the Cancer Drugs Fund to address uncertainties identified during the original appraisal. Further information about the original appraisal is in the committee papers. As a condition of the Cancer Drugs Fund funding and the managed access arrangement, the company was required to collect updated efficacy data from the CheckMate\xa0141 study. Data was also collected using the Systemic Anti-Cancer Therapy (SACT) dataset.\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, page\xa08), and took these into account in its decision making. The committee discussed the following issues, which were outstanding after consultation:\n\nthe generalisability of the trial population to NHS clinical practice\n\nthe cost effectiveness in PD‑L1 subgroups\n\nthe choice of parametric models to predict overall survival\n\nthe choice of parametric models to predict time-to-treatment discontinuation\n\nthe 2‑year stopping rule and the continued duration of treatment benefit if nivolumab is stopped at 2\xa0years\n\nthe choice of utility values\n\nif nivolumab meets the life-extending element of NICE's end of life criteria.\n\n# The condition and clinical management\n\n## Squamous cell carcinoma of the head and neck is a debilitating condition with an unmet need for effective treatment options\n\nRecurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) that has progressed during or after platinum‑based chemotherapy has a poor prognosis. The patient experts described SCCHN as a debilitating condition with multiple distressing symptoms such as disfigurement, a dry and sore mouth, weight loss and decreased appetite. They explained that the disease affects all aspects of life including mental wellbeing, social functioning, mobility and work. The clinical expert explained that people have limited treatment options and their disease is generally considered incurable at this stage. Existing treatments are taxane‑based chemotherapies such as docetaxel or paclitaxel, which can cause serious adverse reactions, and more recently pembrolizumab and cetuximab have become available (for more about comparators, see section\xa03.2). The patient experts stated that the outlook is poor for patients with recurrent or metastatic SCCHN that has relapsed on or after platinum‑based chemotherapy. The committee noted that improved quality of life both during and after treatment is most important to this patient group, as is extending life. The committee concluded that there is an unmet need for effective treatment options for people with recurrent or metastatic SCCHN that has progressed on or after platinum‑based chemotherapy.\n\n## Docetaxel is the most appropriate comparator for people fit enough to have it\n\nThe committee noted that the treatment pathway for recurrent or metastatic SCCHN had changed since the publication of the original appraisal of nivolumab. This is because cetuximab combination therapy and pembrolizumab monotherapy have been recommended for treating recurrent or metastatic SCCHN (see NICE's technology appraisal guidance on cetuximab for treating recurrent or metastatic squamous cell cancer of the head and neck and pembrolizumab for untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma). Although no changes are permitted to the scope in a Cancer Drugs Fund review, the committee noted that there are potential implications for using nivolumab to treat SCCHN that has progressed within 6\xa0months of platinum‑based chemotherapy. It was aware that pembrolizumab is recommended by NICE for untreated metastatic or unresectable recurrent SCCHN in adults whose tumours express PD‑L1 with a combined positive score of 1\xa0or more. The clinical lead for the Cancer Drugs Fund explained that pembrolizumab is administered every 3 or\xa06\xa0weeks, whereas nivolumab is administered every 2\xa0weeks. Therefore, when both drugs are indicated, pembrolizumab would be more likely to be chosen. They also explained that there are people whose PD‑L1 status cannot be determined because of issues accessing tissue or assays not working, and these people would likely get nivolumab because they are not eligible for pembrolizumab. The committee considered that, in NHS clinical practice, this could result in a large proportion of people having nivolumab when they have tumours with a PD‑L1 score of less than\xa01 or indeterminate. This could be different to the proportion of those tumours seen in the clinical trial population. At the time of the original appraisal of nivolumab, treatment options in clinical practice in England included taxane‑based chemotherapies (such as docetaxel and paclitaxel) or methotrexate. In the original appraisal, the clinical experts agreed that although there was no evidence of difference in efficacy between docetaxel and paclitaxel, docetaxel would be the standard single‑agent chemotherapy used for recurrent or metastatic SCCHN that progressed during or after platinum‑based therapy in the NHS (most often prescribed as a 3‑weekly treatment regimen). They agreed that the use of paclitaxel in clinical practice is limited. They also stated that methotrexate is normally only offered to people with a poor performance status who are not fit enough to have a taxane, or as subsequent therapy for people who have had a single‑agent taxane. The committee concluded in the original appraisal that docetaxel would be the most appropriate comparator for people fit enough to have it. For this review, the committee concluded that docetaxel was still the most appropriate comparator for its decision making.\n\n# Clinical effectiveness\n\n## Both the intention-to-treat population and docetaxel subgroup from CheckMate\xa0141 should inform decision making\n\nThe clinical-effectiveness evidence for nivolumab came from 1\xa0randomised controlled trial (CheckMate\xa0141) that compared nivolumab with the investigator's choice of therapy. Patients randomised to the investigator‑choice arm had 1\xa0of 3\xa0possible weekly therapies (docetaxel [47% of patients], methotrexate [41%] and cetuximab [12%]). In the original appraisal, the committee concluded that excluding paclitaxel from the trial and including cetuximab, a drug not used in clinical practice at that time and therefore not included in the NICE scope, introduced uncertainty about the relevance of CheckMate\xa0141 to UK clinical practice. The committee also concluded, based on the opinion of the clinical experts, that it was valid to assume that docetaxel and paclitaxel were equivalent. But it was not persuaded by the company's assumption that docetaxel is equivalent to methotrexate. For this guidance review, the clinical expert acknowledged that the trial took place in several countries where standard care differs from NHS clinical practice. They suggested that the investigator‑choice arm of the trial was an appropriate data source comparison even though cetuximab was not standard care in NHS clinical practice at the time of the original appraisal and methotrexate is only offered to people with poor performance status and may be less effective. The clinical lead for the Cancer Drugs Fund stated that people in the trial (who had an Eastern Cooperative Oncology Group performance status of 0\xa0or\xa01) would have been fit enough to have docetaxel in NHS clinical practice, and therefore the investigator‑choice arm would not be a relevant comparator. The committee noted that the company had presented results for an analysis comparing nivolumab and docetaxel in patients who would have docetaxel (referred to as the 'docetaxel subgroup') in CheckMate\xa0141. The company highlighted that the trial was not powered to detect differences between nivolumab and docetaxel alone and therefore any results had to be treated with caution. The committee acknowledged that this was not a prespecified subgroup analysis and such a comparison was less robust than using the intention-to-treat population, because of the smaller sample size. It acknowledged that use of the intention-to-treat population may underestimate docetaxel's effectiveness because it includes other treatments that are less effective than docetaxel. The committee concluded that the intention-to-treat trial population is the most appropriate data source for this guidance review, as in the original appraisal, but the docetaxel subgroup analysis should also be considered.\n\n## The clinical benefit of nivolumab compared with docetaxel alone is not clear\n\nFor this guidance review, the company provided an additional 37\xa0months of follow-up data (up to October\xa02019) from Checkmate\xa0141. The results for the intention-to-treat population showed that people who had nivolumab lived longer than people who had the investigator‑choice treatment (median overall survival for nivolumab was 7.7\xa0months, 95% confidence interval [CI] 5.7 to 8.7\xa0months; investigator's choice was 5.1\xa0months, 95% CI 4.0 to 6.2\xa0months; hazard ratio\xa00.69, 95% CI 0.55 to 0.86). The clinical lead for the Cancer Drugs Fund referred to an amendment update of the clinical protocol for CheckMate\xa0141, which meant that people in the investigator‑choice arm could have had nivolumab in the extension phase of the trial. In response to consultation, the company provided the number of people who switched to nivolumab in both the intention-to-treat and docetaxel subgroup population (the exact number of people is confidential so cannot be reported here). The ERG explained that the effect of switching to nivolumab in the comparator arm is unclear, but the percentage of people who switched was low and therefore unlikely to have led to substantial bias. The committee acknowledged that the effect of treatment switching was unknown but agreed that it was unlikely to have had a large effect on the results. The company provided results for the docetaxel subgroup that showed a numerical survival benefit for nivolumab compared with docetaxel, but this was not statistically significant (the exact data are confidential and cannot be reported here). The committee acknowledged that there was uncertainty about the results from the docetaxel subgroup because of the small number of people in the subgroup analysis, and in NHS clinical practice not all patients would have docetaxel. However, it agreed that the subgroup analysis was informative for decision making (for more about this decision, see\xa0section\xa03.3). It concluded, based on the evidence that had been presented, that it was uncertain whether nivolumab was clinically effective compared with docetaxel alone.\n\n## There is evidence of nivolumab's benefit for tumours with a PD-L1 score of 1% or higher, but at a lower PD-L1 score the benefit is not clear\n\nIn the original appraisal, the committee concluded that there was evidence of nivolumab's benefit for tumours expressing 1% or more PD‑L1 protein, but at lower expression levels the benefit was not clear. For this guidance review, the company provided subgroup analyses based on the latest available data (up to 15\xa0October\xa02019) for PD‑L1 of\xa01% and above and PD‑L1 of less than 1%\xa0subgroups in the intention-to-treat population of CheckMate\xa0141. For the subgroup with a PD‑L1 score of\xa01% and above, the median overall-survival gain was 3.6\xa0months with nivolumab compared with investigator‑choice treatment (hazard ratio\xa00.54, 95% CI 0.39 to 0.76). For the less than 1%\xa0PD‑L1 group, the median overall-survival gain was 1\xa0month (hazard ratio\xa00.74, 95% CI 0.50 to 1.10). The clinical expert explained that in clinical practice the availability of PD‑L1 testing varies across the NHS in England, and that PD‑L1 scores might not be available for all people at the time when treatment is started. The clinical lead for the Cancer Drugs Fund advised that testing for PD‑L1 status should now be routine for people with recurrent or metastatic SCCHN. Some people do not get testing because of issues with accessing tissue, or they do not get a score because of assays not working. The clinical expert suggested that the PD‑L1 score may not be as good a predictor of treatment outcome as previously thought. The committee noted that PD‑L1 testing in SCCHN would become routine in the NHS now that pembrolizumab is recommended for treating SCCHN in adults whose tumours express 1% or more PD‑L1. It acknowledged that there was uncertainty about the results from the subgroup analyses based on PD‑L1 expression because of the small number of people in the subgroup analysis. However, it considered that it was important to explore them because of NICE's recommendation for using pembrolizumab to treat tumours with a PD‑L1 score of 1\xa0or higher, meaning that nivolumab is likely to be used more often to treat SCCHN with a low or indeterminate PD‑L1 score than in the CheckMate\xa0141 population (for more about comparators at different PD‑L1 scores, see section\xa03.2). The committee concluded that there was evidence that nivolumab is clinically beneficial for tumours with a PD‑L1 score of 1%\xa0and above but the benefit for those with a low PD‑L1 score was less certain.\n\n## Clinical experience with nivolumab in the Cancer Drugs Fund reflects the trial results\n\nAs well as new data from CheckMate\xa0141, data from the SACT Dataset was available for this review. Data was collected from 506\xa0people who had nivolumab through the Cancer Drugs Fund between October\xa02017 and June\xa02019. The clinical expert explained that clinical experience with nivolumab is positive, and outcomes reflect what was seen in the clinical trials. The 1‑year overall survival was similar between the nivolumab arm of the intention-to-treat population in CheckMate\xa0141 and the SACT data (CheckMate\xa0141 data 33.4%, 95% CI 27.5 to 39.5; SACT data 34%, 95% CI 29% to 38%). The median overall survival in CheckMate\xa0141 was longer (7.7\xa0months, 95% CI 5.7 to 8.7\xa0months) than in the SACT data (6.5 months, 95% CI 5.6 to 7.6\xa0months). However, the 95% confidence intervals overlapped. The time-to-treatment discontinuation in the SACT data was 3.0\xa0months (95% CI 2.7 to 3.3\xa0months), which is longer than in CheckMate\xa0141 (results are confidential and cannot be reported). The committee noted that the SACT data had a median follow up of 5.9\xa0months compared with a minimum follow up of 48.2\xa0months in the trial.\n\n# Modelling overall survival and time-to-treatment discontinuation\n\n## The company's piecewise model is appropriate to extrapolate overall survival, but fully parametric models may also be plausible\n\nIn the original appraisal, the committee accepted that a piecewise model was appropriate for estimating overall survival in the intention-to-treat population. The model used Kaplan–Meier data followed by a lognormal distribution, but the time point from which to extrapolate was uncertain. For this guidance review, the company used data from the intention-to-treat population of the trial. It extrapolated from 96\xa0weeks in line with the median follow up of the trial. This resulted in a 5‑year survival of 5.7% and a 10‑year survival of 2.6%. The clinical expert estimated that it was plausible that between 1% and 5% of people having nivolumab will be alive at 5\xa0years, and that few people survive up to 10\xa0years. In its response to technical engagement, the company used the same extrapolation method for the docetaxel subgroup. In response to consultation, it presented evidence of the goodness of fit for this method to the docetaxel subgroup data, and also explored fully parametric methods. The ERG agreed that the company's piecewise method was appropriate to extrapolate overall survival using both the intention-to-treat and docetaxel subgroup data. The committee noted that the company's fully parametric models, in particular the lognormal, could also be plausible and may be useful for decision making. It concluded that the company's piecewise model was appropriate to extrapolate overall survival using both the intention-to-treat and docetaxel subgroup data.\n\n## The company's and the ERG's extrapolation methods for time-to-treatment discontinuation for the docetaxel subgroup are both plausible\n\nIn the original appraisal, using the intention-to-treat population, the committee concluded that none of the parametric distributions fitted the time-to-treatment discontinuation data well. It preferred the generalised gamma distribution for both arms in the model for this population. In this guidance review, the company presented an alternative approach using different distributions for the 2\xa0treatment arms. It used the 2‑spline normal distribution for the nivolumab arm, because it had a better statistical and visual fit to the data than the generalised gamma distribution. The method used for the investigator‑choice arm is confidential and cannot be reported here. In its response to technical engagement, the company used the same extrapolation method for the docetaxel subgroup. The ERG preferred using the generalised gamma distribution for both arms, as in the original appraisal and in line with the NICE Decision Support Unit's technical support document 14. The ERG advised that, when the stopping rule was removed (for more about the stopping rule, see section\xa03.9), using the company's preferred extrapolation for time-to-treatment discontinuation resulted in overall survival falling below time-to-treatment discontinuation, which is implausible. Therefore, the ERG advised that the generalised gamma distribution should be used to extrapolate time-to-treatment discontinuation for both arms in all scenarios in which the stopping rule was removed. The committee noted that real-world treatment discontinuation data was available from the SACT cohort, in which the time-to-treatment discontinuation was generally longer than in CheckMate\xa0141. The committee considered this would result in a higher incremental cost-effectiveness ratio (ICER). In response to consultation, the ERG explained that using different distributions in the 2\xa0arms might introduce bias. Therefore, it preferred to use the generalised gamma distribution to estimate time-to-treatment discontinuation for both treatment arms in the docetaxel subgroup. The committee concluded that both the company's and the ERG's extrapolations for time-to-treatment discontinuation for the docetaxel subgroup were plausible, and it would consider both. It also concluded that the time-to-treatment discontinuation in the SACT cohort was informative.\n\n# Stopping rule and continued treatment effect\n\n## Analyses without a stopping rule are more appropriate for decision making\n\nIn the original appraisal, the committee concluded that analyses without a nivolumab stopping rule are more appropriate for decision making than analyses that included a stopping rule. The 2‑year stopping rule was only accepted in the context of the Cancer Drugs Fund. In this guidance review, the patient experts and the clinical expert agreed that people might be disappointed if treatment was beneficial but was stopped at 2\xa0years. The clinical expert confirmed that people who can tolerate and benefit from treatment should be able to have it until their disease progresses, or they have intolerable side effects or choose to stop. People who stopped nivolumab after 2\xa0years but whose disease has not progressed would be offered platinum‑based chemotherapy. The clinical expert explained that people who are alive 5\xa0years after treatment started are considered 'cured' from the disease. In response to consultation, the company provided an updated base case that included a 5‑year stopping rule. It explained that the 5‑year stopping rule was based on clinical expert opinion that people are considered 'cured' at 5\xa0years. It explained that extrapolated data from the trial resulted in 1% of people remaining on treatment at 5\xa0years. The committee considered there to be no clinical evidence that nivolumab can be curative and questioned whether the low numbers on treatment at 5\xa0years reflects real life. The ERG explained that having low numbers of people on treatment at 5\xa0years is not a plausible reason to include a stopping rule. The committee noted that there was no stopping rule included in the trial, and that some people were still taking nivolumab after 2\xa0years. It acknowledged that a stopping rule had been accepted in previous appraisals for nivolumab and other similar drugs, whether or not it was included in the trial. However, in this instance, the committee concluded that a stopping rule was not appropriate, as stated in the original appraisal that recommended nivolumab for use only in the Cancer Drugs Fund.\n\n## Continued treatment benefit up to 5 years is plausible\n\nIn the original appraisal, the committee concluded that it was plausible that the treatment benefit of nivolumab continued for 5\xa0years after treatment started. For this guidance review, the company provided a smoothed hazard-rates plot for overall survival for the intention-to-treat population for nivolumab and investigator‑choice treatment. The plot suggested that the hazard rates seemed to meet at around 5\xa0years. This indicates that there was no difference in the treatment effect of the 2\xa0arms at 5\xa0years. In response to consultation, the company provided an updated plot, suggesting the hazard rates did not converge at 5\xa0years. However, the ERG concluded that the rates do converge at 5\xa0years and included treatment waning at 5\xa0years after the start of treatment in its base-case analysis. In CheckMate\xa0141, people in the investigator‑choice arm could have had nivolumab during the extension phase of the trial (for more about this trial, see section\xa03.4). The committee acknowledged that this crossover could decrease the apparent relative effectiveness of nivolumab compared with investigator's choice. But the percentage of people who switched to nivolumab was low, so any bias is not likely to be substantial. It concluded that it was plausible that nivolumab's treatment effect matches that of standard care at 5\xa0years after treatment started.\n\n# Utility values in the economic model\n\n## The most appropriate utility values lie between the treatment-dependent and the treatment-independent estimates\n\nIn the original appraisal, the committee agreed that the most appropriate utility estimates would lie between the treatment-dependent utilities and the treatment-independent utilities. The clinical expert explained that the effect on quality of life was similar for the different treatment options available for recurrent and metastatic SCCHN. The patient experts and the clinical expert confirmed that people's quality of life diminishes during the last months of life. In response to consultation, the company updated its base case to use a different set of utility estimates. These utility values varied depending on whether somebody was on or off treatment, progression-free or had progressed disease, and whether they were having nivolumab or investigator‑choice treatment. The committee noted the company's utility values were derived from surveys done during the trial. However, about one-third of people in the intervention arm and half of people in the investigator‑choice arm did not complete the survey, so there is a large amount of missing data. The clinical lead for the Cancer Drugs Fund noted that some of the utilities applied in the company's updated approach were implausible. For example, people in the investigator‑choice arm who were progression-free and having treatment had a higher utility value compared with those who were progression-free and off treatment. The exact utility values are confidential and cannot be reported here. The committee agreed that the company's updated utility model generated implausible values, and it therefore preferred the models used in the original appraisal. The ERG advised that using the company's treatment-dependent utility model meant that utility benefits associated with nivolumab continue for the rest of a person's life. The company attempted to resolve this life-long benefit by including time-to-death disutilities, but the ERG stated this is not a reasonable approach. The ERG preferred to use treatment-independent utility values in its base case. The committee noted that, in the trial, people could continue having nivolumab after they progressed if the investigator thought they were still benefiting. If people were perceived not to be benefiting, they would stop taking nivolumab. Therefore, the committee considered it is not reasonable to assume an ongoing utility benefit after people had stopped treatment. The treatment-independent utilities are based solely on progression state, whereas the treatment-dependent utilities assume nivolumab has a benefit that continues for the rest of a person's life. Therefore, the committee considered that treatment-dependent utilities were likely to lead to better outcomes and lower ICERs. It concluded that the most appropriate utility values are between the treatment-dependent and the treatment-independent estimates and are likely to be closer to the treatment-independent values.\n\n# End of life\n\n## Life expectancy for people with recurrent or metastatic SCCHN is less than 24\xa0months\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. In the original appraisal, the data showed that life expectancy for people with SCCHN that has progressed within 6\xa0months of having platinum‑based chemotherapy was less than 24\xa0months. The committee did not hear any evidence to change this conclusion. Therefore, it concluded that nivolumab met the short life-expectancy criterion.\n\n## Nivolumab meets the life-extending element of the end-of-life criteria\n\nIn the latest data available for CheckMate\xa0141, the median overall survival for the intention-to-treat population for nivolumab was 7.7\xa0months (95% confidence interval 5.7 to 8.7\xa0months) compared with 5.1\xa0months (95% confidence interval 4.0 to 6.2\xa0months) for investigator's choice. The model predicted a mean survival benefit for nivolumab of between 6.8\xa0and 9.2\xa0months in this population. The median overall-survival results for the docetaxel subgroup are confidential and cannot be reported here. When the docetaxel subgroup data were used in the company's base-case model, the mean overall-survival benefit for nivolumab was estimated to be less than when intention-to-treat data were used (the exact values are confidential and cannot be reported here). Although the clinical effectiveness of nivolumab was uncertain in the docetaxel subgroup (for more about this subgroup, see\xa0section\xa03.4), the committee concluded that nivolumab offered a survival benefit of more than 3\xa0months compared with docetaxel. This is regardless of whether the investigator‑choice or docetaxel subgroup data was used in the model. In CheckMate\xa0141, nivolumab also increased the median overall survival by more than 3\xa0months in people whose tumours had a PD‑L1 score of 1% or above (for more about this trial, see section\xa03.5). In people whose tumours had a PD‑L1 score of less than 1% the increase in median survival was only 1\xa0month, and this was not statistically significant. In response to consultation, the company provided updated overall-survival modelling using a variety of extrapolation methods for PD‑L1 with a combined positive score of less than 1%. The model estimated a mean overall-survival benefit of greater than 6\xa0months for the subgroup with PD‑L1 less than 1%. The committee concluded although there is uncertainty about the PD‑L1 less than 1% subgroup, the life-extending element was met in that subgroup. Therefore, nivolumab meets the life-extending element of the end of life criteria.\n\n# Cost effectiveness\n\n## The company's base case does not reflect the committee's preferred assumptions\n\nThe committee agreed it would have preferred the company's base case to:\n\ninclude treatment-dependent and treatment-independent utility values, with committee preference towards treatment-independent utilities (for more about these utility values, see section\xa03.11)\n\nassume no treatment benefit for nivolumab 5\xa0years after the start of treatment, and\n\nexclude the stopping rule.\n\nIn response to consultation, the company did not provide a scenario that included all of the committee's preferred assumptions. The committee concluded the intention-to-treat population is the most appropriate data source, but agreed that the company's analyses using the docetaxel subgroup data and by PD‑L1 status were of interest and would be considered in its decision making. Because of the uncertainty, an acceptable ICER for nivolumab compared with docetaxel using the intention-to-treat population is toward the lower end of the range normally considered a cost-effective use of NHS resources.\n\n## Nivolumab's cost effectiveness is highly uncertain\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible ICER of £20,000 per quality-adjusted life year (QALY) gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER and whether the technology meets the criteria for special consideration as a 'life-extending treatment at the end of life'. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee noted the high level of uncertainty in the docetaxel subgroup and PD‑L1 subgroups, specifically about the clinical effectiveness (for more about docetaxel and the PD‑L1 scores, see\xa0section\xa03.4 and section\xa03.5). There is also uncertainty around the most appropriate utility values (for more about the utility values, see section\xa03.11).\n\n## The maximum acceptable ICER is substantially below £50,000 per QALY gained\n\nBecause the conditions of a life-extending treatment at the end of life had been met, the committee considered the maximum acceptable ICER in the context of applying a QALY weight of 1.7 to the range of ICERs normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained). Because of the uncertainties about docetaxel efficacy being underestimated in the intention-to-treat population (see for more about the docetaxel subgroup, see section\xa03.3), clinical effectiveness in PD‑L1 subgroups (for more about the PD‑L1 scores, see section\xa03.5), different overall-survival extrapolations increasing the ICER (for more about these survival extrapolations, see section\xa03.7), and time-to-treatment discontinuation based on SACT data increasing the ICER (for more about this data, see section\xa03.8), the committee decided that the maximum acceptable ICER would be substantially below £50,000 per QALY gained.\n\n## Nivolumab is likely to be a cost-effective use of NHS resources\n\nThe company's base-case assumptions differed from the committee's preferred assumptions. The company's base case after consultation included a lifetime treatment benefit of nivolumab, its revised treatment-dependent utilities and a 5‑year stopping rule. Also, the time-to-treatment discontinuation was extrapolated using different distributions in the 2\xa0arms. The committee agreed that the most likely ICER for nivolumab compared with docetaxel, based on its preferred assumptions and using treatment-dependent and treatment-independent utilities, would be substantially below £50,000 per QALY gained. Taking into account the updated commercial arrangement, the ICER was within the range that could be considered a cost-effective use of NHS resources when the stopping rule was removed, a 5‑year treatment waning effect was applied, and time-to-treatment discontinuation was extrapolated using the generalised gamma distribution in the 2\xa0arms (for more about these extrapolations, see section\xa03.8). When the treatment-independent utility values were applied instead of the treatment-dependent utilities in the same scenario the ICER increased but it still remained within the range that could be considered cost effective. It concluded that incorporating the company's updated commercial arrangement meant that its preferred ICERs were in the range that could be considered cost effective, even though some uncertainties remained. So, nivolumab is recommended for routine use in the NHS.\n\n# Equality issues\n\n## The recommendations apply equally to all people with SCCHN\n\nA patient expert questioned whether age is an equality issue in this appraisal. The clinical expert confirmed that there is no age limit for treatment with nivolumab. The committee heard from the Cancer Drugs Fund clinical lead that data collected by Public Health England from NHS patients in England showed that many older patients had taken nivolumab while it was available in the Cancer Drugs Fund. The committee concluded that there was no relevant equality issue.\n\n# Other factors\n\nThe company did not highlight any additional benefits that had not been captured in the QALY calculations.\n\n# Conclusion\n\n## Nivolumab is recommended for routine commissioning\n\nThe committee recommended nivolumab, within its marketing authorisation, for recurrent or metastatic SCCHN after platinum‑based chemotherapy in adults. In the original appraisal, the committee concluded that docetaxel was the most relevant comparator, and that assuming clinical equivalence between some of the comparators was uncertain. This meant that using investigator‑choice data from the intention-to-treat population to model all comparators would likely underestimate the effectiveness of docetaxel. In this guidance review, the committee acknowledged the uncertainty surrounding the intention-to-treat population with regard to the docetaxel comparator. Based on the ICERs for nivolumab compared with docetaxel, the committee concluded that the cost-effectiveness estimates were unlikely to exceed its acceptable maximum even though some uncertainties remained. Therefore, nivolumab is recommended."}
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https://www.nice.org.uk/guidance/ta736
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Evidence-based recommendations on nivolumab (Opdivo) for treating recurrent or metastatic squamous cell carcinoma of the head and neck after platinum-based chemotherapy in adults.
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05aa2167d881bd0200a71a42c4a638fbfba00ac4
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nice
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Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer
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Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer
Evidence-based recommendations on pembrolizumab (Keytruda) with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer in adults.
# Recommendations
Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is recommended, within its marketing authorisation, as an option for untreated locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. Pembrolizumab is only recommended if the company provides it according to the commercial arrangement.
Why the committee made these recommendations
Treatment for advanced oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma includes platinum- and fluoropyrimidine-based chemotherapy. Clinical trial evidence shows that for people whose tumours express PD‑L1 with a CPS of 10 or more, adding pembrolizumab increases how long they live. It also increases the time before their disease gets worse.
Pembrolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. Therefore, it is recommended.# Information about pembrolizumab
# Marketing authorisation indication
Pembrolizumab (Keytruda, MSD) has a marketing authorisation in the UK 'in combination with platinum- and fluoropyrimidine-based chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a CPS equal to or greater than 10'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price is £2,630 for a 100‑mg vial (excluding VAT; BNF online accessed July 2021).
The company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## Oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and a large impact on quality of life
The patient experts explained that advanced oesophageal cancer (squamous or adenocarcinoma) or HER2‑negative gastro-oesophageal junction adenocarcinoma have a significant impact on quality of life. They explained that major symptoms include difficulty swallowing and malnutrition, which can lead to severe fatigue, weight loss and the need to use a feeding tube. These symptoms can be both painful and distressing, limiting people's ability to experience and participate in normal activities and social events. Around 40% of all new cases are in people aged 75 years and over, although the patient experts noted that increasing numbers of younger people are being diagnosed. The patient experts also explained that oesophageal and gastro-oesophageal junction cancer is more common in men than women but increasing numbers of women are being diagnosed. Diagnosis is often at an advanced stage. The committee concluded that oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and a large impact on quality of life.
# Treatment pathway
## People would welcome a new treatment option
The patient and clinical experts explained that people with advanced oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and no curative treatment options. Palliative combination chemotherapy regimens are standard first-line treatment for people with a performance status of 0 to 2 and no significant comorbidities. The NICE guideline on oesophago-gastric cancer: assessment and management in adults recommends dual therapy with fluorouracil or capecitabine in combination with cisplatin or oxaliplatin, or triple therapy with the addition of epirubicin. The clinical experts stated that triple therapy is no longer standard of care as it does not provide additional efficacy and increases toxicity. The clinical experts explained that dual therapy regimens are preferred and that most people would have capecitabine and oxaliplatin (XELOX). This is because oxaliplatin is preferred to cisplatin as it is better tolerated and has a shorter infusion time; however, there is no evidence that any one dual therapy combination is more effective than others. They suggested that dual therapy would be the appropriate comparator in this appraisal (see section 3.10). Pembrolizumab is an immunotherapy that has a different mechanism of action to chemotherapy and would be given as an additional treatment alongside chemotherapy. Therefore, it would not significantly add to the treatment administration burden. The patient experts explained that most people with advanced oesophageal or HER2‑negative gastro-oesophageal junction cancer would be willing to accept the additional side effects and treatment burden of pembrolizumab, because of its potential to improve quality of life and help people live longer. The committee concluded that there is an unmet clinical need in this population and people would welcome a new effective treatment option.
## It is preferable to give treatment with a PD-1 inhibitor early in the treatment pathway
The NICE technology appraisal on nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer recommends nivolumab as treatment for oesophageal squamous cell carcinoma (but not adenocarcinoma) after chemotherapy. The clinical experts explained that because pembrolizumab and nivolumab are both PD-1 inhibitors, it would not be suitable to give nivolumab as second-line treatment after pembrolizumab with chemotherapy. They explained that it would be preferable to give pembrolizumab as first-line treatment rather than nivolumab as second-line treatment for people with squamous carcinoma. This is because approximately 60% of people are unable to have second-line treatment and it is likely that immunotherapy is more effective when used earlier. The patient experts agreed that immunotherapy would be welcomed sooner in the treatment pathway. The committee concluded that pembrolizumab would potentially offer a first-line immunotherapy treatment option for people with advanced oesophageal cancer or HER2 gastro-oesophageal junction adenocarcinoma.
# Marketing authorisation
## The population included in the marketing authorisation is narrower than the population in the scope
The marketing authorisation specifies that pembrolizumab is indicated only for adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more and is restricted to treatment of gastro-oesophageal junction adenocarcinoma for tumours that are HER2 negative (see section 2.1). This is narrower than the population included in the scope, which did not specify HER2 or CPS status. The committee agreed that the appropriate population to consider for decision making was adults with unresectable locally advanced or metastatic oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma who had not had previous chemotherapy. The adults in the population should also have tumours that express PD‑L1 with a CPS of 10 or more, in line with the marketing authorisation.
# PD-L1 testing
## PD-L1 testing is not routinely carried out in people with oesophageal cancer and HER2‑negative gastro-oesophageal junction adenocarcinoma
Currently PD‑L1 testing is not part of routine clinical practice in gastrointestinal cancers. However, it is routinely carried out for people with other types of cancer such as head and neck cancer. The clinical experts and the Cancer Drugs Fund clinical lead explained that, ideally, PD‑L1 testing should be done early and before chemotherapy is started, so as to prevent delays in accessing appropriate treatment. They explained that PD‑L1 testing for people with oesophageal cancer and HER2‑negative gastro-oesophageal junction adenocarcinoma should not be problematic, and that current diagnostic tests could be used. The committee concluded that PD‑L1 testing is not currently routine for oesophageal and gastro-oesophageal junction cancers, but that this could be adopted easily in the NHS.
# Clinical evidence
## KEYNOTE-590 data for the subgroup of tumours with CPS of 10 or more is appropriate for decision making
KEYNOTE‑590 is a randomised, double-blind, placebo-controlled trial (n=749). It compared cisplatin and fluorouracil, with or without pembrolizumab, as first-line treatment for locally advanced unresectable or metastatic oesophageal adenocarcinoma, squamous cell carcinoma or advanced gastro-oesophageal junction adenocarcinoma. It excluded people with known HER2 positive gastro-oesophageal junction cancer. The marketing authorisation restricts pembrolizumab to a subgroup whose tumours are PD‑L1 positive with a CPS of 10 or more (see section 3.4). The proportion of people whose tumours had a CPS of 10 or more in the intention-to-treat population was similar in the pembrolizumab plus chemotherapy arm (49.9%) and the placebo plus chemotherapy arm (52.4%). The clinical experts explained that this proportion is comparable to UK clinical practice. The committee concluded that the data from the subgroup with a CPS of 10 or more is appropriate for decision making.
## KEYNOTE-590 data is generalisable to people in NHS clinical practice
KEYNOTE‑590 recruited people from 26 countries including the UK. 54.8% of the CPS of 10 or more subgroup were from Asia. The ERG suggested that KEYNOTE‑590 may not be generalisable if disease prognosis or treatment pathways used in Asia differ from clinical practice in the NHS. However, the clinical experts explained that treatment regimens used in Asia and the NHS are similar, and common international guidelines are used. They also explained that there is no reason, based on molecular biology, that the effect of pembrolizumab on oesophageal cancer or gastro-oesophageal junction adenocarcinoma would differ between the trial population and the population treated in the NHS. The ERG also suggested that the proportion of people with squamous cell carcinoma and adenocarcinoma in KEYNOTE‑590 is different to the distribution seen in UK clinical practice. The clinical experts explained that PD‑L1 status and CPS was a more important biomarker than carcinoma type for predicting treatment effect. They explained that it is possible that people with squamous cell carcinoma (who appear to be more sensitive to immunotherapies) would benefit more from pembrolizumab than people with adenocarcinoma. However, the magnitude of benefit is smaller between the 2 cancer types when CPS is 10 or more. The clinical experts explained that although there is a difference in the proportion of people with squamous cell carcinoma and adenocarcinoma in KEYNOTE‑590 and UK clinical practice, the results are generalisable to people with oesophageal cancer or HER2 gastro-oesophageal junction adenocarcinoma with a CPS of 10 or more. The committee concluded that although this is an area of uncertainty, for the subgroup of interest, KEYNOTE‑590 is generalisable to clinical practice in the NHS.
# Clinical effectiveness
## Pembrolizumab improves progression-free survival and overall survival compared with chemotherapy alone
Median progression-free survival in KEYNOTE‑590 for people with a tumour with a CPS of 10 or more was 7.5 months in the pembrolizumab plus chemotherapy arm and 5.5 months in the placebo plus chemotherapy arm. The difference in median progression-free survival was 2 months (hazard ratio 0.51, 95% confidence interval 0.41 to 0.65; p<0.001). The corresponding median overall survival for the pembrolizumab plus chemotherapy arm was 13.5 months and 9.4 months in the placebo plus chemotherapy arm. The difference in median overall survival was 4.1 months (hazard ratio 0.62, 95% CI 0.49 to 0.78; p<0.001). The committee concluded that adding pembrolizumab to chemotherapy improves both progression-free survival and overall survival for people with locally advanced unresectable or metastatic oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma whose tumours express PD‑L1 with a CPS of 10 or more.
# Company's economic model
## The company's economic model is appropriate for decision making
The company presented a 3‑state partitioned survival model to estimate the cost effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy alone. The 3 health states were progression-free, progressive disease and death. The ERG agreed that the company's model structure captured all relevant health states and partitioned survival models are widely used in cancer modelling. The committee concluded that the company's model structure was acceptable for decision making.
# Assumptions in the economic model
## A dual chemotherapy regimen is the most appropriate comparator
The scope included dual and triple chemotherapy regimens. The company assumed equivalent efficacy between dual and triple regimens and used a dual therapy regimen in its economic model. The ERG stated that all relevant scope comparators, including triple therapy, should be considered. The clinical experts reiterated that dual chemotherapy regimens are more commonly used in UK clinical practice (see section 3.2). The Cancer Drugs Fund clinical lead also confirmed that the use of triple regimens is rapidly diminishing. The committee concluded that a dual chemotherapy regimen would be the appropriate comparator for this appraisal.
## The dual chemotherapy regimen used by the company in its model is acceptable for decision making
The company base case included the dual regimen of cisplatin and fluorouracil as used in KEYNOTE‑590, both in the comparator arm and in combination with pembrolizumab in the intervention arm. The clinical experts explained that dual therapy is the standard of care. However, they explained that several combinations are available, and oxaliplatin is more commonly used than cisplatin in the NHS (see section 3.2). The ERG provided a scenario analysis exploring an alternative dual regimen of oxaliplatin and capecitabine in both the pembrolizumab and comparator arms. This scenario included differences in costs but assumed equal efficacy to cisplatin and fluorouracil used in the company's model. The company also presented a scenario analysis using a blended comparator arm, which applied the costs of chemotherapy based on UK market share data. The company stated that they agreed with the ERG's approach to exploring an additional scenario but that both the ERG's and the company's scenarios have a negligible effect on the cost-effectiveness estimate. The committee agreed that the ERG's scenario using oxaliplatin and capecitabine was most reflective of current clinical practice, and that it was likely that this regimen would also be used in combination with pembrolizumab. However, it noted that there was comparable efficacy between the different dual regimens and that which combination the model used had little effect on the cost-effectiveness estimate. It therefore concluded that, although it was not reflective of clinical practice, it was appropriate to use the dual regimen included in the company's model for decision making.
## Multiple models for estimating overall survival are plausible
The company modelled overall survival in both treatment arms using Kaplan–Meier data from KEYNOTE‑590, with a log-logistic extrapolation from 40 weeks. The ERG considered this approach to be broadly acceptable but focused on 3 alternative scenarios to explore uncertainty associated with overall survival extrapolation: a log-logistic piecewise model plus treatment waning (presented by the company as a scenario analysis); a generalised gamma piecewise model; and a log-logistic fully parametric model. The ERG stated that, according to clinical expert opinion, all the scenarios, including the company's base case, are plausible. The ERG's preferred scenario was the log-logistic piecewise model plus treatment waning, which is the same as the company's preferred model for overall survival but also includes a treatment waning effect between 5 and 7 years. The ERG preferred this scenario as it results in survival estimates in the middle of the range of the 4 plausible scenarios and addressed the uncertainty around pembrolizumab having a lifetime treatment effect. The company suggested that the generalised gamma piecewise model had a poor statistical fit, and the log-logistic fully parametric model did not have as good a visual fit to the observed overall survival data as the piecewise model. The company also commented that clinical evidence indicates a sustained treatment benefit with pembrolizumab and therefore including a treatment waning effect was conservative. The clinical experts agreed that a small proportion of people receiving pembrolizumab could be cured or enter long-term remission. The Cancer Drugs Fund clinical lead also stated that it is very likely there will be long-term survivors but there will also be people who relapse after 2 years, and stated that, although it is unclear if there is a treatment waning effect, it is a reasonable assumption. The committee acknowledged the long-term uncertainty in overall survival and concluded that all 4 scenarios presented provided plausible estimates of overall survival and resulted in a range of cost-effectiveness estimates. However, the scenarios preferred by the company and ERG were not widely different.
## Progression-based utilities are preferred for use in the model because the values are more plausible
Utility values were calculated using EQ‑5D data from KEYNOTE‑590. The company used a time-to-death approach to calculate utility values in its base case, which produced utility values using groupings of utility observations based on how close the values were reported to the patient's overall survival time. The ERG explained that the time-to-death approach was a reasonable method but that it produced utility values that were higher than expected when compared with the general population, especially for the group who were more than 1 year from death. The company responded to this at technical engagement by capping the utility values for the group who were more than 1 year from death to the general population utility values. The ERG suggested that it was not plausible that the quality of life for a person with advanced oesophageal or HER2 gastro-oesophageal junction adenocarcinoma would be equal to or similar to the general population. It preferred to use a progression-based approach to calculate utility values, as the values from this approach appeared more plausible. The company suggested that the time-to-death approach was more appropriate as it captures more health states than the progression-based approach. It stated that this was more important for a condition that has a short life expectancy, as quality of life decreases rapidly as people approach the end of life. The company also explained that EQ‑5D scores were collected once from people who had progressed disease, which may not have fully captured quality of life for the progressed health state. At technical engagement, the company also presented an interaction utility model that combined progression status and time-to-death categories, to aim to address the ERG's concerns around the plausibility of the values produced. The ERG commented that this approach could not be fully evaluated based on the information provided, and that the same issue persisted: the utility values for the group furthest from death were higher than the general population. The committee discussed that any of the time-to-death, progression-based and interaction approaches could be appropriate for capturing quality of life as direct trial data was used for them all. However, it noted that progression-based utilities are more common in cancer appraisals and the values were more plausible. It also noted that the ERG had not been able to fully critique the interaction approach. The committee concluded that it preferred the progression-based utilities for decision making because the values were more plausible.
## It is appropriate to include the cost of subsequent treatment with nivolumab in the model
The NICE technology appraisal on nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer was published before technical engagement. It recommends nivolumab for treating unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma in adults after fluoropyrimidine and platinum-based therapy (see section 3.3). At technical engagement, the company updated its base case to include costs associated with nivolumab. The updated model included costs for nivolumab based on the number of people in the KEYNOTE‑590 CPS of 10 or more subgroup who received an anti‑PD‑1 or anti‑PD‑L1 treatment after pembrolizumab with chemotherapy or placebo with chemotherapy. The ERG agreed that the company's approach is the most suitable method to include nivolumab within the treatment pathway without having to make assumptions about efficacy, because this is captured in the outcomes of people in KEYNOTE‑590 who received a subsequent anti‑PD‑1 or anti‑PD‑L1 treatment. However, the ERG noted that in KEYNOTE‑590 some people received an anti‑PD‑1 or anti‑PD‑L1 treatment after pembrolizumab with chemotherapy, which is not what would happen in UK clinical practice (see section 3.3). The ERG also noted that the proportion of people in KEYNOTE‑590 who received an anti‑PD‑1 or anti‑PD‑L1 treatment was likely to be lower than the number of people who receive nivolumab after first-line chemotherapy without pembrolizumab in UK clinical practice. To address this, it provided a scenario to reflect how nivolumab is likely to be used in clinical practice that estimated the costs and efficacy of nivolumab. This scenario assumed that all participants who had received a subsequent treatment in the placebo with chemotherapy arm in the KEYNOTE‑590 CPS of 10 or more subgroup, received nivolumab as second-line treatment. However, the ERG explained that there were several limitations to this scenario analysis, including uncertainty around the impact nivolumab would have on overall survival, and unconventional adjustments being made to the survival curves as needed by the partitioned survival model framework. Therefore, it did not include this analysis in its base case. The committee was aware that both the company's and the ERG's approaches had limitations but concluded that it was appropriate to include the costs of nivolumab as a subsequent treatment in the model.
## The company and the ERG have appropriately incorporated PD-L1 testing into the model
PD‑L1 testing is currently not routinely funded for oesophageal or gastro-oesophageal junction cancer (see section 3.5). The company and the ERG included the costs of PD‑L1 testing in their models, as this is an additional cost to current care for oesophageal and gastro-oesophageal junction cancer. The committee concluded that introducing PD‑L1 testing for oesophageal and gastro-oesophageal junction cancer would be unlikely to add a significant burden to the NHS and that it was appropriate to include the costs of testing in the model.
# End of life
## Pembrolizumab meets the end of life criteria
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Data from KEYNOTE‑590 showed that, for the subgroup of people whose tumours express PD‑L1 with a CPS of 10 or more, median overall survival was 9.4 months for people receiving placebo with chemotherapy (see section 3.8). The clinical and patient experts also agreed that the average life expectancy of people with advanced oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma was less than 2 years. In the subgroup of interest (people whose tumours express PD‑L1 with a CPS of 10 or more), KEYNOTE‑590 showed an increase in median overall survival with the addition of pembrolizumab to chemotherapy of 4.1 months (see section 3.8). The company's model also indicated that pembrolizumab increased mean overall survival by 13.9 months. The ERG agreed that, in the subgroup of people whose tumours express PD‑L1 with a CPS of 10 or more, there is an improvement in overall survival of at least 3 months with pembrolizumab. The committee concluded that pembrolizumab meets the end of life criteria for this population.
# Cost-effectiveness estimate
## Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is likely to be cost effective
The company's base case included the following assumptions:
Using the dual chemotherapy regimen from KEYNOTE‑590 in the model, both alone as the comparator and in combination with pembrolizumab as the intervention (see section 3.11).
Using a log-logistic extrapolation for modelling overall survival (see section 3.12).
Using utilities obtained using time-to-death methodology (see section 3.13).
Adding the costs of nivolumab as a subsequent treatment into the model (see section 3.14).
Adding the costs of PD‑L1 testing to the model (see section 3.15).The ERG's base case included the same assumptions as the company in its model on the choice of dual chemotherapy (see section 3.11), the costs of nivolumab (see section 3.14), and the costs of PD‑L1 testing (see section 3.15). It included different assumptions to the company on overall survival modelling (using a log-logistic extrapolation plus a treatment waning effect between 5 and 7 years ) and used the committee's preferred assumption of progression-based utilities (see section 3.13). The incremental cost-effectiveness ratios (ICERs) cannot be reported here because of confidential commercial arrangements for pembrolizumab and subsequent treatments. Although including the ERG's assumptions increased the ICER compared with the company's base case, both the company's and the ERG's cost-effectiveness estimates are below £50,000 per quality-adjusted life year gained. As end of life criteria have been met (see section 3.16) the committee concluded that it was likely that pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is likely to be a cost-effective use of NHS resources.
# Conclusion
## Pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy is recommended
The committee noted that both the company's and the ERG's base cases show that pembrolizumab with platinum-based chemotherapy is likely to be cost effective compared with chemotherapy alone, when considering a life-extending treatment for people with short life expectancy (see section 3.17). The committee was aware of continuing uncertainty related to the generalisability of the population in KEYNOTE‑590 to clinical practice in the NHS (see section 3.7) and the most appropriate method to extrapolate overall survival (see section 3.12). However, despite the remaining areas of uncertainty, it was agreed that the cost-effectiveness estimates are likely to be within the range usually considered a cost-effective use of NHS resources for a life-extending treatment for people with short life expectancy. Therefore, pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy is recommended for use in the NHS as an option for treating locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a CPS of 10 or more.
|
{'Recommendations': "Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is recommended, within its marketing authorisation, as an option for untreated locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more. Pembrolizumab is only recommended if the company provides it according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nTreatment for advanced oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma includes platinum- and fluoropyrimidine-based chemotherapy. Clinical trial evidence shows that for people whose tumours express PD‑L1 with a CPS of 10 or more, adding pembrolizumab increases how long they live. It also increases the time before their disease gets worse.\n\nPembrolizumab meets NICE's criteria to be considered a life-extending treatment at the end of life. The cost-effectiveness estimates are likely to be within what NICE considers an acceptable use of NHS resources. Therefore, it is recommended.", 'Information about pembrolizumab': "# Marketing authorisation indication\n\nPembrolizumab (Keytruda, MSD) has a marketing authorisation in the UK 'in combination with platinum- and fluoropyrimidine-based chemotherapy\xa0for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a CPS equal to or greater than\xa010'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price is £2,630 for a 100‑mg vial (excluding VAT; BNF online accessed July\xa02021).\n\nThe company has a commercial arrangement. This makes pembrolizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by MSD, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## Oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and a large impact on quality of life\n\nThe patient experts explained that advanced oesophageal cancer (squamous or adenocarcinoma) or HER2‑negative gastro-oesophageal junction adenocarcinoma have a significant impact on quality of life. They explained that major symptoms include difficulty swallowing and malnutrition, which can lead to severe fatigue, weight loss and the need to use a feeding tube. These symptoms can be both painful and distressing, limiting people's ability to experience and participate in normal activities and social events. Around 40% of all new cases are in people aged 75\xa0years and over, although the patient experts noted that increasing numbers of younger people are being diagnosed. The patient experts also explained that oesophageal and gastro-oesophageal junction cancer is more common in men than women but increasing numbers of women are being diagnosed. Diagnosis is often at an advanced stage. The committee concluded that oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and a large impact on quality of life.\n\n# Treatment pathway\n\n## People would welcome a new treatment option\n\nThe patient and clinical experts explained that people with advanced oesophageal and HER2‑negative gastro-oesophageal junction cancer have a poor prognosis and no curative treatment options. Palliative combination chemotherapy regimens are standard first-line treatment for people with a performance status of 0\xa0to\xa02 and no significant comorbidities. The NICE guideline on oesophago-gastric cancer: assessment and management in adults recommends dual therapy with fluorouracil or capecitabine in combination with cisplatin or oxaliplatin, or triple therapy with the addition of epirubicin. The clinical experts stated that triple therapy is no longer standard of care as it does not provide additional efficacy and increases toxicity. The clinical experts explained that dual therapy regimens are preferred and that most people would have capecitabine and oxaliplatin (XELOX). This is because oxaliplatin is preferred to cisplatin as it is better tolerated and has a shorter infusion time; however, there is no evidence that any one dual therapy combination is more effective than others. They suggested that dual therapy would be the appropriate comparator in this appraisal (see section 3.10). Pembrolizumab is an immunotherapy that has a different mechanism of action to chemotherapy and would be given as an additional treatment alongside chemotherapy. Therefore, it would not significantly add to the treatment administration burden. The patient experts explained that most people with advanced oesophageal or HER2‑negative gastro-oesophageal junction cancer would be willing to accept the additional side effects and treatment burden of pembrolizumab, because of its potential to improve quality of life and help people live longer. The committee concluded that there is an unmet clinical need in this population and people would welcome a new effective treatment option.\n\n## It is preferable to give treatment with a PD-1 inhibitor early in the treatment pathway\n\nThe NICE technology appraisal on nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer recommends nivolumab as treatment for oesophageal squamous cell carcinoma (but not adenocarcinoma) after chemotherapy. The clinical experts explained that because pembrolizumab and nivolumab are both PD-1 inhibitors, it would not be suitable to give nivolumab as second-line treatment after pembrolizumab with chemotherapy. They explained that it would be preferable to give pembrolizumab as first-line treatment rather than nivolumab as second-line treatment for people with squamous carcinoma. This is because approximately 60% of people are unable to have second-line treatment and it is likely that immunotherapy is more effective when used earlier. The patient experts agreed that immunotherapy would be welcomed sooner in the treatment pathway. The committee concluded that pembrolizumab would potentially offer a first-line immunotherapy treatment option for people with advanced oesophageal cancer or HER2 gastro-oesophageal junction adenocarcinoma.\n\n# Marketing authorisation\n\n## The population included in the marketing authorisation is narrower than the population in the scope\n\nThe marketing authorisation specifies that pembrolizumab is indicated only for adults whose tumours express PD‑L1 with a combined positive score (CPS) of 10 or more and is restricted to treatment of gastro-oesophageal junction adenocarcinoma for tumours that are HER2 negative (see section 2.1). This is narrower than the population included in the scope, which did not specify HER2 or CPS status. The committee agreed that the appropriate population to consider for decision making was adults with unresectable locally advanced or metastatic oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma who had not had previous chemotherapy. The adults in the population should also have tumours that express PD‑L1 with a CPS of 10 or more, in line with the marketing authorisation.\n\n# PD-L1 testing\n\n## PD-L1 testing is not routinely carried out in people with oesophageal cancer and HER2‑negative gastro-oesophageal junction adenocarcinoma\n\nCurrently PD‑L1 testing is not part of routine clinical practice in gastrointestinal cancers. However, it is routinely carried out for people with other types of cancer such as head and neck cancer. The clinical experts and the Cancer Drugs Fund clinical lead explained that, ideally, PD‑L1 testing should be done early and before chemotherapy is started, so as to prevent delays in accessing appropriate treatment. They explained that PD‑L1 testing for people with oesophageal cancer and HER2‑negative gastro-oesophageal junction adenocarcinoma should not be problematic, and that current diagnostic tests could be used. The committee concluded that PD‑L1 testing is not currently routine for oesophageal and gastro-oesophageal junction cancers, but that this could be adopted easily in the NHS.\n\n# Clinical evidence\n\n## KEYNOTE-590 data for the subgroup of tumours with CPS of 10 or more is appropriate for decision making\n\nKEYNOTE‑590 is a randomised, double-blind, placebo-controlled trial (n=749). It compared cisplatin and fluorouracil, with or without pembrolizumab, as first-line treatment for locally advanced unresectable or metastatic oesophageal adenocarcinoma, squamous cell carcinoma or advanced gastro-oesophageal junction adenocarcinoma. It excluded people with known HER2 positive gastro-oesophageal junction cancer. The marketing authorisation restricts pembrolizumab to a subgroup whose tumours are PD‑L1 positive with a CPS of 10 or more (see section 3.4). The proportion of people whose tumours had a CPS of 10 or more in the intention-to-treat population was similar in the pembrolizumab plus chemotherapy arm (49.9%) and the placebo plus chemotherapy arm (52.4%). The clinical experts explained that this proportion is comparable to UK clinical practice. The committee concluded that the data from the subgroup with a CPS of 10 or more is appropriate for decision making.\n\n## KEYNOTE-590 data is generalisable to people in NHS clinical practice\n\nKEYNOTE‑590 recruited people from 26\xa0countries including the UK. 54.8% of the CPS of\xa010\xa0or more subgroup were from Asia. The ERG suggested that KEYNOTE‑590 may not be generalisable if disease prognosis or treatment pathways used in Asia differ from clinical practice in the NHS. However, the clinical experts explained that treatment regimens used in Asia and the NHS are similar, and common international guidelines are used. They also explained that there is no reason, based on molecular biology, that the effect of pembrolizumab on oesophageal cancer or gastro-oesophageal junction adenocarcinoma would differ between the trial population and the population treated in the NHS. The ERG also suggested that the proportion of people with squamous cell carcinoma and adenocarcinoma in KEYNOTE‑590 is different to the distribution seen in UK clinical practice. The clinical experts explained that PD‑L1 status and CPS was a more important biomarker than carcinoma type for predicting treatment effect. They explained that it is possible that people with squamous cell carcinoma (who appear to be more sensitive to immunotherapies) would benefit more from pembrolizumab than people with adenocarcinoma. However, the magnitude of benefit is smaller between the 2\xa0cancer types when CPS is 10 or more. The clinical experts explained that although there is a difference in the proportion of people with squamous cell carcinoma and adenocarcinoma in KEYNOTE‑590 and UK clinical practice, the results are generalisable to people with oesophageal cancer or HER2 gastro-oesophageal junction adenocarcinoma with a CPS of 10 or more. The committee concluded that although this is an area of uncertainty, for the subgroup of interest, KEYNOTE‑590 is generalisable to clinical practice in the NHS.\n\n# Clinical effectiveness\n\n## Pembrolizumab improves progression-free survival and overall survival compared with chemotherapy alone\n\nMedian progression-free survival in KEYNOTE‑590 for people with a tumour with a CPS of 10 or more was 7.5\xa0months in the pembrolizumab plus chemotherapy arm and 5.5\xa0months in the placebo plus chemotherapy arm. The difference in median progression-free survival was 2\xa0months (hazard ratio 0.51, 95% confidence interval [CI] 0.41 to 0.65; p<0.001). The corresponding median overall survival for the pembrolizumab plus chemotherapy arm was 13.5\xa0months and 9.4\xa0months in the placebo plus chemotherapy arm. The difference in median overall survival was 4.1\xa0months (hazard ratio 0.62, 95% CI 0.49 to 0.78; p<0.001). The committee concluded that adding pembrolizumab to chemotherapy improves both progression-free survival and overall survival for people with locally advanced unresectable or metastatic oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma whose tumours express PD‑L1 with a CPS of 10 or more.\n\n# Company's economic model\n\n## The company's economic model is appropriate for decision making\n\nThe company presented a 3‑state partitioned survival model to estimate the cost effectiveness of pembrolizumab plus chemotherapy compared with chemotherapy alone. The 3\xa0health states were progression-free, progressive disease and death. The ERG agreed that the company's model structure captured all relevant health states and partitioned survival models are widely used in cancer modelling. The committee concluded that the company's model structure was acceptable for decision making.\n\n# Assumptions in the economic model\n\n## A dual chemotherapy regimen is the most appropriate comparator\n\nThe scope included dual and triple chemotherapy regimens. The company assumed equivalent efficacy between dual and triple regimens and used a dual therapy regimen in its economic model. The ERG stated that all relevant scope comparators, including triple therapy, should be considered. The clinical experts reiterated that dual chemotherapy regimens are more commonly used in UK clinical practice (see section 3.2). The Cancer Drugs Fund clinical lead also confirmed that the use of triple regimens is rapidly diminishing. The committee concluded that a dual chemotherapy regimen would be the appropriate comparator for this appraisal.\n\n## The dual chemotherapy regimen used by the company in its model is acceptable for decision making\n\nThe company base case included the dual regimen of cisplatin and fluorouracil as used in KEYNOTE‑590, both in the comparator arm and in combination with pembrolizumab in the intervention arm. The clinical experts explained that dual therapy is the standard of care. However, they explained that several combinations are available, and oxaliplatin is more commonly used than cisplatin in the NHS (see section 3.2). The ERG provided a scenario analysis exploring an alternative dual regimen of oxaliplatin and capecitabine in both the pembrolizumab and comparator arms. This scenario included differences in costs but assumed equal efficacy to cisplatin and fluorouracil used in the company's model. The company also presented a scenario analysis using a blended comparator arm, which applied the costs of chemotherapy based on UK market share data. The company stated that they agreed with the ERG's approach to exploring an additional scenario but that both the ERG's and the company's scenarios have a negligible effect on the cost-effectiveness estimate. The committee agreed that the ERG's scenario using oxaliplatin and capecitabine was most reflective of current clinical practice, and that it was likely that this regimen would also be used in combination with pembrolizumab. However, it noted that there was comparable efficacy between the different dual regimens and that which combination the model used had little effect on the cost-effectiveness estimate. It therefore concluded that, although it was not reflective of clinical practice, it was appropriate to use the dual regimen included in the company's model for decision making.\n\n## Multiple models for estimating overall survival are plausible\n\nThe company modelled overall survival in both treatment arms using Kaplan–Meier data from KEYNOTE‑590, with a log-logistic extrapolation from 40\xa0weeks. The ERG considered this approach to be broadly acceptable but focused on 3 alternative scenarios to explore uncertainty associated with overall survival extrapolation: a log-logistic piecewise model plus treatment waning (presented by the company as a scenario analysis); a generalised gamma piecewise model; and a log-logistic fully parametric model. The ERG stated that, according to clinical expert opinion, all the scenarios, including the company's base case, are plausible. The ERG's preferred scenario was the log-logistic piecewise model plus treatment waning, which is the same as the company's preferred model for overall survival but also includes a treatment waning effect between 5\xa0and 7\xa0years. The ERG preferred this scenario as it results in survival estimates in the middle of the range of the 4 plausible scenarios and addressed the uncertainty around pembrolizumab having a lifetime treatment effect. The company suggested that the generalised gamma piecewise model had a poor statistical fit, and the log-logistic fully parametric model did not have as good a visual fit to the observed overall survival data as the piecewise model. The company also commented that clinical evidence indicates a sustained treatment benefit with pembrolizumab and therefore including a treatment waning effect was conservative. The clinical experts agreed that a small proportion of people receiving pembrolizumab could be cured or enter long-term remission. The Cancer Drugs Fund clinical lead also stated that it is very likely there will be long-term survivors but there will also be people who relapse after 2\xa0years, and stated that, although it is unclear if there is a treatment waning effect, it is a reasonable assumption. The committee acknowledged the long-term uncertainty in overall survival and concluded that all 4\xa0scenarios presented provided plausible estimates of overall survival and resulted in a range of cost-effectiveness estimates. However, the scenarios preferred by the company and ERG were not widely different.\n\n## Progression-based utilities are preferred for use in the model because the values are more plausible\n\nUtility values were calculated using EQ‑5D data from KEYNOTE‑590. The company used a time-to-death approach to calculate utility values in its base case, which produced utility values using groupings of utility observations based on how close the values were reported to the patient's overall survival time. The ERG explained that the time-to-death approach was a reasonable method but that it produced utility values that were higher than expected when compared with the general population, especially for the group who were more than 1\xa0year from death. The company responded to this at technical engagement by capping the utility values for the group who were more than 1\xa0year from death to the general population utility values. The ERG suggested that it was not plausible that the quality of life for a person with advanced oesophageal or HER2 gastro-oesophageal junction adenocarcinoma would be equal to or similar to the general population. It preferred to use a progression-based approach to calculate utility values, as the values from this approach appeared more plausible. The company suggested that the time-to-death approach was more appropriate as it captures more health states than the progression-based approach. It stated that this was more important for a condition that has a short life expectancy, as quality of life decreases rapidly as people approach the end of life. The company also explained that EQ‑5D scores were collected once from people who had progressed disease, which may not have fully captured quality of life for the progressed health state. At technical engagement, the company also presented an interaction utility model that combined progression status and time-to-death categories, to aim to address the ERG's concerns around the plausibility of the values produced. The ERG commented that this approach could not be fully evaluated based on the information provided, and that the same issue persisted: the utility values for the group furthest from death were higher than the general population. The committee discussed that any of the time-to-death, progression-based and interaction approaches could be appropriate for capturing quality of life as direct trial data was used for them all. However, it noted that progression-based utilities are more common in cancer appraisals and the values were more plausible. It also noted that the ERG had not been able to fully critique the interaction approach. The committee concluded that it preferred the progression-based utilities for decision making because the values were more plausible.\n\n## It is appropriate to include the cost of subsequent treatment with nivolumab in the model\n\nThe NICE technology appraisal on nivolumab for previously treated unresectable advanced or recurrent oesophageal cancer was published before technical engagement. It recommends nivolumab for treating unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma in adults after fluoropyrimidine and platinum-based therapy (see section 3.3). At technical engagement, the company updated its base case to include costs associated with nivolumab. The updated model included costs for nivolumab based on the number of people in the KEYNOTE‑590 CPS of 10 or more subgroup who received an anti‑PD‑1 or anti‑PD‑L1 treatment after pembrolizumab with chemotherapy or placebo with chemotherapy. The ERG agreed that the company's approach is the most suitable method to include nivolumab within the treatment pathway without having to make assumptions about efficacy, because this is captured in the outcomes of people in KEYNOTE‑590 who received a subsequent anti‑PD‑1 or anti‑PD‑L1 treatment. However, the ERG noted that in KEYNOTE‑590 some people received an anti‑PD‑1 or anti‑PD‑L1 treatment after pembrolizumab with chemotherapy, which is not what would happen in UK clinical practice (see section\xa03.3). The ERG also noted that the proportion of people in KEYNOTE‑590 who received an anti‑PD‑1 or anti‑PD‑L1 treatment was likely to be lower than the number of people who receive nivolumab after first-line chemotherapy without pembrolizumab in UK clinical practice. To address this, it provided a scenario to reflect how nivolumab is likely to be used in clinical practice that estimated the costs and efficacy of nivolumab. This scenario assumed that all participants who had received a subsequent treatment in the placebo with chemotherapy arm in the KEYNOTE‑590 CPS of 10 or more subgroup, received nivolumab as second-line treatment. However, the ERG explained that there were several limitations to this scenario analysis, including uncertainty around the impact nivolumab would have on overall survival, and unconventional adjustments being made to the survival curves as needed by the partitioned survival model framework. Therefore, it did not include this analysis in its base case. The committee was aware that both the company's and the ERG's approaches had limitations but concluded that it was appropriate to include the costs of nivolumab as a subsequent treatment in the model.\n\n## The company and the ERG have appropriately incorporated PD-L1 testing into the model\n\nPD‑L1 testing is currently not routinely funded for oesophageal or gastro-oesophageal junction cancer (see section 3.5). The company and the ERG included the costs of PD‑L1 testing in their models, as this is an additional cost to current care for oesophageal and gastro-oesophageal junction cancer. The committee concluded that introducing PD‑L1 testing for oesophageal and gastro-oesophageal junction cancer would be unlikely to add a significant burden to the NHS and that it was appropriate to include the costs of testing in the model.\n\n# End of life\n\n## Pembrolizumab meets the end of life criteria\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. Data from KEYNOTE‑590 showed that, for the subgroup of people whose tumours express PD‑L1 with a CPS of 10 or more, median overall survival was 9.4\xa0months for people receiving placebo with chemotherapy (see section 3.8). The clinical and patient experts also agreed that the average life expectancy of people with advanced oesophageal cancer or HER2‑negative gastro-oesophageal junction adenocarcinoma was less than 2\xa0years. In the subgroup of interest (people whose tumours express PD‑L1 with a CPS of 10 or more), KEYNOTE‑590 showed an increase in median overall survival with the addition of pembrolizumab to chemotherapy of 4.1\xa0months (see section\xa03.8). The company's model also indicated that pembrolizumab increased mean overall survival by 13.9\xa0months. The ERG agreed that, in the subgroup of people whose tumours express PD‑L1 with a CPS of 10 or more, there is an improvement in overall survival of at least 3\xa0months with pembrolizumab. The committee concluded that pembrolizumab meets the end of life criteria for this population.\n\n# Cost-effectiveness estimate\n\n## Pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is likely to be cost effective\n\nThe company's base case included the following assumptions:\n\nUsing the dual chemotherapy regimen from KEYNOTE‑590 in the model, both alone as the comparator and in combination with pembrolizumab as the intervention (see section 3.11).\n\nUsing a log-logistic extrapolation for modelling overall survival (see section 3.12).\n\nUsing utilities obtained using time-to-death methodology (see section 3.13).\n\nAdding the costs of nivolumab as a subsequent treatment into the model (see section 3.14).\n\nAdding the costs of PD‑L1 testing to the model (see section 3.15).The ERG's base case included the same assumptions as the company in its model on the choice of dual chemotherapy (see section\xa03.11), the costs of nivolumab (see section\xa03.14), and the costs of PD‑L1 testing (see section\xa03.15). It included different assumptions to the company on overall survival modelling (using a log-logistic extrapolation plus a treatment waning effect between 5 and 7\xa0years [see section 3.12]) and used the committee's preferred assumption of progression-based utilities (see section 3.13). The incremental cost-effectiveness ratios (ICERs) cannot be reported here because of confidential commercial arrangements for pembrolizumab and subsequent treatments. Although including the ERG's assumptions increased the ICER compared with the company's base case, both the company's and the ERG's cost-effectiveness estimates are below £50,000 per quality-adjusted life year gained. As end of life criteria have been met (see section 3.16) the committee concluded that it was likely that pembrolizumab with platinum- and fluoropyrimidine-based chemotherapy is likely to be a cost-effective use of NHS resources.\n\n# Conclusion\n\n## Pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy is recommended\n\nThe committee noted that both the company's and the ERG's base cases show that pembrolizumab with platinum-based chemotherapy is likely to be cost effective compared with chemotherapy alone, when considering a life-extending treatment for people with short life expectancy (see section\xa03.17). The committee was aware of continuing uncertainty related to the generalisability of the population in KEYNOTE‑590 to clinical practice in the NHS (see section 3.7) and the most appropriate method to extrapolate overall survival (see section 3.12). However, despite the remaining areas of uncertainty, it was agreed that the cost-effectiveness estimates are likely to be within the range usually considered a cost-effective use of NHS resources for a life-extending treatment for people with short life expectancy. Therefore, pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy is recommended for use in the NHS as an option for treating locally advanced unresectable or metastatic carcinoma of the oesophagus or HER2‑negative gastro-oesophageal junction adenocarcinoma in adults whose tumours express PD‑L1 with a CPS of 10 or more."}
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https://www.nice.org.uk/guidance/ta737
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Evidence-based recommendations on pembrolizumab (Keytruda) with platinum- and fluoropyrimidine-based chemotherapy for untreated advanced oesophageal and gastro-oesophageal junction cancer in adults.
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d65ffe5760956262efc2cdbb7d876961b34d1224
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nice
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Tofacitinib for treating juvenile idiopathic arthritis
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Tofacitinib for treating juvenile idiopathic arthritis
Evidence-based recommendations on tofacitinib for treating juvenile idiopathic arthritis.
# Recommendations
Tofacitinib is recommended as an option for treating active polyarticular juvenile idiopathic arthritis (JIA; rheumatoid factor positive or negative polyarthritis and extended oligoarthritis), and juvenile psoriatic arthritis in people 2 years and older. This is if their condition has responded inadequately to previous treatment with disease-modifying antirheumatic drugs (DMARDs), and only if:
a tumour necrosis factor (TNF)‑alpha inhibitor is not suitable or does not control the condition well enough, and
the company provides tofacitinib according to the commercial arrangement.
Tofacitinib can be used with methotrexate, or as monotherapy when methotrexate is not tolerated or if continued treatment with methotrexate is inappropriate.
If tofacitinib is one of a range of treatments considered suitable by patients, or their parents or carers, and their clinicians, choose the least expensive (taking into account administration costs and commercial arrangements).
This recommendation is not intended to affect treatment with tofacitinib that was started in the NHS before this guidance was published. Children and young people having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician, the child or young person, and their parents or carers.
Why the committee made these recommendations
Treatments for JIA that has not responded well enough to DMARDs include adalimumab, etanercept and tocilizumab.
Clinical trial evidence shows that tofacitinib is effective compared with placebo. There are no trials directly comparing tofacitinib with current treatments. But an indirect comparison suggests that tofacitinib has similar effects to adalimumab and tocilizumab. There is no evidence for tofacitinib compared with etanercept.
Tofacitinib has similar costs to tocilizumab. But it costs more than adalimumab and is likely to cost more than etanercept.
Most people with the 2 kinds of JIA being considered have adalimumab or etanercept, which are TNF-alpha inhibitors. So tofacitinib is only recommended when a TNF-alpha inhibitor is unsuitable or has not worked well enough.# Information about tofacitinib
# Marketing authorisation indication
Tofacitinib (Xeljanz, Pfizer) is indicated for: 'the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive or negative polyarthritis and extended oligoarthritis), and juvenile psoriatic arthritis in patients 2 years of age and older, who have responded inadequately to previous therapy with DMARDs'.
Tofacitinib can be used with methotrexate, or as monotherapy when methotrexate is not tolerated or if continued treatment with methotrexate is inappropriate.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of a 56‑tablet pack of 5 mg tofacitinib is £690.03 (excluding VAT; BNF online accessed August 2021). Tofacitinib is also available as an oral 1 mg/ml solution in 240 ml bottles.
The company has a commercial arrangement. This makes tofacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
# Polyarticular juvenile idiopathic arthritis
## Adalimumab and tocilizumab are appropriate comparators
The company positions tofacitinib for people with polyarticular juvenile idiopathic arthritis (JIA) whose disease has responded inadequately to or who are intolerant of, one or more disease-modifying antirheumatic drugs (DMARDs). This corresponds with how biological DMARDs are used in the NHS. The company also positions tofacitinib when biological DMARDs have not controlled disease well enough. The company's cost-comparison case proposes that tofacitinib has similar effects to adalimumab and tocilizumab, which are both recommended in NICE's technology appraisal guidance on abatacept, adalimumab, etanercept and tocilizumab for JIA. The company explained that it selected these comparators because adalimumab is the most frequently used biological DMARD, and tocilizumab represents an alternative mode of action. The ERG's clinical advisers suggested that 50% to 60% of people with JIA currently have adalimumab, 30% to 40% have tocilizumab and around 10% have etanercept. The company's estimates suggested a higher proportion having adalimumab. The committee agreed that adalimumab and tocilizumab are appropriate comparators.
## Tofacitinib is likely to have similar clinical effectiveness to adalimumab and tocilizumab
Tofacitinib has been compared with placebo in a phase 3, randomised, double-blind trial, study A3921104. This showed that tofacitinib was superior to placebo for a range of outcomes at 44 weeks. To compare tofacitinib with adalimumab and tocilizumab, the company carried out indirect comparisons. These suggested that, for the outcomes of disease flare, disease activity (measured by the American College of Rheumatology 30, 50 and 70), tofacitinib is similar to the comparators (the exact results are considered confidential by the company and cannot be reported here). The ERG considered it was plausible that tofacitinib is non-inferior to the comparators. However, it noted that tofacitinib follow-up data was only for 44 weeks, while there is longer follow-up data for tocilizumab and adalimumab. The committee concluded that tofacitinib is likely to have similar clinical effectiveness to adalimumab and tocilizumab, although the long-term effectiveness is uncertain.
## Tofacitinib costs about the same as tocilizumab but more than adalimumab
Adalimumab biosimilars are available in the NHS at a considerable discount to the list price of the originator product (exact prices are confidential and cannot be reported here). There is also a confidential discount for tocilizumab. When this is applied, tofacitinib has similar overall costs to tocilizumab in both the company and the ERG's modelling. However, tofacitinib has higher costs than adalimumab in both the company and the ERG's modelling. The exact results are confidential and cannot be reported here.
# Juvenile psoriatic arthritis
## The evidence for tofacitinib in juvenile psoriatic arthritis is very limited
Although the A3921104 study included a small number of people with juvenile psoriatic arthritis (n=7 tofacitinib, n=8 placebo), this population was not included in the primary end point analysis. Results for people with juvenile psoriatic arthritis favoured tofacitinib for disease flare and ACR response and were similar to those for the polyarticular JIA cohort (exact results are considered confidential by the company and cannot be reported here). The results also favoured tofacitinib for the outcome of body surface area affected by psoriasis. The committee concluded that the results suggest tofacitinib is clinically effective compared with placebo, but the evidence is very limited.
## Etanercept is the relevant comparator for juvenile psoriatic arthritis
The only drug with a marketing authorisation for juvenile psoriatic arthritis is etanercept. Etanercept is recommended in NICE's technology appraisal guidance on abatacept, adalimumab, etanercept and tocilizumab (TA373) for juvenile psoriatic arthritis (referred to as psoriatic JIA). In that appraisal the only evidence available for etanercept came from a single-arm open label trial, CLIPPER. Also in the appraisal:
The committee heard from the clinical experts that it was possible to generalise results for the effectiveness of etanercept for treating adult psoriatic JIA because the immunological effect is expected to be the same in adults and children. (Tofacitinib is recommended in NICE's technology appraisal guidance on tofacitinib for treating active psoriatic arthritis after inadequate response to DMARDs.)
A clinical expert also said that in their experience there was no evidence to suggest that etanercept would be any less effective in reducing disease activity in people with psoriatic JIA than when using these drugs for polyarticular JIA.
The assessment group was unable to separately model psoriatic JIA.
The committee considered that the results of the model for polyarticular JIA were generalisable to people with psoriatic JIA.The committee concluded that etanercept was the relevant comparator for juvenile psoriatic arthritis and that it would consider the conclusions of TA373 in its decision making.
## There is no evidence compared with etanercept
The company did not present any clinical evidence comparing tofacitinib with etanercept. The committee appreciated that this would have been difficult to do, and any analysis would have been very uncertain. This is because of the small number of patients in the A3921104 study and because the CLIPPER trial was single arm. The company also did not provide a cost-comparison analysis comparing tofacitinib with etanercept. However, the committee was aware that etanercept biosimilars are available in the NHS at a considerable discount to the list price of the originator (exact prices are confidential and cannot be reported here).
# Conclusion
## Tofacitinib is recommended only if a TNF-alpha inhibitor is not suitable or does not control the condition well enough
The committee noted that a substantial proportion of people have adalimumab for polyarticular JIA (for more about appropriate comparators, see section 3.1). Although tofacitinib is similarly effective, it costs more than adalimumab. The committee recognised that patients and clinicians would welcome an additional treatment option with an alternative route of administration and mode of action. It noted that if people have already had adalimumab, or it is unsuitable, then tocilizumab may be used. Tofacitinib has similar costs and similar benefits to tocilizumab. Therefore, the committee considered that the cost-comparison case was demonstrated, but only if adalimumab is unsuitable or the condition has not responded well enough to it. The committee considered that the evidence relating to juvenile psoriatic arthritis was limited. But as in TA373 this could be generalised from polyarticular JIA and also from tofacitinib's use in adult psoriatic arthritis. However, the main comparator is etanercept for this population, for which there are low-cost biosimilars. This means tofacitinib is likely to have higher costs than etanercept. So the committee concluded that it could recommend tofacitinib for both polyarticular JIA and juvenile psoriatic arthritis, but only if a tumour necrosis factor (TNF)‑alpha inhibitor (such as adalimumab and etanercept) is not suitable or does not control the condition well enough.
# Other factors
No equality issues were identified.
|
{'Recommendations': 'Tofacitinib is recommended as an option for treating active polyarticular juvenile idiopathic arthritis (JIA; rheumatoid factor positive or negative polyarthritis and extended oligoarthritis), and juvenile psoriatic arthritis in people 2\xa0years and older. This is if their condition has responded inadequately to previous treatment with disease-modifying antirheumatic drugs (DMARDs), and only if:\n\na tumour necrosis factor (TNF)‑alpha inhibitor is not suitable or does not control the condition well enough, and\n\nthe company provides tofacitinib according to the commercial arrangement.\n\nTofacitinib can be used with methotrexate, or as monotherapy when methotrexate is not tolerated or if continued treatment with methotrexate is inappropriate.\n\nIf tofacitinib is one of a range of treatments considered suitable by patients, or their parents or carers, and their clinicians, choose the least expensive (taking into account administration costs and commercial arrangements).\n\nThis recommendation is not intended to affect treatment with tofacitinib that was started in the NHS before this guidance was published. Children and young people having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician, the child or young person, and their parents or carers.\n\nWhy the committee made these recommendations\n\nTreatments for JIA that has not responded well enough to DMARDs include adalimumab, etanercept and tocilizumab.\n\nClinical trial evidence shows that tofacitinib is effective compared with placebo. There are no trials directly comparing tofacitinib with current treatments. But an indirect comparison suggests that tofacitinib has similar effects to adalimumab and tocilizumab. There is no evidence for tofacitinib compared with etanercept.\n\nTofacitinib has similar costs to tocilizumab. But it costs more than adalimumab and is likely to cost more than etanercept.\n\nMost people with the 2 kinds of JIA being considered have adalimumab or etanercept, which are TNF-alpha inhibitors. So tofacitinib is only recommended when a TNF-alpha inhibitor is unsuitable or has not worked well enough.', 'Information about tofacitinib': "# Marketing authorisation indication\n\nTofacitinib (Xeljanz, Pfizer) is indicated for: 'the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive or negative polyarthritis and extended oligoarthritis), and juvenile psoriatic arthritis in patients 2\xa0years of age and older, who have responded inadequately to previous therapy with DMARDs'.\n\nTofacitinib can be used with methotrexate, or as monotherapy when methotrexate is not tolerated or if continued treatment with methotrexate is inappropriate.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of a 56‑tablet pack of 5\xa0mg tofacitinib is £690.03 (excluding VAT; BNF online accessed August\xa02021). Tofacitinib is also available as an oral 1\xa0mg/ml solution in 240\xa0ml bottles.\n\nThe company has a commercial arrangement. This makes tofacitinib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Pfizer and a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Polyarticular juvenile idiopathic arthritis\n\n## Adalimumab and tocilizumab are appropriate comparators\n\nThe company positions tofacitinib for people with polyarticular juvenile idiopathic arthritis (JIA) whose disease has responded inadequately to or who are intolerant of, one or more disease-modifying antirheumatic drugs (DMARDs). This corresponds with how biological DMARDs are used in the NHS. The company also positions tofacitinib when biological DMARDs have not controlled disease well enough. The company's cost-comparison case proposes that tofacitinib has similar effects to adalimumab and tocilizumab, which are both recommended in NICE's technology appraisal guidance on abatacept, adalimumab, etanercept and tocilizumab for JIA. The company explained that it selected these comparators because adalimumab is the most frequently used biological DMARD, and tocilizumab represents an alternative mode of action. The ERG's clinical advisers suggested that 50% to 60% of people with JIA currently have adalimumab, 30% to 40% have tocilizumab and around 10% have etanercept. The company's estimates suggested a higher proportion having adalimumab. The committee agreed that adalimumab and tocilizumab are appropriate comparators.\n\n## Tofacitinib is likely to have similar clinical effectiveness to adalimumab and tocilizumab\n\nTofacitinib has been compared with placebo in a phase\xa03, randomised, double-blind trial, study A3921104. This showed that tofacitinib was superior to placebo for a range of outcomes at 44\xa0weeks. To compare tofacitinib with adalimumab and tocilizumab, the company carried out indirect comparisons. These suggested that, for the outcomes of disease flare, disease activity (measured by the American College of Rheumatology [ACR] 30, 50 and 70), tofacitinib is similar to the comparators (the exact results are considered confidential by the company and cannot be reported here). The ERG considered it was plausible that tofacitinib is non-inferior to the comparators. However, it noted that tofacitinib follow-up data was only for 44\xa0weeks, while there is longer follow-up data for tocilizumab and adalimumab. The committee concluded that tofacitinib is likely to have similar clinical effectiveness to adalimumab and tocilizumab, although the long-term effectiveness is uncertain.\n\n## Tofacitinib costs about the same as tocilizumab but more than adalimumab\n\nAdalimumab biosimilars are available in the NHS at a considerable discount to the list price of the originator product (exact prices are confidential and cannot be reported here). There is also a confidential discount for tocilizumab. When this is applied, tofacitinib has similar overall costs to tocilizumab in both the company and the ERG's modelling. However, tofacitinib has higher costs than adalimumab in both the company and the ERG's modelling. The exact results are confidential and cannot be reported here.\n\n# Juvenile psoriatic arthritis\n\n## The evidence for tofacitinib in juvenile psoriatic arthritis is very limited\n\nAlthough the A3921104 study included a small number of people with juvenile psoriatic arthritis (n=7 tofacitinib, n=8 placebo), this population was not included in the primary end point analysis. Results for people with juvenile psoriatic arthritis favoured tofacitinib for disease flare and ACR response and were similar to those for the polyarticular JIA cohort (exact results are considered confidential by the company and cannot be reported here). The results also favoured tofacitinib for the outcome of body surface area affected by psoriasis. The committee concluded that the results suggest tofacitinib is clinically effective compared with placebo, but the evidence is very limited.\n\n## Etanercept is the relevant comparator for juvenile psoriatic arthritis\n\nThe only drug with a marketing authorisation for juvenile psoriatic arthritis is etanercept. Etanercept is recommended in NICE's technology appraisal guidance on abatacept, adalimumab, etanercept and tocilizumab (TA373) for juvenile psoriatic arthritis (referred to as psoriatic JIA). In that appraisal the only evidence available for etanercept came from a single-arm open label trial, CLIPPER. Also in the appraisal:\n\nThe committee heard from the clinical experts that it was possible to generalise results for the effectiveness of etanercept for treating adult psoriatic JIA because the immunological effect is expected to be the same in adults and children. (Tofacitinib is recommended in NICE's technology appraisal guidance on tofacitinib for treating active psoriatic arthritis after inadequate response to DMARDs.)\n\nA clinical expert also said that in their experience there was no evidence to suggest that etanercept would be any less effective in reducing disease activity in people with psoriatic JIA than when using these drugs for polyarticular JIA.\n\nThe assessment group was unable to separately model psoriatic JIA.\n\nThe committee considered that the results of the model for polyarticular JIA were generalisable to people with psoriatic JIA.The committee concluded that etanercept was the relevant comparator for juvenile psoriatic arthritis and that it would consider the conclusions of TA373 in its decision making.\n\n## There is no evidence compared with etanercept\n\nThe company did not present any clinical evidence comparing tofacitinib with etanercept. The committee appreciated that this would have been difficult to do, and any analysis would have been very uncertain. This is because of the small number of patients in the A3921104 study and because the CLIPPER trial was single arm. The company also did not provide a cost-comparison analysis comparing tofacitinib with etanercept. However, the committee was aware that etanercept biosimilars are available in the NHS at a considerable discount to the list price of the originator (exact prices are confidential and cannot be reported here).\n\n# Conclusion\n\n## Tofacitinib is recommended only if a TNF-alpha inhibitor is not suitable or does not control the condition well enough\n\nThe committee noted that a substantial proportion of people have adalimumab for polyarticular JIA (for more about appropriate comparators, see section 3.1). Although tofacitinib is similarly effective, it costs more than adalimumab. The committee recognised that patients and clinicians would welcome an additional treatment option with an alternative route of administration and mode of action. It noted that if people have already had adalimumab, or it is unsuitable, then tocilizumab may be used. Tofacitinib has similar costs and similar benefits to tocilizumab. Therefore, the committee considered that the cost-comparison case was demonstrated, but only if adalimumab is unsuitable or the condition has not responded well enough to it. The committee considered that the evidence relating to juvenile psoriatic arthritis was limited. But as in TA373 this could be generalised from polyarticular JIA and also from tofacitinib's use in adult psoriatic arthritis. However, the main comparator is etanercept for this population, for which there are low-cost biosimilars. This means tofacitinib is likely to have higher costs than etanercept. So the committee concluded that it could recommend tofacitinib for both polyarticular JIA and juvenile psoriatic arthritis, but only if a tumour necrosis factor (TNF)‑alpha inhibitor (such as adalimumab and etanercept) is not suitable or does not control the condition well enough.\n\n# Other factors\n\nNo equality issues were identified."}
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https://www.nice.org.uk/guidance/ta735
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Evidence-based recommendations on tofacitinib for treating juvenile idiopathic arthritis.
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0991218d89911ee4dfaddbd2990b78c14d20a48f
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nice
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Secukinumab for treating moderate to severe plaque psoriasis in children and young people
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Secukinumab for treating moderate to severe plaque psoriasis in children and young people
Evidence-based recommendations on secukinumab (Cosentyx) for moderate to severe plaque psoriasis in children and young people aged 6 to 17 years.
# Recommendations
Secukinumab is recommended as an option for treating plaque psoriasis in children and young people aged 6 to 17 years, only if:
the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and
the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
the company provides the drug according to the commercial arrangement.
Stop secukinumab treatment at 12 weeks if the psoriasis has not responded adequately. An adequate response is defined as a 75% reduction in the PASI score (PASI 75) from when treatment started.
Choose the least expensive treatment if patients (or their parents or carers) and their clinicians consider secukinumab to be one of a range of suitable treatments. Take into account availability of biosimilar products, administration costs, dosage, price per dose and commercial arrangements.
Take into account how skin colour could affect the PASI score and make any appropriate clinical adjustments.
These recommendations are not intended to affect treatment with secukinumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician, the child or young person and their parents or carers.
Why the committee made these recommendations
Secukinumab is a possible alternative to other biological treatments (adalimumab, etanercept and ustekinumab) already recommended by NICE for treating severe plaque psoriasis in children and young people.
Evidence from clinical trials shows that secukinumab is more effective than etanercept. Evidence from an indirect comparison suggests that it is similarly effective to ustekinumab. How its effectiveness compares with that of adalimumab is uncertain because of a lack of evidence, but adalimumab is thought to be similarly effective to ustekinumab.
Comparing the costs of secukinumab with those of adalimumab, etanercept and ustekinumab is appropriate because they work in a similar way and are all options for plaque psoriasis. The costs of secukinumab are similar to or lower than those of adalimumab, etanercept and ustekinumab. Therefore, secukinumab is recommended.# Information about secukinumab
# Marketing authorisation indication
Secukinumab (Cosentyx, Novartis) has a marketing authorisation for 'the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6 years who are candidates for systemic therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of secukinumab is £609.39 for a 150 mg/ml prefilled syringe (excluding VAT; BNF online, accessed August 2021).
The company has a commercial arrangement. This makes secukinumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Treatments
## It is valuable to have a range of biological treatment options for children and young people with psoriasis
The committee was aware that the aim of treatment for psoriasis is to reduce the area of skin covered with psoriatic lesions and improve symptoms such as redness, flaking and itching. It noted that children and young people have topical treatments first line. Then, if there is an inadequate response to treatment or if it is contraindicated or not tolerated, they can have phototherapy or systemic non-biological therapies second line. These therapies include methotrexate and ciclosporin. Clinicians then offer children and young people biological therapies such as adalimumab, etanercept and ustekinumab. The committee noted that, if the condition no longer responds to a biological treatment, people are offered another biological therapy. It concluded that it is valuable to have a range of biological treatment options for plaque psoriasis that have different mechanisms of action.
# Decision problem
## The company's proposed population is consistent with previous NICE recommendations for biological treatments for psoriasis
The company's proposed population for this appraisal was narrower than secukinumab's marketing authorisation. This was because it excluded people who had not had systemic non‑biological therapy or phototherapy. The company considered that secukinumab would be used to treat psoriasis in children and young people as an alternative to other biological therapies for psoriasis. That is, it would be used for people whose condition has not responded adequately to non‑biological systemic treatment or phototherapy, or if these treatments are contraindicated or not tolerated. The committee concluded that the proposed population was consistent with previous NICE recommendations for biological treatments for psoriasis, and in line with the expected use of secukinumab in clinical practice.
## Ustekinumab, etanercept and adalimumab are relevant comparators
The company provided a comparison with 2 of the biological treatments (etanercept and ustekinumab) recommended in NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people. The committee was aware that, similar to secukinumab, which is a recombinant human monoclonal antibody interleukin (IL)‑17 inhibitor, ustekinumab is an IL‑12 and -23 inhibitor. It also noted that etanercept is a tumour necrosis factor (TNF) inhibitor. The company did not provide a comparison with the other biological treatment in its original submission and recommended in the NICE guidance, that is, adalimumab (also a TNF inhibitor). It explained that it was not possible to connect adalimumab to the network meta-analysis because of a lack of overlap in comparators in paediatric studies. The committee was aware that adalimumab is licensed for children and young people 4 years and older but that ustekinumab is only recommended for young people 12 years and older. So, adalimumab may be an important comparator for the 6 to 17 years age range. The committee also noted that there are several biosimilar adalimumab products available and that it represents a substantial proportion of the market share. However, it recognised that, in a chronic condition that can relapse and remit, people are likely to cycle through multiple treatment options. It was aware that cost‑comparison recommendations include a statement to note that if patients and their clinicians consider the intervention to be one of a range of suitable treatments, the least expensive should be chosen. The committee concluded that ustekinumab, etanercept and adalimumab are all relevant comparators.
## The definition of response is consistent with NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab
The committee recalled that, in NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people, treatment should stop if there is an inadequate disease response after an initial treatment period (etanercept at 12 weeks, and adalimumab and ustekinumab at 16 weeks). An adequate response is defined as a 75% reduction in the Psoriasis Area and Severity Index (PASI) score from the start of treatment. The committee further noted that the definition of response to secukinumab proposed by the company is in line with these criteria. It concluded that the definition of response is consistent with the other NICE technology appraisal guidance, although timing of this assessment varies slightly between different biological treatments.
# Clinical effectiveness
## Secukinumab is more effective than etanercept
Secukinumab has been compared with etanercept and placebo in a randomised control trial (Paediatric Study A2310) including 162 children and young people with plaque psoriasis. The trial showed that people having secukinumab had a higher PASI response rate (PASI 75, that is, a 75% reduction in PASI score from baseline) compared with placebo and etanercept at week 12. The trial also showed that, at week 52, the higher response rates were sustained. The committee accepted the results of these trials and concluded that secukinumab was likely more effective than etanercept.
## Secukinumab has a similar effectiveness to ustekinumab
To provide a comparison of effectiveness with ustekinumab, the company produced network meta‑analyses using a fixed-effect model with data from 4 clinical trials. The model provided PASI response rates and Children's Dermatology Life Quality Index scores comparing secukinumab with etanercept, ustekinumab and placebo. The committee accepted that the model was suitable for decision making. It further noted that the results showed that secukinumab has a similar efficacy to ustekinumab and is likely to be more effective than etanercept and placebo. The committee noted that the safety and outcome results were similar to those for other biologicals used for psoriasis. It concluded that secukinumab has a similar effectiveness to ustekinumab.
## In the absence of evidence, it is reasonable to assume adalimumab and ustekinumab are equally effective
The company's provided network meta-analysis did not include adalimumab as a comparator. It said that this was because there were no paediatric studies of adalimumab with overlapping comparators that would allow it to be connected to the network. The committee acknowledged that it had not been possible to include paediatric adalimumab data within the network. The company presented a scenario that assumed adalimumab to be equal in effectiveness to ustekinumab. The ERG preferred a naive indirect comparison of adalimumab from the paediatric study (comparing methotrexate and adalimumab). This comparison resulted in a lower response rate for adalimumab than etanercept. The committee thought this to be unlikely and recalled conclusions from previous appraisals on treatments for plaque psoriasis in adults and children. It acknowledged that, in NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab, some potential biases in using data from adults had been noted. However, these had been considered to have been mitigated through adjustment. The committee further noted that the conclusion in that appraisal had been that ustekinumab and adalimumab are broadly similar in effectiveness. In the absence of evidence for adalimumab, the committee concluded that it would be reasonable to assume that adalimumab and ustekinumab are equally effective, but that this was likely to be a conservative estimate.
# Cost comparison
## The total costs for secukinumab are similar to or lower than those for ustekinumab, etanercept and adalimumab
The company presented a cost-comparison analysis that modelled the total costs of secukinumab, ustekinumab and etanercept over 5 years. To determine the proportion of people who continue treatment, it took into account stopping treatment based on PASI 75 response rates. This was consistent with the stopping rules specified in previous NICE technology appraisal guidance on treatments for plaque psoriasis. The company's base-case analysis assumed similar monitoring, safety profile, treatment administration and subsequent therapies for all 3 treatments. So, these costs were excluded. That is, the base-case analysis considered only the acquisition costs of secukinumab, ustekinumab and etanercept. The committee agreed that it was reasonable to assume similar healthcare resource use across the 3 treatments. The ERG considered that a 12‑year time horizon was more appropriate. It also thought that the assumption of no further costs after stopping treatment was not reflective of clinical practice. The ERG produced a cost‑comparison analysis over 12 years that included adalimumab as a comparator and a scenario that simplified further treatment costs. The committee preferred the 12‑year time horizon. It considered the results that accounted for the confidential patient access schemes for secukinumab and the comparators. The committee concluded that the total costs for secukinumab were similar to or lower than those for ustekinumab, etanercept and adalimumab (the exact results cannot be reported here because the discounts are confidential).
# Equality issues
## The PASI may not be appropriate for all people with psoriasis
The committee noted, as in previous NICE technology appraisals on psoriasis, the potential equality issues with the PASI because it might underestimate disease severity in people with darker skin. It concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect PASI scores, and make the clinical adjustments they consider appropriate.
# Conclusion
## Secukinumab is recommended as an option for treating severe plaque psoriasis in children and young people
The committee concluded that the criteria for a positive cost comparison were met because:
secukinumab provides similar or greater overall health benefits than ustekinumab, etanercept and adalimumab and
the total costs of secukinumab are similar to or lower than the total costs of ustekinumab, etanercept and adalimumab.The committee therefore recommended secukinumab as an option for treating plaque psoriasis in children and young people. It concluded that the recommendations for secukinumab should be consistent with the company's proposal and NICE's recommendations for other biological therapies, that is:
if the disease is severe (that is, a PASI of 10 or more) and
the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
the treatment is stopped at 12 weeks if the psoriasis has not responded adequately and
if patients and their clinicians consider secukinumab to be one of a range of suitable treatments (for example, ustekinumab, etanercept and adalimumab), the least expensive is chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).
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{'Recommendations': 'Secukinumab is recommended as an option for treating plaque psoriasis in children and young people aged 6\xa0to 17\xa0years, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and\n\nthe disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nthe company provides the drug according to the commercial arrangement.\n\nStop secukinumab treatment at 12\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as a 75% reduction in the PASI score (PASI\xa075) from when treatment started.\n\nChoose the least expensive treatment if patients (or their parents or carers) and their clinicians consider secukinumab to be one of a range of suitable treatments. Take into account availability of biosimilar products, administration costs, dosage, price per dose and commercial arrangements.\n\nTake into account how skin colour could affect the PASI score and make any appropriate clinical adjustments.\n\nThese recommendations are not intended to affect treatment with secukinumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop. This decision should be made jointly by the clinician, the child or young person and their parents or carers.\n\nWhy the committee made these recommendations\n\nSecukinumab is a possible alternative to other biological treatments (adalimumab, etanercept and ustekinumab) already recommended by NICE for treating severe plaque psoriasis in children and young people.\n\nEvidence from clinical trials shows that secukinumab is more effective than etanercept. Evidence from an indirect comparison suggests that it is similarly effective to ustekinumab. How its effectiveness compares with that of adalimumab is uncertain because of a lack of evidence, but adalimumab is thought to be similarly effective to ustekinumab.\n\nComparing the costs of secukinumab with those of adalimumab, etanercept and ustekinumab is appropriate because they work in a similar way and are all options for plaque psoriasis. The costs of secukinumab are similar to or lower than those of adalimumab, etanercept and ustekinumab. Therefore, secukinumab is recommended.', 'Information about secukinumab': "# Marketing authorisation indication\n\nSecukinumab (Cosentyx, Novartis) has a marketing authorisation for 'the treatment of moderate to severe plaque psoriasis in children and adolescents from the age of 6\xa0years who are candidates for systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of secukinumab is £609.39 for a 150\xa0mg/ml prefilled syringe (excluding VAT; BNF online, accessed August 2021).\n\nThe company has a commercial arrangement. This makes secukinumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Treatments\n\n## It is valuable to have a range of biological treatment options for children and young people with psoriasis\n\nThe committee was aware that the aim of treatment for psoriasis is to reduce the area of skin covered with psoriatic lesions and improve symptoms such as redness, flaking and itching. It noted that children and young people have topical treatments first line. Then, if there is an inadequate response to treatment or if it is contraindicated or not tolerated, they can have phototherapy or systemic non-biological therapies second line. These therapies include methotrexate and ciclosporin. Clinicians then offer children and young people biological therapies such as adalimumab, etanercept and ustekinumab. The committee noted that, if the condition no longer responds to a biological treatment, people are offered another biological therapy. It concluded that it is valuable to have a range of biological treatment options for plaque psoriasis that have different mechanisms of action.\n\n# Decision problem\n\n## The company's proposed population is consistent with previous NICE recommendations for biological treatments for psoriasis\n\nThe company's proposed population for this appraisal was narrower than secukinumab's marketing authorisation. This was because it excluded people who had not had systemic non‑biological therapy or phototherapy. The company considered that secukinumab would be used to treat psoriasis in children and young people as an alternative to other biological therapies for psoriasis. That is, it would be used for people whose condition has not responded adequately to non‑biological systemic treatment or phototherapy, or if these treatments are contraindicated or not tolerated. The committee concluded that the proposed population was consistent with previous NICE recommendations for biological treatments for psoriasis, and in line with the expected use of secukinumab in clinical practice.\n\n## Ustekinumab, etanercept and adalimumab are relevant comparators\n\nThe company provided a comparison with 2\xa0of the biological treatments (etanercept and ustekinumab) recommended in NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people. The committee was aware that, similar to secukinumab, which is a recombinant human monoclonal antibody interleukin (IL)‑17 inhibitor, ustekinumab is an IL‑12 and -23\xa0inhibitor. It also noted that etanercept is a tumour necrosis factor (TNF) inhibitor. The company did not provide a comparison with the other biological treatment in its original submission and recommended in the NICE guidance, that is, adalimumab (also a TNF inhibitor). It explained that it was not possible to connect adalimumab to the network meta-analysis because of a lack of overlap in comparators in paediatric studies. The committee was aware that adalimumab is licensed for children and young people 4\xa0years and older but that ustekinumab is only recommended for young people 12\xa0years and older. So, adalimumab may be an important comparator for the 6\xa0to 17\xa0years age range. The committee also noted that there are several biosimilar adalimumab products available and that it represents a substantial proportion of the market share. However, it recognised that, in a chronic condition that can relapse and remit, people are likely to cycle through multiple treatment options. It was aware that cost‑comparison recommendations include a statement to note that if patients and their clinicians consider the intervention to be one of a range of suitable treatments, the least expensive should be chosen. The committee concluded that ustekinumab, etanercept and adalimumab are all relevant comparators.\n\n## The definition of response is consistent with NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab\n\nThe committee recalled that, in NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab for treating plaque psoriasis in children and young people, treatment should stop if there is an inadequate disease response after an initial treatment period (etanercept at 12\xa0weeks, and adalimumab and ustekinumab at 16\xa0weeks). An adequate response is defined as a 75% reduction in the Psoriasis Area and Severity Index (PASI) score from the start of treatment. The committee further noted that the definition of response to secukinumab proposed by the company is in line with these criteria. It concluded that the definition of response is consistent with the other NICE technology appraisal guidance, although timing of this assessment varies slightly between different biological treatments.\n\n# Clinical effectiveness\n\n## Secukinumab is more effective than etanercept\n\nSecukinumab has been compared with etanercept and placebo in a randomised control trial (Paediatric Study A2310) including 162\xa0children and young people with plaque psoriasis. The trial showed that people having secukinumab had a higher PASI response rate (PASI\xa075, that is, a 75%\xa0reduction in PASI score from baseline) compared with placebo and etanercept at week\xa012. The trial also showed that, at week\xa052, the higher response rates were sustained. The committee accepted the results of these trials and concluded that secukinumab was likely more effective than etanercept.\n\n## Secukinumab has a similar effectiveness to ustekinumab\n\nTo provide a comparison of effectiveness with ustekinumab, the company produced network meta‑analyses using a fixed-effect model with data from 4\xa0clinical trials. The model provided PASI response rates and Children's Dermatology Life Quality Index scores comparing secukinumab with etanercept, ustekinumab and placebo. The committee accepted that the model was suitable for decision making. It further noted that the results showed that secukinumab has a similar efficacy to ustekinumab and is likely to be more effective than etanercept and placebo. The committee noted that the safety and outcome results were similar to those for other biologicals used for psoriasis. It concluded that secukinumab has a similar effectiveness to ustekinumab.\n\n## In the absence of evidence, it is reasonable to assume adalimumab and ustekinumab are equally effective\n\nThe company's provided network meta-analysis did not include adalimumab as a comparator. It said that this was because there were no paediatric studies of adalimumab with overlapping comparators that would allow it to be connected to the network. The committee acknowledged that it had not been possible to include paediatric adalimumab data within the network. The company presented a scenario that assumed adalimumab to be equal in effectiveness to ustekinumab. The ERG preferred a naive indirect comparison of adalimumab from the paediatric study (comparing methotrexate and adalimumab). This comparison resulted in a lower response rate for adalimumab than etanercept. The committee thought this to be unlikely and recalled conclusions from previous appraisals on treatments for plaque psoriasis in adults and children. It acknowledged that, in NICE's technology appraisal guidance on adalimumab, etanercept and ustekinumab, some potential biases in using data from adults had been noted. However, these had been considered to have been mitigated through adjustment. The committee further noted that the conclusion in that appraisal had been that ustekinumab and adalimumab are broadly similar in effectiveness. In the absence of evidence for adalimumab, the committee concluded that it would be reasonable to assume that adalimumab and ustekinumab are equally effective, but that this was likely to be a conservative estimate.\n\n# Cost comparison\n\n## The total costs for secukinumab are similar to or lower than those for ustekinumab, etanercept and adalimumab\n\nThe company presented a cost-comparison analysis that modelled the total costs of secukinumab, ustekinumab and etanercept over 5\xa0years. To determine the proportion of people who continue treatment, it took into account stopping treatment based on PASI\xa075 response rates. This was consistent with the stopping rules specified in previous NICE technology appraisal guidance on treatments for plaque psoriasis. The company's base-case analysis assumed similar monitoring, safety profile, treatment administration and subsequent therapies for all 3\xa0treatments. So, these costs were excluded. That is, the base-case analysis considered only the acquisition costs of secukinumab, ustekinumab and etanercept. The committee agreed that it was reasonable to assume similar healthcare resource use across the 3\xa0treatments. The ERG considered that a 12‑year time horizon was more appropriate. It also thought that the assumption of no further costs after stopping treatment was not reflective of clinical practice. The ERG produced a cost‑comparison analysis over 12\xa0years that included adalimumab as a comparator and a scenario that simplified further treatment costs. The committee preferred the 12‑year time horizon. It considered the results that accounted for the confidential patient access schemes for secukinumab and the comparators. The committee concluded that the total costs for secukinumab were similar to or lower than those for ustekinumab, etanercept and adalimumab (the exact results cannot be reported here because the discounts are confidential).\n\n# Equality issues\n\n## The PASI may not be appropriate for all people with psoriasis\n\nThe committee noted, as in previous NICE technology appraisals on psoriasis, the potential equality issues with the PASI because it might underestimate disease severity in people with darker skin. It concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect PASI scores, and make the clinical adjustments they consider appropriate.\n\n# Conclusion\n\n## Secukinumab is recommended as an option for treating severe plaque psoriasis in children and young people\n\nThe committee concluded that the criteria for a positive cost comparison were met because:\n\nsecukinumab provides similar or greater overall health benefits than ustekinumab, etanercept and adalimumab and\n\nthe total costs of secukinumab are similar to or lower than the total costs of ustekinumab, etanercept and adalimumab.The committee therefore recommended secukinumab as an option for treating plaque psoriasis in children and young people. It concluded that the recommendations for secukinumab should be consistent with the company's proposal and NICE's recommendations for other biological therapies, that is:\n\nif the disease is severe (that is, a PASI of 10\xa0or more) and\n\nthe disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nthe treatment is stopped at 12\xa0weeks if the psoriasis has not responded adequately and\n\nif patients and their clinicians consider secukinumab to be one of a range of suitable treatments (for example, ustekinumab, etanercept and adalimumab), the least expensive is chosen (taking into account administration costs, dosage, price per dose and commercial arrangements)."}
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https://www.nice.org.uk/guidance/ta734
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Evidence-based recommendations on secukinumab (Cosentyx) for moderate to severe plaque psoriasis in children and young people aged 6 to 17 years.
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8b9d7a467d5158d4bdc8bcda35b20e85cf7bab9b
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nice
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Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia
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Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia
Evidence-based recommendations on inclisiran (Leqvio) for treating primary hypercholesterolaemia or mixed dyslipidaemia in adults.
# Recommendations
Inclisiran is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults. It is recommended only if:
there is a history of any of the following cardiovascular events:
acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)
coronary or other arterial revascularisation procedures
coronary heart disease
ischaemic stroke or
peripheral arterial disease, and
low-density lipoprotein cholesterol (LDL-C) concentrations are persistently 2.6 mmol/l or more, despite maximum tolerated lipid-lowering therapy, that is:
maximum tolerated statins with or without other lipid-lowering therapies or,
-ther lipid-lowering therapies when statins are not tolerated or are contraindicated, and
the company provides inclisiran according to the commercial arrangement.
Inclisiran is recommended only in research for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia in adults who have no history of cardiovascular events. This research is in the form of a clinical trial currently in development.
These recommendations are not intended to affect treatment with inclisiran that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Current treatment for primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia includes statins for lowering LDL-C levels. Ezetimibe and either alirocumab or evolocumab may be added when a person's LDL-C levels are not lowered enough with the maximum tolerated dose of statins. Inclisiran would be used when statins or other lipid-lowering therapies do not control LDL-C well enough or when people cannot have statins.
Clinical trial evidence shows that inclisiran can lower LDL-C levels when statins or other lipid-lowering therapies have not reduced them enough. But, there is no data directly comparing inclisiran with ezetimibe, alirocumab or evolocumab. There is also no long-term evidence on whether inclisiran reduces cardiovascular events. This means the clinical evidence and the cost-effectiveness estimates are very uncertain.
But, despite the uncertainties, inclisiran is still considered cost effective in people who have previously had a cardiovascular event and have persistently high LDL-C levels (2.6 mmol/l or more) despite maximum lipid-lowering therapy. Therefore, inclisiran is recommended as an option in this population.
In people who have never had a cardiovascular event, the cost-effectiveness estimates were very uncertain and likely to be above what NICE considers an acceptable use of NHS resources. But, a clinical trial is planned that will look at inclisiran's effect on cardiovascular events in this population. So in this population, inclisiran is recommended only in research.# Information about inclisiran
# Marketing authorisation indication
Inclisiran (Leqvio, Novartis) is 'indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:
in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated'.
# Dosage in the marketing authorisation
The dosage schedule for inclisiran is available in the summary of product characteristics.
# Price
Inclisiran costs £1,987.36 per 284-mg dose pack (company submission). The company has a commercial arrangement. This makes inclisiran available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.
# Clinical pathway
## People with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia will welcome a new treatment option
The clinical experts stated that the aim of treatment is to lower, and reduce long-term exposure to, low-density lipoprotein cholesterol (LDL-C) and that statins are the first treatment offered. The clinical experts explained that if people's LDL-C levels remain too high, then ezetimibe may also be offered and, if they are eligible, alirocumab and evolocumab are also options. The patient expert explained that people with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia are at increased risk of cardiovascular events and that the conditions are treated inconsistently across the NHS. They highlighted that it can be difficult to access testing for high cholesterol and that treatments like alirocumab and evolocumab are only offered to people with higher levels of LDL-C. They added that a large proportion of people who are eligible for these treatments are not referred to secondary care to have them. The clinical and patient experts also highlighted that many people do not receive testing for heterozygous familial hypercholesterolaemia. The patient expert stated that inclisiran offers a twice-yearly treatment option, compared with more frequent dosing of currently available treatments, and this would likely increase treatment adherence. The clinical experts explained that it is difficult to reach LDL-C target levels with currently available oral treatments (statins and ezetimibe). The committee concluded that people with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia would welcome a new treatment option.
## The appropriate position of inclisiran in the treatment pathway is after maximum tolerated statins alone or with ezetimibe
The NICE scope outlined 3 separate positions for inclisiran in the treatment pathway:
compared with maximum tolerated statins
when maximum tolerated statins do not appropriately control LDL-C, and
when maximum tolerated statins with ezetimibe do not appropriately control LDL-C.The NICE scope also requested analyses for when statins are contraindicated or not tolerated. The company positioned inclisiran as a treatment option if LDL-C levels were too high after standard of care treatment. The company defined standard of care as a mix of maximum tolerated statins and other lipid-lowering therapy, including a small proportion of ezetimibe use based on the ORION trials (see section 3.5 and section 3.7). The clinical experts stated that inclisiran could be used after maximum tolerated statins, or after maximum tolerated statins and ezetimibe. The committee noted that this was in line with the treatment pathway defined by inclisiran's marketing authorisation, which allows its use after maximum tolerated statins or maximum tolerated statins and other lipid-lowering therapies. The committee concluded that the appropriate position of inclisiran in the treatment pathway is after maximum tolerated statins or after maximum tolerated statins with ezetimibe.
## Inclisiran is likely to be used in a primary care setting
The company proposes that inclisiran would be given by a healthcare professional in a primary care setting. After an initial dose, it would be given again after 3 months and then twice a year. The committee was aware that other currently available treatments, such as alirocumab and evolocumab, are usually prescribed in secondary care. The clinical experts stated that the primary care setting could be appropriate, although it would need some changes in how the condition is currently managed. The committee noted that, in general, the responses to technical engagement from professional organisations supported the use of inclisiran in a primary care setting. These responses also noted that primary care can be used to identify and provide treatment for people who would be eligible for inclisiran. The committee noted that there were some concerns in submissions received surrounding the implementation of inclisiran in a primary care setting but noted that the Accelerated Access Collaborative and NHS England had plans to support the implementation of inclisiran within a primary care setting. The committee was also aware of an ongoing implementation research project (SPIRIT) that aims to assess the feasibility of delivering inclisiran within a primary care setting in England. The committee noted that this trial was due to complete in 2022 and considered that it could provide some relevant information on how inclisiran can be delivered in a primary care setting. The committee accepted that inclisiran is likely to be used in a primary care setting.
# Population
## The populations included in the company's submission are clinically relevant but are narrower than inclisiran's marketing authorisation and trial data
The marketing authorisation for inclisiran does not specify a minimum LDL-C level before beginning treatment. The company presented analysis by 3 populations:
Secondary prevention: people who have had a previous cardiovascular event, including acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation), coronary or other arterial revascularisation procedures, coronary heart disease, ischaemic stroke or peripheral arterial disease. The committee noted that NICE's technology appraisal guidance on alirocumab and evolocumab defined this population as having a high risk of cardiovascular disease.
Primary prevention with elevated risk: people who have not had a cardiovascular event and have type 2 diabetes or heterozygous familial hypercholesterolaemia, or who have a 10-year cardiovascular disease risk of 20% or more based on Framingham risk score or equivalent.
Primary prevention with heterozygous familial hypercholesterolaemia.In each of the 3 populations, the company submitted evidence based on a minimum LDL-C level of 2.6 mmol/l. This was narrower than the marketing authorisation in all 3 populations and narrower than the clinical trial data for the secondary prevention population (see section 3.7). The company stated that a minimum LDL-C level of 2.6 mmol/l was selected because a greater clinical benefit was observed in the ODYSSEY OUTCOMES trial (alirocumab compared with placebo after acute coronary syndrome) in people with a baseline LDL-C of 2.6 mmol/l or more. The company also highlighted that an LDL-C of 2.6 mmol/l was close to the mean baseline LDL-C in the ORION clinical trials and the company's clinical experts supported the use of this threshold. The clinical experts at the meeting highlighted that the use of a 2.6 mmol/l threshold meant that inclisiran, if approved, would enable more people to access a treatment that could significantly reduce LDL-C levels, meaning that they were more likely to reach LDL‑C goals. The clinical experts noted that the ORION-11 trial used a 10-year cardiovascular disease risk of 20% or higher, based on Framingham risk score or equivalent, as part of its criteria for the primary prevention with elevated risk population. They explained that NHS practice uses the QRISK score to identify risk and this measure would be used instead and adjusted to identify this population. The evidence review group (ERG) highlighted that a lack of genetic testing for all people with suspected heterozygous familial hypercholesterolaemia may result in cases either being missed or being incorrectly classified as other population groups (see section 3.1). The committee concluded that the populations included in the company's submission are clinically relevant but are narrower than inclisiran's marketing authorisation and the clinical trial data.
# Comparators
## The appropriate comparators are ezetimibe, alirocumab, evolocumab and maximum tolerated statins
NICE technology appraisal guidance recommends ezetimibe, alirocumab and evolocumab as treatment options in the same part of the treatment pathway as inclisiran (see section 3.2). The company did not consider ezetimibe to be a relevant comparator. Instead, the company included a small amount of ezetimibe use as part of standard of care, based on the ORION clinical trial programme (see section 3.7), and did not include the efficacy of ezetimibe as estimated by the network meta-analysis (NMA; see section 3.8). The company highlighted that ezetimibe use in the NHS was low and that NICE's guideline on cardiovascular disease: risk assessment and reduction includes ezetimibe only as an option and not a required pathway step before further treatment. The ERG believed that ezetimibe should be a distinct comparator and their base case used the efficacy from the company's NMA for ezetimibe, rather than comparing with the company's definition of standard of care, which was assumed to provide no reduction in baseline LDL-C (see section 3.2). The ERG had been informed by its clinical experts that if LDL-C is too high after maximum tolerated statins, then there is a clinical decision to either switch to rosuvastatin (another statin, which is not yet generic) or add ezetimibe. The ERG also highlighted that, unlike for treatment with alirocumab or evolocumab, there are no minimum LDL-C thresholds needed for treatment with ezetimibe (see section 3.6). It also noted that ezetimibe is now available as a generic treatment, which means its cost is low, and highlighted that ezetimibe was considered a relevant comparator in each of NICE's previous technology appraisals in this condition. The ERG also highlighted that hypercholesterolemia is undertreated, and this applies to all treatments. The committee agreed with the ERG that ezetimibe should be considered as a relevant comparator. The committee also agreed that it would not eliminate the company's definition of standard of care from its decision-making, noting that this was a mix of predominately maximum tolerated statins, with low amounts of ezetimibe use (but did not include the efficacy of ezetimibe as estimated by the NMA), as in the ORION trials. The committee concluded that the appropriate comparators are ezetimibe, alirocumab, evolocumab and maximum tolerated statins (when inclisiran is given in combination with statins).
## The relevant comparators are dependent on alirocumab or evolocumab eligibility
The committee noted that the populations in the company submission included people with a minimum LDL-C level of 2.6 mmol/l (see section 3.4). Therefore, a proportion of people would be eligible for alirocumab or evolocumab based on recommendations in NICE's technology appraisal guidance on alirocumab and evolocumab. This includes people in:
secondary prevention, if their LDL-C levels are persistently above 4 mmol/l and they have a high risk of cardiovascular disease, defined as any history of:
acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation)
coronary or other arterial revascularisation procedures
coronary heart disease
ischaemic stroke
peripheral arterial disease
secondary prevention who have a very high risk for cardiovascular disease (defined as recurrent cardiovascular events or cardiovascular events in more than one vascular bed ), only if LDL-C levels are persistently above 3.5 mmol/l
secondary prevention with heterozygous familial hypercholesterolaemia, only if LDL-C levels are persistently above 3.5 mmol/l, and
primary prevention with heterozygous familial hypercholesterolaemia, only if LDL-C levels are persistently above 5 mmol/l.The committee was also aware that there are populations in the company's submission who would not be eligible for alirocumab or evolocumab as outlined by previous NICE recommendations, specifically people in:
secondary prevention who have a high risk for cardiovascular disease and an LDL-C level between 2.6 mmol/l and 4.0 mmol/l
secondary prevention who have a very high risk for cardiovascular disease and an LDL-C level between 2.6 mmol/l and 3.5 mmol/l
secondary prevention with heterozygous familial hypercholesterolaemia and an LDL-C level between 2.6 mmol/l and 3.5 mmol/l
primary prevention with elevated risk (excluding heterozygous familial hypercholesterolaemia) with an LDL-C level of 2.6 mmol/l or more
primary prevention with heterozygous familial hypercholesterolaemia and an LDL-C level between 2.6 mmol/l and 5.0 mmol/l.The committee noted that, based on NICE's technology appraisal guidance on ezetimibe, ezetimibe was available as an option in all populations and also a relevant comparator in all populations included in the company's submission (see section 3.4 and section 3.5). The committee considered that for people who are ineligible for alirocumab or evolocumab, ezetimibe was the only relevant NICE-recommended comparator. But, it acknowledged that maximum tolerated statins was also a treatment option and a relevant comparator in this population (see section 3.5). For people who are eligible for alirocumab or evolocumab, the committee agreed that ezetimibe, alirocumab, evolocumab and maximum tolerated statins are relevant comparators. The committee were aware that mean baseline LDL-C would be lower in the population ineligible for alirocumab or evolocumab compared with people who are eligible. The committee concluded that the relevant comparators are dependent on alirocumab or evolocumab eligibility.
# Clinical evidence
## Results from ORION-9, ORION-10 and ORION-11 show inclisiran reduces LDL-C levels and are generalisable to people with primary hypercholesterolaemia or mixed dyslipidaemia in the NHS
The clinical trial evidence in the company submission came from 3 randomised 18-month trials comparing inclisiran with placebo:
ORION-9 included people with heterozygous familial hypercholesterolaemia and elevated LDL-C levels (2.6 mmol/l or more)
ORION-10 included people with atherosclerotic cardiovascular disease (secondary prevention) and elevated LDL-C levels (1.8 mmol/l or more)
ORION-11 included people with atherosclerotic cardiovascular disease (secondary prevention) and elevated LDL-C levels (1.8 mmol/l or more) and people who had not had a cardiovascular event (primary prevention) but had elevated risks of atherosclerotic cardiovascular disease and LDL-C levels (2.6 mmol/l or more).The trials included people on lipid-lowering therapies (such as statins or ezetimibe or both). The ERG noted that the proportion of people in the ORION trials receiving ezetimibe was 51% in ORION-9, 11% in ORION-10 and 9% in ORION-11. In the trials, people who were on a statin were on their maximum tolerated dose. The trials also included people who had documented evidence of statin intolerance. All 3 trials had co-primary endpoints of mean LDL-C percentage change from baseline to 510 days and time-adjusted LDL-C percentage change by day 90 and up to day 540. The results showed that inclisiran compared with placebo significantly reduced levels of LDL-C. From baseline to day 510, LDL-C was reduced by 47.9% (95% confidence interval 53.5 to 42.3), 52.3% (95% CI 55.7 to 48.8) and 49.9% (95% CI 53.1 to 46.6) in ORION-9, ORION-10 and ORION-11 respectively. Similar results were also seen in the co-primary end point of time-adjusted LDL-C percentage change from day 90 to day 540. The committee was aware that the clinical trials were mostly carried out in the US but noted that the clinical expert submissions stated that the trial results were generalisable to the NHS. The clinical trial results also showed that rates of adverse events were similar for people treated with inclisiran compared with placebo, with the exception of injection site reactions, which were more common in people treated with inclisiran (8.2% compared with 1.8% in those treated with placebo). The committee concluded that results from ORION-9, ORION-10 and ORION-11 show that inclisiran reduces LDL-C levels compared with placebo and these results are generalisable to people with primary hypercholesterolaemia or mixed dyslipidaemia seen in NHS clinical practice.
# Indirect treatment comparison
## The network meta-analyses used by the company are appropriate but are associated with some uncertainties
Because the ORION trials only included a placebo comparator, the company undertook NMAs to indirectly compare inclisiran with alirocumab, evolocumab and ezetimibe. The company produced 3 NMAs for different populations, based on a common placebo comparator:
secondary prevention or primary prevention with elevated risk on maximum tolerated statins
secondary prevention or primary prevention with elevated risk and statin intolerance
heterozygous familial hypercholesterolaemia on maximum tolerated statins.The company used a 24-week timepoint in its NMAs. The company explained that this choice reflected the longest available timepoint for which data was available from comparator treatment trials included in the NMAs. The results from the random-effects model showed that inclisiran was associated with a greater LDL-C reduction compared with ezetimibe and compared with placebo. The NMAs estimated that inclisiran was associated with an LDL-C reduction that was marginally less than with alirocumab or evolocumab, although this result was not statistically significant. The company explained that it could not provide effectiveness estimates for ezetimibe in the heterozygous familial hypercholesterolaemia on maximum tolerated statins NMA, as no trials were identified for ezetimibe in that population. The ERG agreed that the methods used by the company to undertake the NMA were appropriate. But they noted that the NMAs included trials with high levels of heterogeneity and that some trials in the NMAs were inconsistent in their definitions of cardiovascular risks. The committee noted that the 24-week timepoint used in the NMA added some uncertainty to the clinical outcomes as there was limited evidence of whether LDL-C reduction achieved at 24 weeks would be maintained over a lifetime, as assumed in the model (see section 3.10). The committee was also aware that the estimates from the NMA were more favourable for inclisiran than the co-primary endpoints from the clinical trials. The committee concluded that the network meta-analyses used by the company are appropriate but are associated with some uncertainties.
# Long-term treatment effect of inclisiran
## The effect of inclisiran on cardiovascular event risk is uncertain as there is a lack of long-term evidence
The completed ORION clinical trials (see section 3.7) were unable to provide enough data on the effectiveness of inclisiran in reducing cardiovascular events and mortality. This was because the follow up of 18 months was not long enough to provide these outcomes. The company used the reduction in LDL-C from the indirect treatment comparison (see section 3.8) to estimate the assumed reduction in cardiovascular events. The company used the Cholesterol Treatment Trialist Collaboration (CTT) meta-analyses, which reported change in cardiovascular event risk per 1 mmol/l reduction in LDL-C by statin use. The ERG agreed that these analyses were appropriate and noted that earlier versions of this source were used in past NICE technology appraisals in this disease area (NICE technology appraisal guidance on ezetimibe, alirocumab, evolocumab and bempedoic acid with ezetimibe). The committee expressed a concern that the link between changes in LDL-C levels and cardiovascular outcomes used in the company model, may not be appropriate for inclisiran because the mechanism of action is different to that of statins. The clinical experts stated that the CTT meta-analyses were appropriate and that a similar relationship between LDL-C lowering and a reduction in cardiovascular event risk as seen with statin use could be expected with inclisiran. The committee was aware that longer-term trial evidence was available for alirocumab (ODYSSEY OUTCOMES) and evolocumab (FOURIER) but noted that the follow-up period of these trials may not have been long enough to estimate the full effect on cardiovascular outcomes. The committee also noted that the ODYSSEY OUTCOMES trial was restricted to people who had had a recent cardiovascular event. The committee was also aware that an ongoing UK clinical trial, ORION-4, would provide outcome data on cardiovascular events with a median follow up of 5 years for inclisiran compared with placebo in people who have already had a cardiovascular event. The committee noted, however, that this trial would not report until 2026. The company explained that a global clinical trial with a similar design was in development. The company also confirmed that it is planning a clinical trial (ORION‑17) to collect data on cardiovascular outcomes of inclisiran compared with placebo, in people who have not experienced a cardiovascular event. The committee considered that the lack of data on inclisiran's effect on cardiovascular outcomes was a key uncertainty in the appraisal and was a major driver of the cost-effectiveness results. The committee concluded that the effect of inclisiran on cardiovascular event risk is uncertain as there is a lack of long-term evidence.
## The assumptions of no treatment effect waning, and no treatment discontinuation may be appropriate but adds uncertainty
The company's economic model assumed that the treatment effect as estimated by the NMA at 24 weeks (see section 3.8) would be maintained at the same level over a lifetime. The company stated that this assumption was based on previous NICE technology appraisals of alirocumab and evolocumab in the same condition. The ERG noted that given the lack of long-term trial evidence beyond 18 months to support this assumption, the company could have provided a scenario in which inclisiran's effectiveness is assumed to reduce over time. The clinical experts stated that inclisiran would likely be used over the course of a lifetime, as LDL-C levels would be expected to return to baseline if discontinued. The company highlighted that the assumption of no treatment discontinuation was also based on previous NICE technology appraisals of alirocumab and evolocumab and stated that the treatment discontinuation rate for inclisiran in the ORION clinical trials was low (annual discontinuation rate of 1.7% in ORION-9 and 3.2% in ORION-10 and ORION-11). The committee noted that there was a lack of long-term data for inclisiran to support this assumption. The committee concluded that assumptions of no waning of treatment effect and no treatment discontinuation may be appropriate but add uncertainty.
# Innovation
## Inclisiran is innovative, however all relevant benefits are likely to be captured in the quality-adjusted life year calculations
The company highlighted that inclisiran was the first cholesterol-lowering small interfering RNA (siRNA) and has the potential to be a step change in how the condition is managed. The company, clinical and patient experts highlighted that treatment with inclisiran had the potential to increase treatment adherence, because of its twice-yearly dosing schedule (see section 3.1). The committee considered the potential additional benefits inclisiran might provide but concluded that there was no evidence of additional gains in health-related quality of life over those already included in the quality-adjusted life year (QALY) calculations. The committee concluded that inclisiran is innovative, however all relevant benefits are likely to be captured in the QALY calculations.
# Cost-effectiveness estimates
## The ERG's base case includes the committee's preferred assumptions
The ERG's base-case analyses included ezetimibe as a separate comparator and also included comparisons with maximum tolerated statins. Therefore, it differed from the company's base case, which included a small amount of ezetimibe use as part of standard care (see section 3.5). The committee was aware that the ERG's base-case analyses was otherwise the same as the company's. This included using the company's NMA estimate for treatment efficacy (see section 3.8) and no treatment waning or treatment discontinuation (see section 3.10). The committee concluded that it preferred the ERG base case but would take the company analyses into account in its decision making.
## Because of the uncertainty the acceptable incremental cost-effectiveness ratios are £20,000 per QALY gained and above £30,000 per QALY lost
NICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee also needs to be increasingly certain of the cost effectiveness of a technology as the impact of its adoption on NHS resources increases and may need more robust evidence for technologies that are expected to have a larger impact. Therefore, because of the high level of uncertainty in the clinical and economic evidence, primarily caused by the lack of outcome data on inclisiran's effect on cardiovascular events (see section 3.9), the NMA clinical effectiveness estimates (see section 3.8) and long-term treatment effects and discontinuation assumptions (see section 3.10), the committee agreed that an acceptable ICER would be no higher than £20,000 per QALY gained or above £30,000 per QALY lost when considering each of the population groups and their respective LDL-C ranges (see section 3.6).
## Inclisiran is cost effective for secondary prevention in people who are eligible for alirocumab and evolocumab
The cost-effectiveness results for the secondary prevention population who are eligible for alirocumab or evolocumab were assessed by calculating net monetary benefit. This was because inclisiran was estimated to provide marginally fewer incremental QALYs compared with alirocumab or evolocumab (see section 3.8). The incremental net monetary benefit of inclisiran was compared with alirocumab or evolocumab, at threshold values of £30,000 saved per QALY lost using the committee preferred assumptions (see section 3.12 and section 3.13). This resulted in a positive incremental net monetary benefit at that threshold value, meaning that the amount of lost QALYs associated with inclisiran compared with alirocumab or evolocumab was acceptable when considering the differences in costs between these treatments. The committee considered that net monetary benefit was appropriate for decision making as it was likely that any differences in QALYs between inclisiran and alirocumab or evolocumab are small. This confirmed that inclisiran is cost effective compared with alirocumab and evolocumab in the following secondary prevention populations in which alirocumab and evolocumab are available:
secondary prevention with a high risk for cardiovascular disease, only if LDL-C levels are persistently above 4 mmol/l
secondary prevention with a very high risk for cardiovascular disease, only if LDL-C levels are persistently above 3.5 mmol/l
secondary prevention with heterozygous familial hypercholesterolaemia, only if LDL-C levels are persistently above 3.5 mmol/l.Inclisiran was associated with an ICER of below £20,000 per QALY gained compared with either ezetimibe or maximum tolerated statins in the populations eligible for treatment with alirocumab and evolocumab described above. The committee concluded that inclisiran is cost effective in these populations for both pairwise and fully incremental analysis. Because of the confidential discount for inclisiran, the exact ICERs have not been reported here.
## Inclisiran is cost effective for secondary prevention in people who are not eligible for alirocumab or evolocumab
Using the committee's preferred assumptions (see section 3.12) the most plausible ICERs for inclisiran compared with ezetimibe or maximum tolerated statins for the secondary prevention population who are not eligible for alirocumab or evolocumab (see section 3.6), were likely to be around or below £20,000 per QALY gained in pairwise and fully incremental analysis. Therefore, the committee concluded that inclisiran is cost effective in this population. Because of the confidential discount for inclisiran, the exact ICERs cannot be reported here.
## Inclisiran is not cost effective in the primary prevention population with elevated risk
Using the committee's preferred assumptions (see section 3.12) the most plausible ICERs for inclisiran in the primary prevention with elevated risk population and an LDL-C of at least 2.6 mmol/l, were likely to be above £20,000 per QALY gained. This was based on considering comparisons with ezetimibe or maximum tolerated statins in pairwise and fully incremental analysis. Therefore, the committee concluded that inclisiran is not cost effective in the primary prevention population with elevated risk.
## Inclisiran is recommended only in research in the primary prevention population
The committee considered that the cost-effectiveness estimates were highly uncertain for the primary prevention with elevated risk population. The committee highlighted that smaller numbers from ORION-11 informed the cost-effectiveness estimates for this population (see section 3.9). The committee also noted that the budget impact for inclisiran was estimated to be high in the primary prevention population. The committee was aware that NICE's guide to the methods of technology appraisal notes, in general, that the committee will want to be increasingly certain of the cost effectiveness of a technology as the impact of its adoption on NHS resources increases. The committee was also aware that the company is developing a UK clinical trial (ORION-17) to evaluate the effect of inclisiran compared with placebo on cardiovascular outcomes in people who have not had a cardiovascular event. The committee therefore recommended that inclisiran is used only in the context of research in this population.
## Inclisiran is not cost effective in the primary prevention with heterozygous familial hypercholesterolaemia population
Using the committee's preferred assumptions (see section 3.12) the most plausible ICERs for the primary prevention with heterozygous familial hypercholesterolaemia populations were as follows:
In people who are not eligible for alirocumab or evolocumab (LDL-C levels between 2.6 mmol/l and 5 mmol/l; see section 3.6) the ICERs were significantly above £20,000 per QALY gained when compared with maximum tolerated statins.
In people who are eligible for alirocumab or evolocumab (LDL-C levels of at least 5 mmol/l; see section 3.6), the ICER was below £20,000 per QALY gained when compared with maximum tolerated statins. The incremental net monetary benefit of inclisiran was compared with alirocumab or evolocumab, at threshold values of £30,000 saved per QALY lost (see section 3.13) in this population. This resulted in a positive incremental net monetary benefit for inclisiran compared with these treatments.The committee noted that the company did not provide cost-effectiveness results for inclisiran compared with ezetimibe in the heterozygous familial hypercholesterolaemia populations. Comparisons with ezetimibe were part of the committee's preferred base case (see section 3.12). This was because there was no clinical trial data for ezetimibe in these populations to inform the NMA (see section 3.8). For the alirocumab- or evolocumab-eligible and -ineligible populations, the committee considered that the ICERs for inclisiran compared with ezetimibe would be higher than the ICERs comparing inclisiran with maximum tolerated statins and would be significantly above £20,000 per QALY gained if incorporated into a pairwise and fully incremental analyses. The committee concluded that inclisiran is not cost effective in the primary prevention with heterozygous familial hypercholesterolaemia population.
## Inclisiran is recommended only in research in the primary prevention with heterozygous familial hypercholesterolaemia population
The committee considered that the cost-effectiveness estimates were highly uncertain for the primary prevention with heterozygous familial hypercholesterolaemia population. The committee also noted that many people do not receive testing for heterozygous familial hypercholesterolaemia. This means cases may either be missed or classified as other population groups (see section 3.1 and section 3.4). The committee was also aware that the company is developing a UK clinical trial (ORION-17) to evaluate the effect of inclisiran compared with placebo on cardiovascular outcomes in people who have not had a cardiovascular event. The committee therefore recommended that inclisiran is used only in the context of research in this population.
# Other factors
## There are no equalities issues that can be addressed in this appraisal
A number of potential equality issues were raised during the appraisal. These included the higher prevalence of cardiovascular conditions in more deprived areas and in some specific populations (such as minority ethnic groups or people with severe mental health conditions or learning disabilities). The committee also heard that the treatments provided could vary across the NHS depending on region and availability of specialist care, and that there may be difficulties in accessing treatment for older people. The committee concluded that its recommendations for inclisiran would apply to all patients and that the recommendation would not affect people protected by the equality legislation any differently. The committee also considered that further evidence should be collected to assess whether the implementation of inclisiran into the treatment pathway would reduce health inequalities in this condition (see section 5.4).
# Conclusion
## Inclisiran is recommended for people with a history of cardiovascular events (secondary prevention) if LDL-C levels are at least 2.6 mmol/l
The committee was concerned that there was a lack of long-term data on cardiovascular outcomes from the clinical trials that compared inclisiran with placebo. However, it noted that ongoing clinical trials would provide more data on these outcomes. The cost-effectiveness results based on the committee's preferred modelling assumptions with a commercial arrangement for inclisiran, represent a cost-effective use of NHS resources for adults with a history of cardiovascular events and persistent LDL-C levels of at least 2.6 mmol/l despite having the maximum tolerated lipid-lowering therapy. The committee therefore concluded that inclisiran is recommended for this group.
## Inclisiran is recommended only in research for people who do not have a history of cardiovascular events (primary prevention)
The cost-effectiveness results for both the primary prevention with elevated risk, and primary prevention with heterozygous familial hypercholesterolaemia were highly uncertain and the ICERs for these populations were likely above £20,000 per QALY gained. The committee considered that inclisiran had the potential to be cost effective in these populations. Based on the information it had heard about ORION-17, it considered that it was likely that the research needed would be commissioned and successfully report, and that its potential value to the NHS would likely represent good value in the context of limited research resources. It therefore recommended inclisiran only in the context of research in this group.# Recommendations for research and data collection
The company confirmed to the committee that it was developing a randomised controlled trial (ORION-17) of the effectiveness of inclisiran compared with placebo. This will be a UK-based trial in people who have not previously had a cardiovascular event (primary prevention). The main outcomes of interest are cardiovascular events and mortality.
The committee was also aware that ORION-4, an ongoing randomised controlled UK trial of inclisiran compared with placebo in people with a history of cardiovascular disease (secondary prevention), is due to complete in 2026. In addition, the company stated that an additional global trial of a similar design was also in development. The main outcomes of interest in these trials are also cardiovascular events and mortality.
The committee noted that there was an ongoing trial that aimed to compare inclisiran and lipid-lowering medication with or without behavioural support and lipid-lowering medication without inclisiran with behavioural support (SPIRIT). This trial will also assess the feasibility of delivering inclisiran within a primary care setting in England and is due to complete in 2022. The committee considered that this evidence was also of interest.
The committee also recommended that additional evidence collection should be carried out. Mindful of the issues raised concerning equality (see section 3.19), the committee strongly encouraged the collection of data to assess whether implementing inclisiran into the treatment pathway leads to a reduction in health inequalities. This should include real-world evidence on assessing inclisiran uptake in areas of high deprivation and across various population groups, as well as data on treatment adherence. The committee encouraged the collection of this data as it would be of interest in a review of this guidance.
|
{'Recommendations': "Inclisiran is recommended as an option for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia as an adjunct to diet in adults. It is recommended only if:\n\nthere is a history of any of the following cardiovascular events:\n\n\n\nacute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation)\n\ncoronary or other arterial revascularisation procedures\n\ncoronary heart disease\n\nischaemic stroke or\n\nperipheral arterial disease, and\n\n\n\nlow-density lipoprotein cholesterol (LDL-C) concentrations are persistently 2.6\xa0mmol/l or more, despite maximum tolerated lipid-lowering therapy, that is:\n\n\n\nmaximum tolerated statins with or without other lipid-lowering therapies or,\n\nother lipid-lowering therapies when statins are not tolerated or are contraindicated, and\n\n\n\nthe company provides inclisiran according to the commercial arrangement.\n\nInclisiran is recommended only in research for treating primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia in adults who have no history of cardiovascular events. This research is in the form of a clinical trial currently in development.\n\nThese recommendations are not intended to affect treatment with inclisiran that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nCurrent treatment for primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia includes statins for lowering LDL-C levels. Ezetimibe and either alirocumab or evolocumab may be added when a person's LDL-C levels are not lowered enough with the maximum tolerated dose of statins. Inclisiran would be used when statins or other lipid-lowering therapies do not control LDL-C well enough or when people cannot have statins.\n\nClinical trial evidence shows that inclisiran can lower LDL-C levels when statins or other lipid-lowering therapies have not reduced them enough. But, there is no data directly comparing inclisiran with ezetimibe, alirocumab or evolocumab. There is also no long-term evidence on whether inclisiran reduces cardiovascular events. This means the clinical evidence and the cost-effectiveness estimates are very uncertain.\n\nBut, despite the uncertainties, inclisiran is still considered cost effective in people who have previously had a cardiovascular event and have persistently high LDL-C levels (2.6\xa0mmol/l or more) despite maximum lipid-lowering therapy. Therefore, inclisiran is recommended as an option in this population.\n\nIn people who have never had a cardiovascular event, the cost-effectiveness estimates were very uncertain and likely to be above what NICE considers an acceptable use of NHS resources. But, a clinical trial is planned that will look at inclisiran's effect on cardiovascular events in this population. So in this population, inclisiran is recommended only in research.", 'Information about inclisiran': "# Marketing authorisation indication\n\nInclisiran (Leqvio, Novartis) is 'indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:\n\nin combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,\n\nalone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule for inclisiran is available in the summary of product characteristics.\n\n# Price\n\nInclisiran costs £1,987.36 per 284-mg dose pack (company submission). The company has a commercial arrangement. This makes inclisiran available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence from a number of sources. See the committee papers for full details of the evidence.\n\n# Clinical pathway\n\n## People with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia will welcome a new treatment option\n\nThe clinical experts stated that the aim of treatment is to lower, and reduce long-term exposure to, low-density lipoprotein cholesterol (LDL-C) and that statins are the first treatment offered. The clinical experts explained that if people's LDL-C levels remain too high, then ezetimibe may also be offered and, if they are eligible, alirocumab and evolocumab are also options. The patient expert explained that people with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia are at increased risk of cardiovascular events and that the conditions are treated inconsistently across the NHS. They highlighted that it can be difficult to access testing for high cholesterol and that treatments like alirocumab and evolocumab are only offered to people with higher levels of LDL-C. They added that a large proportion of people who are eligible for these treatments are not referred to secondary care to have them. The clinical and patient experts also highlighted that many people do not receive testing for heterozygous familial hypercholesterolaemia. The patient expert stated that inclisiran offers a twice-yearly treatment option, compared with more frequent dosing of currently available treatments, and this would likely increase treatment adherence. The clinical experts explained that it is difficult to reach LDL-C target levels with currently available oral treatments (statins and ezetimibe). The committee concluded that people with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia would welcome a new treatment option.\n\n## The appropriate position of inclisiran in the treatment pathway is after maximum tolerated statins alone or with ezetimibe\n\nThe NICE scope outlined 3 separate positions for inclisiran in the treatment pathway:\n\ncompared with maximum tolerated statins\n\nwhen maximum tolerated statins do not appropriately control LDL-C, and\n\nwhen maximum tolerated statins with ezetimibe do not appropriately control LDL-C.The NICE scope also requested analyses for when statins are contraindicated or not tolerated. The company positioned inclisiran as a treatment option if LDL-C levels were too high after standard of care treatment. The company defined standard of care as a mix of maximum tolerated statins and other lipid-lowering therapy, including a small proportion of ezetimibe use based on the ORION trials (see section 3.5 and section 3.7). The clinical experts stated that inclisiran could be used after maximum tolerated statins, or after maximum tolerated statins and ezetimibe. The committee noted that this was in line with the treatment pathway defined by inclisiran's marketing authorisation, which allows its use after maximum tolerated statins or maximum tolerated statins and other lipid-lowering therapies. The committee concluded that the appropriate position of inclisiran in the treatment pathway is after maximum tolerated statins or after maximum tolerated statins with ezetimibe.\n\n## Inclisiran is likely to be used in a primary care setting\n\nThe company proposes that inclisiran would be given by a healthcare professional in a primary care setting. After an initial dose, it would be given again after 3\xa0months and then twice a year. The committee was aware that other currently available treatments, such as alirocumab and evolocumab, are usually prescribed in secondary care. The clinical experts stated that the primary care setting could be appropriate, although it would need some changes in how the condition is currently managed. The committee noted that, in general, the responses to technical engagement from professional organisations supported the use of inclisiran in a primary care setting. These responses also noted that primary care can be used to identify and provide treatment for people who would be eligible for inclisiran. The committee noted that there were some concerns in submissions received surrounding the implementation of inclisiran in a primary care setting but noted that the Accelerated Access Collaborative and NHS England had plans to support the implementation of inclisiran within a primary care setting. The committee was also aware of an ongoing implementation research project (SPIRIT) that aims to assess the feasibility of delivering inclisiran within a primary care setting in England. The committee noted that this trial was due to complete in 2022 and considered that it could provide some relevant information on how inclisiran can be delivered in a primary care setting. The committee accepted that inclisiran is likely to be used in a primary care setting.\n\n# Population\n\n## The populations included in the company's submission are clinically relevant but are narrower than inclisiran's marketing authorisation and trial data\n\nThe marketing authorisation for inclisiran does not specify a minimum LDL-C level before beginning treatment. The company presented analysis by 3 populations:\n\nSecondary prevention: people who have had a previous cardiovascular event, including acute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation), coronary or other arterial revascularisation procedures, coronary heart disease, ischaemic stroke or peripheral arterial disease. The committee noted that NICE's technology appraisal guidance on alirocumab and evolocumab defined this population as having a high risk of cardiovascular disease.\n\nPrimary prevention with elevated risk: people who have not had a cardiovascular event and have type 2 diabetes or heterozygous familial hypercholesterolaemia, or who have a 10-year cardiovascular disease risk of 20% or more based on Framingham risk score or equivalent.\n\nPrimary prevention with heterozygous familial hypercholesterolaemia.In each of the 3 populations, the company submitted evidence based on a minimum LDL-C level of 2.6\xa0mmol/l. This was narrower than the marketing authorisation in all 3 populations and narrower than the clinical trial data for the secondary prevention population (see section\xa03.7). The company stated that a minimum LDL-C level of 2.6\xa0mmol/l was selected because a greater clinical benefit was observed in the ODYSSEY OUTCOMES trial (alirocumab compared with placebo after acute coronary syndrome) in people with a baseline LDL-C of 2.6\xa0mmol/l or more. The company also highlighted that an LDL-C of 2.6\xa0mmol/l was close to the mean baseline LDL-C in the ORION clinical trials and the company's clinical experts supported the use of this threshold. The clinical experts at the meeting highlighted that the use of a 2.6\xa0mmol/l threshold meant that inclisiran, if approved, would enable more people to access a treatment that could significantly reduce LDL-C levels, meaning that they were more likely to reach LDL‑C goals. The clinical experts noted that the ORION-11 trial used a 10-year cardiovascular disease risk of 20% or higher, based on Framingham risk score or equivalent, as part of its criteria for the primary prevention with elevated risk population. They explained that NHS practice uses the QRISK score to identify risk and this measure would be used instead and adjusted to identify this population. The evidence review group (ERG) highlighted that a lack of genetic testing for all people with suspected heterozygous familial hypercholesterolaemia may result in cases either being missed or being incorrectly classified as other population groups (see section 3.1). The committee concluded that the populations included in the company's submission are clinically relevant but are narrower than inclisiran's marketing authorisation and the clinical trial data.\n\n# Comparators\n\n## The appropriate comparators are ezetimibe, alirocumab, evolocumab and maximum tolerated statins\n\nNICE technology appraisal guidance recommends ezetimibe, alirocumab and evolocumab as treatment options in the same part of the treatment pathway as inclisiran (see section 3.2). The company did not consider ezetimibe to be a relevant comparator. Instead, the company included a small amount of ezetimibe use as part of standard of care, based on the ORION clinical trial programme (see section\xa03.7), and did not include the efficacy of ezetimibe as estimated by the network meta-analysis (NMA; see section 3.8). The company highlighted that ezetimibe use in the NHS was low and that NICE's guideline on cardiovascular disease: risk assessment and reduction includes ezetimibe only as an option and not a required pathway step before further treatment. The ERG believed that ezetimibe should be a distinct comparator and their base case used the efficacy from the company's NMA for ezetimibe, rather than comparing with the company's definition of standard of care, which was assumed to provide no reduction in baseline LDL-C (see section 3.2). The ERG had been informed by its clinical experts that if LDL-C is too high after maximum tolerated statins, then there is a clinical decision to either switch to rosuvastatin (another statin, which is not yet generic) or add ezetimibe. The ERG also highlighted that, unlike for treatment with alirocumab or evolocumab, there are no minimum LDL-C thresholds needed for treatment with ezetimibe (see section 3.6). It also noted that ezetimibe is now available as a generic treatment, which means its cost is low, and highlighted that ezetimibe was considered a relevant comparator in each of NICE's previous technology appraisals in this condition. The ERG also highlighted that hypercholesterolemia is undertreated, and this applies to all treatments. The committee agreed with the ERG that ezetimibe should be considered as a relevant comparator. The committee also agreed that it would not eliminate the company's definition of standard of care from its decision-making, noting that this was a mix of predominately maximum tolerated statins, with low amounts of ezetimibe use (but did not include the efficacy of ezetimibe as estimated by the NMA), as in the ORION trials. The committee concluded that the appropriate comparators are ezetimibe, alirocumab, evolocumab and maximum tolerated statins (when inclisiran is given in combination with statins).\n\n## The relevant comparators are dependent on alirocumab or evolocumab eligibility\n\nThe committee noted that the populations in the company submission included people with a minimum LDL-C level of 2.6\xa0mmol/l (see section\xa03.4). Therefore, a proportion of people would be eligible for alirocumab or evolocumab based on recommendations in NICE's technology appraisal guidance on alirocumab and evolocumab. This includes people in:\n\nsecondary prevention, if their LDL-C levels are persistently above 4\xa0mmol/l and they have a high risk of cardiovascular disease, defined as any history of:\n\n\n\nacute coronary syndrome (such as myocardial infarction or unstable angina requiring hospitalisation)\n\ncoronary or other arterial revascularisation procedures\n\ncoronary heart disease\n\nischaemic stroke\n\nperipheral arterial disease\n\n\n\nsecondary prevention who have a very high risk for cardiovascular disease (defined as recurrent cardiovascular events or cardiovascular events in more than one vascular bed [that is, polyvascular disease]), only if LDL-C levels are persistently above 3.5\xa0mmol/l\n\nsecondary prevention with heterozygous familial hypercholesterolaemia, only if LDL-C levels are persistently above 3.5\xa0mmol/l, and\n\nprimary prevention with heterozygous familial hypercholesterolaemia, only if LDL-C levels are persistently above 5\xa0mmol/l.The committee was also aware that there are populations in the company's submission who would not be eligible for alirocumab or evolocumab as outlined by previous NICE recommendations, specifically people in:\n\nsecondary prevention who have a high risk for cardiovascular disease and an LDL-C level between 2.6\xa0mmol/l and 4.0\xa0mmol/l\n\nsecondary prevention who have a very high risk for cardiovascular disease and an LDL-C level between 2.6\xa0mmol/l and 3.5\xa0mmol/l\n\nsecondary prevention with heterozygous familial hypercholesterolaemia and an LDL-C level between 2.6 mmol/l and 3.5\xa0mmol/l\n\nprimary prevention with elevated risk (excluding heterozygous familial hypercholesterolaemia) with an LDL-C level of 2.6\xa0mmol/l or more\n\nprimary prevention with heterozygous familial hypercholesterolaemia and an LDL-C level between 2.6 mmol/l and 5.0\xa0mmol/l.The committee noted that, based on NICE's technology appraisal guidance on ezetimibe, ezetimibe was available as an option in all populations and also a relevant comparator in all populations included in the company's submission (see section 3.4 and section 3.5). The committee considered that for people who are ineligible for alirocumab or evolocumab, ezetimibe was the only relevant NICE-recommended comparator. But, it acknowledged that maximum tolerated statins was also a treatment option and a relevant comparator in this population (see section 3.5). For people who are eligible for alirocumab or evolocumab, the committee agreed that ezetimibe, alirocumab, evolocumab and maximum tolerated statins are relevant comparators. The committee were aware that mean baseline LDL-C would be lower in the population ineligible for alirocumab or evolocumab compared with people who are eligible. The committee concluded that the relevant comparators are dependent on alirocumab or evolocumab eligibility.\n\n# Clinical evidence\n\n## Results from ORION-9, ORION-10 and ORION-11 show inclisiran reduces LDL-C levels and are generalisable to people with primary hypercholesterolaemia or mixed dyslipidaemia in the NHS\n\nThe clinical trial evidence in the company submission came from 3\xa0randomised 18-month trials comparing inclisiran with placebo:\n\nORION-9 included people with heterozygous familial hypercholesterolaemia and elevated LDL-C levels (2.6\xa0mmol/l or more)\n\nORION-10 included people with atherosclerotic cardiovascular disease (secondary prevention) and elevated LDL-C levels (1.8\xa0mmol/l or more)\n\nORION-11 included people with atherosclerotic cardiovascular disease (secondary prevention) and elevated LDL-C levels (1.8\xa0mmol/l or more) and people who had not had a cardiovascular event (primary prevention) but had elevated risks of atherosclerotic cardiovascular disease and LDL-C levels (2.6\xa0mmol/l or more).The trials included people on lipid-lowering therapies (such as statins or ezetimibe or both). The ERG noted that the proportion of people in the ORION trials receiving ezetimibe was 51% in ORION-9, 11% in ORION-10 and 9% in ORION-11. In the trials, people who were on a statin were on their maximum tolerated dose. The trials also included people who had documented evidence of statin intolerance. All 3 trials had co-primary endpoints of mean LDL-C percentage change from baseline to 510\xa0days and time-adjusted LDL-C percentage change by day\xa090 and up to day\xa0540. The results showed that inclisiran compared with placebo significantly reduced levels of LDL-C. From baseline to day\xa0510, LDL-C was reduced by 47.9% (95% confidence interval [CI] 53.5 to 42.3), 52.3% (95% CI 55.7 to 48.8) and 49.9% (95% CI 53.1 to 46.6) in ORION-9, ORION-10 and ORION-11 respectively. Similar results were also seen in the co-primary end point of time-adjusted LDL-C percentage change from day\xa090 to day\xa0540. The committee was aware that the clinical trials were mostly carried out in the US but noted that the clinical expert submissions stated that the trial results were generalisable to the NHS. The clinical trial results also showed that rates of adverse events were similar for people treated with inclisiran compared with placebo, with the exception of injection site reactions, which were more common in people treated with inclisiran (8.2% compared with 1.8% in those treated with placebo). The committee concluded that results from ORION-9, ORION-10 and ORION-11 show that inclisiran reduces LDL-C levels compared with placebo and these results are generalisable to people with primary hypercholesterolaemia or mixed dyslipidaemia seen in NHS clinical practice.\n\n# Indirect treatment comparison\n\n## The network meta-analyses used by the company are appropriate but are associated with some uncertainties\n\nBecause the ORION trials only included a placebo comparator, the company undertook NMAs to indirectly compare inclisiran with alirocumab, evolocumab and ezetimibe. The company produced 3\xa0NMAs for different populations, based on a common placebo comparator:\n\nsecondary prevention or primary prevention with elevated risk on maximum tolerated statins\n\nsecondary prevention or primary prevention with elevated risk and statin intolerance\n\nheterozygous familial hypercholesterolaemia on maximum tolerated statins.The company used a 24-week timepoint in its NMAs. The company explained that this choice reflected the longest available timepoint for which data was available from comparator treatment trials included in the NMAs. The results from the random-effects model showed that inclisiran was associated with a greater LDL-C reduction compared with ezetimibe and compared with placebo. The NMAs estimated that inclisiran was associated with an LDL-C reduction that was marginally less than with alirocumab or evolocumab, although this result was not statistically significant. The company explained that it could not provide effectiveness estimates for ezetimibe in the heterozygous familial hypercholesterolaemia on maximum tolerated statins NMA, as no trials were identified for ezetimibe in that population. The ERG agreed that the methods used by the company to undertake the NMA were appropriate. But they noted that the NMAs included trials with high levels of heterogeneity and that some trials in the NMAs were inconsistent in their definitions of cardiovascular risks. The committee noted that the 24-week timepoint used in the NMA added some uncertainty to the clinical outcomes as there was limited evidence of whether LDL-C reduction achieved at 24\xa0weeks would be maintained over a lifetime, as assumed in the model (see section 3.10). The committee was also aware that the estimates from the NMA were more favourable for inclisiran than the co-primary endpoints from the clinical trials. The committee concluded that the network meta-analyses used by the company are appropriate but are associated with some uncertainties.\n\n# Long-term treatment effect of inclisiran\n\n## The effect of inclisiran on cardiovascular event risk is uncertain as there is a lack of long-term evidence\n\nThe completed ORION clinical trials (see section 3.7) were unable to provide enough data on the effectiveness of inclisiran in reducing cardiovascular events and mortality. This was because the follow up of 18\xa0months was not long enough to provide these outcomes. The company used the reduction in LDL-C from the indirect treatment comparison (see section 3.8) to estimate the assumed reduction in cardiovascular events. The company used the Cholesterol Treatment Trialist Collaboration (CTT) meta-analyses, which reported change in cardiovascular event risk per 1\xa0mmol/l reduction in LDL-C by statin use. The ERG agreed that these analyses were appropriate and noted that earlier versions of this source were used in past NICE technology appraisals in this disease area (NICE technology appraisal guidance on ezetimibe, alirocumab, evolocumab and bempedoic acid with ezetimibe). The committee expressed a concern that the link between changes in LDL-C levels and cardiovascular outcomes used in the company model, may not be appropriate for inclisiran because the mechanism of action is different to that of statins. The clinical experts stated that the CTT meta-analyses were appropriate and that a similar relationship between LDL-C lowering and a reduction in cardiovascular event risk as seen with statin use could be expected with inclisiran. The committee was aware that longer-term trial evidence was available for alirocumab (ODYSSEY OUTCOMES) and evolocumab (FOURIER) but noted that the follow-up period of these trials may not have been long enough to estimate the full effect on cardiovascular outcomes. The committee also noted that the ODYSSEY OUTCOMES trial was restricted to people who had had a recent cardiovascular event. The committee was also aware that an ongoing UK clinical trial, ORION-4, would provide outcome data on cardiovascular events with a median follow\xa0up of 5\xa0years for inclisiran compared with placebo in people who have already had a cardiovascular event. The committee noted, however, that this trial would not report until 2026. The company explained that a global clinical trial with a similar design was in development. The company also confirmed that it is planning a clinical trial (ORION‑17) to collect data on cardiovascular outcomes of inclisiran compared with placebo, in people who have not experienced a cardiovascular event. The committee considered that the lack of data on inclisiran's effect on cardiovascular outcomes was a key uncertainty in the appraisal and was a major driver of the cost-effectiveness results. The committee concluded that the effect of inclisiran on cardiovascular event risk is uncertain as there is a lack of long-term evidence.\n\n## The assumptions of no treatment effect waning, and no treatment discontinuation may be appropriate but adds uncertainty\n\nThe company's economic model assumed that the treatment effect as estimated by the NMA at 24\xa0weeks (see section 3.8) would be maintained at the same level over a lifetime. The company stated that this assumption was based on previous NICE technology appraisals of alirocumab and evolocumab in the same condition. The ERG noted that given the lack of long-term trial evidence beyond 18\xa0months to support this assumption, the company could have provided a scenario in which inclisiran's effectiveness is assumed to reduce over time. The clinical experts stated that inclisiran would likely be used over the course of a lifetime, as LDL-C levels would be expected to return to baseline if discontinued. The company highlighted that the assumption of no treatment discontinuation was also based on previous NICE technology appraisals of alirocumab and evolocumab and stated that the treatment discontinuation rate for inclisiran in the ORION clinical trials was low (annual discontinuation rate of 1.7% in ORION-9 and 3.2% in ORION-10 and ORION-11). The committee noted that there was a lack of long-term data for inclisiran to support this assumption. The committee concluded that assumptions of no waning of treatment effect and no treatment discontinuation may be appropriate but add uncertainty.\n\n# Innovation\n\n## Inclisiran is innovative, however all relevant benefits are likely to be captured in the quality-adjusted life year calculations\n\nThe company highlighted that inclisiran was the first cholesterol-lowering small interfering RNA (siRNA) and has the potential to be a step change in how the condition is managed. The company, clinical and patient experts highlighted that treatment with inclisiran had the potential to increase treatment adherence, because of its twice-yearly dosing schedule (see section 3.1). The committee considered the potential additional benefits inclisiran might provide but concluded that there was no evidence of additional gains in health-related quality of life over those already included in the quality-adjusted life year (QALY) calculations. The committee concluded that inclisiran is innovative, however all relevant benefits are likely to be captured in the QALY calculations.\n\n# Cost-effectiveness estimates\n\n## The ERG's base case includes the committee's preferred assumptions\n\nThe ERG's base-case analyses included ezetimibe as a separate comparator and also included comparisons with maximum tolerated statins. Therefore, it differed from the company's base case, which included a small amount of ezetimibe use as part of standard care (see section 3.5). The committee was aware that the ERG's base-case analyses was otherwise the same as the company's. This included using the company's NMA estimate for treatment efficacy (see section 3.8) and no treatment waning or treatment discontinuation (see section 3.10). The committee concluded that it preferred the ERG base case but would take the company analyses into account in its decision making.\n\n## Because of the uncertainty the acceptable incremental cost-effectiveness ratios are £20,000 per QALY gained and above £30,000 per QALY lost\n\nNICE's guide to the methods of technology appraisal notes that above a most plausible incremental cost-effectiveness ratio (ICER) of £20,000 per QALY gained, judgements about the acceptability of a technology as an effective use of NHS resources will take into account the degree of certainty around the ICER. The committee will be more cautious about recommending a technology if it is less certain about the ICERs presented. The committee also needs to be increasingly certain of the cost effectiveness of a technology as the impact of its adoption on NHS resources increases and may need more robust evidence for technologies that are expected to have a larger impact. Therefore, because of the high level of uncertainty in the clinical and economic evidence, primarily caused by the lack of outcome data on inclisiran's effect on cardiovascular events (see section 3.9), the NMA clinical effectiveness estimates (see section 3.8) and long-term treatment effects and discontinuation assumptions (see section 3.10), the committee agreed that an acceptable ICER would be no higher than £20,000 per QALY gained or above £30,000 per QALY lost when considering each of the population groups and their respective LDL-C ranges (see section 3.6).\n\n## Inclisiran is cost effective for secondary prevention in people who are eligible for alirocumab and evolocumab\n\nThe cost-effectiveness results for the secondary prevention population who are eligible for alirocumab or evolocumab were assessed by calculating net monetary benefit. This was because inclisiran was estimated to provide marginally fewer incremental QALYs compared with alirocumab or evolocumab (see section 3.8). The incremental net monetary benefit of inclisiran was compared with alirocumab or evolocumab, at threshold values of £30,000 saved per QALY lost using the committee preferred assumptions (see section 3.12 and section 3.13). This resulted in a positive incremental net monetary benefit at that threshold value, meaning that the amount of lost QALYs associated with inclisiran compared with alirocumab or evolocumab was acceptable when considering the differences in costs between these treatments. The committee considered that net monetary benefit was appropriate for decision making as it was likely that any differences in QALYs between inclisiran and alirocumab or evolocumab are small. This confirmed that inclisiran is cost effective compared with alirocumab and evolocumab in the following secondary prevention populations in which alirocumab and evolocumab are available:\n\nsecondary prevention with a high risk for cardiovascular disease, only if LDL-C levels are persistently above 4\xa0mmol/l\n\nsecondary prevention with a very high risk for cardiovascular disease, only if LDL-C levels are persistently above 3.5\xa0mmol/l\n\nsecondary prevention with heterozygous familial hypercholesterolaemia, only if LDL-C levels are persistently above 3.5\xa0mmol/l.Inclisiran was associated with an ICER of below £20,000 per QALY gained compared with either ezetimibe or maximum tolerated statins in the populations eligible for treatment with alirocumab and evolocumab described above. The committee concluded that inclisiran is cost effective in these populations for both pairwise and fully incremental analysis. Because of the confidential discount for inclisiran, the exact ICERs have not been reported here.\n\n## Inclisiran is cost effective for secondary prevention in people who are not eligible for alirocumab or evolocumab\n\nUsing the committee's preferred assumptions (see section 3.12) the most plausible ICERs for inclisiran compared with ezetimibe or maximum tolerated statins for the secondary prevention population who are not eligible for alirocumab or evolocumab (see section 3.6), were likely to be around or below £20,000 per QALY gained in pairwise and fully incremental analysis. Therefore, the committee concluded that inclisiran is cost effective in this population. Because of the confidential discount for inclisiran, the exact ICERs cannot be reported here.\n\n## Inclisiran is not cost effective in the primary prevention population with elevated risk\n\nUsing the committee's preferred assumptions (see section 3.12) the most plausible ICERs for inclisiran in the primary prevention with elevated risk population and an LDL-C of at least 2.6\xa0mmol/l, were likely to be above £20,000 per QALY gained. This was based on considering comparisons with ezetimibe or maximum tolerated statins in pairwise and fully incremental analysis. Therefore, the committee concluded that inclisiran is not cost effective in the primary prevention population with elevated risk.\n\n## Inclisiran is recommended only in research in the primary prevention population\n\nThe committee considered that the cost-effectiveness estimates were highly uncertain for the primary prevention with elevated risk population. The committee highlighted that smaller numbers from ORION-11 informed the cost-effectiveness estimates for this population (see section 3.9). The committee also noted that the budget impact for inclisiran was estimated to be high in the primary prevention population. The committee was aware that NICE's guide to the methods of technology appraisal notes, in general, that the committee will want to be increasingly certain of the cost effectiveness of a technology as the impact of its adoption on NHS resources increases. The committee was also aware that the company is developing a UK clinical trial (ORION-17) to evaluate the effect of inclisiran compared with placebo on cardiovascular outcomes in people who have not had a cardiovascular event. The committee therefore recommended that inclisiran is used only in the context of research in this population.\n\n## Inclisiran is not cost effective in the primary prevention with heterozygous familial hypercholesterolaemia population\n\nUsing the committee's preferred assumptions (see section 3.12) the most plausible ICERs for the primary prevention with heterozygous familial hypercholesterolaemia populations were as follows:\n\nIn people who are not eligible for alirocumab or evolocumab (LDL-C levels between 2.6\xa0mmol/l and 5\xa0mmol/l; see section 3.6) the ICERs were significantly above £20,000 per QALY gained when compared with maximum tolerated statins.\n\nIn people who are eligible for alirocumab or evolocumab (LDL-C levels of at least 5\xa0mmol/l; see section 3.6), the ICER was below £20,000 per QALY gained when compared with maximum tolerated statins. The incremental net monetary benefit of inclisiran was compared with alirocumab or evolocumab, at threshold values of £30,000 saved per QALY lost (see section 3.13) in this population. This resulted in a positive incremental net monetary benefit for inclisiran compared with these treatments.The committee noted that the company did not provide cost-effectiveness results for inclisiran compared with ezetimibe in the heterozygous familial hypercholesterolaemia populations. Comparisons with ezetimibe were part of the committee's preferred base case (see section 3.12). This was because there was no clinical trial data for ezetimibe in these populations to inform the NMA (see section 3.8). For the alirocumab- or evolocumab-eligible and -ineligible populations, the committee considered that the ICERs for inclisiran compared with ezetimibe would be higher than the ICERs comparing inclisiran with maximum tolerated statins and would be significantly above £20,000 per QALY gained if incorporated into a pairwise and fully incremental analyses. The committee concluded that inclisiran is not cost effective in the primary prevention with heterozygous familial hypercholesterolaemia population.\n\n## Inclisiran is recommended only in research in the primary prevention with heterozygous familial hypercholesterolaemia population\n\nThe committee considered that the cost-effectiveness estimates were highly uncertain for the primary prevention with heterozygous familial hypercholesterolaemia population. The committee also noted that many people do not receive testing for heterozygous familial hypercholesterolaemia. This means cases may either be missed or classified as other population groups (see section 3.1 and section 3.4). The committee was also aware that the company is developing a UK clinical trial (ORION-17) to evaluate the effect of inclisiran compared with placebo on cardiovascular outcomes in people who have not had a cardiovascular event. The committee therefore recommended that inclisiran is used only in the context of research in this population.\n\n# Other factors\n\n## There are no equalities issues that can be addressed in this appraisal\n\nA number of potential equality issues were raised during the appraisal. These included the higher prevalence of cardiovascular conditions in more deprived areas and in some specific populations (such as minority ethnic groups or people with severe mental health conditions or learning disabilities). The committee also heard that the treatments provided could vary across the NHS depending on region and availability of specialist care, and that there may be difficulties in accessing treatment for older people. The committee concluded that its recommendations for inclisiran would apply to all patients and that the recommendation would not affect people protected by the equality legislation any differently. The committee also considered that further evidence should be collected to assess whether the implementation of inclisiran into the treatment pathway would reduce health inequalities in this condition (see section 5.4).\n\n# Conclusion\n\n## Inclisiran is recommended for people with a history of cardiovascular events (secondary prevention) if LDL-C levels are at least 2.6\xa0mmol/l\n\nThe committee was concerned that there was a lack of long-term data on cardiovascular outcomes from the clinical trials that compared inclisiran with placebo. However, it noted that ongoing clinical trials would provide more data on these outcomes. The cost-effectiveness results based on the committee's preferred modelling assumptions with a commercial arrangement for inclisiran, represent a cost-effective use of NHS resources for adults with a history of cardiovascular events and persistent LDL-C levels of at least 2.6\xa0mmol/l despite having the maximum tolerated lipid-lowering therapy. The committee therefore concluded that inclisiran is recommended for this group.\n\n## Inclisiran is recommended only in research for people who do not have a history of cardiovascular events (primary prevention)\n\nThe cost-effectiveness results for both the primary prevention with elevated risk, and primary prevention with heterozygous familial hypercholesterolaemia were highly uncertain and the ICERs for these populations were likely above £20,000 per QALY gained. The committee considered that inclisiran had the potential to be cost effective in these populations. Based on the information it had heard about ORION-17, it considered that it was likely that the research needed would be commissioned and successfully report, and that its potential value to the NHS would likely represent good value in the context of limited research resources. It therefore recommended inclisiran only in the context of research in this group.", 'Recommendations for research and data collection': 'The company confirmed to the committee that it was developing a randomised controlled trial (ORION-17) of the effectiveness of inclisiran compared with placebo. This will be a UK-based trial in people who have not previously had a cardiovascular event (primary prevention). The main outcomes of interest are cardiovascular events and mortality.\n\nThe committee was also aware that ORION-4, an ongoing randomised controlled UK trial of inclisiran compared with placebo in people with a history of cardiovascular disease (secondary prevention), is due to complete in 2026. In addition, the company stated that an additional global trial of a similar design was also in development. The main outcomes of interest in these trials are also cardiovascular events and mortality.\n\nThe committee noted that there was an ongoing trial that aimed to compare inclisiran and lipid-lowering medication with or without behavioural support and lipid-lowering medication without inclisiran with behavioural support (SPIRIT). This trial will also assess the feasibility of delivering inclisiran within a primary care setting in England and is due to complete in 2022. The committee considered that this evidence was also of interest.\n\nThe committee also recommended that additional evidence collection should be carried out. Mindful of the issues raised concerning equality (see section\xa03.19), the committee strongly encouraged the collection of data to assess whether implementing inclisiran into the treatment pathway leads to a reduction in health inequalities. This should include real-world evidence on assessing inclisiran uptake in areas of high deprivation and across various population groups, as well as data on treatment adherence. The committee encouraged the collection of this data as it would be of interest in a review of this guidance.'}
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https://www.nice.org.uk/guidance/ta733
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Evidence-based recommendations on inclisiran (Leqvio) for treating primary hypercholesterolaemia or mixed dyslipidaemia in adults.
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b73af6d05ed781331a995ecc3de86091e662ba6e
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nice
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DyeVert Systems for reducing the risk of acute kidney injury in coronary and peripheral angiography
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DyeVert Systems for reducing the risk of acute kidney injury in coronary and peripheral angiography
Evidence-based recommendations on DyeVert Systems for reducing the risk of acute kidney injury in coronary and peripheral angiography.
# Recommendations
DyeVert Systems show promise for reducing the risk of acute kidney injury (AKI) in coronary and peripheral angiography after using contrast media. However, there is not enough evidence to support the case for routine adoption. This is because there is not enough good-quality evidence that using the system reduces AKI incidence after having contrast media.
A randomised controlled trial is recommended to compare DyeVert Systems with standard care. The aim of this research would be to address uncertainties about whether using DyeVert Systems reduces AKI incidence and rate of renal replacement therapy after using contrast media. This must include people with stage 4 chronic kidney disease (with an estimated glomerular filtration rate under 30 ml/min/1.73 m2), who are at risk of AKI and need elective coronary or peripheral angiography.Find out details of required outcomes in the section on further research in this guidance.
Why the committee made these recommendations
Current standard care to reduce the risk of AKI in people having contrast dye (media) during coronary and peripheral angiography involves giving them fluids.
Clinical evidence shows that DyeVert Systems reduce the amount of contrast that enters the blood vessel. Contrast dye is thought to increase the risk of AKI in people at risk. There is some evidence to suggest that, by reducing the amount of contrast media given during coronary angiography, DyeVert Systems could reduce AKI risk. But stronger evidence is needed to be certain of a causal relationship. Also, almost all the current evidence is from coronary angiography, which may not apply to peripheral angiography.
Because of the uncertainty about whether DyeVert Systems reduce AKI, any potential cost savings are also uncertain.
Therefore, NICE recommends further research.# The technology
# Technology
DyeVert Systems (Osprey Medical) are designed to reduce the amount of contrast media given during coronary and peripheral angiography in a cardiac catheterisation or vascular radiology suite. The system uses a pressure-responsive valve to divert excess contrast medium while maintaining image quality, to reduce the risk of contrast-induced acute kidney injury (AKI).
There are 2 models of the DyeVert System. DyeVert Plus EZ Contrast Reduction System is compatible with manual contrast injectors. A smart syringe connects to a standard manifold and is manually operated by the clinician to inject the dye into the module that contains the diversion valve. A monitor displays both the total administered and total diverted contrast volume using Bluetooth communication with the smart syringe. DyeVert Power XT Contrast Reduction System is compatible with power injectors. There is no reusable monitor, but the contrast collection bag has a digital display showing the diverted dye volume.
# Care pathway
People having contrast agents for non-emergency imaging should be assessed for their risk of AKI in line with NICE's guideline on acute kidney injury. Chronic kidney disease should be investigated by measuring estimated glomerular filtration rate (eGFR) or by checking an eGFR result from the past 3 months. Emergency imaging should not be delayed but clinicians should be aware of who is at increased risk of developing contrast-induced AKI. Risk reduction strategies, including oral hydration before and after procedures, and intravenous volume expansion with isotonic sodium bicarbonate or 0.9% sodium chloride, should be considered in anyone at risk. DyeVert Systems are designed to be used in addition to these risk reduction strategies.
# Innovative aspects
The company says that DyeVert Systems are non-invasive technologies that reduce contrast media, with real-time contrast media dose monitoring. The system reduces the total contrast media volume delivered during coronary or peripheral imaging while maintaining adequate image quality.
# Intended use
DyeVert Systems would be used to reduce the total contrast media volume delivered during coronary or peripheral imaging in people identified as at risk of contrast-induced AKI. It can be added to the equipment currently used for angiography procedures.
# Costs
The DyeVert Systems cost £350 (excluding VAT) per procedure. This includes the diversion module, contrast collection bag, smart syringe (for DyeVert Plus EZ) and reusable monitor (for DyeVert Plus EZ).For more details, see the website for DyeVert Systems.# Evidence
NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.
# Clinical evidence
## The main clinical evidence comprises 19 studies
The EAC assessed 19 studies. Eight were full text publications: 1 randomised controlled trial, 3 prospective studies (2 of which were comparative), and 4 retrospective studies (2 of which were comparative). One abstract reported results from a randomised controlled trial, and 8 abstracts and posters reported retrospective studies. Two posters reported results from the same acute kidney injury (AKI) reduction programme. Two unpublished papers were included: 1 retrospective comparative study and 1 prospective comparative study. For full details of the clinical evidence, see section 3 of the assessment report in the supporting documentation on the NICE website.
## DyeVert Systems reduce contrast volume received during angiographic procedures
The evidence from comparative studies showed that using DyeVert Systems reduced the amount of contrast media injected by between 17% (Sattar et al. 2018) and 41% (Desch et al. 2018) compared with standard coronary angiography. A company meta-analysis estimated that contrast volume received by the patient was lowered by 39.43% when using DyeVert Systems compared with when they were not used (calculated from 5 single-arm studies and 3 comparative studies).
## Image quality is maintained while using DyeVert Systems
Seven published studies reported no loss to image quality with DyeVert Systems (Desch et al. 2018, Gurm et al. 2019a, Briguori et al. 2020, Bruno et al. 2019, Sapontis et al. 2017, Corcione et al. 2017, Zimin et al. 2020) and 2 abstracts (Amoroso et al. 2020, Rao et al. 2019). A company meta-analysis estimated that image quality was 98.2% of that when the system was not used (calculated from 6 published clinical studies and 1 abstract).
## Evidence on AKI risk reduction is limited
Evidence on the risk reduction in AKI was from 1 published paper (Briguori et al. 2020) and 5 abstracts and posters (Sattar et al. 2018, Kutschman et al. 2019, Bunney et al. 2019, Cameron et al. 2020, Turner and Tucker 2020). These studies reported outcomes from people who were identified as having chronic kidney disease (CKD) stages 2 and 3 before their angiography procedure. Briguori et al. (2020) was a single-centre, observational, non-randomised design, which used a control group of patients treated in the same centre. Propensity score matching was used to match the control group to the DyeVert group, resulting in 90 patients in each group. This study reported AKI in 8% of the DyeVert Systems group and 19% of the control group (p=0.047). A company meta-analysis estimated the relative risk of contrast-induced AKI in a DyeVert Systems group compared with a control group to be 0.59, calculated from Briguori et al. (2020) and 3 comparative studies reported as an abstract or poster.
## Study designs and insufficient reporting of outcomes limited the assessment of AKI incidence
The evidence presented was limited because measurements were only taken during the procedure in the studies that looked primarily at contrast volume used or reduced, and image quality. In the studies that followed up after the procedure, the methodology around collecting and reporting of the outcomes was not clear. Briguori et al. (2020) did report serum creatinine for 72 hours after the procedure, and AKI incidence and major adverse events within 1 month of the procedure. But the studies were limited by their retrospective design, which meant not all AKI incidents could be identified.
## Evidence on the Power XT version of the DyeVert System is limited
The only evidence on the DyeVert Power XT device was on the first version of the system and from 1 full text single-arm retrospective study (Bruno et al. 2019) and 1 retrospective study presented as an abstract (Amoroso et al. 2020). This was from a total of 35 people having angiography procedures. No studies included the current version of the Power XT system.
## Evidence on DyeVert Systems for peripheral angiography is limited
The evidence presented was mostly for coronary angiography, with only 2 studies (Corcione et al. 2017 and Rao et al. 2019) including 9 people having peripheral angiography.
# Cost evidence
## The company's cost model is based on a published cost–utility analysis
The company presented 1 published UK-based cost–utility analysis (Javanbakht et al. 2020) and 3 economic studies based in the US. Javanbakht et al. (2020) found DyeVert Systems were cost saving by £435 and estimated a quality-adjusted life year (QALY) gain of 0.028 over an individual's lifetime compared with current practice. The company's cost model was based on an updated version of this published model. For full details of the cost evidence, see section 4 of the assessment report in the supporting documentation on the NICE website.
## The company's model uses a decision tree and Markov model
The company's model included people with CKD stages 3 and 4. It used a decision tree for the first 3 months after the procedure, then a Markov model for the remainder of the individual's lifetime. The Markov model transitions between 6 health states in 3‑month cycles. The company's model had some differences to Javanbakht et al. (2020). The relative risk reduction of AKI because of DyeVert Systems use was increased from 21.4% to 41% (based on the company meta-analysis results). Unit costs were also updated, peripheral angiography procedures included in the population, and the age of the cohort entering the model was reduced from 72 years to 65 years.
## DyeVert Systems remain cost saving in the EAC's update to the model
The EAC agreed with the company's cost model overall. The EAC corrected small errors in the model and parameter inflation costs, lowered the relative risk of contrast-induced AKI, and differentiated the costs of fatal and non-fatal myocardial infarctions. The EAC found that DyeVert Systems remained cost saving by £22 with a QALY gain of 0.013.
## If the baseline risk of contrast-induced AKI is below 8.2%, DyeVert Systems are no longer cost saving
The EAC updated the company's model and applied a baseline risk of contrast-induced AKI of 8.72% for people with CKD stage 3 and 4 aged 65. The EAC considered the company's stated risk of 30% to be too high if people are appropriately hydrated. The EAC estimated that, if the risk of contrast-induced AKI was below 8.2%, DyeVert Systems would no longer be cost saving.
## The reduction in relative risk of contrast-induced AKI after using DyeVert Systems is uncertain
The company's model used a relative risk reduction of contrast-induced AKI after DyeVert Systems use of 41% based on its meta-analysis results. The EAC accepted the statistical validity of the meta-analysis but noted that the strength of the included studies was low to moderate. The EAC did sensitivity analysis around the risk reduction of contrast-induced AKI from DyeVert Systems and found that the break-even relative risk reduction was 38.5%, assuming a baseline AKI risk of 8.72%.# Committee discussion
# Clinical-effectiveness overview
## DyeVert Systems are effective in reducing contrast media volume, but more evidence is needed on acute kidney injury incidence
There is consistent evidence that DyeVert Systems can reduce contrast volume received by the patient by up to 40%. Clinical experts said that using DyeVert Systems can maintain the pressure of the injection needed to preserve image quality, while reducing the overall amount of contrast given. The committee acknowledged national and international guidance that says that increasing volume of contrast agent is a risk factor for acute kidney injury (AKI), including NICE's guideline on acute kidney injury. Clinical experts said that contrast volume is a modifiable parameter that could help to reduce AKI risk. They said that accepted practice is to minimise the amount of contrast given, especially for patients with an estimated glomerular filtration rate (eGFR) less than 30 ml/min/1.73 m2 who need complex procedures that are likely to need larger volumes of contrast. However, clinical experts also explained that the cause of AKI is multifactorial and complex. Although contrast media is 1 risk factor for AKI, it can be difficult to identify its direct cause (or causes), given other confounding factors such as comorbidities (which are often significant in people having angiography) and procedural complexities. As a result, it was uncertain whether reducing the contrast dye received using DyeVert Systems would directly lead to reduced incidence of AKI. The committee felt that the strength of evidence on AKI incidence reduction after using DyeVert Systems was not convincing enough to address these concerns, and it could not be confident in the results of the meta-analyses (for more about the meta-analyses results, see section 4.4).
## The evidence for coronary angiography is not generalisable to peripheral angiography
The evidence presented on peripheral angiography included 9 people in 2 studies. Clinical experts explained that it was unlikely that the evidence for coronary angiography was transferable to peripheral angiography procedures. Types of peripheral angiography procedure vary. Different volumes of contrast dye and different injection pressures are needed, making comparisons with coronary angiography difficult. Clinical experts also explained that peripheral angiography can be done without using contrast media, for example when used for diagnosis.
## Generalisability of the evidence for the PLUS EZ device to the Power XT device is uncertain
The evidence presented on the Power XT version of the DyeVert System included 2 studies on 35 people and was based on an older model of the system. The company said that the PLUS EZ and Power XT versions work in a similar way, with both devices responding to pressure going through the valve. Clinical experts thought that the power injector was more likely to be used in peripheral angiographies, especially when large volumes of contrast dye are needed to be given quickly. The committee was uncertain if the evidence on the PLUS EZ device was generalisable to the Power XT device. It felt that more evidence was needed before the devices could be considered comparable.
## The meta-analyses are statistically robust, but the risk of bias is uncertain
The company submitted meta-analyses for several parameters, which the EAC said were statistically valid. However, some of the analyses, such as a reduced risk of AKI because of DyeVert Systems use, mainly used data from abstracts and posters. The committee was concerned that it was difficult to assess the methodological quality of some studies, making it difficult to quantify the size and direction of bias in the meta-analysis. This made the reliability of the outcome measures uncertain.
# Outcome measures
## Better quality long-term follow up is needed to identify most cases of AKI
Most of the clinical evidence was limited by only having data during the procedure. If AKI incidence was reported, not all may have been identified because the studies were retrospective. Clinical experts said that most AKI events happen 4 to 5 days after the contrast exposure, and sometimes as late as 7 to 10 days afterwards. Incidence of AKI may be difficult to track because serum creatinine measurements may not be done routinely and there may not be consistent post-procedure renal monitoring. Overall, the committee felt that more long-term evidence on AKI incidence was needed.
## Longer-term follow up is needed to collect data on secondary end points
Because the clinical evidence was limited by the follow-up evidence, the committee thought that further data collection was needed to capture secondary end points. This includes the need for temporary or end-stage dialysis and hospital stay.
# NHS considerations overview
## DyeVert Systems may be of most benefit to people with chronic kidney disease stage 4 and over
The clinical experts said that people with chronic kidney disease (CKD) stage 4 and over (eGFR less than 30 ml/min/1.73 m2) would most benefit from DyeVert Systems and are likely to be the target population in clinical practice. The committee acknowledged that there are several factors that could increase the risk of developing AKI after procedures that use iodine-based contrast media. Evidence presented on DyeVert Systems was in people with CKD stages 2 and 3 (eGFR 30 ml/min/1.73 m2 to 89 ml/min/1.73 m2), so the evidence on people with CKD stage 4 and over was limited. The company said that the population included in the studies had additional comorbidities, making them at greater risk of developing AKI after a contrast procedure.
## DyeVert Systems have greatest promise for procedures that are expected to use large contrast volumes
Clinical experts said that procedures that are expected to use larger contrast volumes could lead to a higher risk for AKI. Larger volumes of contrast would likely be given during more complex procedures such as percutaneous coronary intervention, rather than diagnostic angiography. The clinical experts felt that procedure type should be considered when deciding whether to use DyeVert Systems.
# Cost modelling overview
## The cost model for DyeVert Systems is well constructed
The cost model for DyeVert Systems used a well-constructed decision tree and Markov model, with appropriate outcomes based on NICE clinical guidelines, and an appropriate time horizon. The clinical experts thought that the EAC's revised assumption of a relative risk of AKI of 8.72% was reasonable.
## Because the reduction in relative risk of AKI is not certain, the cost savings are not certain
The committee considered that the most robust evidence for DyeVert Systems was on surrogate markers, such as contrast volume reduction, rather than AKI incidence. Clinical experts explained that the direct causal relationship between contrast agent and AKI is not certain (for more about AKI incidence and the relationship with contrast agents, see section 4.1). The results of the cost analysis were sensitive to the reduction in relative risk of AKI from using DyeVert Systems. Three of the 4 studies that reported that DyeVert Systems reduced the relative risk of AKI were abstracts or posters. These were included in the meta-analysis that provided the values used in the economic model. Including these studies led the committee to question the robustness of and risk of bias in the meta-analysis. The reduction in relative risk of AKI for DyeVert was reported as 42% in the 1 full text published study and 41% in the meta-analysis. The EAC's sensitivity analysis found the break-even reduction in relative risk to be 38.5%. Because the economic model was very sensitive to this parameter, there was uncertainty around whether using DyeVert Systems would lead to a cost saving.
# Further research
## Further good-quality research is needed to address uncertainties about the clinical efficacy of DyeVert Systems
The committee concluded that further research is needed to address uncertainties in the clinical effectiveness of DyeVert Systems compared with standard care. It concluded that, although there is clear evidence that DyeVert Systems can reduce contrast volume received while maintaining image quality, the evidence around AKI incidence was weaker. The committee concluded that a randomised controlled trial was needed. It should collect data on AKI incidence, renal replacement therapy, hospital stay, and biochemical markers of kidney injury, and should follow up for enough time to capture these outcomes. The population must include people having an elective coronary or peripheral angiography procedure who have an eGFR less than 30 ml/min/1.73 m2. Further evidence should be collected to resolve the uncertainties around the generalisability between the 2 DyeVert devices. The committee noted that collecting evidence for DyeVert in peripheral angiography will be more difficult because of the different ways the procedure is done. It concluded that for peripheral angiography, it may be appropriate to trial the system in procedures that use a consistent volume of contrast, such as endovascular aneurysm repair.
## Real-world evidence may be difficult to interpret because of confounding factors
The committee thought that confounding factors make interpreting real-world evidence challenging. Comorbidities and procedural factors affect the risk of developing AKI after a contrast procedure, and these may not be clearly reported. There may also be inconsistencies in routine post-procedure renal monitoring, including timing and frequency of serum creatinine measurements.
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{'Recommendations': 'DyeVert Systems show promise for reducing the risk of acute kidney injury (AKI) in coronary and peripheral angiography after using contrast media. However, there is not enough evidence to support the case for routine adoption. This is because there is not enough good-quality evidence that using the system reduces AKI incidence after having contrast media.\n\nA randomised controlled trial is recommended to compare DyeVert Systems with standard care. The aim of this research would be to address uncertainties about whether using DyeVert Systems reduces AKI incidence and rate of renal replacement therapy after using contrast media. This must include people with stage\xa04 chronic kidney disease (with an estimated glomerular filtration rate [eGFR] under 30\xa0ml/min/1.73\xa0m2), who are at risk of AKI and need elective coronary or peripheral angiography.Find out details of required outcomes in the section on further research in this guidance.\n\nWhy the committee made these recommendations\n\nCurrent standard care to reduce the risk of AKI in people having contrast dye (media) during coronary and peripheral angiography involves giving them fluids.\n\nClinical evidence shows that DyeVert Systems reduce the amount of contrast that enters the blood vessel. Contrast dye is thought to increase the risk of AKI in people at risk. There is some evidence to suggest that, by reducing the amount of contrast media given during coronary angiography, DyeVert Systems could reduce AKI risk. But stronger evidence is needed to be certain of a causal relationship. Also, almost all the current evidence is from coronary angiography, which may not apply to peripheral angiography.\n\nBecause of the uncertainty about whether DyeVert Systems reduce AKI, any potential cost savings are also uncertain.\n\nTherefore, NICE recommends further research.', 'The technology': "# Technology\n\nDyeVert Systems (Osprey Medical) are designed to reduce the amount of contrast media given during coronary and peripheral angiography in a cardiac catheterisation or vascular radiology suite. The system uses a pressure-responsive valve to divert excess contrast medium while maintaining image quality, to reduce the risk of contrast-induced acute kidney injury (AKI).\n\nThere are 2\xa0models of the DyeVert System. DyeVert Plus EZ Contrast Reduction System is compatible with manual contrast injectors. A smart syringe connects to a standard manifold and is manually operated by the clinician to inject the dye into the module that contains the diversion valve. A monitor displays both the total administered and total diverted contrast volume using Bluetooth communication with the smart syringe. DyeVert Power XT Contrast Reduction System is compatible with power injectors. There is no reusable monitor, but the contrast collection bag has a digital display showing the diverted dye volume.\n\n# Care pathway\n\nPeople having contrast agents for non-emergency imaging should be assessed for their risk of AKI in line with NICE's guideline on acute kidney injury. Chronic kidney disease should be investigated by measuring estimated glomerular filtration rate (eGFR) or by checking an eGFR result from the past 3\xa0months. Emergency imaging should not be delayed but clinicians should be aware of who is at increased risk of developing contrast-induced AKI. Risk reduction strategies, including oral hydration before and after procedures, and intravenous volume expansion with isotonic sodium bicarbonate or 0.9% sodium chloride, should be considered in anyone at risk. DyeVert Systems are designed to be used in addition to these risk reduction strategies.\n\n# Innovative aspects\n\nThe company says that DyeVert Systems are non-invasive technologies that reduce contrast media, with real-time contrast media dose monitoring. The system reduces the total contrast media volume delivered during coronary or peripheral imaging while maintaining adequate image quality.\n\n# Intended use\n\nDyeVert Systems would be used to reduce the total contrast media volume delivered during coronary or peripheral imaging in people identified as at risk of contrast-induced AKI. It can be added to the equipment currently used for angiography procedures.\n\n# Costs\n\nThe DyeVert Systems cost £350 (excluding VAT) per procedure. This includes the diversion module, contrast collection bag, smart syringe (for DyeVert Plus EZ) and reusable monitor (for DyeVert Plus EZ).For more details, see the website for DyeVert Systems.", 'Evidence': "NICE commissioned an external assessment centre (EAC) to review the evidence submitted by the company. This section summarises that review. Full details of all the evidence are in the project documents on the NICE website.\n\n# Clinical evidence\n\n## The main clinical evidence comprises 19\xa0studies\n\nThe EAC assessed 19\xa0studies. Eight were full text publications: 1\xa0randomised controlled trial, 3\xa0prospective studies (2 of which were comparative), and 4\xa0retrospective studies (2 of which were comparative). One abstract reported results from a randomised controlled trial, and 8\xa0abstracts and posters reported retrospective studies. Two posters reported results from the same acute kidney injury (AKI) reduction programme. Two unpublished papers were included: 1\xa0retrospective comparative study and 1\xa0prospective comparative study. For full details of the clinical evidence, see section\xa03 of the assessment report in the supporting documentation on the NICE website.\n\n## DyeVert Systems reduce contrast volume received during angiographic procedures\n\nThe evidence from comparative studies showed that using DyeVert Systems reduced the amount of contrast media injected by between 17% (Sattar et al. 2018) and 41% (Desch et al. 2018) compared with standard coronary angiography. A company meta-analysis estimated that contrast volume received by the patient was lowered by 39.43% when using DyeVert Systems compared with when they were not used (calculated from 5\xa0single-arm studies and 3\xa0comparative studies).\n\n## Image quality is maintained while using DyeVert Systems\n\nSeven published studies reported no loss to image quality with DyeVert Systems (Desch et al. 2018, Gurm et al. 2019a, Briguori et al. 2020, Bruno et al. 2019, Sapontis et al. 2017, Corcione et al. 2017, Zimin et al. 2020) and 2\xa0abstracts (Amoroso et al. 2020, Rao et al. 2019). A company meta-analysis estimated that image quality was 98.2% of that when the system was not used (calculated from 6\xa0published clinical studies and 1\xa0abstract).\n\n## Evidence on AKI risk reduction is limited\n\nEvidence on the risk reduction in AKI was from 1\xa0published paper (Briguori et al. 2020) and 5\xa0abstracts and posters (Sattar et al. 2018, Kutschman et al. 2019, Bunney et al. 2019, Cameron et al. 2020, Turner and Tucker 2020). These studies reported outcomes from people who were identified as having chronic kidney disease (CKD) stages\xa02 and\xa03 before their angiography procedure. Briguori et al. (2020) was a single-centre, observational, non-randomised design, which used a control group of patients treated in the same centre. Propensity score matching was used to match the control group to the DyeVert group, resulting in 90\xa0patients in each group. This study reported AKI in 8% of the DyeVert Systems group and 19% of the control group (p=0.047). A company meta-analysis estimated the relative risk of contrast-induced AKI in a DyeVert Systems group compared with a control group to be 0.59, calculated from Briguori et al. (2020) and 3\xa0comparative studies reported as an abstract or poster.\n\n## Study designs and insufficient reporting of outcomes limited the assessment of AKI incidence\n\nThe evidence presented was limited because measurements were only taken during the procedure in the studies that looked primarily at contrast volume used or reduced, and image quality. In the studies that followed up after the procedure, the methodology around collecting and reporting of the outcomes was not clear. Briguori et al. (2020) did report serum creatinine for 72\xa0hours after the procedure, and AKI incidence and major adverse events within 1\xa0month of the procedure. But the studies were limited by their retrospective design, which meant not all AKI incidents could be identified.\n\n## Evidence on the Power XT version of the DyeVert System is limited\n\nThe only evidence on the DyeVert Power XT device was on the first version of the system and from 1\xa0full text single-arm retrospective study (Bruno et al. 2019) and 1\xa0retrospective study presented as an abstract (Amoroso et al. 2020). This was from a total of 35\xa0people having angiography procedures. No studies included the current version of the Power XT system.\n\n## Evidence on DyeVert Systems for peripheral angiography is limited\n\nThe evidence presented was mostly for coronary angiography, with only 2\xa0studies (Corcione et al. 2017 and Rao et al. 2019) including 9\xa0people having peripheral angiography.\n\n# Cost evidence\n\n## The company's cost model is based on a published cost–utility analysis\n\nThe company presented 1\xa0published UK-based cost–utility analysis (Javanbakht et al. 2020) and 3\xa0economic studies based in the US. Javanbakht et al. (2020) found DyeVert Systems were cost saving by £435 and estimated a quality-adjusted life year (QALY) gain of 0.028 over an individual's lifetime compared with current practice. The company's cost model was based on an updated version of this published model. For full details of the cost evidence, see section\xa04 of the assessment report in the supporting documentation on the NICE website.\n\n## The company's model uses a decision tree and Markov model\n\nThe company's model included people with CKD stages\xa03 and\xa04. It used a decision tree for the first 3\xa0months after the procedure, then a Markov model for the remainder of the individual's lifetime. The Markov model transitions between 6\xa0health states in 3‑month cycles. The company's model had some differences to Javanbakht et al. (2020). The relative risk reduction of AKI because of DyeVert Systems use was increased from 21.4% to 41% (based on the company meta-analysis results). Unit costs were also updated, peripheral angiography procedures included in the population, and the age of the cohort entering the model was reduced from 72\xa0years to 65\xa0years.\n\n## DyeVert Systems remain cost saving in the EAC's update to the model\n\nThe EAC agreed with the company's cost model overall. The EAC corrected small errors in the model and parameter inflation costs, lowered the relative risk of contrast-induced AKI, and differentiated the costs of fatal and non-fatal myocardial infarctions. The EAC found that DyeVert Systems remained cost saving by £22 with a QALY gain of 0.013.\n\n## If the baseline risk of contrast-induced AKI is below 8.2%, DyeVert Systems are no longer cost saving\n\nThe EAC updated the company's model and applied a baseline risk of contrast-induced AKI of 8.72% for people with CKD stage\xa03 and\xa04 aged\xa065. The EAC considered the company's stated risk of 30% to be too high if people are appropriately hydrated. The EAC estimated that, if the risk of contrast-induced AKI was below 8.2%, DyeVert Systems would no longer be cost saving.\n\n## The reduction in relative risk of contrast-induced AKI after using DyeVert Systems is uncertain\n\nThe company's model used a relative risk reduction of contrast-induced AKI after DyeVert Systems use of 41% based on its meta-analysis results. The EAC accepted the statistical validity of the meta-analysis but noted that the strength of the included studies was low to moderate. The EAC did sensitivity analysis around the risk reduction of contrast-induced AKI from DyeVert Systems and found that the break-even relative risk reduction was 38.5%, assuming a baseline AKI risk of 8.72%.", 'Committee discussion': "# Clinical-effectiveness overview\n\n## DyeVert Systems are effective in reducing contrast media volume, but more evidence is needed on acute kidney injury incidence\n\nThere is consistent evidence that DyeVert Systems can reduce contrast volume received by the patient by up to 40%. Clinical experts said that using DyeVert Systems can maintain the pressure of the injection needed to preserve image quality, while reducing the overall amount of contrast given. The committee acknowledged national and international guidance that says that increasing volume of contrast agent is a risk factor for acute kidney injury (AKI), including NICE's guideline on acute kidney injury. Clinical experts said that contrast volume is a modifiable parameter that could help to reduce AKI risk. They said that accepted practice is to minimise the amount of contrast given, especially for patients with an estimated glomerular filtration rate (eGFR) less than 30\xa0ml/min/1.73\xa0m2 who need complex procedures that are likely to need larger volumes of contrast. However, clinical experts also explained that the cause of AKI is multifactorial and complex. Although contrast media is 1\xa0risk factor for AKI, it can be difficult to identify its direct cause (or causes), given other confounding factors such as comorbidities (which are often significant in people having angiography) and procedural complexities. As a result, it was uncertain whether reducing the contrast dye received using DyeVert Systems would directly lead to reduced incidence of AKI. The committee felt that the strength of evidence on AKI incidence reduction after using DyeVert Systems was not convincing enough to address these concerns, and it could not be confident in the results of the meta-analyses (for more about the meta-analyses results, see section\xa04.4).\n\n## The evidence for coronary angiography is not generalisable to peripheral angiography\n\nThe evidence presented on peripheral angiography included 9\xa0people in 2\xa0studies. Clinical experts explained that it was unlikely that the evidence for coronary angiography was transferable to peripheral angiography procedures. Types of peripheral angiography procedure vary. Different volumes of contrast dye and different injection pressures are needed, making comparisons with coronary angiography difficult. Clinical experts also explained that peripheral angiography can be done without using contrast media, for example when used for diagnosis.\n\n## Generalisability of the evidence for the PLUS EZ device to the Power XT device is uncertain\n\nThe evidence presented on the Power XT version of the DyeVert System included 2\xa0studies on 35\xa0people and was based on an older model of the system. The company said that the PLUS EZ and Power XT versions work in a similar way, with both devices responding to pressure going through the valve. Clinical experts thought that the power injector was more likely to be used in peripheral angiographies, especially when large volumes of contrast dye are needed to be given quickly. The committee was uncertain if the evidence on the PLUS EZ device was generalisable to the Power XT device. It felt that more evidence was needed before the devices could be considered comparable.\n\n## The meta-analyses are statistically robust, but the risk of bias is uncertain\n\nThe company submitted meta-analyses for several parameters, which the EAC said were statistically valid. However, some of the analyses, such as a reduced risk of AKI because of DyeVert Systems use, mainly used data from abstracts and posters. The committee was concerned that it was difficult to assess the methodological quality of some studies, making it difficult to quantify the size and direction of bias in the meta-analysis. This made the reliability of the outcome measures uncertain.\n\n# Outcome measures\n\n## Better quality long-term follow up is needed to identify most cases of AKI\n\nMost of the clinical evidence was limited by only having data during the procedure. If AKI incidence was reported, not all may have been identified because the studies were retrospective. Clinical experts said that most AKI events happen 4\xa0to 5\xa0days after the contrast exposure, and sometimes as late as 7\xa0to 10\xa0days afterwards. Incidence of AKI may be difficult to track because serum creatinine measurements may not be done routinely and there may not be consistent post-procedure renal monitoring. Overall, the committee felt that more long-term evidence on AKI incidence was needed.\n\n## Longer-term follow up is needed to collect data on secondary end points\n\nBecause the clinical evidence was limited by the follow-up evidence, the committee thought that further data collection was needed to capture secondary end points. This includes the need for temporary or end-stage dialysis and hospital stay.\n\n# NHS considerations overview\n\n## DyeVert Systems may be of most benefit to people with chronic kidney disease stage\xa04 and over\n\nThe clinical experts said that people with chronic kidney disease (CKD) stage\xa04 and over (eGFR less than 30\xa0ml/min/1.73\xa0m2) would most benefit from DyeVert Systems and are likely to be the target population in clinical practice. The committee acknowledged that there are several factors that could increase the risk of developing AKI after procedures that use iodine-based contrast media. Evidence presented on DyeVert Systems was in people with CKD stages\xa02 and\xa03 (eGFR 30\xa0ml/min/1.73\xa0m2 to 89\xa0ml/min/1.73\xa0m2), so the evidence on people with CKD stage\xa04 and over was limited. The company said that the population included in the studies had additional comorbidities, making them at greater risk of developing AKI after a contrast procedure.\n\n## DyeVert Systems have greatest promise for procedures that are expected to use large contrast volumes\n\nClinical experts said that procedures that are expected to use larger contrast volumes could lead to a higher risk for AKI. Larger volumes of contrast would likely be given during more complex procedures such as percutaneous coronary intervention, rather than diagnostic angiography. The clinical experts felt that procedure type should be considered when deciding whether to use DyeVert Systems.\n\n# Cost modelling overview\n\n## The cost model for DyeVert Systems is well constructed\n\nThe cost model for DyeVert Systems used a well-constructed decision tree and Markov model, with appropriate outcomes based on NICE clinical guidelines, and an appropriate time horizon. The clinical experts thought that the EAC's revised assumption of a relative risk of AKI of 8.72% was reasonable.\n\n## Because the reduction in relative risk of AKI is not certain, the cost savings are not certain\n\nThe committee considered that the most robust evidence for DyeVert Systems was on surrogate markers, such as contrast volume reduction, rather than AKI incidence. Clinical experts explained that the direct causal relationship between contrast agent and AKI is not certain (for more about AKI incidence and the relationship with contrast agents, see section\xa04.1). The results of the cost analysis were sensitive to the reduction in relative risk of AKI from using DyeVert Systems. Three of the 4\xa0studies that reported that DyeVert Systems reduced the relative risk of AKI were abstracts or posters. These were included in the meta-analysis that provided the values used in the economic model. Including these studies led the committee to question the robustness of and risk of bias in the meta-analysis. The reduction in relative risk of AKI for DyeVert was reported as 42% in the 1\xa0full text published study and 41% in the meta-analysis. The EAC's sensitivity analysis found the break-even reduction in relative risk to be 38.5%. Because the economic model was very sensitive to this parameter, there was uncertainty around whether using DyeVert Systems would lead to a cost saving.\n\n# Further research\n\n## Further good-quality research is needed to address uncertainties about the clinical efficacy of DyeVert Systems\n\nThe committee concluded that further research is needed to address uncertainties in the clinical effectiveness of DyeVert Systems compared with standard care. It concluded that, although there is clear evidence that DyeVert Systems can reduce contrast volume received while maintaining image quality, the evidence around AKI incidence was weaker. The committee concluded that a randomised controlled trial was needed. It should collect data on AKI incidence, renal replacement therapy, hospital stay, and biochemical markers of kidney injury, and should follow up for enough time to capture these outcomes. The population must include people having an elective coronary or peripheral angiography procedure who have an eGFR less than 30\xa0ml/min/1.73\xa0m2. Further evidence should be collected to resolve the uncertainties around the generalisability between the 2\xa0DyeVert devices. The committee noted that collecting evidence for DyeVert in peripheral angiography will be more difficult because of the different ways the procedure is done. It concluded that for peripheral angiography, it may be appropriate to trial the system in procedures that use a consistent volume of contrast, such as endovascular aneurysm repair.\n\n## Real-world evidence may be difficult to interpret because of confounding factors\n\nThe committee thought that confounding factors make interpreting real-world evidence challenging. Comorbidities and procedural factors affect the risk of developing AKI after a contrast procedure, and these may not be clearly reported. There may also be inconsistencies in routine post-procedure renal monitoring, including timing and frequency of serum creatinine measurements."}
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https://www.nice.org.uk/guidance/mtg60
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Evidence-based recommendations on DyeVert Systems for reducing the risk of acute kidney injury in coronary and peripheral angiography.
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8863a081482c2ec6e89f905266deb94e0e6065fd
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nice
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Transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis
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Transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis
Evidence-based recommendations on transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis in adults. This involves inserting a new valve inside a failed bioprosthetic valve to replace the faulty one without needing repeat open heart surgery.
# Recommendations
Evidence on the safety of transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis is adequate and shows some serious but well‑recognised complications. Evidence on its efficacy is limited in quality. So, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients have been told and understand about all alternative treatment options and their advantages and disadvantages.
Enter details about all patients having transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis onto a national registry when 1 is available.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by a multidisciplinary team which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging, and where appropriate, a cardiac anaesthetist and a specialist in medicine for older people. The multidisciplinary team should determine the risk level for each patient and the device most suitable for them.
The procedure is technically challenging and should only be done in specialised centres, and only by clinical teams with special training and experience in complex endovascular cardiac interventions, including regular experience in transcatheter valve implantation procedures. Centres doing these procedures should have cardiac surgical support for emergency treatment of complications and subsequent patient care.
Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.
NICE encourages further research into transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis. Studies should include details on patient selection, type and size of valve used, functional outcomes (New York Heart Association functional class, mitral valve regurgitation), quality of life, patient‑reported outcome measures, survival and complications. Studies should report long‑term follow up of clinical outcomes and valve durability. NICE may update this guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Mitral valve replacement is where an artificial prosthetic valve (bioprosthetic or mechanical) is inserted by open heart surgery. It is most commonly done for severe symptomatic mitral regurgitation but may also be done in patients with severe mitral valve stenosis or a combination of both. Symptoms of severe mitral valve disease typically include shortness of breath, fatigue and palpitations (because of atrial fibrillation).
Bioprosthetic valves have some advantages over mechanical valves, but they are more likely to degenerate and fail over time. This can result in severe stenosis or regurgitation, needing replacement of the bioprosthetic valve.
# Current treatments
The standard treatment for a failed bioprosthetic valve is repeat open heart surgery to replace the valve. Repeat open heart surgery is associated with a higher risk of morbidity and mortality than primary surgery. Transapical transcatheter mitral valve‑in‑valve implantation is a less invasive alternative when repeat open heart surgery is considered to have a high risk. It avoids the need for routine cardiopulmonary bypass and can be used to treat failed bioprosthetic mitral valves originally placed during open heart surgery.
# The procedure
The procedure is done with the patient under general anaesthesia and using imaging guidance including fluoroscopy, angiography and transoesophageal echocardiography (TEE). Prophylactic antibiotics and anticoagulants are given before and during the procedure. Temporary peripheral extracorporeal circulatory support (usually through the femoral vessels) is sometimes used.
The mitral valve is accessed surgically through an apical puncture of the left ventricle using an anterior or left lateral mini thoracotomy (transapical approach). A guidewire is placed across the existing mitral prosthetic valve and into a pulmonary vein. A balloon catheter delivery system is then advanced over the guidewire. When there is severe prosthetic mitral valve stenosis a balloon valvuloplasty may be done first. The inner diameter of the degenerated valve is measured using TEE to establish the size of the new bioprosthetic valve needed. Using the delivery system, the new bioprosthetic valve is then introduced, manipulated into position and slowly deployed within the degenerated mitral valve under fluoroscopic and TEE guidance. Often rapid ventricular pacing is used to reduce movement of the heart. After valve deployment, the catheter delivery system, guidewires and pacing wires are removed and the left ventricular puncture and chest incisions are closed. Valve performance is then assessed using echocardiography and fluoroscopy.
|
{'Recommendations': "Evidence on the safety of transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis is adequate and shows some serious but well‑recognised complications. Evidence on its efficacy is limited in quality. So, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers, as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients have been told and understand about all alternative treatment options and their advantages and disadvantages.\n\nEnter details about all patients having transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis onto a national registry when 1 is available.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging, and where appropriate, a cardiac anaesthetist and a specialist in medicine for older people. The multidisciplinary team should determine the risk level for each patient and the device most suitable for them.\n\nThe procedure is technically challenging and should only be done in specialised centres, and only by clinical teams with special training and experience in complex endovascular cardiac interventions, including regular experience in transcatheter valve implantation procedures. Centres doing these procedures should have cardiac surgical support for emergency treatment of complications and subsequent patient care.\n\nReport any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nNICE encourages further research into transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis. Studies should include details on patient selection, type and size of valve used, functional outcomes (New York Heart Association functional class, mitral valve regurgitation), quality of life, patient‑reported outcome measures, survival and complications. Studies should report long‑term follow up of clinical outcomes and valve durability. NICE may update this guidance on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nMitral valve replacement is where an artificial prosthetic valve (bioprosthetic or mechanical) is inserted by open heart surgery. It is most commonly done for severe symptomatic mitral regurgitation but may also be done in patients with severe mitral valve stenosis or a combination of both. Symptoms of severe mitral valve disease typically include shortness of breath, fatigue and palpitations (because of atrial fibrillation).\n\nBioprosthetic valves have some advantages over mechanical valves, but they are more likely to degenerate and fail over time. This can result in severe stenosis or regurgitation, needing replacement of the bioprosthetic valve.\n\n# Current treatments\n\nThe standard treatment for a failed bioprosthetic valve is repeat open heart surgery to replace the valve. Repeat open heart surgery is associated with a higher risk of morbidity and mortality than primary surgery. Transapical transcatheter mitral valve‑in‑valve implantation is a less invasive alternative when repeat open heart surgery is considered to have a high risk. It avoids the need for routine cardiopulmonary bypass and can be used to treat failed bioprosthetic mitral valves originally placed during open heart surgery.\n\n# The procedure\n\nThe procedure is done with the patient under general anaesthesia and using imaging guidance including fluoroscopy, angiography and transoesophageal echocardiography (TEE). Prophylactic antibiotics and anticoagulants are given before and during the procedure. Temporary peripheral extracorporeal circulatory support (usually through the femoral vessels) is sometimes used.\n\nThe mitral valve is accessed surgically through an apical puncture of the left ventricle using an anterior or left lateral mini thoracotomy (transapical approach). A guidewire is placed across the existing mitral prosthetic valve and into a pulmonary vein. A balloon catheter delivery system is then advanced over the guidewire. When there is severe prosthetic mitral valve stenosis a balloon valvuloplasty may be done first. The inner diameter of the degenerated valve is measured using TEE to establish the size of the new bioprosthetic valve needed. Using the delivery system, the new bioprosthetic valve is then introduced, manipulated into position and slowly deployed within the degenerated mitral valve under fluoroscopic and TEE guidance. Often rapid ventricular pacing is used to reduce movement of the heart. After valve deployment, the catheter delivery system, guidewires and pacing wires are removed and the left ventricular puncture and chest incisions are closed. Valve performance is then assessed using echocardiography and fluoroscopy.'}
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https://www.nice.org.uk/guidance/ipg706
|
Evidence-based recommendations on transapical transcatheter mitral valve-in-valve implantation for a failed surgically implanted mitral valve bioprosthesis in adults. This involves inserting a new valve inside a failed bioprosthetic valve to replace the faulty one without needing repeat open heart surgery.
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2ea094e9896ed81a6783becc97f333602c14df35
|
nice
|
Transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair
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Transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair
Evidence-based recommendations on transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair in adults. This involves inserting a bioprosthetic mitral valve into an existing mitral valve ring to treat a leaking mitral valve, without needing repeat open heart surgery.
# Recommendations
Evidence on the safety of transapical transcatheter mitral valve-in-ring implantation after failed mitral valve repair surgery is adequate and shows some serious but well recognised complications. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients have been told and understand about all alternative treatment options and their advantages and disadvantages.
Enter details about all patients having transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair onto a national registry when 1 is available.
Audit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
Patient selection should be done by a multidisciplinary team which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging, and where appropriate, a cardiac anaesthetist and a specialist in medicine for older people. The multidisciplinary team should determine the risk level for each patient and the device most suitable for them.
The procedure is technically challenging and should only be done in specialised centres, and only by clinician teams with special training and experience in complex endovascular cardiac interventions, including regular experience in transcatheter valve implantation procedures. Centres doing these procedures should have cardiac surgical support for emergency treatment of complications and subsequent patient care.
Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.
NICE encourages further research into transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair. Studies should include details on patient selection, type and size of valve used, functional outcomes (New York Heart Association functional class, mitral valve regurgitation), quality of life, patient-reported outcome measures, survival and complications. Studies should report long‑term follow up of clinical outcomes and valve durability. NICE may update this guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
The mitral valve allows blood to flow from the left atrium to the left ventricle. Mitral valve regurgitation happens when the valve does not close properly and blood flows back into the atrium from the ventricle. The heart has to work harder to pump blood from the left ventricle to the aorta, resulting in an enlarged left ventricle. If not treated, this can lead to shortness of breath, fatigue and palpitations (because of atrial fibrillation) and eventually heart failure.
If symptoms of mitral valve regurgitation are severe enough, mitral valve annulus surgical repair may be done by open heart surgery in patients who are well enough for this kind of operation. A surgical valve annulus repair may fail over time and can result in the need for further intervention.
# Current treatments
The standard treatment after a failed mitral valve annuloplasty is repeat open heart surgery. Repeat open heart surgery is associated with a higher risk of morbidity and mortality than primary surgery. Transapical transcatheter mitral valve-in-ring implantation is a less invasive alternative. It avoids the need for cardiopulmonary bypass and can be used to treat failed annuloplasty rings originally placed during open heart surgery.
# The procedure
The procedure is usually done with the patient under general anaesthesia and using imaging guidance including fluoroscopy, angiography and transoesophageal echocardiography. Prophylactic antibiotics and anticoagulants are given before and during the procedure. Temporary peripheral extracorporeal circulatory support (usually through the femoral vessels) is sometimes used.
The mitral valve is accessed surgically through an apical puncture of the left ventricle using an anterior or left lateral mini thoracotomy (transapical approach). A guidewire is placed across the existing native mitral valve and into a pulmonary vein. A balloon catheter delivery system is then advanced over the guidewire into the left atrium. The inner diameter of the mitral valve annulus is measured using transoesophageal echocardiography to establish the size of bioprosthetic valve needed. Using the delivery system, the bioprosthetic valve is then introduced, manipulated into position (to align the valve with the mitral annulus) and slowly deployed within the surgically implanted mitral valve ring under fluoroscopic and echocardiographic guidance. Often, rapid ventricular pacing is used to reduce movement of the heart. After valve deployment, the catheter delivery system, guidewires and pacing wires are removed from the left ventricle and the left ventricular puncture and chest incisions are closed. Valve performance is then assessed using echocardiography and fluoroscopy.
|
{'Recommendations': "Evidence on the safety of transapical transcatheter mitral valve-in-ring implantation after failed mitral valve repair surgery is adequate and shows some serious but well recognised complications. Evidence on its efficacy is limited in quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients have been told and understand about all alternative treatment options and their advantages and disadvantages.\n\nEnter details about all patients having transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair onto a national registry when 1 is available.\n\nAudit and review clinical outcomes of all patients having the procedure. The main efficacy and safety outcomes identified in this guidance can be entered into NICE's interventional procedure outcomes audit tool (for use at local discretion).\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nPatient selection should be done by a multidisciplinary team which must include interventional cardiologists experienced in the procedure, cardiac surgeons, an expert in cardiac imaging, and where appropriate, a cardiac anaesthetist and a specialist in medicine for older people. The multidisciplinary team should determine the risk level for each patient and the device most suitable for them.\n\nThe procedure is technically challenging and should only be done in specialised centres, and only by clinician teams with special training and experience in complex endovascular cardiac interventions, including regular experience in transcatheter valve implantation procedures. Centres doing these procedures should have cardiac surgical support for emergency treatment of complications and subsequent patient care.\n\nReport any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nNICE encourages further research into transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair. Studies should include details on patient selection, type and size of valve used, functional outcomes (New York Heart Association functional class, mitral valve regurgitation), quality of life, patient-reported outcome measures, survival and complications. Studies should report long‑term follow up of clinical outcomes and valve durability. NICE may update this guidance on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nThe mitral valve allows blood to flow from the left atrium to the left ventricle. Mitral valve regurgitation happens when the valve does not close properly and blood flows back into the atrium from the ventricle. The heart has to work harder to pump blood from the left ventricle to the aorta, resulting in an enlarged left ventricle. If not treated, this can lead to shortness of breath, fatigue and palpitations (because of atrial fibrillation) and eventually heart failure.\n\nIf symptoms of mitral valve regurgitation are severe enough, mitral valve annulus surgical repair may be done by open heart surgery in patients who are well enough for this kind of operation. A surgical valve annulus repair may fail over time and can result in the need for further intervention.\n\n# Current treatments\n\nThe standard treatment after a failed mitral valve annuloplasty is repeat open heart surgery. Repeat open heart surgery is associated with a higher risk of morbidity and mortality than primary surgery. Transapical transcatheter mitral valve-in-ring implantation is a less invasive alternative. It avoids the need for cardiopulmonary bypass and can be used to treat failed annuloplasty rings originally placed during open heart surgery.\n\n# The procedure\n\nThe procedure is usually done with the patient under general anaesthesia and using imaging guidance including fluoroscopy, angiography and transoesophageal echocardiography. Prophylactic antibiotics and anticoagulants are given before and during the procedure. Temporary peripheral extracorporeal circulatory support (usually through the femoral vessels) is sometimes used.\n\nThe mitral valve is accessed surgically through an apical puncture of the left ventricle using an anterior or left lateral mini thoracotomy (transapical approach). A guidewire is placed across the existing native mitral valve and into a pulmonary vein. A balloon catheter delivery system is then advanced over the guidewire into the left atrium. The inner diameter of the mitral valve annulus is measured using transoesophageal echocardiography to establish the size of bioprosthetic valve needed. Using the delivery system, the bioprosthetic valve is then introduced, manipulated into position (to align the valve with the mitral annulus) and slowly deployed within the surgically implanted mitral valve ring under fluoroscopic and echocardiographic guidance. Often, rapid ventricular pacing is used to reduce movement of the heart. After valve deployment, the catheter delivery system, guidewires and pacing wires are removed from the left ventricle and the left ventricular puncture and chest incisions are closed. Valve performance is then assessed using echocardiography and fluoroscopy.'}
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https://www.nice.org.uk/guidance/ipg707
|
Evidence-based recommendations on transapical transcatheter mitral valve-in-ring implantation after failed annuloplasty for mitral valve repair in adults. This involves inserting a bioprosthetic mitral valve into an existing mitral valve ring to treat a leaking mitral valve, without needing repeat open heart surgery.
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959f1796e6540b742d9334250a5a6c2548f809fe
|
nice
|
Lateral elbow resurfacing for arthritis
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Lateral elbow resurfacing for arthritis
Evidence-based recommendations on lateral elbow resurfacing for arthritis. This involves inserting an implant into the 2 bones that form the joint at the outer part of the elbow, under general anaesthetic.
# Recommendations
Evidence on the safety and efficacy of lateral elbow resurfacing for arthritis is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.
Clinicians wishing to do lateral elbow resurfacing for arthritis should:
Inform the clinical governance leads in their healthcare organisation.
Give patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.
Ensure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.
Enter details about all patients having the procedure onto the National Joint Registry. Clinicians should also audit and review their outcomes locally.
Discuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.
Healthcare organisations should:
Ensure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.
Regularly review data on outcomes and safety for this procedure.
The procedure should only be done in specialist centres by surgeons who do elbow arthroplasty regularly and have training in this specific technique.
Report any problems with a medical device using the Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.
Further research, which could include case series with long-term follow up, should report range of motion, patient-reported outcomes and complications.
NICE may update the guidance on publication of further evidence.# The condition, current treatments and procedure
# The condition
Rheumatoid arthritis is the most common form of arthritis in the elbow. Osteoarthritis that needs surgery is less common in the elbow than in weight-bearing joints, such as the knee and hip. Symptoms include pain, swelling and stiffness in the elbow.
# Current treatments
Treatment for elbow arthritis depends on the severity of the disease. Conservative treatments include analgesics and corticosteroid injections to relieve pain and inflammation, and physiotherapy and prescribed exercise to improve function and mobility. When symptoms are severe, surgery may be indicated. Options include arthroscopic debridement, interposition arthroplasty, replacement or excision of the radial head, or total elbow replacement.
# The procedure
Lateral resurfacing of the elbow for arthritis is usually done under general anaesthesia. An incision is made through muscle tendon to access the elbow joint, and the articular surfaces prepared. The capitellum of the humerus is reamed using a surface cutter, and a peg hole is created. A trial component is inserted. A guidewire is inserted into the radial head, then the surface is shaped with a cutter to produce a concave face. A peg hole is then created in the radial head and a trial component inserted. Once the trial components have been tested for stability and range of movement the definitive components are implanted and the joint reduced. The soft tissues are repaired, and the skin is closed with sutures. A cast or splint may be used for 4 to 6 weeks.
A potential advantage of this procedure over a total elbow replacement is that it preserves the natural inner compartment of the elbow. Movements are therefore likely to be more like a natural elbow joint.
|
{'Recommendations': "Evidence on the safety and efficacy of lateral elbow resurfacing for arthritis is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. Find out what special arrangements mean on the NICE interventional procedures guidance page.\n\nClinicians wishing to do lateral elbow resurfacing for arthritis should:\n\nInform the clinical governance leads in their healthcare organisation.\n\nGive patients (and their families and carers as appropriate) clear written information to support shared decision making, including NICE's information for the public.\n\nEnsure that patients (and their families and carers as appropriate) understand the procedure's safety and efficacy, and any uncertainties about these.\n\nEnter details about all patients having the procedure onto the National Joint Registry. Clinicians should also audit and review their outcomes locally.\n\nDiscuss the outcomes of the procedure during their annual appraisal to reflect, learn and improve.\n\nHealthcare organisations should:\n\nEnsure systems are in place that support clinicians to collect and report data on outcomes and safety for every patient having this procedure.\n\nRegularly review data on outcomes and safety for this procedure.\n\nThe procedure should only be done in specialist centres by surgeons who do elbow arthroplasty regularly and have training in this specific technique.\n\nReport any problems with a medical device using the\xa0Medicines and Healthcare products Regulatory Agency's Yellow Card Scheme.\n\nFurther research, which could include case series with long-term follow up, should report range of motion, patient-reported outcomes and complications.\n\nNICE may update the guidance on publication of further evidence.", 'The condition, current treatments and procedure': '# The condition\n\nRheumatoid arthritis is the most common form of arthritis in the elbow. Osteoarthritis that needs surgery is less common in the elbow than in weight-bearing joints, such as the knee and hip. Symptoms include pain, swelling and stiffness in the elbow.\n\n# Current treatments\n\nTreatment for elbow arthritis depends on the severity of the disease. Conservative treatments include analgesics and corticosteroid injections to relieve pain and inflammation, and physiotherapy and prescribed exercise to improve function and mobility. When symptoms are severe, surgery may be indicated. Options include arthroscopic debridement, interposition arthroplasty, replacement or excision of the radial head, or total elbow replacement.\n\n# The procedure\n\nLateral resurfacing of the elbow for arthritis is usually done under general anaesthesia. An incision is made through muscle tendon to access the elbow joint, and the articular surfaces prepared. The capitellum of the humerus is reamed using a surface cutter, and a peg hole is created. A trial component is inserted. A guidewire is inserted into the radial head, then the surface is shaped with a cutter to produce a concave face. A peg hole is then created in the radial head and a trial component inserted. Once the trial components have been tested for stability and range of movement the definitive components are implanted and the joint reduced. The soft tissues are repaired, and the skin is closed with sutures. A cast or splint may be used for 4 to 6\xa0weeks.\n\nA potential advantage of this procedure over a total elbow replacement is that it preserves the natural inner compartment of the elbow. Movements are therefore likely to be more like a natural elbow joint.'}
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https://www.nice.org.uk/guidance/ipg705
|
Evidence-based recommendations on lateral elbow resurfacing for arthritis. This involves inserting an implant into the 2 bones that form the joint at the outer part of the elbow, under general anaesthetic.
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6f4a0fb5d663bfc3ec7cd0c53c4aaf9248252335
|
nice
|
Midostaurin for treating advanced systemic mastocytosis
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Midostaurin for treating advanced systemic mastocytosis
Evidence-based recommendations on midostaurin (Rydapt) for treating advanced systemic mastocytosis in adults.
# Recommendations
Midostaurin monotherapy is recommended, within its marketing authorisation, as an option for treating aggressive systemic mastocytosis, systemic mastocytosis with associated haematological neoplasm, or mast cell leukaemia in adults. It is recommended only if the company provides midostaurin according to the commercial arrangement.
Why the committee made these recommendations
There is no standard treatment for advanced systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis with associated haematological neoplasm, or mast cell leukaemia). Current treatments include interferon alpha, pegylated interferon alpha, cladribine, imatinib, and treatments usually used for acute myeloid leukaemia. Midostaurin aims to treat the disease and its symptoms.
Evidence suggests that midostaurin is more effective than current treatments, but this is uncertain because it was not compared directly with these. Also, better quality comparative evidence is unlikely to become available.
Midostaurin meets NICE's criteria for a life-extending treatment at the end of life, which means that higher cost-effectiveness estimates can be considered. This means that, despite the uncertainty about the clinical evidence, the cost-effectiveness estimates are within the range that NICE considers acceptable. So, midostaurin is recommended.# Information about midostaurin
# Marketing authorisation indication
Midostaurin (Rydapt, Novartis) is indicated 'as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM‑AHN), or mast cell leukaemia (MCL)'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of midostaurin is £5,609.94 for a 56‑pack of 25 mg capsules (excluding VAT; BNF online, accessed September 2020), which equates to an annual cost of £292,719 at the standard dose of 100 mg twice daily.
The company has a commercial arrangement. This makes midostaurin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
The 2 single-arm midostaurin clinical trials, D2201 and A2213, are sufficiently generalisable to NHS practice in England for decision making.
The 3 subtypes of advanced systemic mastocytosis (aggressive systemic mastocytosis , systemic mastocytosis with associated haematological neoplasm , and mast cell leukaemia ) are usually clinically distinct.
It is appropriate to pool the D2201 and A2213 studies to inform the comparative effectiveness estimate used in decision making.
It recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, key issues summary, page 2), and took these into account in its decision making. It discussed the following issues in further detail which were outstanding after the technical engagement stage.
# Treatment pathway and comparator
## There is an unmet need for a disease-modifying treatment for advanced systemic mastocytosis
Mastocytosis is a rare group of heterogenous diseases characterised by excessive mast cells. It includes advanced systemic mastocytosis, which is a severe form of the disease with 3 diverse subtypes. ASM is typically the least severe subtype, followed by SM-AHN, then MCL which has a life expectancy of less than 1 year. The clinical experts advised that the treatment pathway for advanced systemic mastocytosis is complex. Treatment is individualised based on symptoms, and because of the diversity of the disease subtypes. There are no licensed, targeted or disease-modifying therapies to treat advanced systemic mastocytosis currently available in the NHS. The patient and clinical experts advised that the condition has a poor prognosis with current treatment options, particularly for SM‑AHN or MCL. The patient experts also explained that the symptoms of advanced systemic mastocytosis have a major debilitating effect on their daily activities and quality of life. These include frequent and unexpected anaphylaxis, diarrhoea and vomiting. Available treatments do little to improve these symptoms and may cause additional side effects. The committee concluded that there is an unmet need for people with advanced systemic mastocytosis, and that people with the condition would welcome a disease-modifying treatment option like midostaurin.
## A mixture of treatments used in current clinical practice is the most appropriate comparator
The company's evidence submission compared midostaurin with how advanced systemic mastocytosis is currently treated in clinical practice (current clinical management). It used a composite comparator (a representative mixture of treatments currently used) including interferon alpha, cladribine, imatinib, pegylated interferon alpha and treatments that are typically used to treat acute myeloid leukaemia, such as azacitidine. The proportion of the composite comparator made up by each treatment was informed by opinions from 5 clinical experts. The committee recalled that there are no treatments licensed for advanced systemic mastocytosis in current NHS practice, and that treatment is highly individualised (see section 3.1). The clinical experts confirmed that the company's composite comparator is a reasonable representation of the treatments used in current NHS practice. The committee recognised that it would be difficult to identify a single treatment option to use as the comparator. It concluded that current clinical management, as defined by the company, was the appropriate comparator for decision making.
# Clinical effectiveness evidence
## The clinical effectiveness evidence for midostaurin is from 2 single-arm non-randomised trials
The clinical evidence for midostaurin came from D2201 and A2213, 2 non-randomised, open-label, single-arm clinical trials. Both trials included people with the 3 subtypes of advanced systemic mastocytosis (see section 3.1). D2201 was an international trial, including 4 patients from the UK, and A2213 was a US study. The median overall survival (OS) for advanced systemic mastocytosis from D2201 (December 2014 data, n=89) was 26.8 months. The median OS was shortest for MCL (9.4 months), followed by SM‑AHN (20.7 months), then ASM (51.1 months). The results of a more recent data cut were similar (August 2017; results are confidential and cannot be reported here). Median OS in the overall population in A2213 (n=26) was 40 months. The committee noted that more than half of the people in D2201 had stopped treatment with midostaurin within 1 year, with 19% of patients still having treatment at 3 years. The committee concluded that because D2201 and A2213 are single-arm trials, they do not provide evidence of the relative effectiveness of midostaurin compared with current treatment options. But it acknowledged that doing a phase 3 trial for advanced systemic mastocytosis would be difficult.
# Comparative effectiveness evidence
## The comparative evidence for midostaurin is uncertain, but estimates from Reiter et al. (2017) are suitable for decision making
The company's evidence submission did not include any studies that directly compared midostaurin with treatments currently used in NHS practice. The main comparative effectiveness evidence was from 2 non-randomised studies, Reiter et al. (2017) and CEREMAST. Reiter et al. pooled midostaurin time-to-event data from the D2201 and A2213 trials and compared it with outcomes from German registry data for treatment without midostaurin. The CEREMAST study compared outcomes from a midostaurin compassionate use programme in France with outcomes from French registry data for treatment without midostaurin. The company's preferred analyses used results from Reiter et al. The committee noted that the study was presented at a conference, but was otherwise unpublished, meaning it had received less scrutiny than if it had been fully peer reviewed. The company explained that it was not aware of planned publications by the study investigators, but that it had identified very little comparative effectiveness evidence because advanced systemic mastocytosis is rare. It had determined Reiter et al. to be the best evidence available. The clinical expert explained that the registry used in Reiter et al. remains the main source of data used internationally. The ERG agreed with the company's conclusion that Reiter et al. was the best available source of comparative effectiveness evidence. But it highlighted its limitations, which included its small sample size, and limited information about what treatments were used and study recruitment. It also noted the risk of bias present in all non-randomised evidence. The ERG also advised that there are potential limitations to pooling data from the D2201 and A2213 trials, because they have different study protocols and median follow-up durations. In response to technical engagement, a clinical expert advised that the A2213 study is likely to be less generalisable to NHS clinical practice than D2201. The committee agreed that there is limited evidence for midostaurin because the condition is rare, so data from the 2 studies could be pooled for decision making. It agreed that Reiter et al. was more robust than the CEREMAST study. The committee noted ongoing data collection by the European Competence Network on Mastocytosis registry and considered whether it might provide more robust evidence on outcomes with current treatments. A patient expert advised that, although the registry has data for approximately 500 people with advanced systemic mastocytosis, some of them might already be having treatment with midostaurin, and the frequency of follow up is unclear. The committee concluded that the quality of comparative effectiveness evidence was poor, but in the absence of more robust evidence it would consider outcomes from Reiter et al. in its decision making. It agreed that it would interpret the resulting estimates (see section 3.5) with caution.
## The propensity score matched hazard ratio suggests midostaurin is more effective than current clinical management, but this is uncertain
The comparative OS of midostaurin was by far the most important clinical factor affecting its cost effectiveness. In its evidence submission, the company considered several OS hazard ratios (HRs), based on Reiter et al. (2017), as options to inform the comparative effectiveness of midostaurin. After technical engagement, the company updated some of the HR analyses using a more recent D2201 data cut (containing 1 extra year of data). The committee noted that the company's preferred HR was from a multivariable regression analysis using pooled D2201 and A2213 data for midostaurin (0.52, 95% confidence interval 0.32 to 0.84). This analysis attempted to account for potential imbalances in patient characteristics between the midostaurin clinical trials and the German registry data from Reiter et al. The committee was concerned that the company's preferred HR was similar to the HR that did not adjust for imbalances (0.50, 95% CI 0.33 to 0.76). This suggested that the regression analysis might not have fully captured important observed or unobserved differences between the datasets. The committee considered that the propensity score matching analysis might provide a more unbiased estimate of the HR (0.64, 95% CI 0.33 to 1.24). The ERG advised that the propensity score matching analysis meant reducing the sample size (to achieve 2 groups of 'matched' pairs of patients), and it may be preferable to retain the bigger sample size used by the multivariable regression analysis. It also advised that, like the regression analysis, the matching analysis cannot adjust for any unobserved imbalances in patient characteristics. The committee noted that in the propensity score matched analysis the number of patients was substantially lower, which led to a wider CI but suggested that the unadjusted patient groups were not well matched. It considered that, on balance, it would prefer an unbiased estimate of the HR with a wider CI, rather than a potentially biased estimate of the HR with a narrower CI. The committee concluded that, from the available HRs to inform comparative survival, the propensity score matched HR was the most robust estimate to inform the economic model and decision making. The committee also concluded that, based on its preferred HR, midostaurin does appear to be clinically effective compared with current clinical management, but the estimate remains uncertain.
# Economic model
## The company's economic model is broadly acceptable for decision making
The company presented a partitioned survival model with 4 mutually exclusive health states: 2 progression-free survival (PFS) states (with either sustained response, or lack or loss of response), progressed disease and death. The model used a lifetime time horizon. People entered the model in 1 of the 2 PFS states depending on the disease's initial response to treatment. They could move from PFS (sustained response) to PFS (lack or loss of response), informed by duration of response data. The company fitted parametric curves to D2201 time-to-event data to estimate transition probabilities, and applied HRs from Reiter et al. (see section 3.5) to estimate outcomes for current clinical management. The ERG advised that the parametric curves for midostaurin had been selected appropriately and appeared to be reasonable. The committee concluded that the company's economic model was broadly acceptable for decision making.
## The model should use 1 health state with a single utility value for progression-free survival
The company's model partitioned PFS by response status (see section 3.6), to allow the utility value for progression-free disease to differ depending on response to treatment. The company stated that this was supported by clinical advice stating that quality of life is affected by treatment response. The ERG recognised that PFS may be different for people whose disease responded and those whose disease did not, based on the trial data. However, it had concerns about the reliability of the response rate and duration data used by the company to partition the progression-free health state. It considered that the data was not appropriate for this purpose. The ERG also advised that it is inconsistent to partition PFS by response status without similarly partitioning OS, because the trial data also suggested that OS was affected by treatment response. In response to technical engagement, the company provided a revised analysis using a single utility value for the progression-free health state. The committee recognised the limitations of the data for partitioning PFS and the inconsistency in not partitioning OS. It agreed that partitioning OS would increase the model's reliance on uncertain response data. Therefore, the committee concluded that the model should have 1 PFS health state, with a single utility value from the company's revised analysis.
## The utility estimates might not capture the full effect of midostaurin on quality of life
The committee noted that the utility values used in the model had been derived from the single-arm D2201 trial, so it had not seen quality-of-life evidence from people having current clinical management. It recalled that advanced systemic mastocytosis often has a major debilitating effect on a person's life (see section 3.1). The patient experts advised that the quality-of-life improvement after starting treatment with midostaurin was rapid and substantial. One patient expert explained that they had beneficial effects after 1 week of starting treatment, and up to 10 hours of normal life per day after 1 month of treatment. The clinical experts also reiterated the large improvement in quality of life with midostaurin. They advised that there is very little comparator quality-of-life data available because midostaurin is increasingly being used before other treatments in other countries. The committee considered that, although it had not seen quality-of-life evidence directly related to current clinical management, it is likely that the utility estimates used in the model did not capture all of the benefits of midostaurin that had been described by the patient and clinical experts. It recalled its earlier conclusion that the response data was too uncertain to implement response-based utility values (see section 3.7), which might have been a way to include the quality-of-life benefits of midostaurin. The committee concluded that the incremental quality-adjusted life years (QALYs) estimated by the model may be conservative for midostaurin, and that it would consider this in its decision making.
## A 3-year treatment benefit is suitable for decision making, although this might be optimistic
The company's base-case model applied the comparative effectiveness HR for the duration of the model (38 years), which assumed that the benefit of starting treatment with midostaurin lasts for a person's lifetime. The ERG considered that a lifetime treatment benefit was unlikely to be plausible, and that the progression and survival rates with midostaurin would instead become equal to other treatments over time. In response to technical engagement, the company presented alternative analyses in which the HR became 1 (no treatment effect) after 3, 5 and 10 years. The clinical experts advised that the longer a person has midostaurin, the more sustained disease response is. But they noted that disease response can be lost because of associated haematological malignancy instead of mastocytosis itself. They also advised that while there is no known resistance to midostaurin, its effect dissipates rapidly after stopping treatment, even if doses are only missed for a few days. The committee considered whether it was appropriate to include a lifetime treatment benefit in the model. It recalled that most people did not continue to have midostaurin in the long term (see section 3.3). The committee considered that it was implausible to retain the Reiter et al. (2017) HR for people who were no longer having midostaurin. It also noted that it had not seen long-term, robust comparative effectiveness evidence, so the duration of treatment benefit is uncertain. The committee considered that a 3‑year midostaurin benefit duration is likely to be optimistic for people who stop having treatment before 3 years. But it considered it potentially pessimistic for the minority of people who remain on treatment beyond 3 years, to an unknown extent. On balance, the committee concluded that it would consider a 3‑year treatment benefit duration for midostaurin in its decision making, even though this was likely to be optimistic.
# End of life
## Midostaurin is considered to be a life-extending treatment at the end of life
The committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee considered whether midostaurin meets both end of life criteria for people with advanced systemic mastocytosis. For the life expectancy criterion, the committee noted that Reiter et al. (2017), which it had accepted as a source of comparative effectiveness evidence (see section 3.4), reported a median survival with current clinical management of 19.5 months. The committee agreed that life expectancy was clearly lower than 24 months for people with MCL, but that this is less clear for advanced systemic mastocytosis overall. Some sources of evidence reported median survival estimates above 24 months, but the company explained that these studies often included people with indolent systemic mastocytosis, which is much less severe and has a longer life expectancy than advanced systematic mastocytosis. For the life extension criterion, the committee noted that Reiter et al. reported a median survival benefit of 21.9 months for midostaurin compared with current clinical management. It also noted that the economic model predicted a mean survival benefit far higher than the 3 months stipulated by the life extension criterion. The patient and clinical experts advised that there is increasing clinical experience and evidence, albeit non-randomised, suggesting that midostaurin improves life expectancy considerably. Therefore, the committee concluded that midostaurin could be considered a life-extending treatment at the end of life.
# Cost-effectiveness estimates
## Cost-effectiveness estimates are below £50,000 per QALY gained so midostaurin is recommended
The committee noted that midostaurin could be considered a life-extending treatment at the end of life (see section 3.10), so an acceptable incremental cost-effectiveness ratio (ICER) would be below £50,000 per QALY gained. The committee recalled its preferred assumptions for decision making:
Using the Reiter et al. (2017) propensity score matched OS HR (see section 3.4 and section 3.5).
Using a single PFS health state, with a single utility value from the company's revised analysis (see section 3.7).
Assuming that the treatment benefit of midostaurin lasts for 3 years, after which its progression and survival rates become equal to the comparator (see section 3.9).With the preferred assumptions, and taking all relevant commercial arrangements into consideration, the cost-effectiveness estimates for the overall population and the subgroup with more severe disease (SM‑AHN or MCL) were below £50,000 per QALY gained. The committee considered that the estimates were uncertain because of limitations in the clinical and comparative effectiveness evidence (see section 3.4, section 3.5 and section 3.9). It also recalled its conclusion that the incremental QALY estimates from the model might not capture all the quality-of-life benefits associated with midostaurin compared with current treatment options (see section 3.8). Despite the limitations in the evidence, the cost-effectiveness estimates were within what NICE considers acceptable. So, the committee concluded that midostaurin could be recommended.
# Innovation
## Midostaurin is an innovative treatment for advanced systemic mastocytosis
The company considered midostaurin to be innovative because there are currently no other licensed or targeted disease-modifying treatment options for people with advanced systemic mastocytosis. The patient and clinical experts emphasised the importance of alleviating debilitating symptoms and improving health-related quality of life, and the potential benefit from midostaurin in achieving this (see section 3.1). The committee recalled that the utility values used in the economic model might not capture all quality-of-life benefits associated with midostaurin, because there were no quality-of-life data from people having current clinical management (see section 3.8). However, it had taken this potential uncertainty into account in its decision making (see section 3.11). The committee concluded that midostaurin is innovative.
# Equality
## There are no equality issues relevant to the recommendation
No equalities issues were raised during scoping and technical engagement. No potential equality issues were identified in the company submission. The committee concluded that there were no equalities issues relevant to the recommendation.
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{'Recommendations': "Midostaurin monotherapy is recommended, within its marketing authorisation, as an option for treating aggressive systemic mastocytosis, systemic mastocytosis with associated haematological neoplasm, or mast cell leukaemia in adults. It is recommended only if the company provides midostaurin according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThere is no standard treatment for advanced systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis with associated haematological neoplasm, or mast cell leukaemia). Current treatments include interferon alpha, pegylated interferon alpha, cladribine, imatinib, and treatments usually used for acute myeloid leukaemia. Midostaurin aims to treat the disease and its symptoms.\n\nEvidence suggests that midostaurin is more effective than current treatments, but this is uncertain because it was not compared directly with these. Also, better quality comparative evidence is unlikely to become available.\n\nMidostaurin meets NICE's criteria for a life-extending treatment at the end of life, which means that higher cost-effectiveness estimates can be considered. This means that, despite the uncertainty about the clinical evidence, the cost-effectiveness estimates are within the range that NICE considers acceptable. So, midostaurin is recommended.", 'Information about midostaurin': "# Marketing authorisation indication\n\nMidostaurin (Rydapt, Novartis) is indicated 'as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM‑AHN), or mast cell leukaemia (MCL)'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of midostaurin is £5,609.94 for a 56‑pack of 25\xa0mg capsules (excluding VAT; BNF online, accessed September\xa02020), which equates to an annual cost of £292,719 at the standard dose of 100\xa0mg twice daily.\n\nThe company has a commercial arrangement. This makes midostaurin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Novartis, a review of this submission by the evidence review group (ERG), NICE's technical report, and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nThe 2\xa0single-arm midostaurin clinical trials, D2201 and A2213, are sufficiently generalisable to NHS practice in England for decision making.\n\nThe 3\xa0subtypes of advanced systemic mastocytosis (aggressive systemic mastocytosis [ASM], systemic mastocytosis with associated haematological neoplasm [SM‑AHN], and mast cell leukaemia [MCL]) are usually clinically distinct.\n\nIt is appropriate to pool the D2201 and A2213 studies to inform the comparative effectiveness estimate used in decision making.\n\nIt recognised that there were remaining areas of uncertainty associated with the analyses presented (see technical report, key issues summary, page\xa02), and took these into account in its decision making. It discussed the following issues in further detail which were outstanding after the technical engagement stage.\n\n# Treatment pathway and comparator\n\n## There is an unmet need for a disease-modifying treatment for advanced systemic mastocytosis\n\nMastocytosis is a rare group of heterogenous diseases characterised by excessive mast cells. It includes advanced systemic mastocytosis, which is a severe form of the disease with 3\xa0diverse subtypes. ASM is typically the least severe subtype, followed by SM-AHN, then MCL which has a life expectancy of less than 1\xa0year. The clinical experts advised that the treatment pathway for advanced systemic mastocytosis is complex. Treatment is individualised based on symptoms, and because of the diversity of the disease subtypes. There are no licensed, targeted or disease-modifying therapies to treat advanced systemic mastocytosis currently available in the NHS. The patient and clinical experts advised that the condition has a poor prognosis with current treatment options, particularly for SM‑AHN or MCL. The patient experts also explained that the symptoms of advanced systemic mastocytosis have a major debilitating effect on their daily activities and quality of life. These include frequent and unexpected anaphylaxis, diarrhoea and vomiting. Available treatments do little to improve these symptoms and may cause additional side effects. The committee concluded that there is an unmet need for people with advanced systemic mastocytosis, and that people with the condition would welcome a disease-modifying treatment option like midostaurin.\n\n## A mixture of treatments used in current clinical practice is the most appropriate comparator\n\nThe company's evidence submission compared midostaurin with how advanced systemic mastocytosis is currently treated in clinical practice (current clinical management). It used a composite comparator (a representative mixture of treatments currently used) including interferon alpha, cladribine, imatinib, pegylated interferon alpha and treatments that are typically used to treat acute myeloid leukaemia, such as azacitidine. The proportion of the composite comparator made up by each treatment was informed by opinions from 5\xa0clinical experts. The committee recalled that there are no treatments licensed for advanced systemic mastocytosis in current NHS practice, and that treatment is highly individualised (see section 3.1). The clinical experts confirmed that the company's composite comparator is a reasonable representation of the treatments used in current NHS practice. The committee recognised that it would be difficult to identify a single treatment option to use as the comparator. It concluded that current clinical management, as defined by the company, was the appropriate comparator for decision making.\n\n# Clinical effectiveness evidence\n\n## The clinical effectiveness evidence for midostaurin is from 2\xa0single-arm non-randomised trials\n\nThe clinical evidence for midostaurin came from D2201 and A2213, 2\xa0non-randomised, open-label, single-arm clinical trials. Both trials included people with the 3\xa0subtypes of advanced systemic mastocytosis (see section 3.1). D2201 was an international trial, including 4\xa0patients from the UK, and A2213 was a US study. The median overall survival (OS) for advanced systemic mastocytosis from D2201 (December\xa02014 data, n=89) was 26.8\xa0months. The median OS was shortest for MCL (9.4\xa0months), followed by SM‑AHN (20.7\xa0months), then ASM (51.1\xa0months). The results of a more recent data cut were similar (August\xa02017; results are confidential and cannot be reported here). Median OS in the overall population in A2213 (n=26) was 40\xa0months. The committee noted that more than half of the people in D2201 had stopped treatment with midostaurin within 1\xa0year, with 19% of patients still having treatment at 3\xa0years. The committee concluded that because D2201 and A2213 are single-arm trials, they do not provide evidence of the relative effectiveness of midostaurin compared with current treatment options. But it acknowledged that doing a phase\xa03 trial for advanced systemic mastocytosis would be difficult.\n\n# Comparative effectiveness evidence\n\n## The comparative evidence for midostaurin is uncertain, but estimates from Reiter et al. (2017) are suitable for decision making\n\nThe company's evidence submission did not include any studies that directly compared midostaurin with treatments currently used in NHS practice. The main comparative effectiveness evidence was from 2\xa0non-randomised studies, Reiter et al. (2017) and CEREMAST. Reiter et al. pooled midostaurin time-to-event data from the D2201 and A2213 trials and compared it with outcomes from German registry data for treatment without midostaurin. The CEREMAST study compared outcomes from a midostaurin compassionate use programme in France with outcomes from French registry data for treatment without midostaurin. The company's preferred analyses used results from Reiter et al. The committee noted that the study was presented at a conference, but was otherwise unpublished, meaning it had received less scrutiny than if it had been fully peer reviewed. The company explained that it was not aware of planned publications by the study investigators, but that it had identified very little comparative effectiveness evidence because advanced systemic mastocytosis is rare. It had determined Reiter et al. to be the best evidence available. The clinical expert explained that the registry used in Reiter et al. remains the main source of data used internationally. The ERG agreed with the company's conclusion that Reiter et al. was the best available source of comparative effectiveness evidence. But it highlighted its limitations, which included its small sample size, and limited information about what treatments were used and study recruitment. It also noted the risk of bias present in all non-randomised evidence. The ERG also advised that there are potential limitations to pooling data from the D2201 and A2213 trials, because they have different study protocols and median follow-up durations. In response to technical engagement, a clinical expert advised that the A2213 study is likely to be less generalisable to NHS clinical practice than D2201. The committee agreed that there is limited evidence for midostaurin because the condition is rare, so data from the 2\xa0studies could be pooled for decision making. It agreed that Reiter et al. was more robust than the CEREMAST study. The committee noted ongoing data collection by the European Competence Network on Mastocytosis registry and considered whether it might provide more robust evidence on outcomes with current treatments. A patient expert advised that, although the registry has data for approximately 500\xa0people with advanced systemic mastocytosis, some of them might already be having treatment with midostaurin, and the frequency of follow up is unclear. The committee concluded that the quality of comparative effectiveness evidence was poor, but in the absence of more robust evidence it would consider outcomes from Reiter et al. in its decision making. It agreed that it would interpret the resulting estimates (see section 3.5) with caution.\n\n## The propensity score matched hazard ratio suggests midostaurin is more effective than current clinical management, but this is uncertain\n\nThe comparative OS of midostaurin was by far the most important clinical factor affecting its cost effectiveness. In its evidence submission, the company considered several OS hazard ratios (HRs), based on Reiter et al. (2017), as options to inform the comparative effectiveness of midostaurin. After technical engagement, the company updated some of the HR analyses using a more recent D2201 data cut (containing 1\xa0extra year of data). The committee noted that the company's preferred HR was from a multivariable regression analysis using pooled D2201 and A2213 data for midostaurin (0.52, 95% confidence interval [CI] 0.32 to 0.84). This analysis attempted to account for potential imbalances in patient characteristics between the midostaurin clinical trials and the German registry data from Reiter et al. The committee was concerned that the company's preferred HR was similar to the HR that did not adjust for imbalances (0.50, 95% CI 0.33 to 0.76). This suggested that the regression analysis might not have fully captured important observed or unobserved differences between the datasets. The committee considered that the propensity score matching analysis might provide a more unbiased estimate of the HR (0.64, 95% CI 0.33 to 1.24). The ERG advised that the propensity score matching analysis meant reducing the sample size (to achieve 2\xa0groups of 'matched' pairs of patients), and it may be preferable to retain the bigger sample size used by the multivariable regression analysis. It also advised that, like the regression analysis, the matching analysis cannot adjust for any unobserved imbalances in patient characteristics. The committee noted that in the propensity score matched analysis the number of patients was substantially lower, which led to a wider CI but suggested that the unadjusted patient groups were not well matched. It considered that, on balance, it would prefer an unbiased estimate of the HR with a wider CI, rather than a potentially biased estimate of the HR with a narrower CI. The committee concluded that, from the available HRs to inform comparative survival, the propensity score matched HR was the most robust estimate to inform the economic model and decision making. The committee also concluded that, based on its preferred HR, midostaurin does appear to be clinically effective compared with current clinical management, but the estimate remains uncertain.\n\n# Economic model\n\n## The company's economic model is broadly acceptable for decision making\n\nThe company presented a partitioned survival model with 4\xa0mutually exclusive health states: 2\xa0progression-free survival (PFS) states (with either sustained response, or lack or loss of response), progressed disease and death. The model used a lifetime time horizon. People entered the model in 1\xa0of the 2\xa0PFS states depending on the disease's initial response to treatment. They could move from PFS (sustained response) to PFS (lack or loss of response), informed by duration of response data. The company fitted parametric curves to D2201 time-to-event data to estimate transition probabilities, and applied HRs from Reiter et al. (see section 3.5) to estimate outcomes for current clinical management. The ERG advised that the parametric curves for midostaurin had been selected appropriately and appeared to be reasonable. The committee concluded that the company's economic model was broadly acceptable for decision making.\n\n## The model should use 1\xa0health state with a single utility value for progression-free survival\n\nThe company's model partitioned PFS by response status (see section 3.6), to allow the utility value for progression-free disease to differ depending on response to treatment. The company stated that this was supported by clinical advice stating that quality of life is affected by treatment response. The ERG recognised that PFS may be different for people whose disease responded and those whose disease did not, based on the trial data. However, it had concerns about the reliability of the response rate and duration data used by the company to partition the progression-free health state. It considered that the data was not appropriate for this purpose. The ERG also advised that it is inconsistent to partition PFS by response status without similarly partitioning OS, because the trial data also suggested that OS was affected by treatment response. In response to technical engagement, the company provided a revised analysis using a single utility value for the progression-free health state. The committee recognised the limitations of the data for partitioning PFS and the inconsistency in not partitioning OS. It agreed that partitioning OS would increase the model's reliance on uncertain response data. Therefore, the committee concluded that the model should have 1\xa0PFS health state, with a single utility value from the company's revised analysis.\n\n## The utility estimates might not capture the full effect of midostaurin on quality of life\n\nThe committee noted that the utility values used in the model had been derived from the single-arm D2201 trial, so it had not seen quality-of-life evidence from people having current clinical management. It recalled that advanced systemic mastocytosis often has a major debilitating effect on a person's life (see section 3.1). The patient experts advised that the quality-of-life improvement after starting treatment with midostaurin was rapid and substantial. One patient expert explained that they had beneficial effects after 1\xa0week of starting treatment, and up to 10\xa0hours of normal life per day after 1\xa0month of treatment. The clinical experts also reiterated the large improvement in quality of life with midostaurin. They advised that there is very little comparator quality-of-life data available because midostaurin is increasingly being used before other treatments in other countries. The committee considered that, although it had not seen quality-of-life evidence directly related to current clinical management, it is likely that the utility estimates used in the model did not capture all of the benefits of midostaurin that had been described by the patient and clinical experts. It recalled its earlier conclusion that the response data was too uncertain to implement response-based utility values (see section 3.7), which might have been a way to include the quality-of-life benefits of midostaurin. The committee concluded that the incremental quality-adjusted life years (QALYs) estimated by the model may be conservative for midostaurin, and that it would consider this in its decision making.\n\n## A 3-year treatment benefit is suitable for decision making, although this might be optimistic\n\nThe company's base-case model applied the comparative effectiveness HR for the duration of the model (38\xa0years), which assumed that the benefit of starting treatment with midostaurin lasts for a person's lifetime. The ERG considered that a lifetime treatment benefit was unlikely to be plausible, and that the progression and survival rates with midostaurin would instead become equal to other treatments over time. In response to technical engagement, the company presented alternative analyses in which the HR became 1 (no treatment effect) after 3, 5 and 10\xa0years. The clinical experts advised that the longer a person has midostaurin, the more sustained disease response is. But they noted that disease response can be lost because of associated haematological malignancy instead of mastocytosis itself. They also advised that while there is no known resistance to midostaurin, its effect dissipates rapidly after stopping treatment, even if doses are only missed for a few days. The committee considered whether it was appropriate to include a lifetime treatment benefit in the model. It recalled that most people did not continue to have midostaurin in the long term (see section 3.3). The committee considered that it was implausible to retain the Reiter et al. (2017) HR for people who were no longer having midostaurin. It also noted that it had not seen long-term, robust comparative effectiveness evidence, so the duration of treatment benefit is uncertain. The committee considered that a 3‑year midostaurin benefit duration is likely to be optimistic for people who stop having treatment before 3\xa0years. But it considered it potentially pessimistic for the minority of people who remain on treatment beyond 3\xa0years, to an unknown extent. On balance, the committee concluded that it would consider a 3‑year treatment benefit duration for midostaurin in its decision making, even though this was likely to be optimistic.\n\n# End of life\n\n## Midostaurin is considered to be a life-extending treatment at the end of life\n\nThe committee considered the advice about life-extending treatments for people with a short life expectancy in NICE's guide to the methods of technology appraisal. The committee considered whether midostaurin meets both end of life criteria for people with advanced systemic mastocytosis. For the life expectancy criterion, the committee noted that Reiter et al. (2017), which it had accepted as a source of comparative effectiveness evidence (see section 3.4), reported a median survival with current clinical management of 19.5\xa0months. The committee agreed that life expectancy was clearly lower than 24\xa0months for people with MCL, but that this is less clear for advanced systemic mastocytosis overall. Some sources of evidence reported median survival estimates above 24\xa0months, but the company explained that these studies often included people with indolent systemic mastocytosis, which is much less severe and has a longer life expectancy than advanced systematic mastocytosis. For the life extension criterion, the committee noted that Reiter et al. reported a median survival benefit of 21.9\xa0months for midostaurin compared with current clinical management. It also noted that the economic model predicted a mean survival benefit far higher than the 3\xa0months stipulated by the life extension criterion. The patient and clinical experts advised that there is increasing clinical experience and evidence, albeit non-randomised, suggesting that midostaurin improves life expectancy considerably. Therefore, the committee concluded that midostaurin could be considered a life-extending treatment at the end of life.\n\n# Cost-effectiveness estimates\n\n## Cost-effectiveness estimates are below £50,000 per QALY gained so midostaurin is recommended\n\nThe committee noted that midostaurin could be considered a life-extending treatment at the end of life (see section 3.10), so an acceptable incremental cost-effectiveness ratio (ICER) would be below £50,000 per QALY gained. The committee recalled its preferred assumptions for decision making:\n\nUsing the Reiter et al. (2017) propensity score matched OS HR (see section 3.4 and section 3.5).\n\nUsing a single PFS health state, with a single utility value from the company's revised analysis (see section 3.7).\n\nAssuming that the treatment benefit of midostaurin lasts for 3\xa0years, after which its progression and survival rates become equal to the comparator (see section 3.9).With the preferred assumptions, and taking all relevant commercial arrangements into consideration, the cost-effectiveness estimates for the overall population and the subgroup with more severe disease (SM‑AHN or MCL) were below £50,000 per QALY gained. The committee considered that the estimates were uncertain because of limitations in the clinical and comparative effectiveness evidence (see section 3.4, section 3.5 and section 3.9). It also recalled its conclusion that the incremental QALY estimates from the model might not capture all the quality-of-life benefits associated with midostaurin compared with current treatment options (see section 3.8). Despite the limitations in the evidence, the cost-effectiveness estimates were within what NICE considers acceptable. So, the committee concluded that midostaurin could be recommended.\n\n# Innovation\n\n## Midostaurin is an innovative treatment for advanced systemic mastocytosis\n\nThe company considered midostaurin to be innovative because there are currently no other licensed or targeted disease-modifying treatment options for people with advanced systemic mastocytosis. The patient and clinical experts emphasised the importance of alleviating debilitating symptoms and improving health-related quality of life, and the potential benefit from midostaurin in achieving this (see section 3.1). The committee recalled that the utility values used in the economic model might not capture all quality-of-life benefits associated with midostaurin, because there were no quality-of-life data from people having current clinical management (see section 3.8). However, it had taken this potential uncertainty into account in its decision making (see section 3.11). The committee concluded that midostaurin is innovative.\n\n# Equality\n\n## There are no equality issues relevant to the recommendation\n\nNo equalities issues were raised during scoping and technical engagement. No potential equality issues were identified in the company submission. The committee concluded that there were no equalities issues relevant to the recommendation."}
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https://www.nice.org.uk/guidance/ta728
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Evidence-based recommendations on midostaurin (Rydapt) for treating advanced systemic mastocytosis in adults.
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Sapropterin for treating hyperphenylalaninaemia in phenylketonuria
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Sapropterin for treating hyperphenylalaninaemia in phenylketonuria
Evidence-based recommendations on sapropterin for treating hyperphenylalaninaemia in phenylketonuria.
# Recommendations
Sapropterin is recommended as an option for treating hyperphenylalaninaemia that responds to sapropterin (response as defined in the summary of product characteristics) in people with phenylketonuria (PKU), only if they are:
under 18 and a dose of 10 mg/kg is used, only using a higher dose if target blood phenylalanine levels cannot be achieved at 10 mg/kg
aged 18 to 21 inclusive, continuing the dose they were having before turning 18 or at a maximum dose of 10 mg/kg
pregnant (from a positive pregnancy test until birth).Sapropterin is recommended only if the company provides it according to the commercial arrangement.
This recommendation is not intended to affect treatment with sapropterin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
PKU is an inherited condition that causes raised levels of phenylalanine in the blood. Without treatment, this causes irreversible brain damage in babies and children and can affect brain function in adults. The only treatment for PKU is a diet to manage phenylalanine and overall protein intake (protein-restricted diet) and prescribed supplements. The diet is challenging and time-consuming, so it is difficult for some people to maintain. Sapropterin, plus a protein-restricted diet, is used for people whose PKU has been shown to respond to it. The aim of treatment is to maintain satisfactory blood phenylalanine levels to reduce PKU symptoms and complications, and potentially allow a less restricted diet.
Clinical trial evidence compares sapropterin plus a protein-restricted diet with diet alone. It shows that sapropterin effectively reduces blood phenylalanine levels in the short term for people whose PKU has been shown to respond to it, but it is uncertain how well it works in the long term. There is no clinical trial or registry evidence to show how much sapropterin reduces the need for a protein-restricted diet, or how it affects quality of life or brain development.
In people under 18, treatment for PKU is particularly important because of the higher risk of irreversible brain damage to the developing brain. This risk is highest in younger children, particularly up to age 12. Sapropterin may reduce the risk of brain damage for these children, but there is no clinical evidence to confirm this, and this potential benefit is not captured in the cost-effectiveness estimates. Taking uncaptured benefits and the clinical evidence into account, cost-effectiveness estimates are acceptable at the upper limit of what NICE considers an acceptable use of NHS resources. Sapropterin is therefore recommended for people under 18. The dose for children can be increased above the starting dose of 10 mg/kg, only if target blood phenylalanine levels are not achieved at a dose of 10 mg/kg. So, it is recommended for treating PKU in people under 18, normally at a dose of 10 mg/kg.
Stopping treatment and relying on diet alone at 18 years old is not clinically ideal. It would benefit young adults if treatment with sapropterin could be continued for as long as possible during final brain development and transition into adulthood. Taking this into account the maximum age at which sapropterin can be considered a cost‑effective use of NHS resources is 21. However, for this use to be cost effective people would need to continue the dose they were having when they were under 18. In practice this may mean that some young adults may need more dietary control alongside sapropterin between the ages of 18 and 21 (inclusive) than they would with a higher dose. Sapropterin is recommended for people aged 18 to 21, continuing the dose they were having before turning 18. People who have not had sapropterin before turning 18 can still have it until they turn 22. But the purpose of recommending sapropterin for this age group is to allow more control of phenylalanine levels while transitioning from sapropterin to dietary control alone by age 22, when the brain is nearly fully developed.
The risk of irreversible brain damage reduces with age, particularly after brain development is complete. So the adverse effects of being unable to follow the protein-restricted diet are considerably reduced in adults compared with the risks in childhood. Adults may still gain considerable benefit from sapropterin because of fewer symptoms related to raised phenylalanine levels, without having to follow the protein-restricted diet as strictly. However, these benefits are included in the economic modelling. Also, in adults the weight-based dose together with the higher average mg per kg dose results in costs that are considerably higher than in children, but the benefits are not correspondingly higher for adults. Even taking into account any uncaptured benefits in adults, the cost-effectiveness estimates are substantially higher than what NICE considers an acceptable use of NHS resources. So, it is not recommended for adults after they reach the age of 22.
Raised phenylalanine levels in pregnant women with PKU can cause severe birth defects in their unborn children. This could increase maternal anxiety, with the additional burden of the even more restrictive diet that is needed during pregnancy to maintain the stricter recommended phenylalanine levels. There is not enough evidence to predict how much sapropterin might prevent harm to the unborn child. If the risk of major harm is reduced, which is possible, then there are likely to be major lifelong benefits for the unborn child. The benefits for the pregnant woman with PKU who has the treatment are included in the cost-effectiveness analysis, but benefits for the unborn child have not been included. Taking the benefits for both these individuals into account, the cost-effectiveness estimates are likely to be within what NICE considers acceptable. So, sapropterin is recommended during pregnancy until birth.# Information about sapropterin
# Marketing authorisation indication
Sapropterin (Kuvan, BioMarin) is indicated 'for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with phenylketonuria (PKU) who have been shown to be responsive to such treatment'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of sapropterin is £597.22 per 30‑tablet pack. Each tablet contains 100 mg sapropterin dihydrochloride (excluding VAT; BNF online, accessed January 2021).
The company has a commercial arrangement. This makes sapropterin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by BioMarin, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
# The condition
## PKU is associated with high blood phenylalanine levels that can lead to irreversible damage to the developing brain
Phenylketonuria (PKU) is a rare, inherited metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutations of the PAH gene result in reduced activity of the PAH enzyme, which is responsible for breaking down the amino acid phenylalanine (Phe) to tyrosine. The reduced activity of PAH means that people with PKU are unable or less able to break down Phe, leading to increased levels in the blood. High blood concentrations of Phe are toxic for the brain and can cause irreversible damage during brain development. The European PKU guidelines recommend target blood Phe ranges of 120 to 360 micromoles per litre for children up to age 12, and 120 to 600 micromoles per litre for people aged 13 and over, recognising the particular risk in children under 13. Around 1 in 10,000 babies are diagnosed with PKU in the UK each year and there are currently about 2,000 people with PKU in NHS care in England. Childhood is the most critical period for brain development. Therefore, high Phe concentrations during this period can lead to long-term disability such as a severe learning disability, microcephaly (smaller head size than expected), seizures and tremors, stunted growth, delayed speech and reduced executive function (working memory, flexible thinking, and self-control). To avoid long-term brain effects in children with PKU, current treatment in the NHS consists of a protein-restricted diet and dietary supplements to control blood Phe levels. This diet should be continued as an adult. Clinical experts noted that poor control of blood Phe levels during childhood and the resulting irreversible brain damage can then mean that some adults who have been affected are less able to follow the diet. One patient expert confirmed that there are adults with PKU in the National Society for Phenylketonuria (NSPKU) who have severe symptoms and irreversible brain damage. Clinical experts explained that brain development peaks at around age 12. After this, high Phe levels are unlikely to affect IQ. However, young people above this age may still be at some risk of less severe long-term brain damage from high Phe levels, because brain maturation is probably not complete until around age 25. The committee concluded that PKU is associated with high blood Phe levels that can lead to irreversible damage to the developing brain.
## High blood Phe levels in adults with PKU can affect the brain but the risk of new irreversible damage is less than in children
In adults, high Phe concentrations can result in short-term symptoms, which are considered largely reversible by lowering Phe levels through adherence to diet. These include impaired executive function, reduced autonomy, impaired social maturity, difficulty forming relationships and neuropsychiatric symptoms such as depression, anxiety, and inattention. Clinical experts estimate that many adults with PKU find it difficult to maintain good control of blood Phe levels. However, 1 clinical expert noted that from their research many adults with PKU who have had treatment in the NHS have quality of life and academic and employment performance within the normal range. This is despite some evidence of impaired executive function, and some no longer following the diet. The experts noted that timing, duration, and intensity of exposure to high Phe levels in childhood and adolescence determine the severity of symptoms and long-term brain effects experienced by people with PKU. The committee also noted comments received in response to consultation that symptoms experienced by adults with PKU may not be completely reversible when a protein-restricted diet is restarted or adhered to more closely. Also, it was stated that brain development continues beyond the age of 18, possibly until 25 or even 30. The clinical experts explained that some neuropsychological outcomes are improved when Phe levels are reduced with diet, which suggests that some of the changes are reversible. While there could be the potential for subtle brain damage to happen between 18 and 25 in people with PKU, there is little evidence to confirm or quantify this. Also, the clinical experts agreed that patients were unlikely to suffer significant or permanent harm by stopping sapropterin treatment at 18 rather than 25. However, patient experts stated that the chronic effects of high Phe levels on the adult brain cannot be ignored or undermined, particularly when they lead to significant damage or deteriorating mental health outcomes such as depression and anxiety. The clinical experts acknowledged that some adults with PKU have brain damage because of high Phe levels, but there is no systematic evidence available to quantify the effects of high Phe on the adult brain or whether damage is irreversible in adults. One clinical expert noted that it is challenging to determine if brain damage is caused by high Phe levels in childhood (when the brain is still developing) or in adulthood. This can be further complicated by non-PKU-related brain damage that can happen because of nutritional deficiencies such as lack of vitamin B12. However, patient experts highlighted that any treatment that allowed patients to follow a less restricted diet could also alleviate damage from nutritional deficiencies. Another clinical expert stated that the effects of Phe on the brain can differ widely among adults with PKU. For example, some people experience brain effects within a few months of having high Phe levels compared with years for other people, and some people experience brain effects even when Phe levels are not particularly high. The committee accepted that high blood Phe levels in adults can affect the brain and may lead to brain damage. However, because brain development peaks at age 12, it concluded that the risk of irreversible damage decreases after that age and is less in adults than in children.
## High blood Phe levels in pregnancy can have harmful effects on the unborn child
In pregnancy, high blood Phe levels can have harmful effects on the unborn child and lead to abnormal development. These effects include birth defects such as congenital heart disease and heart defects, microcephaly, a learning disability, delayed learning and development, permanent brain damage, low birth weight, miscarriage, attention deficit hyperactivity disorder and autism spectrum disorders, impaired growth and impaired learning ability. Clinical experts explained that the effects of maternal PKU syndrome can be worse than the effects of PKU itself because the unborn child is exposed to high Phe levels which are teratogenic, during a crucial phase of development. The European PKU guidelines recommend pregnant women's Phe levels should stay between 120 and 360 micromoles per litre. Also, the committee heard from the experts that in practice good control of blood Phe levels (below 200 micromoles per litre) should be maintained if possible. This is very challenging to maintain with diet alone. The experts explained that Phe levels should be kept low throughout the whole pregnancy and that every 60 micromoles of Phe per litre over the 360 micromoles per litre target results in about a 3‑point IQ reduction for the unborn child. Dietary measures should ideally be started before conception to avoid congenital effects, but at least at the earliest possible opportunity to avoid harmful effects on the unborn child. Comments received in consultation indicated that women who are trying to become pregnant find achieving the target Phe levels safe for pregnancy very difficult using protein-restricted diet because of the much stricter levels compared with what they are normally used to. Also, women find it difficult to maintain very low Phe levels for long periods of time before becoming pregnant and during pregnancy. As a result, some women are fearful of becoming pregnant or completely stop having intimate or sexual relationships because of worries that they may not be able to cope with the protein-restricted diet during pregnancy and harm their unborn child. At the first committee meeting, a patient expert highlighted that there is an NHS policy in place for providing sapropterin for pregnant women with PKU. The NHS England commissioning expert and the patient expert indicated that the current NHS policy only covers pregnant women with PKU who are unable to establish safe Phe levels for the unborn child (100 to 360 micromoles per litre) on a protein-restricted diet. Only then can they be tested for a response to sapropterin. The experts stated this delay in starting sapropterin can result in the unborn baby being exposed to high Phe levels in the critical phase of early pregnancy before sapropterin is given. The patient and clinical experts highlighted that treatment with sapropterin is started too late in clinical practice because women with PKU must first show that they cannot achieve recommended Phe levels on diet alone. A clinical expert stated that the outcomes for unborn children are much better if blood Phe levels are brought down very early, within the first 6 weeks of pregnancy, before the organs start developing. They stated that in practice this approach is more likely to work when pregnancies are planned, and pre-conception plans can be developed with the woman's metabolic teams. The NHS England commissioning expert agreed that the current NHS policy for sapropterin works better for planned pregnancies than unplanned ones. Patient and clinical experts stated that about half of pregnancies in women with PKU are unplanned, which is similar to the rate seen in the general population. The committee concluded that high blood Phe levels in pregnancy can have harmful effects on the unborn child and this causes tremendous anxiety for many women with PKU. Early control of phenylalanine levels in all pregnancies was desirable to minimise the risk of PKU syndrome in the unborn child, with potential lifelong consequences for the child. The committee noted that the importance of protection of the unborn child had already been recognised by the NHS in NHS England's policy to provide sapropterin for some pregnant women.
# Treatment pathway
## The only treatment option available for people with PKU is a self-managed protein-restricted diet
Current clinical management of PKU is through a lifelong protein-restricted diet. This consists of prescribed low-protein and Phe-free medical foods to help reduce natural Phe consumption, and Phe-free amino acid supplements to improve nutrition and prevent nutritional deficiencies. The protein-restricted diet also involves reducing natural protein consumption according to individual Phe tolerance. Clinical experts stated that 80% of people with PKU can tolerate less than 10 grams of protein per day, equal to 1 or 2 slices of bread. To adhere to a protein-restricted diet, people with PKU must avoid foods and drinks containing protein or aspartame, which can be converted into Phe. This includes foods that are rich in protein (for example, meat, fish, dairy products and soya), foods with less natural protein (for example, fruit, vegetables, cereals, flour or pasta) and alcoholic drinks containing protein (for example, beer and stout). People with PKU routinely take blood samples at home, which are then sent to a central laboratory to measure blood Phe levels. A healthcare professional provides blood Phe concentration level results through a telephone consultation and, if necessary, will give advice on adjusting the diet to manage blood Phe concentration levels. The committee concluded that the only treatment option available for people with PKU is a self-managed protein-restricted diet.
## People with PKU and their carers would welcome a treatment that allows a less strict protein-restricted diet
The primary aim of clinical management and the protein-restricted diet is to prevent irreversible and reversible brain damage by keeping blood Phe concentration levels within the ranges recommended in European guidelines. However, both clinical and patient experts highlighted that people with PKU may be outside recommended Phe ranges. In childhood, the dietary restrictions put great pressure on carers and families because of the constant fear of irreversible damage. Adults can have raised Phe levels because they struggle to adhere to, or have completely stopped, their diet. Clinical experts noted that around 50% of adults with PKU are on a protein-restricted diet. Patient experts explained that being on a strict protein-restricted diet is burdensome and demanding for people with PKU and their carers for several reasons:
The time-consuming nature of food shopping and meal preparation. Also, the wide range of skills needed to understand food labels, calculate precisely, and weigh the amount of Phe in different foods that can be eaten in each meal, and prepare and cook meals regularly. This can take 2 to 3 times as long as normal and make managing the diet a dominant activity of daily life.
Poor taste and disagreeable smell and texture of low-Phe foods and synthetic protein substitutes. These have to be taken in large volumes 3 to 4 times a day and can cause digestive problems.
Costs of 'free-from' foods and difficulties accessing prescription food because of limits on which low-protein foods can be prescribed, as some are considered luxury items.
Problems such as weight gain resulting from the high carbohydrate content of the protein-restricted diet.At the second committee meeting a clinical expert highlighted research that suggests that 5% of adults with PKU have comorbidities unrelated to PKU such as cystic fibrosis, cancer, type 1 diabetes, renal insufficiency and inflammatory bowel disease. This makes sticking to the diet very difficult. It has also been reported that people with PKU are 4 times more likely to have other conditions such as a learning disability, autism spectrum disorder, eating disorders, bipolar and epilepsy than the general population, which also make it harder to follow the diet. Comments received in consultation also advised that a further contribution to overall reduced health is the constraints of a restricted diet on exercise. In particular, the low-protein diet makes it difficult to achieve satiety from food, which leads to many adults reporting high levels of fatigue before and after exercise. This limits people's ability to lead a healthy lifestyle and may account for the higher rates of comorbidities such as diabetes mellitus and ischaemic heart disease. Comments from consultation also indicated that poor housing stability, lower household income and being a member of Gypsy, Roma and Traveller communities could affect people's ability to stick to the PKU diet. Other consultation comments noted that diet can be very expensive even when the cost of low-protein foods and amino acid supplements are not taken into account. For example, people with PKU end up spending more money on protein-free healthier foods and ingredients to keep their diet varied and palatable, to make it easier to stick to. In addition, because of the high sugar content of the PKU diet people also experience teeth issues and need regular dental care, whether that is provided through the NHS or privately. Living arrangements and availability of storage space can also cause difficulties with sticking to the diet. PKU diets involve cooking all meals from scratch so need cooking facilities and equipment, and ample storage for medication, Phe-free foods, amino acid supplements and kitchen equipment. In some cases, this needs as much as an entire room just for storage, but this is not always available when living in small or shared accommodation. The committee understood that carers of children with PKU also report additional difficulties related to diet management. These include strains on their relationships, struggling to get the right support, and having to give up work or working part-time to dedicate more time to diet management. They also need to educate professionals, teachers, other children's parents, their families, and other carers about PKU and the diet restrictions. The known risk of irreversible brain damage if Phe levels are not controlled is a permanent source of stress for parents. The committee concluded that the protein-restricted diet was extremely burdensome and difficult to stick to, and people with PKU and their carers would welcome a treatment that allows a less strict protein-restricted diet.
# Experiences of people with PKU and their carers
## There is a need for a treatment that can reduce Phe levels and give people with PKU and their carers peace of mind
Many adults describe the effects of high Phe levels as 'brain fog', forgetfulness, tiredness, confusion, low mood and feelings of irritability. This can affect their ability to control their diet and maintain appropriate blood Phe levels. Additionally, adults with PKU may find it difficult to juggle work, studies and family commitments with controlling their diet and maintaining Phe levels. Some adults are unable to engage in full-time work because it creates a vicious cycle of less time to control diet and higher Phe levels, leading to reduced ability to focus and organise the diet. In addition, they can have a sense of being dependent on other people for support, feel socially isolated and constantly worry about maintaining their diet (see section 3.5). The committee noted that people with PKU have higher rates of comorbidities than the general population. The comorbidities seen more often in adults with PKU are: chronic ischaemic disease, urticaria, oesophageal disorders, gastroesophageal reflux disease, gastritis, anaemia, obesity, asthma, renal insufficiency, eczema, alopecia, osteoporosis, rhinitis, gall bladder disease and kidney calculus. Studies suggest that high Phe levels in people with PKU could be associated with biological mechanisms that increase the risk of chronic diseases. Also, the PKU diet, medical food and nutritional deficiencies because of the PKU diet may also contribute to the increased risk of chronic diseases. Consultation comments reiterated that PKU and the PKU diet have a substantial effect on all aspects of adults' lives. The patient and clinical experts advised that adults with PKU who have the best health outcomes typically have support from family, friends, partners, and carers.Concerns about high blood Phe levels can also affect other groups of people with PKU, some of whom have characteristics protected under the Equality Act 2010. These include:
Women: PKU can affect women's sexual and reproductive health and choices. In some cases, women completely forego sex because they are afraid of becoming pregnant and accidentally harming their unborn child (see section 3.3).
Pregnant women: Pregnant women with PKU describe pregnancy as traumatic because of the strictness of the PKU diet and the anxieties and stress of high Phe levels harming their unborn child (see section 3.3). Mothers with PKU describe being unable to cope with the pressures of strict dietary management while caring for their child, and experiencing anxiety, depression and inability to focus as a result.
Children: PKU is very limiting for children, who face isolation and feel restricted in their ability to join social events such as school trips, festivities, travelling, or meals out because of their diet. Children, as well as adults with PKU, frequently experience difficulty with focus, depression or anxiety, disordered eating, digestive problems, headaches, low mood and sadness, feeling tired all the time and being in a heightened emotional state (including aggressiveness, psychosis and paranoia) because of high Phe levels. At the second committee meeting, a patient expert highlighted how vulnerable families often struggle to control their child's Phe levels.
Young adults: In response to consultation, stakeholders and members of the public did not agree with the draft recommendation to stop sapropterin at 18 years of age. Consultation comments stated that high Phe levels can exacerbate the difficulties that young adults face as they transition from adolescent to adult life. Some young adults are in the process of moving out of their parents' home, undertaking further education, starting jobs, and learning to live independently. All of this can be affected by symptoms of high Phe levels or having to deal with the challenges of organising and maintaining the PKU diet without the support of their parents or carers for the first time. The committee also heard that as young adults transition from child clinical services to adult services, they may have reduced support from metabolic teams. One patient expert gave an example that the clinic her adult children attend is not equipped to support all patients appropriately because it is an add-on to an existing diabetes clinic. One clinical expert indicated that people with PKU may not be well supported in their transition from child to adult services unless they are seen in a big centre. Patient and clinical experts explained this is because some adult clinical services are not well resourced or have the right kitchen space and equipment to support all adults with PKU across the country. However, 1 expert noted that some of the larger metabolic centres did include metabolic kitchens for adults. A clinical expert also highlighted that most adult clinics tend to focus on supporting pregnant women with PKU rather than all adults. The committee appreciated that a recommendation to stop treatment at 18 years of age would mean people have to begin managing Phe levels through diet alone for the first time at that age, which would not be ideal. The committee has recommended treatment until people reach the age of 22, but it could only recommend sapropterin for people aged 18 to 21 (inclusive) at the dose they had when they were under 18 (and not escalating to the adult dose). It recognised that for some young adults this may mean the dose they have is considered a tapering dose and so dietary control may still need to increase at age 18. However, while that may be challenging it is inevitable for any age-based recommendation, and the committee had no evidence that this would be harder to manage at age 18 or 22, rather than at any older age. Also, the reason for the committee's recommendation that treatment should stop at age 22, considered as a tapering off of sapropterin from age 18, was related to the underlying biology of brain development and diminishing irreversible risk with age, associated with the higher treatment costs in adults. Having examined the options up to age 25, 21 was the maximum age that treatment could be considered cost effective.
Disabled adults: High Phe levels in adults with PKU- and non-PKU-related disabilities can lead to severe behavioural problems. At the second committee meeting, 1 clinical expert explained that people with late-treated PKU who have sustained long-term brain damage have a lifespan that is severely reduced by almost 20 years compared with the general population. Patient and clinical experts also highlighted that people with late-treated or untreated PKU have severe behavioural problems, strict food habits or food neophobia. This results in challenges managing the PKU diet and blood Phe levels, additional nursing and care home needs, and other costs. One patient expert confirmed that there are extreme examples of people with PKU who need more care, attention and support because of severe behavioural problems, in some cases even needing to be restrained. The patient expert added that reducing Phe levels in these people would be expected to lead to less challenging care provision and reductions in care plans, need to calculate natural protein 'exchanges' and close supervision of either the person themselves or what they eat. The committee was mindful that some disabilities may mean that adults are less able to adhere to the PKU diet and therefore these people would possibly get more benefit from sapropterin.The committee noted the many personal stories that had been received in response to consultation. It concluded that there is a clear need for a treatment that could reduce Phe levels, allow a less restricted diet, and give people with PKU and their carers peace of mind. However, the appraisal process requires that the costs of the treatment must be taken into consideration in relation to the benefits shown.
## Sapropterin is clinically appropriate and beneficial for people with PKU that responds to sapropterin
Sapropterin is a synthetic version of the naturally occurring tetrahydrobiopterin. The marketing authorisation for sapropterin is for adults and children of all ages with PKU that has been shown to be responsive to such treatment. Response to sapropterin is determined by a reduction in blood Phe levels. Blood Phe levels are checked before sapropterin treatment and weekly after starting treatment for 1 month. Response is defined as a reduction in blood Phe levels of at least 30% or achieving blood Phe levels defined for an individual patient by the treating physician. One clinical expert highlighted that there is a need for clearer response criteria to define who would benefit most from sapropterin. Another clinical expert noted that there is a response relationship between sapropterin and the levels of PAH activity and mutations. However, mutation analysis is not routine practice in the UK. The company estimated that 391 people with PKU in England and Wales are eligible, consisting of 366 current patients and an increase of 25 patients with PKU each year. Patient experts advised that adults with PKU who have taken sapropterin report improved day-to-day functioning, particularly concentration and mood. In addition, they were able to resume other activities such as studies or work. Parents of children with PKU report similar benefits in the mood, energy, concentration and behaviour of their children. They also report large increases in natural protein consumption, with children having a wider and more socially normal diet and greater freedom to participate in social activities. In addition, sapropterin also led to health benefits in children. These included increased bodyweight and growth, improvements in gastrointestinal symptoms and fewer mouth ulcers. Carers of people with PKU reported a significant easing of burden of care. This included not needing to prepare special prescribed low phenylalanine foods and being able to delegate childcare to others for the first time. Some carers reported being able to return to work or study, increase working hours, spend more time with other children, and have time for other family responsibilities. At the second committee meeting, an expert stated that using sapropterin could prevent a child being taken into care because it could keep the child's Phe levels within the target range for families struggling to follow the diet. The committee concluded that sapropterin could be highly beneficial for those people with PKU that responds to sapropterin.
# Clinical effectiveness
## The trial evidence shows sapropterin plus protein-restricted diet is clinically effective compared with protein-restricted diet alone
Evidence for the clinical effectiveness of sapropterin plus protein-restricted diet came from several randomised controlled trials (RCTs). These included 3 double-blind studies and 1 open-label study. The number of people in the studies was between 56 and 206 and the RCTs were short, between 6 and 26 weeks. The population included was different across the RCTs according to age, response to sapropterin and blood Phe concentration levels at screening stage. In 3 of the RCTs, sapropterin plus protein-restricted diet was compared with either placebo plus protein-restricted diet or protein-restricted diet alone. Results from the RCTs show that people having treatment with sapropterin plus protein-restricted diet had significantly reduced blood Phe concentration levels and maintained target levels compared with people having diet only. They also increased or maintained their consumption of natural Phe compared with people having treatment with protein-restricted diet. However, none of the RCTs were included in the company model because of their short duration and small sample sizes. The committee agreed that this was appropriate but concluded that the available trial evidence shows that sapropterin in combination with a protein-restricted diet is clinically effective compared with protein-restricted diet alone.
## The PKUDOS registry has evidence for long-term efficacy of sapropterin plus protein-restricted diet for the whole PKU population and is generalisable to the NHS
The company presented evidence for long-term efficacy of sapropterin from 2 multicentre registries. These are the PKUDOS registry in the US and the KAMPER registry in 8 European countries. The PKUDOS registry enrolled 1,922 people while KAMPER enrolled 576. Follow up was up to 9 years at the time of the most recent interim analyses. KAMPER includes people whose PKU was shown to respond to sapropterin or tetrahydrobiopterin and who were having sapropterin. But it does not provide a comparison with protein-restricted diet alone. In addition, 83.5% of those enrolled in KAMPER were children (under 18) and only 16.5% were adults. People were enrolled in the PKUDOS registry if they had blood Phe levels over 360 micromoles per litre and had previously had sapropterin, were currently having sapropterin, or were due to have sapropterin within 90 days of enrolment. In the PKUDOS study 59.1% of people enrolled were children (under 18) and 40.8% were adults. The company used data from 191 people who were due to have sapropterin within 90 days to represent the sapropterin plus protein-restricted diet cohort in the economic model. There were 160 people who had previously had sapropterin before enrolling or stopped taking it while in the registry, who were considered to represent the protein-restricted diet cohort. The committee concluded that only the PKUDOS registry provides evidence for long-term efficacy of sapropterin plus protein-restricted diet compared with diet alone in the whole PKU population. One clinical expert highlighted that people included in the PKUDOS registry may differ from adults with PKU in the NHS because of difficulties in obtaining the protein-restricted diet in the US. The committee reasoned that everyone enrolled in the PKUDOS registry, both those on diet alone and those having sapropterin plus diet, would be equally affected by difficulties in obtaining a protein-restricted diet. Therefore, the relative benefit seen would be a fair estimate of the relative benefit that would be seen in the NHS, where both groups would have equal access to the diet. It concluded that people with PKU enrolled in the PKUDOS registry were likely to reflect people with PKU in the NHS.
## The results of the PKUDOS registry are likely to be generalisable to NHS clinical practice
Results from the PKUDOS registry show the proportion of people achieving Phe levels between 120 and 360 micromoles per litre were similar over time for all age groups. Higher proportions of people achieved target Phe levels in the younger age subgroups (under 4 and under 12) than adults (18 and over). However, the committee noted that this is expected because the target range of 120 to 360 micromoles per litre is for children under 12 and the target for adults is up to 600 micromoles per litre. The proportion of people achieving target Phe levels between 120 and 600 micromoles per litre were similar across the under 4 and 18 and over age groups but decreased for the under 12 and under 18 groups over time. Higher proportions of people achieved target Phe levels between 120 and 600 micromoles per litre in younger age subgroups (under 4, under 12 and under 18) than adults (18 and over). The committee noted that for each target range the numbers of people contributing long-term data at 9 years were small (between 4 and 52 people). It also recalled that people were assigned to age group based on age at registry enrolment. One clinical expert explained that the results should be interpreted in the context of a protein-restricted diet. That is, the baseline proportions of people achieving target Phe levels are based on Phe control with protein-restricted diet alone. Therefore, people taking sapropterin in addition to protein-restricted diet are able to maintain and achieve target Phe levels long-term while increasing natural protein consumption and reducing supplements. The committee concluded that the results of the PKUDOS registry are likely to be generalisable to NHS clinical practice.
## The sapropterin dose used in clinical practice in the UK would be in line with the NHS England impact assessment report for sapropterin
The company stated that the mean dose of sapropterin for children is 10 mg/kg and the mean dose for adults is 12.5 mg/kg, according to the NHS England Integrated Impact Assessment Report for sapropterin. The committee noted that the total dose given was not just age related but also weight related, that is, per kg body weight. Because average adults have a higher kg weight than the average child, there are 2 factors which result in much higher drug costs for adults than children and mean that the annual drug costs for adults are 3 times higher than for children. The ERG was concerned that the doses of 10 mg/kg and 12.5 mg/kg for children and adults suggested by the company are underestimates of the doses used in clinical practice. In KAMPER, the average sapropterin dose was 12.7 mg/day and this included 83.5% children under 18 (see section 3.9). In the PKUDOS registry the average dose was 18.7 mg/kg and around 60% of people were under 18 (see section 3.9). The company indicated that sapropterin dosages in the KAMPER registry were left to the discretion of the treating clinicians, so they reflect clinical practice in the 8 European countries that contribute to the registry. Clinical experts highlighted that European clinical practice is likely to be similar to UK practice. Clinical experts explained that the difference in mean dose between PKUDOS and KAMPER is because clinicians in the US use lower blood Phe targets than in Europe and will use any sapropterin dose necessary to achieve those targets. In contrast, in Europe, target Phe levels and sapropterin response are not well defined and clinicians are more cost-sensitive because they must justify using higher doses of sapropterin. The committee noted that if outcome data from PKUDOS were used, then logically the same dose should be used to ensure the same efficacy. However, the company estimated an average dose for children of 10 mg/kg and 12.5 mg/kg for adults. The committee noted that although this was lower than the average doses in the PKUDOS registry, it corresponds to the doses in the NHS England Integrated Impact Assessment Report for sapropterin. One clinical expert stated that in their experience using between 10 mg/kg and 20 mg/kg resulted in little difference in outcome. Clinical experts further explained that increasing sapropterin dose does not improve efficacy because response to sapropterin primarily depends on the level of PAH activity and mutations, not the dose. They highlighted that people whose PKU responds to sapropterin increase their tolerance to natural Phe consumption by 2 to 4 times, regardless of dose. All clinical experts agreed that it is not just blood Phe levels that are important, but also the amount of natural protein that can be consumed. The committee concluded that the sapropterin dose per kg used in clinical practice in the UK is likely to be in line with the NHS England impact assessment report.
## The estimate of 71.2% reduction in protein-restricted diet is not evidence-based and could be an overestimate
The company assumed that people taking sapropterin with controlled blood Phe levels can relax their protein-restricted diet with a 71.2% reduction in protein supplements and low-protein food. This is important because savings can offset the costs of sapropterin treatment. The ERG noted that it could not determine the robustness of the methods used to calculate this value. Clinical experts highlighted that some people with PKU who take sapropterin can completely remove protein substitutes from their diet, referencing a forthcoming systematic review. The committee also heard from the company that a study in Netherlands (Evers et al. 2018) has shown that, over 5 years, patients had an average 68% reduction in amino acid supplements. However, 1 clinical expert cautioned that the results of the studies are likely to be influenced by clinical practice and the definition of sapropterin response used in the country of study. For example, in Switzerland it is recommended that only people with PKU that responds very well can have sapropterin. Therefore, everyone who has sapropterin would be expected to completely eliminate protein substitutes. The committee concluded that it seemed likely that people would reduce their protein-restricted diet, but it could not be sure that the reduction would be as high as 71.2%.
## Long-term brain damage happening in childhood is an important aspect of PKU
Irreversible brain damage in people with PKU can manifest as:
lower IQ score compared with people without PKU or unaffected relatives
clinically relevant neuropsychological impairments (about 25% of people with PKU)
minor neurological symptoms such as tremor, brisk lower limb reflexes, mild motor impairment (20% to 40% of people with PKU). Additional care needs for people with PKU and long-term brain damage can include: additional blood Phe monitoring, hospital appointments and telephone contacts by health professionals, possible hospital admissions, education, health and care plans for learning needs, additional teacher and teaching assistant time to supervise protein substitutes (for all children with PKU), use of home support workers and possible involvement of safeguarding and social services such as referral to early help services for people with very poor phenylalanine control (according to European PKU guidelines). However, information is not routinely collected on long-term brain damage because of PKU, or the number of children referred to early help services and social services, and the costs involved. The committee concluded that long-term brain damage because of high Phe levels in childhood is an important aspect of PKU and has a substantial effect on quality of life. However, while there is an expectation that sapropterin would reduce the risk of permanent damage, there is no direct evidence to substantiate or quantify any long-term benefit.
# The company's economic model
## The model time horizon is not long enough to capture any effect of sapropterin on long-term brain damage, and the model is not appropriate to capture the effects of PKU in pregnancy
The ERG had concerns about the company's original model. So, after technical engagement the company submitted a new decision tree model with a 1‑year time horizon to estimate the cost effectiveness of sapropterin plus a protein-restricted diet compared with protein-restricted diet alone. The model cohort was split into sapropterin plus diet and diet alone arms and included 3 health states for each group based on symptom severity (mild, moderate, and severe). The company added additional utility weighting for a learning disability (none, mild and moderate). The ERG explained that the 1‑year time horizon was appropriate for the model because of a lack of data for long-term brain damage and because registry data showed that the benefits associated with sapropterin only happen while a person takes sapropterin. Therefore, the model focused on the drivers of the cost effectiveness of sapropterin plus a protein-restricted diet compared with a protein-restricted diet. This included reduction in the costs of a protein-restricted diet, a gain in quality of life from not having to follow a strict diet, and potentially a lower PKU symptom burden for people with PKU. None of these, or any other benefits, were captured for the unborn child in pregnant women with PKU. The committee concluded that the model time horizon is not long enough to capture any beneficial effect on long-term brain damage in people with PKU, and the model is not appropriate to capture the effects of PKU in pregnancy.
# Utility values
## The utility values from the time trade-off study are highly uncertain, but are the only available evidence
Quality of life was not assessed in sapropterin studies because of difficulties in measuring it in people with PKU. The company obtained health state utility values from a time trade-off (TTO) study done in Sweden. It used hypothetical vignettes, which were developed to represent the experience of adults with PKU in the UK and were modified for children with PKU by UK clinicians. The vignettes were valued by a sample of more than 1,000 adults in Sweden from the general population and validated by UK clinical experts (3 specialist adult metabolic physicians, 2 specialist paediatric metabolic physicians, and 1 advanced practitioner in metabolic disease and experienced metabolic dietitian). The ERG and clinical experts acknowledged that quality of life is difficult to measure in people with PKU because of small patient samples and range of disease states. However, the ERG highlighted that the TTO study is not aligned with the NICE reference case, which states that health state measurements should be obtained from patients and valued by the public, whereas hypothetical patient vignettes were used in this study. Despite this, the committee noted that the TTO study is the best available source of utility values for PKU symptom states and, although not necessarily robust, it is the only available evidence.
## The utility reductions estimated for learning disability are not captured appropriately in the company model
The company captured the effect of irreversible long-term brain damage in the form of IQ reductions (learning disability) resulting from PKU symptoms. It used data from a meta-analysis by Waisbren et al. 2007 in children under 12 with PKU having early treatment (the most critical period for brain development and maturation, see section 3.1). It used this to estimate an average 3‑point reduction in IQ per 100 micromole per litre increase in blood Phe levels and applied it to different symptom severities. The company applied the estimated IQ reduction to moderate and severe PKU symptoms to calculate utility reductions associated with long-term brain damage in the model. However, it applied similar utility reductions to people of all ages, despite children being at higher risk of irreversible long-term brain damage because of increased blood Phe levels. Also, the ERG was concerned that the utility reductions may be double counted, because the reductions were already captured for different PKU symptom states (see section 3.15). Furthermore, the committee noted that the long-term effect of brain damage from uncontrolled blood Phe levels cannot be captured in the model because of the 1‑year time horizon. It concluded that the utility reductions estimated for learning disability are not captured appropriately in the company model.
## The company's methods used to calculate health state utility values are inappropriate and make the utility values highly uncertain
The company estimated the health state utility values for people with PKU by applying utility reductions because of a learning disability, utility reductions because of PKU symptoms and utility reductions because of protein-restricted diet to the baseline utility values of people without PKU or a learning disability. The estimated utility values for people with severe PKU and on a protein-restricted diet are very low (less than 0.1 and close to the utility associated with death ) or negative (state worse than death). The ERG highlighted that very low or negative utility values are unusual, but possible. However, the company did not provide any justification for such low values. The clinical experts pointed out that there are people with severe PKU symptoms and an IQ below 50, but with good care provision their quality of life would not be expected to be so poor as to be close to death. However, 1 patient expert confirmed that they are aware of a patient with severe symptoms and a learning disability who has communicated that they wish to die on several occasions. Even so, the committee was not persuaded that such low values would be typical of the patient population. In addition to the extremely low values, the committee was concerned that the company chose to subtract the different utility reductions from baseline under the assumption that they are completely independent of each other. The company explained that utility multiplication methods, which would have accounted for relationships between the different elements, were not possible because of the short time horizon of the model. It also confirmed that learning disability was not captured in the TTO study and was considered independent from the rest of the elements. The ERG only included utility reductions because of PKU symptoms and protein-restricted diet in the protein-restricted diet cohort, which the committee also did not consider ideal. The committee concluded that the company's methods used to calculate health state utility values were inappropriate and make the utility values highly uncertain. However, the committee noted that the differences between the company and ERG estimates of utility values in PKU was not a major contributor to the differences in calculated cost effectiveness.
## The company's added utility gains are not justified and are the key drivers of differences between the company and ERG cost-effectiveness estimates
The company included additional utility gains for all patients with mild, moderate or severe symptoms having sapropterin. This was over and above the utility gain from reducing PKU symptoms and relaxing the protein-restricted diet, which were included by the ERG. The company did not explain the reasoning behind this added utility gain. The committee noted that for adults some of the values were counterintuitive, for example the added utility gain was the same for people with mild and severe symptoms but less for people with moderate symptoms. The committee concluded that the added utility values were not explained or justified but were key drivers of the differences between the company and ERG's cost-effectiveness estimates.
## The utility gains modelled by the company for all women of childbearing age are not evidence-based, but could be used as a proxy for maternal anxiety and stress experienced during pregnancy
The company included additional utility gains for all women of childbearing age who have sapropterin, to capture the benefit to the unborn child. The ERG noted that these values are arbitrary, and the company did not give any justification for including them. During the second committee meeting, the company clarified that the additional utility gain for all women of childbearing age represented the anxiety and stress associated with pregnancy and maintaining the lower target Phe levels needed during pregnancy. The ERG recognised that the utility gains included by the company could be used as a proxy for anxiety in pregnancy and that the value used is reasonable but is in the higher range of values. One patient expert indicated that including a higher value would be reasonable when considering that pregnant women with PKU not only have to deal with the stress of pregnancy, but also the worries of miscarriage. The patient and clinical experts added that treatment for PKU in pregnant women could be improved, because they felt the current NHS policy meant pregnant women were having treatment too late (see section 3.2). The committee agreed that with the current NHS policy in place, the effects of uncontrolled Phe levels on the unborn child could be substantial before the woman had access to sapropterin. It considered that the maximum benefit of sapropterin during pregnancy would be obtained by it being available from conception, but this was complicated by the fact that a substantial number of pregnancies are unplanned. The committee concluded that the utility gain suggested by the company could be used as proxy for anxiety in pregnant women, and that ideally sapropterin would be offered as early as possible in the pregnancy.
## The lifelong benefits to the unborn child by reducing Phe levels in the mother could be substantial but are uncounted in the modelling
Although there are known benefits for the pregnant woman having sapropterin that were included in the cost-effectiveness analysis, there are major potential secondary and uncounted benefits to the unborn child. This potential benefit to a second individual, the unborn child, from the pregnant woman having treatment would be achieved through reducing the risk of damage in the uterus from high Phe levels (see section 3.3). During the second committee meeting, a clinical expert highlighted that sapropterin could also help pregnant women cope with the PKU diet, especially if they experience pregnancy symptoms such as morning sickness or hormone changes. Sapropterin could also allow women to tolerate more protein in their diet, which would lead to a better nutritional state and help with the growth and development of the unborn child. The ERG acknowledged that increased blood Phe levels can harm the unborn child, but the extent of lost utility is unclear, as is the effectiveness of sapropterin in reducing the risk of harm. The committee appreciated that avoiding harm to the unborn child was the reasoning behind the stricter recommended Phe levels in pregnancy. But it was not aware of any evidence to estimate the benefit to the unborn child from enhanced Phe level control or greater natural protein consumption from conception to birth. It accepted that this is challenging to model. However, it acknowledged that the risk of high Phe levels on the unborn child during pregnancy is potentially catastrophic and should be avoided if possible. It concluded that the potential lifelong benefits to the unborn child by reducing Phe levels in the mother during pregnancy could be substantial.
# Costs in the economic model
## Doses of 10 mg/kg for children and 12.5 mg/kg for adults have been assumed in the model but, if higher, would have a significant effect on the cost effectiveness of sapropterin
The company used the mean sapropterin dose for children (10 mg/kg) and adults (12.5 mg/kg) from the NHS England Integrated Impact Assessment Report to calculate the costs of sapropterin. The committee noted that because the dose is both weight-related (mg per kg of body weight), and higher in the number of mg per kg in adults than children, the total drug costs would be considerably higher for adults than children. The ERG highlighted that the proposed values may underestimate real-world dosages and costs of sapropterin and were lower than used in the PKUDOS registry. The committee concluded that any escalation above an average dose of 10 mg/kg for children and 12.5 mg/kg for adults would have a significant effect on the cost effectiveness of the treatment.
## The costs of a protein-restricted diet estimated by the company are reasonable, but the cost savings with sapropterin are uncertain
The company estimated the costs of protein-restricted diet food and supplements based on expert advice and averaging the cost of 3 brands. It estimated costs for children under 4, children between 4 and 17, and adults, based on different rates of protein substitute and low-protein food consumption. The committee noted the high annual costs of protein-restricted diet for each group (£10,326 to £15,973). The company suggested that there would be cost savings with sapropterin, based on a 71.2% reduction in the need for low-protein foods and supplements. While the ERG considered that the total costs of protein-restricted diet calculated by the company are reasonable, it did not consider the evidence for a 71.2% reduction to be robust (see section 3.12). The ERG produced 2 scenarios with 0% and 71.2% reductions. The committee noted that sapropterin did not replace the need for diet in most people but had been shown to be effective in combination with a protein restrictive diet in trials. Ideally this would allow people to consume more natural protein, relax the diet to a varying degree and need less low-protein food and supplements. However, the committee concluded that the cost savings related to a reduction in protein-restricted diet are uncertain.
## The costs of long-term brain damage, carers' costs, carer disutilities and comorbidities associated with PKU have not been modelled
Clinical and patient experts highlighted that people with PKU are at risk of long-term brain damage if blood Phe levels are not maintained within target ranges in childhood (see section 3.1). Also, the burden of long-term brain damage in people with PKU is substantial and people are likely to have significant additional care needs (see section 3.13). However, information on long-term brain damage because of PKU is not routinely collected in the NHS. Consultation comments stated that potential long-term brain damage can also happen during adulthood (see section 3.2). The committee was also aware that high levels of Phe levels and the protein-restricted diet may contribute to comorbidities in people with PKU (see section 3.6). In addition to long-term brain damage, comments at consultation highlighted that PKU and managing the PKU diet affects the entire family and can have substantial effects on quality of life and mental health. The patients and clinical experts confirmed during the second committee meeting that both children and adults with PKU have care needs. However, they explained that the level of care varies. Children, as well as adults with disabilities or long-term brain damage caused by high Phe levels in childhood, need the highest levels. Adults are often supported by family, friends, and carers to maintain the PKU diet and deal with PKU symptoms. The committee acknowledged that comorbidities could complicate managing the PKU diet and that caregiving for people with PKU is a burden for families, parents, and partners of people with PKU. However, it had not been presented with any evidence estimating the costs of comorbidities or caregiving, or carer disutility. It concluded that the costs of long-term brain damage after uncontrolled Phe levels in childhood, cost of potential comorbidities, and costs of caregiving and carer disutilities may be substantial and need to be considered. It also concluded that high blood Phe levels in adulthood might lead to long-term brain damage. But, the risk of new irreversible damage is considerably less than in young children and it is not known if sapropterin would prevent late effects in adults. The committee acknowledged that the costs of long-term brain damage, comorbidities, or caregiving for people with PKU are unknown and cannot be included in a model with a 1‑year time horizon.
## The costs of damage to the unborn child in pregnancy may be substantial, but these have not been modelled
The effects of high Phe levels in pregnancy can be severe for the unborn child and lead to significant disability (see section 3.3). The committee noted that the effects of high Phe on the unborn child could have substantial associated NHS costs, which are not captured in the company or ERG analyses. The committee concluded that the costs of damage to the unborn child in maternal PKU syndrome may be substantial. However, these costs are unknown and are not appropriate to include in a model with a 1‑year time horizon.
# Cost-effectiveness estimates
## Because of the potential uncounted benefits, an acceptable ICER is at the higher end of the range of £20,000 to £30,000 per QALY gained
The committee does not use a precise maximum acceptable cost-effectiveness level above which a technology would automatically be defined as not cost effective or below which it would. Given current limitations, NICE considers that it is most appropriate to use a range of levels, that is, below £20,000 per quality adjusted life year (QALY) gained, between £20,000 and £30,000 per QALY gained and over £30,000 per QALY gained. Additionally, consideration of the cost effectiveness of a technology is necessary but is not the only basis for decision making. So, NICE considers technologies in relation to this range of maximum typically acceptable cost-effectiveness levels, such that the influence of other factors on the decision to recommend a technology is greater when the cost-effectiveness estimates are closer to the top of the range. Below a most plausible estimate of £20,000 per QALY gained, the decision to recommend a technology is normally based on the cost-effectiveness estimate and the acceptability of a technology as an effective use of NHS resources. Above a most plausible estimate of £20,000 per QALY gained, the committee's judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of the following factors (as relevant here):
The degree of certainty around the cost-effectiveness estimates. In particular, the committee will be more cautious about recommending a technology when it is less certain about the estimates presented.
Whether there are strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured and may therefore misrepresent the health utility gained.
The innovative nature of the technology.
Aspects that relate to non-health objectives of the NHS.As the cost-effectiveness estimate of an intervention increases in the range of £20,000 to £30,000 per QALY gained, the committee's judgement about the acceptability of the technology as an effective use of NHS resources will make explicit reference to the relevant factors listed above. Above a most plausible estimate of £30,000 per QALY gained, it will need to identify an increasingly stronger case for supporting the technology as an effective use of NHS resources based on the factors listed above. The committee considered that the cost-effectiveness estimates were moderately uncertain, that there were strong reasons to believe that the treatment may have benefits not captured in the modelling. No non-health objectives of the NHS were identified that have not already been discussed in this guidance. Considering these factors and because of the potential uncounted but unquantifiable benefits in this appraisal, the committee agreed that an acceptable ICER would be towards the higher end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained).
## A 10 mg/kg dose in children and 12.5 mg/kg in adults, and a 71.2% reduction in protein-restricted diet are acceptable model inputs, but both assumptions are favourable to the cost-effectiveness estimates
The company's utilities were not considered appropriate for decision making (see section 3.17). The committee expressed a preference for the ERG's approach, which focuses on the main drivers of cost effectiveness. These were: reduction in protein-restricted diet, cost of sapropterin treatment and quality-of-life benefits because of better Phe level control and reduced need for a protein-restricted diet. It was not possible to include some factors in the ERG's calculations because of the structure of the model. The most important factors are preventing permanent damage to children, young people, and unborn babies from poorly controlled Phe levels. The ERG presented 4 scenarios that differ according to combinations of 2 main assumptions: the dose (10 mg/kg for children and 12.5 mg/kg for adults, or 12.7 mg/kg for all) and the reduction in protein-restricted diet (0% or 71.2% reduction). The ICERs cannot be presented here to protect the company's confidential patient access scheme. The committee accepted that there would be some reduction in protein-restricted diet when a person was having sapropterin, but it could not be certain that it would be reduced by 71.2% (see section 3.12). However, given the lack of alternative assumptions, the committee accepted this more optimistic scenario over the 0% alternative as a basis for modelling. The scenarios also differed in dose. The committee accepted that the dose used in the PKUDOS registry would better match the efficacy estimates from the same registry (see section 3.11). Also, the assumption that the lower dose from the NHS England impact assessment report used in the model would have the same efficacy was an assumption, and could be optimistic. The committee concluded that the ERG's scenario, using the lower dose of 10 mg/kg for children and 12.5 mg/kg for adults, and a 71.2% reduction in protein-restricted diet was acceptable. However, 71.2% may be an optimistic assumption and there was an inherent assumption that the 10 mg/kg and 12.5 mg/kg doses had the same efficacy as shown in the registry data, which could also be optimistic.
## There is no cost-effectiveness estimate presented for all ages and there are differences in the modelling for adults and children, so the age groups have been considered separately
The committee was not presented with a cost-effectiveness estimate that included all ages from the company, or the ERG. Given that different doses and different costs are used in the modelling for adults and children the committee concluded that it would consider the age groups separately.
## Sapropterin is likely to be cost effective in children under 18 assuming an average dose of 10 mg/kg
The committee considered the ERG's cost-effectiveness estimates for children under 18 in the scenario presented in section 3.26. Despite concerns about the model structure and the potentially optimistic assumption about reduction in protein-restricted diet, the committee acknowledged that there would be potential unmodelled additional benefits from sapropterin for these patients. These would particularly relate to the prevention of long-term irreversible brain damage in children, which had not been captured in the modelling and could be substantial. It noted that the ICERs for this group are likely to be within what NICE considers a cost-effective use of NHS resources, assuming an average dose of 10 mg/kg is used. In response to consultation, many comments indicated that limiting the dose to 10 mg/kg would lead to the exclusion of children whose PKU only responds to higher doses. In addition, they felt that the dose of sapropterin should be based on individual needs and that clinicians should have flexibility in prescribing sapropterin between 5 mg/kg and 20 mg/kg according to the summary of product characteristics. During the second committee meeting, patient and clinical experts indicated that higher doses of sapropterin up to 20 mg/kg are not needed often, but flexibility in offering higher doses would be useful. Patient experts further emphasised that some children's PKU stabilises on lower doses than 10 mg/kg, while others will need higher doses. So, in practice the average dose is expected to average out at 10 mg/kg. Clinical experts explained that they would start patients with the 10 mg/kg dose but would not immediately raise it because response is not directly related to dose. In fact, 1 clinician advised that they would prescribe the 10 mg/kg dose to start with based on a fixed number of pills and would aim to keep the same number of pills as children grow up and their weight increases. This would be expected to decrease the dose per kg over time. One response to consultation indicated that a fixed dose approach could discriminate against children with disabilities who may be overweight because of their disability and need a consistent dose of sapropterin over time. The clinical experts confirmed that the per kg dose would apply so an overweight person would still have the higher dose they needed on a weight basis, even if limited to 10 mg/kg. One clinical expert emphasised that a robust system and criteria for determining response to sapropterin is needed because this could guide clinicians on whether they should treat PKU with sapropterin until target Phe levels are achieved or go further than this, but the committee considered this to be outside its remit. It noted that the model was highly sensitive to dosage. An analysis using an average dose of 12.7 mg/kg in children resulted in a cost-effectiveness estimate which is above the level that could be considered a cost-effective use of NHS resources, even using the higher end of the typical range. The committee agreed that the dose of sapropterin used in practice could average out, but it questioned whether there were any mechanisms in place to ensure that happens. The NHS England commissioning expert confirmed that no such process is in place. The committee understood that for some children a dose of 10 mg/kg may not be high enough to bring their Phe levels down to reach the target levels, and a higher dose may be needed. The committee concluded that a dose of over 10 mg/kg would be justified in these circumstances based on the expectation that some children would need less than 10 mg/kg as had been stated in a consultation response. It accepted the NHS England impact assessment estimate of an average childhood dose of 10 mg/kg but noted the risk that if this dose was regularly exceeded it could then become cost ineffective for the whole child population. The committee concluded that sapropterin is likely to be cost effective in children under 18 when using an average dose of 10 mg/kg, and that it could recommend higher doses but only when this is shown to be needed to achieve acceptable Phe levels.
## Sapropterin has not been shown to be cost effective in adults with PKU
The committee noted that the both the company's cost-effectiveness analysis for adults, and the ERG's most optimistic scenario (using the adult dose of 12.5 mg/kg and a reduction in protein-restricted diet of 71.2%) resulted in ICERs for adults that were higher than could be considered a cost-effective use of NHS resources, by a very considerable margin. The committee noted that the difference in cost effectiveness in adults and children is largely driven by the drug costs (see section 3.21). This is because the sapropterin dose is based on weight. Therefore, the annual costs of sapropterin are almost 3 times higher in adults than children; but the increases in quality of life for adults do not offset these significant additional costs. Children may have more benefit because they are more likely to avoid lifelong effects of poorly controlled Phe levels, although this was not captured in the model. The committee considered the case of adults with PKU and disabilities. It acknowledged that people with PKU and disabilities have specific care needs, which can incur more costs (see section 3.6) and noted that these were not captured in the modelling. The committee was also aware of the associated comorbidities that people with PKU may experience and that these associated costs and benefits had also not been captured in the model (see section 3.23). It was uncertain how much sapropterin alone could reduce these care needs and comorbidities. However, it agreed that any additional benefits and cost savings would not be enough to lower the very high ICERs for adults to within an acceptable range. It concluded that sapropterin is not a cost-effective use of NHS resources for adults with PKU.
## Sapropterin is not cost effective for the whole PKU population up to age 25, but it is likely to be cost effective between 18 and 21 when the same dose used under 18 is continued
Comments received at consultation indicated that stopping treatment with sapropterin would be disruptive for young adults as they transition from childhood to adulthood, and some areas of England lack of adequate adult services (see section 3.6). The committee acknowledged this and was concerned about stopping sapropterin at this difficult period for young adults. It therefore requested that the ERG do a cost-effectiveness analysis including adults aged 18 to 25 by considering children and young adults aged 0 to 25 as 1 group. The committee appreciated that this would involve including a subpopulation of adults for whom treatment is otherwise not cost effective, and adding this to the average childhood population where the costs were very much lower and the treatment was cost effective. The committee noted that the ICERs for this analysis were above the accepted threshold despite optimistic assumptions included in the analyses, that is, 10 mg/kg dose being as effective as 12.5 mg/kg dose for adults, alongside other factors in the model that are potentially optimistic. It also gave careful consideration to potential wider benefits for young adults that are not captured in the analyses, such as risk of irreversible brain damage, need for carer or parent support, carer quality of life and successful transition into adulthood. However, it recalled that the risk of irreversible brain damage between 18 and 25 is lower than in children because the maximum benefit of keeping Phe levels low is accrued up to 12 years of age (see section 3.1 and section 3.2). Also, the committee acknowledged that some young adults will still need carer and family support and that the PKU diet can affect carer quality of life. However, it noted that these effects are also usually lower compared with children under 18. It entirely understood the difficulties facing young adults having to transition to adult services at a sensitive time in their life and stopping sapropterin at the same time. Overall the committee considered that the additional risks in people aged 18 to 25 are lower than those for people under 18 and are not large enough to bring down the cost-effectiveness estimate into the acceptable range. However, the committee accepted that it would be beneficial if treatment could be continued for a long as possible during final brain maturation and the transition into adulthood and independence at 18. After the third meeting, the committee requested that the ERG do further analyses to explore what age above 18 sapropterin might remain a cost-effective use of NHS resources. Having reviewed this new data, the committee decided that the maximum age it could recommend treatment for was until people reach the age of 22, after which treatment became cost ineffective. These new analyses, as with the analysis up to age 25, assumed an average dose of 10 mg/kg. The committee accepted that not increasing the dose may be suboptimal for some people, but if sapropterin was escalated to the adult dose it would become cost ineffective and would have to be stopped at an earlier age. Keeping the dose the same as when the person was under 18 was considered a better choice and would allow a transition over a 4‑year period to diet alone. The committee therefore concluded that sapropterin is not cost effective for the whole of the PKU population up to age 25. But, extending the treatment to age 21 is likely to be cost effective if the dose that was used under 18 is continued.
## Sapropterin is likely to be cost effective in pregnancy by reducing the risk of maternal PKU syndrome
The company had specifically addressed a subgroup of all women between 18 and 40, defined as childbearing age. As discussed in section 3.19, the company added an additional utility gain to people in this group to capture the benefit of reducing the anxiety and stress during pregnancy. However, the company's cost-effectiveness estimate for all women of childbearing age was above the accepted range considered to be a cost-effective use of NHS resources. The committee noted that the quantified benefits of sapropterin treatment would be accrued by the pregnant woman, but the benefits to the unborn child were potentially greater and were not included in the modelling (see section 3.20). It also considered whether there are any benefits to the unborn child from providing sapropterin before conception and after birth. One clinical expert explained that the mother's nutrition before conception can affect the development of the unborn child. Also, they highlighted that women with PKU give up breastfeeding because of PKU and this can affect the newborn baby's nutrition. However, the committee recalled the challenges raised during the first committee meeting in defining the optimal period of sapropterin treatment before conception and after birth. Also, it was aware that sapropterin 'should not be used during breastfeeding' according to the summary of product characteristics. Therefore, it considered that women with PKU would have to be advised to give up breastfeeding anyway if they were having sapropterin after birth. The committee noted the risk of high maternal Phe levels on the unborn child and that this can have potentially catastrophic consequences. It was also aware that pregnant women with PKU are currently offered sapropterin later than is ideal in their pregnancy under the current NHS policy and that there is an opportunity to provide sapropterin earlier. The committee noted that the effects of high Phe on the unborn child could have substantial associated NHS costs, which would be incurred throughout the child's life and are not captured in the company or ERG analyses. When taking into account the reduction in the risk of maternal PKU syndrome and the potential lifetime benefits to the unborn child, the committee considered that these would bring the cost-effectiveness estimates below the accepted threshold. Therefore, it concluded that sapropterin is likely to be cost effective during pregnancy (from a positive pregnancy test until birth) in women with PKU.
# Equalities
## Recommending sapropterin for certain groups of adults cannot be justified given the cost-effectiveness estimates
The committee understood that some people may have greater difficulty sticking to conventional dietary management of PKU and are at higher risk of being unable to control their phenylalanine levels. Some people may also have difficulty accessing healthcare services. People who face such difficulties include:
people with a learning disability, sensory impairment, or cognitive impairment
autistic people and people with comorbidities such as diabetes and gut disorders
people on low incomes, with lower socioeconomic status or in insecure housing
certain ethnic groups including people who do not speak English and Gypsy, Roma and Traveller communities
people in social care settings
women with PKU who need to establish controlled phenylalanine levels before conception to avoid damage to the unborn baby.The committee considered that a positive recommendation for children and young people until they turn 22, but not for adults, was appropriate based on differing disease risk and cost-effectiveness estimates. Age is a direct indicator of greater likely benefit and lower treatment cost. Additionally, it considered that a positive recommendation for pregnant women with PKU, but not all adults, was also appropriate based on risk to the unborn child and cost-effectiveness estimates. The committee empathised with the needs of all patients with PKU, and especially with the groups suggested above who it accepted might plausibly benefit from treatment to a somewhat greater (but unquantified) extent than the adult population at large. But, while the committee was mindful of the need to seek to reduce inequalities and advance equality of opportunity, given the high ICERs for treatment in the adult population it did not consider that any wider recommendation would be an appropriate use of NHS resources.
# Conclusion
## Sapropterin is recommended, normally at a dose of 10 mg/kg, for people under 18 with PKU for treating HPA that has been shown to respond to sapropterin
Despite the uncertainty around the assumption of reduction in protein-restricted diet (see section 3.12) and taking into account the uncaptured benefits (see section 3.28), the committee concluded that the ICER for children under 18 is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, sapropterin is recommended, normally at a dose of 10 mg/kg, in people under 18 with PKU for treating hyperphenylalaninaemia (HPA) that has been shown to respond to sapropterin. A higher dose should only be used if target blood phenylalanine levels cannot be achieved at 10 mg/kg.
## Sapropterin is recommended for people with PKU aged 18 to 21, at the same dose that was used under 18, for treating HPA that has been shown to respond to sapropterin
Despite the uncertainty around the assumption of reduction in protein-restricted diet (see section 3.12) and taking into account the uncaptured benefits (see section 3.28), the committee concluded that the ICER for young adults aged 18 to 21 is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, sapropterin is recommended in people with PKU aged 18 to 21, at the same dose that was used under 18, or at a maximum dose of 10 mg/kg, for treating HPA that has been shown to respond to sapropterin.
## Sapropterin is not recommended in adults over 21 with PKU for treating HPA that has been shown to respond to sapropterin
The costs of sapropterin are higher in adults than in children, but there is no corresponding increase in quality of life to offset these costs, and there is a lower risk of long-term brain damage in adults. Therefore, sapropterin could not be recommended for adults over 21 because it is not within what NICE considers a cost-effective use of NHS resources.
## The committee explored alternative approaches to age-based recommendations but could not find a better alternative
The committee was aware that age-based recommendations must be objectively justified, and they should be avoided when possible. It considered the justification in this case is the need to secure acceptable cost effectiveness in the interests of the NHS as a whole. Age itself is both an indicator of potentially greater benefit, coupled with lower cost of treatment. The reason for the cost-effectiveness estimates being higher in the over 18 population are explained in this guidance, as are the reasons for having 22 as the age for stopping treatment. The committee explored alternative approaches but could not find any better alternative to this approach.
## Sapropterin is recommended for pregnant women with PKU for treating HPA that has been shown to respond to sapropterin
The committee recognised that pregnant women with PKU needed to be considered differently, particularly taking into account the benefits to the unborn child. The committee concluded that the ICER for pregnant women with PKU is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, sapropterin is recommended for pregnant women with PKU (if treatment is offered during pregnancy, that is, from positive pregnancy test until birth) for treating HPA that has been shown to respond to sapropterin. NICE is aware that a recommendation for use during pregnancy is necessarily only of benefit to people who become pregnant. This is permitted by s.17(6)(a) of the Equality Act 2010.
## Potential future generic products may allow access to sapropterin for all adults with PKU
The committee was disappointed not to have been able to extend the recommendation at least to all young adults aged up to 25, or indeed all adults. However, it was acutely aware of the lack of evidence in this disease area and the limitations of the model, which does not include several factors. It was also aware that the model has a 1‑year time horizon so the long-term benefits and cost savings for people with PKU are unable to be modelled. However, even when considering these additional potential benefits of sapropterin, the price of the drug was too high to allow the ICERs to be considered an acceptable use of NHS resources. The committee was aware that generic products could be available in the near future and hoped these would be priced to allow access to this drug for all adults with PKU. This possibility has not affected the committee's consideration of sapropterin in this appraisal.
|
{'Recommendations': 'Sapropterin is recommended as an option for treating hyperphenylalaninaemia that responds to sapropterin (response as defined in the summary of product characteristics) in people with phenylketonuria (PKU), only if they are:\n\nunder\xa018 and a dose of 10\xa0mg/kg is used, only using a higher dose if target blood phenylalanine levels cannot be achieved at 10\xa0mg/kg\n\naged 18 to 21 inclusive, continuing the dose they were having before turning 18 or at a maximum dose of 10\xa0mg/kg\n\npregnant (from a positive pregnancy test until birth).Sapropterin is recommended only if the company provides it according to the commercial arrangement.\n\nThis recommendation is not intended to affect treatment with sapropterin that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nPKU is an inherited condition that causes raised levels of phenylalanine in the blood. Without treatment, this causes irreversible brain damage in babies and children and can affect brain function in adults. The only treatment for PKU is a diet to manage phenylalanine and overall protein intake (protein-restricted diet) and prescribed supplements. The diet is challenging and time-consuming, so it is difficult for some people to maintain. Sapropterin, plus a protein-restricted diet, is used for people whose PKU has been shown to respond to it. The aim of treatment is to maintain satisfactory blood phenylalanine levels to reduce PKU symptoms and complications, and potentially allow a less restricted diet.\n\nClinical trial evidence compares sapropterin plus a protein-restricted diet with diet alone. It shows that sapropterin effectively reduces blood phenylalanine levels in the short term for people whose PKU has been shown to respond to it, but it is uncertain how well it works in the long term. There is no clinical trial or registry evidence to show how much sapropterin reduces the need for a protein-restricted diet, or how it affects quality of life or brain development.\n\nIn people under\xa018, treatment for PKU is particularly important because of the higher risk of irreversible brain damage to the developing brain. This risk is highest in younger children, particularly up to age\xa012. Sapropterin may reduce the risk of brain damage for these children, but there is no clinical evidence to confirm this, and this potential benefit is not captured in the cost-effectiveness estimates. Taking uncaptured benefits and the clinical evidence into account, cost-effectiveness estimates are acceptable at the upper limit of what NICE considers an acceptable use of NHS resources. Sapropterin is therefore recommended for people under\xa018. The dose for children can be increased above the starting dose of 10\xa0mg/kg, only if target blood phenylalanine levels are not achieved at a dose of 10\xa0mg/kg. So, it is recommended for treating PKU in people under\xa018, normally at a dose of 10\xa0mg/kg.\n\nStopping treatment and relying on diet alone at 18\xa0years old is not clinically ideal. It would benefit young adults if treatment with sapropterin could be continued for as long as possible during final brain development and transition into adulthood. Taking this into account the maximum age at which sapropterin can be considered a cost‑effective use of NHS resources is 21. However, for this use to be cost effective people would need to continue the dose they were having when they were under\xa018. In practice this may mean that some young adults may need more dietary control alongside sapropterin between the ages of 18 and 21 (inclusive) than they would with a higher dose. Sapropterin is recommended for people aged 18 to 21, continuing the dose they were having before turning 18. People who have not had sapropterin before turning 18 can still have it until they turn 22. But the purpose of recommending sapropterin for this age group is to allow more control of phenylalanine levels while transitioning from sapropterin to dietary control alone by age\xa022, when the brain is nearly fully developed.\n\nThe risk of irreversible brain damage reduces with age, particularly after brain development is complete. So the adverse effects of being unable to follow the protein-restricted diet are considerably reduced in adults compared with the risks in childhood. Adults may still gain considerable benefit from sapropterin because of fewer symptoms related to raised phenylalanine levels, without having to follow the protein-restricted diet as strictly. However, these benefits are included in the economic modelling. Also, in adults the weight-based dose together with the higher average mg per kg dose results in costs that are considerably higher than in children, but the benefits are not correspondingly higher for adults. Even taking into account any uncaptured benefits in adults, the cost-effectiveness estimates are substantially higher than what NICE considers an acceptable use of NHS resources. So, it is not recommended for adults after they reach the age of 22.\n\nRaised phenylalanine levels in pregnant women with PKU can cause severe birth defects in their unborn children. This could increase maternal anxiety, with the additional burden of the even more restrictive diet that is needed during pregnancy to maintain the stricter recommended phenylalanine levels. There is not enough evidence to predict how much sapropterin might prevent harm to the unborn child. If the risk of major harm is reduced, which is possible, then there are likely to be major lifelong benefits for the unborn child. The benefits for the pregnant woman with PKU who has the treatment are included in the cost-effectiveness analysis, but benefits for the unborn child have not been included. Taking the benefits for both these individuals into account, the cost-effectiveness estimates are likely to be within what NICE considers acceptable. So, sapropterin is recommended during pregnancy until birth.', 'Information about sapropterin': "# Marketing authorisation indication\n\nSapropterin (Kuvan, BioMarin) is indicated 'for the treatment of hyperphenylalaninaemia (HPA) in adults and paediatric patients of all ages with phenylketonuria (PKU) who have been shown to be responsive to such treatment'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of sapropterin is £597.22 per 30‑tablet pack. Each tablet contains 100\xa0mg sapropterin dihydrochloride (excluding VAT; BNF online, accessed January\xa02021).\n\nThe company has a commercial arrangement. This makes sapropterin available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by BioMarin, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# The condition\n\n## PKU is associated with high blood phenylalanine levels that can lead to irreversible damage to the developing brain\n\nPhenylketonuria (PKU) is a rare, inherited metabolic disorder caused by mutations in the phenylalanine hydroxylase (PAH) gene. Mutations of the PAH gene result in reduced activity of the PAH enzyme, which is responsible for breaking down the amino acid phenylalanine (Phe) to tyrosine. The reduced activity of PAH means that people with PKU are unable or less able to break down Phe, leading to increased levels in the blood. High blood concentrations of Phe are toxic for the brain and can cause irreversible damage during brain development. The European PKU guidelines recommend target blood Phe ranges of 120 to 360\xa0micromoles per litre for children up to age\xa012, and 120 to 600\xa0micromoles per litre for people aged\xa013 and over, recognising the particular risk in children under\xa013. Around 1 in 10,000\xa0babies are diagnosed with PKU in the UK each year and there are currently about 2,000\xa0people with PKU in NHS care in England. Childhood is the most critical period for brain development. Therefore, high Phe concentrations during this period can lead to long-term disability such as a severe learning disability, microcephaly (smaller head size than expected), seizures and tremors, stunted growth, delayed speech and reduced executive function (working memory, flexible thinking, and self-control). To avoid long-term brain effects in children with PKU, current treatment in the NHS consists of a protein-restricted diet and dietary supplements to control blood Phe levels. This diet should be continued as an adult. Clinical experts noted that poor control of blood Phe levels during childhood and the resulting irreversible brain damage can then mean that some adults who have been affected are less able to follow the diet. One patient expert confirmed that there are adults with PKU in the National Society for Phenylketonuria (NSPKU) who have severe symptoms and irreversible brain damage. Clinical experts explained that brain development peaks at around age\xa012. After this, high Phe levels are unlikely to affect IQ. However, young people above this age may still be at some risk of less severe long-term brain damage from high Phe levels, because brain maturation is probably not complete until around age\xa025. The committee concluded that PKU is associated with high blood Phe levels that can lead to irreversible damage to the developing brain.\n\n## High blood Phe levels in adults with PKU can affect the brain but the risk of new irreversible damage is less than in children\n\nIn adults, high Phe concentrations can result in short-term symptoms, which are considered largely reversible by lowering Phe levels through adherence to diet. These include impaired executive function, reduced autonomy, impaired social maturity, difficulty forming relationships and neuropsychiatric symptoms such as depression, anxiety, and inattention. Clinical experts estimate that many adults with PKU find it difficult to maintain good control of blood Phe levels. However, 1 clinical expert noted that from their research many adults with PKU who have had treatment in the NHS have quality of life and academic and employment performance within the normal range. This is despite some evidence of impaired executive function, and some no longer following the diet. The experts noted that timing, duration, and intensity of exposure to high Phe levels in childhood and adolescence determine the severity of symptoms and long-term brain effects experienced by people with PKU. The committee also noted comments received in response to consultation that symptoms experienced by adults with PKU may not be completely reversible when a protein-restricted diet is restarted or adhered to more closely. Also, it was stated that brain development continues beyond the age of\xa018, possibly until 25 or even 30. The clinical experts explained that some neuropsychological outcomes are improved when Phe levels are reduced with diet, which suggests that some of the changes are reversible. While there could be the potential for subtle brain damage to happen between 18 and 25 in people with PKU, there is little evidence to confirm or quantify this. Also, the clinical experts agreed that patients were unlikely to suffer significant or permanent harm by stopping sapropterin treatment at 18 rather than 25. However, patient experts stated that the chronic effects of high Phe levels on the adult brain cannot be ignored or undermined, particularly when they lead to significant damage or deteriorating mental health outcomes such as depression and anxiety. The clinical experts acknowledged that some adults with PKU have brain damage because of high Phe levels, but there is no systematic evidence available to quantify the effects of high Phe on the adult brain or whether damage is irreversible in adults. One clinical expert noted that it is challenging to determine if brain damage is caused by high Phe levels in childhood (when the brain is still developing) or in adulthood. This can be further complicated by non-PKU-related brain damage that can happen because of nutritional deficiencies such as lack of vitamin\xa0B12. However, patient experts highlighted that any treatment that allowed patients to follow a less restricted diet could also alleviate damage from nutritional deficiencies. Another clinical expert stated that the effects of Phe on the brain can differ widely among adults with PKU. For example, some people experience brain effects within a few months of having high Phe levels compared with years for other people, and some people experience brain effects even when Phe levels are not particularly high. The committee accepted that high blood Phe levels in adults can affect the brain and may lead to brain damage. However, because brain development peaks at age\xa012, it concluded that the risk of irreversible damage decreases after that age and is less in adults than in children.\n\n## High blood Phe levels in pregnancy can have harmful effects on the unborn child\n\nIn pregnancy, high blood Phe levels can have harmful effects on the unborn child and lead to abnormal development. These effects include birth defects such as congenital heart disease and heart defects, microcephaly, a learning disability, delayed learning and development, permanent brain damage, low birth weight, miscarriage, attention deficit hyperactivity disorder and autism spectrum disorders, impaired growth and impaired learning ability. Clinical experts explained that the effects of maternal PKU syndrome can be worse than the effects of PKU itself because the unborn child is exposed to high Phe levels which are teratogenic, during a crucial phase of development. The European PKU guidelines recommend pregnant women's Phe levels should stay between 120 and 360\xa0micromoles per litre. Also, the committee heard from the experts that in practice good control of blood Phe levels (below 200\xa0micromoles per litre) should be maintained if possible. This is very challenging to maintain with diet alone. The experts explained that Phe levels should be kept low throughout the whole pregnancy and that every 60\xa0micromoles of Phe per litre over the 360\xa0micromoles per litre target results in about a 3‑point IQ reduction for the unborn child. Dietary measures should ideally be started before conception to avoid congenital effects, but at least at the earliest possible opportunity to avoid harmful effects on the unborn child. Comments received in consultation indicated that women who are trying to become pregnant find achieving the target Phe levels safe for pregnancy very difficult using protein-restricted diet because of the much stricter levels compared with what they are normally used to. Also, women find it difficult to maintain very low Phe levels for long periods of time before becoming pregnant and during pregnancy. As a result, some women are fearful of becoming pregnant or completely stop having intimate or sexual relationships because of worries that they may not be able to cope with the protein-restricted diet during pregnancy and harm their unborn child. At the first committee meeting, a patient expert highlighted that there is an NHS policy in place for providing sapropterin for pregnant women with PKU. The NHS England commissioning expert and the patient expert indicated that the current NHS policy only covers pregnant women with PKU who are unable to establish safe Phe levels for the unborn child (100 to 360\xa0micromoles per litre) on a protein-restricted diet. Only then can they be tested for a response to sapropterin. The experts stated this delay in starting sapropterin can result in the unborn baby being exposed to high Phe levels in the critical phase of early pregnancy before sapropterin is given. The patient and clinical experts highlighted that treatment with sapropterin is started too late in clinical practice because women with PKU must first show that they cannot achieve recommended Phe levels on diet alone. A clinical expert stated that the outcomes for unborn children are much better if blood Phe levels are brought down very early, within the first 6\xa0weeks of pregnancy, before the organs start developing. They stated that in practice this approach is more likely to work when pregnancies are planned, and pre-conception plans can be developed with the woman's metabolic teams. The NHS England commissioning expert agreed that the current NHS policy for sapropterin works better for planned pregnancies than unplanned ones. Patient and clinical experts stated that about half of pregnancies in women with PKU are unplanned, which is similar to the rate seen in the general population. The committee concluded that high blood Phe levels in pregnancy can have harmful effects on the unborn child and this causes tremendous anxiety for many women with PKU. Early control of phenylalanine levels in all pregnancies was desirable to minimise the risk of PKU syndrome in the unborn child, with potential lifelong consequences for the child. The committee noted that the importance of protection of the unborn child had already been recognised by the NHS in NHS England's policy to provide sapropterin for some pregnant women.\n\n# Treatment pathway\n\n## The only treatment option available for people with PKU is a self-managed protein-restricted diet\n\nCurrent clinical management of PKU is through a lifelong protein-restricted diet. This consists of prescribed low-protein and Phe-free medical foods to help reduce natural Phe consumption, and Phe-free amino acid supplements to improve nutrition and prevent nutritional deficiencies. The protein-restricted diet also involves reducing natural protein consumption according to individual Phe tolerance. Clinical experts stated that 80% of people with PKU can tolerate less than 10\xa0grams of protein per day, equal to 1 or 2 slices of bread. To adhere to a protein-restricted diet, people with PKU must avoid foods and drinks containing protein or aspartame, which can be converted into Phe. This includes foods that are rich in protein (for example, meat, fish, dairy products and soya), foods with less natural protein (for example, fruit, vegetables, cereals, flour or pasta) and alcoholic drinks containing protein (for example, beer and stout). People with PKU routinely take blood samples at home, which are then sent to a central laboratory to measure blood Phe levels. A healthcare professional provides blood Phe concentration level results through a telephone consultation and, if necessary, will give advice on adjusting the diet to manage blood Phe concentration levels. The committee concluded that the only treatment option available for people with PKU is a self-managed protein-restricted diet.\n\n## People with PKU and their carers would welcome a treatment that allows a less strict protein-restricted diet\n\nThe primary aim of clinical management and the protein-restricted diet is to prevent irreversible and reversible brain damage by keeping blood Phe concentration levels within the ranges recommended in European guidelines. However, both clinical and patient experts highlighted that people with PKU may be outside recommended Phe ranges. In childhood, the dietary restrictions put great pressure on carers and families because of the constant fear of irreversible damage. Adults can have raised Phe levels because they struggle to adhere to, or have completely stopped, their diet. Clinical experts noted that around 50% of adults with PKU are on a protein-restricted diet. Patient experts explained that being on a strict protein-restricted diet is burdensome and demanding for people with PKU and their carers for several reasons:\n\nThe time-consuming nature of food shopping and meal preparation. Also, the wide range of skills needed to understand food labels, calculate precisely, and weigh the amount of Phe in different foods that can be eaten in each meal, and prepare and cook meals regularly. This can take 2 to 3 times as long as normal and make managing the diet a dominant activity of daily life.\n\nPoor taste and disagreeable smell and texture of low-Phe foods and synthetic protein substitutes. These have to be taken in large volumes 3 to 4 times a day and can cause digestive problems.\n\nCosts of 'free-from' foods and difficulties accessing prescription food because of limits on which low-protein foods can be prescribed, as some are considered luxury items.\n\nProblems such as weight gain resulting from the high carbohydrate content of the protein-restricted diet.At the second committee meeting a clinical expert highlighted research that suggests that 5% of adults with PKU have comorbidities unrelated to PKU such as cystic fibrosis, cancer, type\xa01 diabetes, renal insufficiency and inflammatory bowel disease. This makes sticking to the diet very difficult. It has also been reported that people with PKU are 4 times more likely to have other conditions such as a learning disability, autism spectrum disorder, eating disorders, bipolar and epilepsy than the general population, which also make it harder to follow the diet. Comments received in consultation also advised that a further contribution to overall reduced health is the constraints of a restricted diet on exercise. In particular, the low-protein diet makes it difficult to achieve satiety from food, which leads to many adults reporting high levels of fatigue before and after exercise. This limits people's ability to lead a healthy lifestyle and may account for the higher rates of comorbidities such as diabetes mellitus and ischaemic heart disease. Comments from consultation also indicated that poor housing stability, lower household income and being a member of Gypsy, Roma and Traveller communities could affect people's ability to stick to the PKU diet. Other consultation comments noted that diet can be very expensive even when the cost of low-protein foods and amino acid supplements are not taken into account. For example, people with PKU end up spending more money on protein-free healthier foods and ingredients to keep their diet varied and palatable, to make it easier to stick to. In addition, because of the high sugar content of the PKU diet people also experience teeth issues and need regular dental care, whether that is provided through the NHS or privately. Living arrangements and availability of storage space can also cause difficulties with sticking to the diet. PKU diets involve cooking all meals from scratch so need cooking facilities and equipment, and ample storage for medication, Phe-free foods, amino acid supplements and kitchen equipment. In some cases, this needs as much as an entire room just for storage, but this is not always available when living in small or shared accommodation. The committee understood that carers of children with PKU also report additional difficulties related to diet management. These include strains on their relationships, struggling to get the right support, and having to give up work or working part-time to dedicate more time to diet management. They also need to educate professionals, teachers, other children's parents, their families, and other carers about PKU and the diet restrictions. The known risk of irreversible brain damage if Phe levels are not controlled is a permanent source of stress for parents. The committee concluded that the protein-restricted diet was extremely burdensome and difficult to stick to, and people with PKU and their carers would welcome a treatment that allows a less strict protein-restricted diet.\n\n# Experiences of people with PKU and their carers\n\n## There is a need for a treatment that can reduce Phe levels and give people with PKU and their carers peace of mind\n\nMany adults describe the effects of high Phe levels as 'brain fog', forgetfulness, tiredness, confusion, low mood and feelings of irritability. This can affect their ability to control their diet and maintain appropriate blood Phe levels. Additionally, adults with PKU may find it difficult to juggle work, studies and family commitments with controlling their diet and maintaining Phe levels. Some adults are unable to engage in full-time work because it creates a vicious cycle of less time to control diet and higher Phe levels, leading to reduced ability to focus and organise the diet. In addition, they can have a sense of being dependent on other people for support, feel socially isolated and constantly worry about maintaining their diet (see section\xa03.5). The committee noted that people with PKU have higher rates of comorbidities than the general population. The comorbidities seen more often in adults with PKU are: chronic ischaemic disease, urticaria, oesophageal disorders, gastroesophageal reflux disease, gastritis, anaemia, obesity, asthma, renal insufficiency, eczema, alopecia, osteoporosis, rhinitis, gall bladder disease and kidney calculus. Studies suggest that high Phe levels in people with PKU could be associated with biological mechanisms that increase the risk of chronic diseases. Also, the PKU diet, medical food and nutritional deficiencies because of the PKU diet may also contribute to the increased risk of chronic diseases. Consultation comments reiterated that PKU and the PKU diet have a substantial effect on all aspects of adults' lives. The patient and clinical experts advised that adults with PKU who have the best health outcomes typically have support from family, friends, partners, and carers.Concerns about high blood Phe levels can also affect other groups of people with PKU, some of whom have characteristics protected under the Equality Act 2010. These include:\n\nWomen: PKU can affect women's sexual and reproductive health and choices. In some cases, women completely forego sex because they are afraid of becoming pregnant and accidentally harming their unborn child (see section\xa03.3).\n\nPregnant women: Pregnant women with PKU describe pregnancy as traumatic because of the strictness of the PKU diet and the anxieties and stress of high Phe levels harming their unborn child (see section\xa03.3). Mothers with PKU describe being unable to cope with the pressures of strict dietary management while caring for their child, and experiencing anxiety, depression and inability to focus as a result.\n\nChildren: PKU is very limiting for children, who face isolation and feel restricted in their ability to join social events such as school trips, festivities, travelling, or meals out because of their diet. Children, as well as adults with PKU, frequently experience difficulty with focus, depression or anxiety, disordered eating, digestive problems, headaches, low mood and sadness, feeling tired all the time and being in a heightened emotional state (including aggressiveness, psychosis and paranoia) because of high Phe levels. At the second committee meeting, a patient expert highlighted how vulnerable families often struggle to control their child's Phe levels.\n\nYoung adults: In response to consultation, stakeholders and members of the public did not agree with the draft recommendation to stop sapropterin at 18\xa0years of age. Consultation comments stated that high Phe levels can exacerbate the difficulties that young adults face as they transition from adolescent to adult life. Some young adults are in the process of moving out of their parents' home, undertaking further education, starting jobs, and learning to live independently. All of this can be affected by symptoms of high Phe levels or having to deal with the challenges of organising and maintaining the PKU diet without the support of their parents or carers for the first time. The committee also heard that as young adults transition from child clinical services to adult services, they may have reduced support from metabolic teams. One patient expert gave an example that the clinic her adult children attend is not equipped to support all patients appropriately because it is an add-on to an existing diabetes clinic. One clinical expert indicated that people with PKU may not be well supported in their transition from child to adult services unless they are seen in a big centre. Patient and clinical experts explained this is because some adult clinical services are not well resourced or have the right kitchen space and equipment to support all adults with PKU across the country. However, 1 expert noted that some of the larger metabolic centres did include metabolic kitchens for adults. A clinical expert also highlighted that most adult clinics tend to focus on supporting pregnant women with PKU rather than all adults. The committee appreciated that a recommendation to stop treatment at 18\xa0years of age would mean people have to begin managing Phe levels through diet alone for the first time at that age, which would not be ideal. The committee has recommended treatment until people reach the age of 22, but it could only recommend sapropterin for people aged 18 to 21 (inclusive) at the dose they had when they were under\xa018 (and not escalating to the adult dose). It recognised that for some young adults this may mean the dose they have is considered a tapering dose and so dietary control may still need to increase at age\xa018. However, while that may be challenging it is inevitable for any age-based recommendation, and the committee had no evidence that this would be harder to manage at age\xa018 or 22, rather than at any older age. Also, the reason for the committee's recommendation that treatment should stop at age\xa022, considered as a tapering off of sapropterin from age\xa018, was related to the underlying biology of brain development and diminishing irreversible risk with age, associated with the higher treatment costs in adults. Having examined the options up to age\xa025, 21 was the maximum age that treatment could be considered cost effective.\n\nDisabled adults: High Phe levels in adults with PKU- and non-PKU-related disabilities can lead to severe behavioural problems. At the second committee meeting, 1 clinical expert explained that people with late-treated PKU who have sustained long-term brain damage have a lifespan that is severely reduced by almost 20\xa0years compared with the general population. Patient and clinical experts also highlighted that people with late-treated or untreated PKU have severe behavioural problems, strict food habits or food neophobia. This results in challenges managing the PKU diet and blood Phe levels, additional nursing and care home needs, and other costs. One patient expert confirmed that there are extreme examples of people with PKU who need more care, attention and support because of severe behavioural problems, in some cases even needing to be restrained. The patient expert added that reducing Phe levels in these people would be expected to lead to less challenging care provision and reductions in care plans, need to calculate natural protein 'exchanges' and close supervision of either the person themselves or what they eat. The committee was mindful that some disabilities may mean that adults are less able to adhere to the PKU diet and therefore these people would possibly get more benefit from sapropterin.The committee noted the many personal stories that had been received in response to consultation. It concluded that there is a clear need for a treatment that could reduce Phe levels, allow a less restricted diet, and give people with PKU and their carers peace of mind. However, the appraisal process requires that the costs of the treatment must be taken into consideration in relation to the benefits shown.\n\n## Sapropterin is clinically appropriate and beneficial for people with PKU that responds to sapropterin\n\nSapropterin is a synthetic version of the naturally occurring tetrahydrobiopterin. The marketing authorisation for sapropterin is for adults and children of all ages with PKU that has been shown to be responsive to such treatment. Response to sapropterin is determined by a reduction in blood Phe levels. Blood Phe levels are checked before sapropterin treatment and weekly after starting treatment for 1\xa0month. Response is defined as a reduction in blood Phe levels of at least 30% or achieving blood Phe levels defined for an individual patient by the treating physician. One clinical expert highlighted that there is a need for clearer response criteria to define who would benefit most from sapropterin. Another clinical expert noted that there is a response relationship between sapropterin and the levels of PAH activity and mutations. However, mutation analysis is not routine practice in the UK. The company estimated that 391\xa0people with PKU in England and Wales are eligible, consisting of 366\xa0current patients and an increase of 25\xa0patients with PKU each year. Patient experts advised that adults with PKU who have taken sapropterin report improved day-to-day functioning, particularly concentration and mood. In addition, they were able to resume other activities such as studies or work. Parents of children with PKU report similar benefits in the mood, energy, concentration and behaviour of their children. They also report large increases in natural protein consumption, with children having a wider and more socially normal diet and greater freedom to participate in social activities. In addition, sapropterin also led to health benefits in children. These included increased bodyweight and growth, improvements in gastrointestinal symptoms and fewer mouth ulcers. Carers of people with PKU reported a significant easing of burden of care. This included not needing to prepare special prescribed low phenylalanine foods and being able to delegate childcare to others for the first time. Some carers reported being able to return to work or study, increase working hours, spend more time with other children, and have time for other family responsibilities. At the second committee meeting, an expert stated that using sapropterin could prevent a child being taken into care because it could keep the child's Phe levels within the target range for families struggling to follow the diet. The committee concluded that sapropterin could be highly beneficial for those people with PKU that responds to sapropterin.\n\n# Clinical effectiveness\n\n## The trial evidence shows sapropterin plus protein-restricted diet is clinically effective compared with protein-restricted diet alone\n\nEvidence for the clinical effectiveness of sapropterin plus protein-restricted diet came from several randomised controlled trials (RCTs). These included 3 double-blind studies and 1 open-label study. The number of people in the studies was between 56 and 206 and the RCTs were short, between 6 and 26\xa0weeks. The population included was different across the RCTs according to age, response to sapropterin and blood Phe concentration levels at screening stage. In 3 of the RCTs, sapropterin plus protein-restricted diet was compared with either placebo plus protein-restricted diet or protein-restricted diet alone. Results from the RCTs show that people having treatment with sapropterin plus protein-restricted diet had significantly reduced blood Phe concentration levels and maintained target levels compared with people having diet only. They also increased or maintained their consumption of natural Phe compared with people having treatment with protein-restricted diet. However, none of the RCTs were included in the company model because of their short duration and small sample sizes. The committee agreed that this was appropriate but concluded that the available trial evidence shows that sapropterin in combination with a protein-restricted diet is clinically effective compared with protein-restricted diet alone.\n\n## The PKUDOS registry has evidence for long-term efficacy of sapropterin plus protein-restricted diet for the whole PKU population and is generalisable to the NHS\n\nThe company presented evidence for long-term efficacy of sapropterin from 2\xa0multicentre registries. These are the PKUDOS registry in the US and the KAMPER registry in 8\xa0European countries. The PKUDOS registry enrolled 1,922\xa0people while KAMPER enrolled 576. Follow up was up to 9\xa0years at the time of the most recent interim analyses. KAMPER includes people whose PKU was shown to respond to sapropterin or tetrahydrobiopterin and who were having sapropterin. But it does not provide a comparison with protein-restricted diet alone. In addition, 83.5% of those enrolled in KAMPER were children (under\xa018) and only 16.5% were adults. People were enrolled in the PKUDOS registry if they had blood Phe levels over 360\xa0micromoles per litre and had previously had sapropterin, were currently having sapropterin, or were due to have sapropterin within 90\xa0days of enrolment. In the PKUDOS study 59.1% of people enrolled were children (under\xa018) and 40.8% were adults. The company used data from 191\xa0people who were due to have sapropterin within 90\xa0days to represent the sapropterin plus protein-restricted diet cohort in the economic model. There were 160\xa0people who had previously had sapropterin before enrolling or stopped taking it while in the registry, who were considered to represent the protein-restricted diet cohort. The committee concluded that only the PKUDOS registry provides evidence for long-term efficacy of sapropterin plus protein-restricted diet compared with diet alone in the whole PKU population. One clinical expert highlighted that people included in the PKUDOS registry may differ from adults with PKU in the NHS because of difficulties in obtaining the protein-restricted diet in the US. The committee reasoned that everyone enrolled in the PKUDOS registry, both those on diet alone and those having sapropterin plus diet, would be equally affected by difficulties in obtaining a protein-restricted diet. Therefore, the relative benefit seen would be a fair estimate of the relative benefit that would be seen in the NHS, where both groups would have equal access to the diet. It concluded that people with PKU enrolled in the PKUDOS registry were likely to reflect people with PKU in the NHS.\n\n## The results of the PKUDOS registry are likely to be generalisable to NHS clinical practice\n\nResults from the PKUDOS registry show the proportion of people achieving Phe levels between 120 and 360\xa0micromoles per litre were similar over time for all age groups. Higher proportions of people achieved target Phe levels in the younger age subgroups (under\xa04 and under\xa012) than adults (18 and over). However, the committee noted that this is expected because the target range of 120 to 360\xa0micromoles per litre is for children under\xa012 and the target for adults is up to 600\xa0micromoles per litre. The proportion of people achieving target Phe levels between 120\xa0and 600\xa0micromoles per litre were similar across the under\xa04 and 18\xa0and\xa0over age groups but decreased for the under\xa012 and under\xa018 groups over time. Higher proportions of people achieved target Phe levels between 120 and 600\xa0micromoles per litre in younger age subgroups (under\xa04, under\xa012 and under\xa018) than adults (18 and over). The committee noted that for each target range the numbers of people contributing long-term data at 9\xa0years were small (between 4 and 52\xa0people). It also recalled that people were assigned to age group based on age at registry enrolment. One clinical expert explained that the results should be interpreted in the context of a protein-restricted diet. That is, the baseline proportions of people achieving target Phe levels are based on Phe control with protein-restricted diet alone. Therefore, people taking sapropterin in addition to protein-restricted diet are able to maintain and achieve target Phe levels long-term while increasing natural protein consumption and reducing supplements. The committee concluded that the results of the PKUDOS registry are likely to be generalisable to NHS clinical practice.\n\n## The sapropterin dose used in clinical practice in the UK would be in line with the NHS England impact assessment report for sapropterin\n\nThe company stated that the mean dose of sapropterin for children is 10\xa0mg/kg and the mean dose for adults is 12.5\xa0mg/kg, according to the NHS England Integrated Impact Assessment Report for sapropterin. The committee noted that the total dose given was not just age related but also weight related, that is, per kg body weight. Because average adults have a higher kg weight than the average child, there are 2\xa0factors which result in much higher drug costs for adults than children and mean that the annual drug costs for adults are 3 times higher than for children. The ERG was concerned that the doses of 10\xa0mg/kg and 12.5\xa0mg/kg for children and adults suggested by the company are underestimates of the doses used in clinical practice. In KAMPER, the average sapropterin dose was 12.7\xa0mg/day and this included 83.5% children under\xa018 (see section\xa03.9). In the PKUDOS registry the average dose was 18.7\xa0mg/kg and around 60% of people were under\xa018 (see section\xa03.9). The company indicated that sapropterin dosages in the KAMPER registry were left to the discretion of the treating clinicians, so they reflect clinical practice in the 8\xa0European countries that contribute to the registry. Clinical experts highlighted that European clinical practice is likely to be similar to UK practice. Clinical experts explained that the difference in mean dose between PKUDOS and KAMPER is because clinicians in the US use lower blood Phe targets than in Europe and will use any sapropterin dose necessary to achieve those targets. In contrast, in Europe, target Phe levels and sapropterin response are not well defined and clinicians are more cost-sensitive because they must justify using higher doses of sapropterin. The committee noted that if outcome data from PKUDOS were used, then logically the same dose should be used to ensure the same efficacy. However, the company estimated an average dose for children of 10\xa0mg/kg and 12.5\xa0mg/kg for adults. The committee noted that although this was lower than the average doses in the PKUDOS registry, it corresponds to the doses in the NHS England Integrated Impact Assessment Report for sapropterin. One clinical expert stated that in their experience using between 10\xa0mg/kg and 20\xa0mg/kg resulted in little difference in outcome. Clinical experts further explained that increasing sapropterin dose does not improve efficacy because response to sapropterin primarily depends on the level of PAH activity and mutations, not the dose. They highlighted that people whose PKU responds to sapropterin increase their tolerance to natural Phe consumption by 2 to 4 times, regardless of dose. All clinical experts agreed that it is not just blood Phe levels that are important, but also the amount of natural protein that can be consumed. The committee concluded that the sapropterin dose per kg used in clinical practice in the UK is likely to be in line with the NHS England impact assessment report.\n\n## The estimate of 71.2% reduction in protein-restricted diet is not evidence-based and could be an overestimate\n\nThe company assumed that people taking sapropterin with controlled blood Phe levels can relax their protein-restricted diet with a 71.2% reduction in protein supplements and low-protein food. This is important because savings can offset the costs of sapropterin treatment. The ERG noted that it could not determine the robustness of the methods used to calculate this value. Clinical experts highlighted that some people with PKU who take sapropterin can completely remove protein substitutes from their diet, referencing a forthcoming systematic review. The committee also heard from the company that a study in Netherlands (Evers et al. 2018) has shown that, over 5\xa0years, patients had an average 68% reduction in amino acid supplements. However, 1 clinical expert cautioned that the results of the studies are likely to be influenced by clinical practice and the definition of sapropterin response used in the country of study. For example, in Switzerland it is recommended that only people with PKU that responds very well can have sapropterin. Therefore, everyone who has sapropterin would be expected to completely eliminate protein substitutes. The committee concluded that it seemed likely that people would reduce their protein-restricted diet, but it could not be sure that the reduction would be as high as 71.2%.\n\n## Long-term brain damage happening in childhood is an important aspect of PKU\n\nIrreversible brain damage in people with PKU can manifest as:\n\nlower IQ score compared with people without PKU or unaffected relatives\n\nclinically relevant neuropsychological impairments (about 25% of people with PKU)\n\nminor neurological symptoms such as tremor, brisk lower limb reflexes, mild motor impairment (20% to 40% of people with PKU). Additional care needs for people with PKU and long-term brain damage can include: additional blood Phe monitoring, hospital appointments and telephone contacts by health professionals, possible hospital admissions, education, health and care plans for learning needs, additional teacher and teaching assistant time to supervise protein substitutes (for all children with PKU), use of home support workers and possible involvement of safeguarding and social services such as referral to early help services for people with very poor phenylalanine control (according to European PKU guidelines). However, information is not routinely collected on long-term brain damage because of PKU, or the number of children referred to early help services and social services, and the costs involved. The committee concluded that long-term brain damage because of high Phe levels in childhood is an important aspect of PKU and has a substantial effect on quality of life. However, while there is an expectation that sapropterin would reduce the risk of permanent damage, there is no direct evidence to substantiate or quantify any long-term benefit.\n\n# The company's economic model\n\n## The model time horizon is not long enough to capture any effect of sapropterin on long-term brain damage, and the model is not appropriate to capture the effects of PKU in pregnancy\n\nThe ERG had concerns about the company's original model. So, after technical engagement the company submitted a new decision tree model with a 1‑year time horizon to estimate the cost effectiveness of sapropterin plus a protein-restricted diet compared with protein-restricted diet alone. The model cohort was split into sapropterin plus diet and diet alone arms and included 3\xa0health states for each group based on symptom severity (mild, moderate, and severe). The company added additional utility weighting for a learning disability (none, mild and moderate). The ERG explained that the 1‑year time horizon was appropriate for the model because of a lack of data for long-term brain damage and because registry data showed that the benefits associated with sapropterin only happen while a person takes sapropterin. Therefore, the model focused on the drivers of the cost effectiveness of sapropterin plus a protein-restricted diet compared with a protein-restricted diet. This included reduction in the costs of a protein-restricted diet, a gain in quality of life from not having to follow a strict diet, and potentially a lower PKU symptom burden for people with PKU. None of these, or any other benefits, were captured for the unborn child in pregnant women with PKU. The committee concluded that the model time horizon is not long enough to capture any beneficial effect on long-term brain damage in people with PKU, and the model is not appropriate to capture the effects of PKU in pregnancy.\n\n# Utility values\n\n## The utility values from the time trade-off study are highly uncertain, but are the only available evidence\n\nQuality of life was not assessed in sapropterin studies because of difficulties in measuring it in people with PKU. The company obtained health state utility values from a time trade-off (TTO) study done in Sweden. It used hypothetical vignettes, which were developed to represent the experience of adults with PKU in the UK and were modified for children with PKU by UK clinicians. The vignettes were valued by a sample of more than 1,000\xa0adults in Sweden from the general population and validated by UK clinical experts (3\xa0specialist adult metabolic physicians, 2\xa0specialist paediatric metabolic physicians, and 1\xa0advanced practitioner in metabolic disease and experienced metabolic dietitian). The ERG and clinical experts acknowledged that quality of life is difficult to measure in people with PKU because of small patient samples and range of disease states. However, the ERG highlighted that the TTO study is not aligned with the NICE reference case, which states that health state measurements should be obtained from patients and valued by the public, whereas hypothetical patient vignettes were used in this study. Despite this, the committee noted that the TTO study is the best available source of utility values for PKU symptom states and, although not necessarily robust, it is the only available evidence.\n\n## The utility reductions estimated for learning disability are not captured appropriately in the company model\n\nThe company captured the effect of irreversible long-term brain damage in the form of IQ reductions (learning disability) resulting from PKU symptoms. It used data from a meta-analysis by Waisbren et al. 2007 in children under\xa012 with PKU having early treatment (the most critical period for brain development and maturation, see section\xa03.1). It used this to estimate an average 3‑point reduction in IQ per 100\xa0micromole per litre increase in blood Phe levels and applied it to different symptom severities. The company applied the estimated IQ reduction to moderate and severe PKU symptoms to calculate utility reductions associated with long-term brain damage in the model. However, it applied similar utility reductions to people of all ages, despite children being at higher risk of irreversible long-term brain damage because of increased blood Phe levels. Also, the ERG was concerned that the utility reductions may be double counted, because the reductions were already captured for different PKU symptom states (see section\xa03.15). Furthermore, the committee noted that the long-term effect of brain damage from uncontrolled blood Phe levels cannot be captured in the model because of the 1‑year time horizon. It concluded that the utility reductions estimated for learning disability are not captured appropriately in the company model.\n\n## The company's methods used to calculate health state utility values are inappropriate and make the utility values highly uncertain\n\nThe company estimated the health state utility values for people with PKU by applying utility reductions because of a learning disability, utility reductions because of PKU symptoms and utility reductions because of protein-restricted diet to the baseline utility values of people without PKU or a learning disability. The estimated utility values for people with severe PKU and on a protein-restricted diet are very low (less than 0.1 and close to the utility associated with death ) or negative (state worse than death). The ERG highlighted that very low or negative utility values are unusual, but possible. However, the company did not provide any justification for such low values. The clinical experts pointed out that there are people with severe PKU symptoms and an IQ below\xa050, but with good care provision their quality of life would not be expected to be so poor as to be close to death. However, 1 patient expert confirmed that they are aware of a patient with severe symptoms and a learning disability who has communicated that they wish to die on several occasions. Even so, the committee was not persuaded that such low values would be typical of the patient population. In addition to the extremely low values, the committee was concerned that the company chose to subtract the different utility reductions from baseline under the assumption that they are completely independent of each other. The company explained that utility multiplication methods, which would have accounted for relationships between the different elements, were not possible because of the short time horizon of the model. It also confirmed that learning disability was not captured in the TTO study and was considered independent from the rest of the elements. The ERG only included utility reductions because of PKU symptoms and protein-restricted diet in the protein-restricted diet cohort, which the committee also did not consider ideal. The committee concluded that the company's methods used to calculate health state utility values were inappropriate and make the utility values highly uncertain. However, the committee noted that the differences between the company and ERG estimates of utility values in PKU was not a major contributor to the differences in calculated cost effectiveness.\n\n## The company's added utility gains are not justified and are the key drivers of differences between the company and ERG cost-effectiveness estimates\n\nThe company included additional utility gains for all patients with mild, moderate or severe symptoms having sapropterin. This was over and above the utility gain from reducing PKU symptoms and relaxing the protein-restricted diet, which were included by the ERG. The company did not explain the reasoning behind this added utility gain. The committee noted that for adults some of the values were counterintuitive, for example the added utility gain was the same for people with mild and severe symptoms but less for people with moderate symptoms. The committee concluded that the added utility values were not explained or justified but were key drivers of the differences between the company and ERG's cost-effectiveness estimates.\n\n## The utility gains modelled by the company for all women of childbearing age are not evidence-based, but could be used as a proxy for maternal anxiety and stress experienced during pregnancy\n\nThe company included additional utility gains for all women of childbearing age who have sapropterin, to capture the benefit to the unborn child. The ERG noted that these values are arbitrary, and the company did not give any justification for including them. During the second committee meeting, the company clarified that the additional utility gain for all women of childbearing age represented the anxiety and stress associated with pregnancy and maintaining the lower target Phe levels needed during pregnancy. The ERG recognised that the utility gains included by the company could be used as a proxy for anxiety in pregnancy and that the value used is reasonable but is in the higher range of values. One patient expert indicated that including a higher value would be reasonable when considering that pregnant women with PKU not only have to deal with the stress of pregnancy, but also the worries of miscarriage. The patient and clinical experts added that treatment for PKU in pregnant women could be improved, because they felt the current NHS policy meant pregnant women were having treatment too late (see section\xa03.2). The committee agreed that with the current NHS policy in place, the effects of uncontrolled Phe levels on the unborn child could be substantial before the woman had access to sapropterin. It considered that the maximum benefit of sapropterin during pregnancy would be obtained by it being available from conception, but this was complicated by the fact that a substantial number of pregnancies are unplanned. The committee concluded that the utility gain suggested by the company could be used as proxy for anxiety in pregnant women, and that ideally sapropterin would be offered as early as possible in the pregnancy.\n\n## The lifelong benefits to the unborn child by reducing Phe levels in the mother could be substantial but are uncounted in the modelling\n\nAlthough there are known benefits for the pregnant woman having sapropterin that were included in the cost-effectiveness analysis, there are major potential secondary and uncounted benefits to the unborn child. This potential benefit to a second individual, the unborn child, from the pregnant woman having treatment would be achieved through reducing the risk of damage in the uterus from high Phe levels (see section\xa03.3). During the second committee meeting, a clinical expert highlighted that sapropterin could also help pregnant women cope with the PKU diet, especially if they experience pregnancy symptoms such as morning sickness or hormone changes. Sapropterin could also allow women to tolerate more protein in their diet, which would lead to a better nutritional state and help with the growth and development of the unborn child. The ERG acknowledged that increased blood Phe levels can harm the unborn child, but the extent of lost utility is unclear, as is the effectiveness of sapropterin in reducing the risk of harm. The committee appreciated that avoiding harm to the unborn child was the reasoning behind the stricter recommended Phe levels in pregnancy. But it was not aware of any evidence to estimate the benefit to the unborn child from enhanced Phe level control or greater natural protein consumption from conception to birth. It accepted that this is challenging to model. However, it acknowledged that the risk of high Phe levels on the unborn child during pregnancy is potentially catastrophic and should be avoided if possible. It concluded that the potential lifelong benefits to the unborn child by reducing Phe levels in the mother during pregnancy could be substantial.\n\n# Costs in the economic model\n\n## Doses of 10\xa0mg/kg for children and 12.5\xa0mg/kg for adults have been assumed in the model but, if higher, would have a significant effect on the cost effectiveness of sapropterin\n\nThe company used the mean sapropterin dose for children (10\xa0mg/kg) and adults (12.5\xa0mg/kg) from the NHS England Integrated Impact Assessment Report to calculate the costs of sapropterin. The committee noted that because the dose is both weight-related (mg per kg of body weight), and higher in the number of mg per kg in adults than children, the total drug costs would be considerably higher for adults than children. The ERG highlighted that the proposed values may underestimate real-world dosages and costs of sapropterin and were lower than used in the PKUDOS registry. The committee concluded that any escalation above an average dose of 10\xa0mg/kg for children and 12.5\xa0mg/kg for adults would have a significant effect on the cost effectiveness of the treatment.\n\n## The costs of a protein-restricted diet estimated by the company are reasonable, but the cost savings with sapropterin are uncertain\n\nThe company estimated the costs of protein-restricted diet food and supplements based on expert advice and averaging the cost of 3\xa0brands. It estimated costs for children under\xa04, children between 4 and 17, and adults, based on different rates of protein substitute and low-protein food consumption. The committee noted the high annual costs of protein-restricted diet for each group (£10,326 to £15,973). The company suggested that there would be cost savings with sapropterin, based on a 71.2% reduction in the need for low-protein foods and supplements. While the ERG considered that the total costs of protein-restricted diet calculated by the company are reasonable, it did not consider the evidence for a 71.2% reduction to be robust (see section\xa03.12). The ERG produced 2\xa0scenarios with 0% and 71.2% reductions. The committee noted that sapropterin did not replace the need for diet in most people but had been shown to be effective in combination with a protein restrictive diet in trials. Ideally this would allow people to consume more natural protein, relax the diet to a varying degree and need less low-protein food and supplements. However, the committee concluded that the cost savings related to a reduction in protein-restricted diet are uncertain.\n\n## The costs of long-term brain damage, carers' costs, carer disutilities and comorbidities associated with PKU have not been modelled\n\nClinical and patient experts highlighted that people with PKU are at risk of long-term brain damage if blood Phe levels are not maintained within target ranges in childhood (see section\xa03.1). Also, the burden of long-term brain damage in people with PKU is substantial and people are likely to have significant additional care needs (see section\xa03.13). However, information on long-term brain damage because of PKU is not routinely collected in the NHS. Consultation comments stated that potential long-term brain damage can also happen during adulthood (see section\xa03.2). The committee was also aware that high levels of Phe levels and the protein-restricted diet may contribute to comorbidities in people with PKU (see section\xa03.6). In addition to long-term brain damage, comments at consultation highlighted that PKU and managing the PKU diet affects the entire family and can have substantial effects on quality of life and mental health. The patients and clinical experts confirmed during the second committee meeting that both children and adults with PKU have care needs. However, they explained that the level of care varies. Children, as well as adults with disabilities or long-term brain damage caused by high Phe levels in childhood, need the highest levels. Adults are often supported by family, friends, and carers to maintain the PKU diet and deal with PKU symptoms. The committee acknowledged that comorbidities could complicate managing the PKU diet and that caregiving for people with PKU is a burden for families, parents, and partners of people with PKU. However, it had not been presented with any evidence estimating the costs of comorbidities or caregiving, or carer disutility. It concluded that the costs of long-term brain damage after uncontrolled Phe levels in childhood, cost of potential comorbidities, and costs of caregiving and carer disutilities may be substantial and need to be considered. It also concluded that high blood Phe levels in adulthood might lead to long-term brain damage. But, the risk of new irreversible damage is considerably less than in young children and it is not known if sapropterin would prevent late effects in adults. The committee acknowledged that the costs of long-term brain damage, comorbidities, or caregiving for people with PKU are unknown and cannot be included in a model with a 1‑year time horizon.\n\n## The costs of damage to the unborn child in pregnancy may be substantial, but these have not been modelled\n\nThe effects of high Phe levels in pregnancy can be severe for the unborn child and lead to significant disability (see section\xa03.3). The committee noted that the effects of high Phe on the unborn child could have substantial associated NHS costs, which are not captured in the company or ERG analyses. The committee concluded that the costs of damage to the unborn child in maternal PKU syndrome may be substantial. However, these costs are unknown and are not appropriate to include in a model with a 1‑year time horizon.\n\n# Cost-effectiveness estimates\n\n## Because of the potential uncounted benefits, an acceptable ICER is at the higher end of the range of £20,000 to £30,000 per QALY gained\n\nThe committee does not use a precise maximum acceptable cost-effectiveness level above which a technology would automatically be defined as not cost effective or below which it would. Given current limitations, NICE considers that it is most appropriate to use a range of levels, that is, below £20,000 per quality adjusted life year (QALY) gained, between £20,000 and £30,000 per QALY gained and over £30,000 per QALY gained. Additionally, consideration of the cost effectiveness of a technology is necessary but is not the only basis for decision making. So, NICE considers technologies in relation to this range of maximum typically acceptable cost-effectiveness levels, such that the influence of other factors on the decision to recommend a technology is greater when the cost-effectiveness estimates are closer to the top of the range. Below a most plausible estimate of £20,000 per QALY gained, the decision to recommend a technology is normally based on the cost-effectiveness estimate and the acceptability of a technology as an effective use of NHS resources. Above a most plausible estimate of £20,000 per QALY gained, the committee's judgements about the acceptability of the technology as an effective use of NHS resources will specifically take account of the following factors (as relevant here):\n\nThe degree of certainty around the cost-effectiveness estimates. In particular, the committee will be more cautious about recommending a technology when it is less certain about the estimates presented.\n\nWhether there are strong reasons to indicate that the assessment of the change in health-related quality of life has been inadequately captured and may therefore misrepresent the health utility gained.\n\nThe innovative nature of the technology.\n\nAspects that relate to non-health objectives of the NHS.As the cost-effectiveness estimate of an intervention increases in the range of £20,000 to £30,000 per QALY gained, the committee's judgement about the acceptability of the technology as an effective use of NHS resources will make explicit reference to the relevant factors listed above. Above a most plausible estimate of £30,000 per QALY gained, it will need to identify an increasingly stronger case for supporting the technology as an effective use of NHS resources based on the factors listed above. The committee considered that the cost-effectiveness estimates were moderately uncertain, that there were strong reasons to believe that the treatment may have benefits not captured in the modelling. No non-health objectives of the NHS were identified that have not already been discussed in this guidance. Considering these factors and because of the potential uncounted but unquantifiable benefits in this appraisal, the committee agreed that an acceptable ICER would be towards the higher end of the range normally considered a cost-effective use of NHS resources (£20,000 to £30,000 per QALY gained).\n\n## A 10\xa0mg/kg dose in children and 12.5\xa0mg/kg in adults, and a 71.2% reduction in protein-restricted diet are acceptable model inputs, but both assumptions are favourable to the cost-effectiveness estimates\n\nThe company's utilities were not considered appropriate for decision making (see section\xa03.17). The committee expressed a preference for the ERG's approach, which focuses on the main drivers of cost effectiveness. These were: reduction in protein-restricted diet, cost of sapropterin treatment and quality-of-life benefits because of better Phe level control and reduced need for a protein-restricted diet. It was not possible to include some factors in the ERG's calculations because of the structure of the model. The most important factors are preventing permanent damage to children, young people, and unborn babies from poorly controlled Phe levels. The ERG presented 4\xa0scenarios that differ according to combinations of 2 main assumptions: the dose (10\xa0mg/kg for children and 12.5\xa0mg/kg for adults, or 12.7\xa0mg/kg for all) and the reduction in protein-restricted diet (0% or 71.2% reduction). The ICERs cannot be presented here to protect the company's confidential patient access scheme. The committee accepted that there would be some reduction in protein-restricted diet when a person was having sapropterin, but it could not be certain that it would be reduced by 71.2% (see section\xa03.12). However, given the lack of alternative assumptions, the committee accepted this more optimistic scenario over the 0% alternative as a basis for modelling. The scenarios also differed in dose. The committee accepted that the dose used in the PKUDOS registry would better match the efficacy estimates from the same registry (see section\xa03.11). Also, the assumption that the lower dose from the NHS England impact assessment report used in the model would have the same efficacy was an assumption, and could be optimistic. The committee concluded that the ERG's scenario, using the lower dose of 10\xa0mg/kg for children and 12.5\xa0mg/kg for adults, and a 71.2% reduction in protein-restricted diet was acceptable. However, 71.2% may be an optimistic assumption and there was an inherent assumption that the 10\xa0mg/kg and 12.5\xa0mg/kg doses had the same efficacy as shown in the registry data, which could also be optimistic.\n\n## There is no cost-effectiveness estimate presented for all ages and there are differences in the modelling for adults and children, so the age groups have been considered separately\n\nThe committee was not presented with a cost-effectiveness estimate that included all ages from the company, or the ERG. Given that different doses and different costs are used in the modelling for adults and children the committee concluded that it would consider the age groups separately.\n\n## Sapropterin is likely to be cost effective in children under\xa018 assuming an average dose of 10\xa0mg/kg\n\nThe committee considered the ERG's cost-effectiveness estimates for children under\xa018 in the scenario presented in section\xa03.26. Despite concerns about the model structure and the potentially optimistic assumption about reduction in protein-restricted diet, the committee acknowledged that there would be potential unmodelled additional benefits from sapropterin for these patients. These would particularly relate to the prevention of long-term irreversible brain damage in children, which had not been captured in the modelling and could be substantial. It noted that the ICERs for this group are likely to be within what NICE considers a cost-effective use of NHS resources, assuming an average dose of 10\xa0mg/kg is used. In response to consultation, many comments indicated that limiting the dose to 10\xa0mg/kg would lead to the exclusion of children whose PKU only responds to higher doses. In addition, they felt that the dose of sapropterin should be based on individual needs and that clinicians should have flexibility in prescribing sapropterin between 5\xa0mg/kg and 20\xa0mg/kg according to the summary of product characteristics. During the second committee meeting, patient and clinical experts indicated that higher doses of sapropterin up to 20\xa0mg/kg are not needed often, but flexibility in offering higher doses would be useful. Patient experts further emphasised that some children's PKU stabilises on lower doses than 10\xa0mg/kg, while others will need higher doses. So, in practice the average dose is expected to average out at 10\xa0mg/kg. Clinical experts explained that they would start patients with the 10\xa0mg/kg dose but would not immediately raise it because response is not directly related to dose. In fact, 1 clinician advised that they would prescribe the 10\xa0mg/kg dose to start with based on a fixed number of pills and would aim to keep the same number of pills as children grow up and their weight increases. This would be expected to decrease the dose per kg over time. One response to consultation indicated that a fixed dose approach could discriminate against children with disabilities who may be overweight because of their disability and need a consistent dose of sapropterin over time. The clinical experts confirmed that the per kg dose would apply so an overweight person would still have the higher dose they needed on a weight basis, even if limited to 10\xa0mg/kg. One clinical expert emphasised that a robust system and criteria for determining response to sapropterin is needed because this could guide clinicians on whether they should treat PKU with sapropterin until target Phe levels are achieved or go further than this, but the committee considered this to be outside its remit. It noted that the model was highly sensitive to dosage. An analysis using an average dose of 12.7\xa0mg/kg in children resulted in a cost-effectiveness estimate which is above the level that could be considered a cost-effective use of NHS resources, even using the higher end of the typical range. The committee agreed that the dose of sapropterin used in practice could average out, but it questioned whether there were any mechanisms in place to ensure that happens. The NHS England commissioning expert confirmed that no such process is in place. The committee understood that for some children a dose of 10\xa0mg/kg may not be high enough to bring their Phe levels down to reach the target levels, and a higher dose may be needed. The committee concluded that a dose of over 10\xa0mg/kg would be justified in these circumstances based on the expectation that some children would need less than 10\xa0mg/kg as had been stated in a consultation response. It accepted the NHS England impact assessment estimate of an average childhood dose of 10\xa0mg/kg but noted the risk that if this dose was regularly exceeded it could then become cost ineffective for the whole child population. The committee concluded that sapropterin is likely to be cost effective in children under\xa018 when using an average dose of 10\xa0mg/kg, and that it could recommend higher doses but only when this is shown to be needed to achieve acceptable Phe levels.\n\n## Sapropterin has not been shown to be cost effective in adults with PKU\n\nThe committee noted that the both the company's cost-effectiveness analysis for adults, and the ERG's most optimistic scenario (using the adult dose of 12.5\xa0mg/kg and a reduction in protein-restricted diet of 71.2%) resulted in ICERs for adults that were higher than could be considered a cost-effective use of NHS resources, by a very considerable margin. The committee noted that the difference in cost effectiveness in adults and children is largely driven by the drug costs (see section\xa03.21). This is because the sapropterin dose is based on weight. Therefore, the annual costs of sapropterin are almost 3 times higher in adults than children; but the increases in quality of life for adults do not offset these significant additional costs. Children may have more benefit because they are more likely to avoid lifelong effects of poorly controlled Phe levels, although this was not captured in the model. The committee considered the case of adults with PKU and disabilities. It acknowledged that people with PKU and disabilities have specific care needs, which can incur more costs (see section\xa03.6) and noted that these were not captured in the modelling. The committee was also aware of the associated comorbidities that people with PKU may experience and that these associated costs and benefits had also not been captured in the model (see section\xa03.23). It was uncertain how much sapropterin alone could reduce these care needs and comorbidities. However, it agreed that any additional benefits and cost savings would not be enough to lower the very high ICERs for adults to within an acceptable range. It concluded that sapropterin is not a cost-effective use of NHS resources for adults with PKU.\n\n## Sapropterin is not cost effective for the whole PKU population up to age\xa025, but it is likely to be cost effective between 18 and 21 when the same dose used under 18 is continued\n\nComments received at consultation indicated that stopping treatment with sapropterin would be disruptive for young adults as they transition from childhood to adulthood, and some areas of England lack of adequate adult services (see section\xa03.6). The committee acknowledged this and was concerned about stopping sapropterin at this difficult period for young adults. It therefore requested that the ERG do a cost-effectiveness analysis including adults aged 18 to 25 by considering children and young adults aged 0 to 25 as 1\xa0group. The committee appreciated that this would involve including a subpopulation of adults for whom treatment is otherwise not cost effective, and adding this to the average childhood population where the costs were very much lower and the treatment was cost effective. The committee noted that the ICERs for this analysis were above the accepted threshold despite optimistic assumptions included in the analyses, that is, 10\xa0mg/kg dose being as effective as 12.5\xa0mg/kg dose for adults, alongside other factors in the model that are potentially optimistic. It also gave careful consideration to potential wider benefits for young adults that are not captured in the analyses, such as risk of irreversible brain damage, need for carer or parent support, carer quality of life and successful transition into adulthood. However, it recalled that the risk of irreversible brain damage between 18 and 25 is lower than in children because the maximum benefit of keeping Phe levels low is accrued up to 12\xa0years of age (see section 3.1 and section 3.2). Also, the committee acknowledged that some young adults will still need carer and family support and that the PKU diet can affect carer quality of life. However, it noted that these effects are also usually lower compared with children under\xa018. It entirely understood the difficulties facing young adults having to transition to adult services at a sensitive time in their life and stopping sapropterin at the same time. Overall the committee considered that the additional risks in people aged 18 to 25 are lower than those for people under\xa018 and are not large enough to bring down the cost-effectiveness estimate into the acceptable range. However, the committee accepted that it would be beneficial if treatment could be continued for a long as possible during final brain maturation and the transition into adulthood and independence at 18. After the third meeting, the committee requested that the ERG do further analyses to explore what age above\xa018 sapropterin might remain a cost-effective use of NHS resources. Having reviewed this new data, the committee decided that the maximum age it could recommend treatment for was until people reach the age of 22, after which treatment became cost ineffective. These new analyses, as with the analysis up to age\xa025, assumed an average dose of 10\xa0mg/kg. The committee accepted that not increasing the dose may be suboptimal for some people, but if sapropterin was escalated to the adult dose it would become cost ineffective and would have to be stopped at an earlier age. Keeping the dose the same as when the person was under\xa018 was considered a better choice and would allow a transition over a 4‑year period to diet alone. The committee therefore concluded that sapropterin is not cost effective for the whole of the PKU population up to age\xa025. But, extending the treatment to age\xa021 is likely to be cost effective if the dose that was used under\xa018 is continued.\n\n## Sapropterin is likely to be cost effective in pregnancy by reducing the risk of maternal PKU syndrome\n\nThe company had specifically addressed a subgroup of all women between 18 and 40, defined as childbearing age. As discussed in section\xa03.19, the company added an additional utility gain to people in this group to capture the benefit of reducing the anxiety and stress during pregnancy. However, the company's cost-effectiveness estimate for all women of childbearing age was above the accepted range considered to be a cost-effective use of NHS resources. The committee noted that the quantified benefits of sapropterin treatment would be accrued by the pregnant woman, but the benefits to the unborn child were potentially greater and were not included in the modelling (see section\xa03.20). It also considered whether there are any benefits to the unborn child from providing sapropterin before conception and after birth. One clinical expert explained that the mother's nutrition before conception can affect the development of the unborn child. Also, they highlighted that women with PKU give up breastfeeding because of PKU and this can affect the newborn baby's nutrition. However, the committee recalled the challenges raised during the first committee meeting in defining the optimal period of sapropterin treatment before conception and after birth. Also, it was aware that sapropterin 'should not be used during breastfeeding' according to the summary of product characteristics. Therefore, it considered that women with PKU would have to be advised to give up breastfeeding anyway if they were having sapropterin after birth. The committee noted the risk of high maternal Phe levels on the unborn child and that this can have potentially catastrophic consequences. It was also aware that pregnant women with PKU are currently offered sapropterin later than is ideal in their pregnancy under the current NHS policy and that there is an opportunity to provide sapropterin earlier. The committee noted that the effects of high Phe on the unborn child could have substantial associated NHS costs, which would be incurred throughout the child's life and are not captured in the company or ERG analyses. When taking into account the reduction in the risk of maternal PKU syndrome and the potential lifetime benefits to the unborn child, the committee considered that these would bring the cost-effectiveness estimates below the accepted threshold. Therefore, it concluded that sapropterin is likely to be cost effective during pregnancy (from a positive pregnancy test until birth) in women with PKU.\n\n# Equalities\n\n## Recommending sapropterin for certain groups of adults cannot be justified given the cost-effectiveness estimates\n\nThe committee understood that some people may have greater difficulty sticking to conventional dietary management of PKU and are at higher risk of being unable to control their phenylalanine levels. Some people may also have difficulty accessing healthcare services. People who face such difficulties include:\n\npeople with a learning disability, sensory impairment, or cognitive impairment\n\nautistic people and people with comorbidities such as diabetes and gut disorders\n\npeople on low incomes, with lower socioeconomic status or in insecure housing\n\ncertain ethnic groups including people who do not speak English and Gypsy, Roma and Traveller communities\n\npeople in social care settings\n\nwomen with PKU who need to establish controlled phenylalanine levels before conception to avoid damage to the unborn baby.The committee considered that a positive recommendation for children and young people until they turn 22, but not for adults, was appropriate based on differing disease risk and cost-effectiveness estimates. Age is a direct indicator of greater likely benefit and lower treatment cost. Additionally, it considered that a positive recommendation for pregnant women with PKU, but not all adults, was also appropriate based on risk to the unborn child and cost-effectiveness estimates. The committee empathised with the needs of all patients with PKU, and especially with the groups suggested above who it accepted might plausibly benefit from treatment to a somewhat greater (but unquantified) extent than the adult population at large. But, while the committee was mindful of the need to seek to reduce inequalities and advance equality of opportunity, given the high ICERs for treatment in the adult population it did not consider that any wider recommendation would be an appropriate use of NHS resources.\n\n# Conclusion\n\n## Sapropterin is recommended, normally at a dose of 10\xa0mg/kg, for people under\xa018 with PKU for treating HPA that has been shown to respond to sapropterin\n\nDespite the uncertainty around the assumption of reduction in protein-restricted diet (see section\xa03.12) and taking into account the uncaptured benefits (see section\xa03.28), the committee concluded that the ICER for children under\xa018 is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, sapropterin is recommended, normally at a dose of 10\xa0mg/kg, in people under\xa018 with PKU for treating hyperphenylalaninaemia (HPA) that has been shown to respond to sapropterin. A higher dose should only be used if target blood phenylalanine levels cannot be achieved at 10\xa0mg/kg.\n\n## Sapropterin is recommended for people with PKU aged 18 to 21, at the same dose that was used under\xa018, for treating HPA that has been shown to respond to sapropterin\n\nDespite the uncertainty around the assumption of reduction in protein-restricted diet (see section\xa03.12) and taking into account the uncaptured benefits (see section\xa03.28), the committee concluded that the ICER for young adults aged 18 to 21 is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, sapropterin is recommended in people with PKU aged 18 to 21, at the same dose that was used under\xa018, or at a maximum dose of 10\xa0mg/kg, for treating HPA that has been shown to respond to sapropterin.\n\n## Sapropterin is not recommended in adults over 21 with PKU for treating HPA that has been shown to respond to sapropterin\n\nThe costs of sapropterin are higher in adults than in children, but there is no corresponding increase in quality of life to offset these costs, and there is a lower risk of long-term brain damage in adults. Therefore, sapropterin could not be recommended for adults over 21 because it is not within what NICE considers a cost-effective use of NHS resources.\n\n## The committee explored alternative approaches to age-based recommendations but could not find a better alternative\n\nThe committee was aware that age-based recommendations must be objectively justified, and they should be avoided when possible. It considered the justification in this case is the need to secure acceptable cost effectiveness in the interests of the NHS as a whole. Age itself is both an indicator of potentially greater benefit, coupled with lower cost of treatment. The reason for the cost-effectiveness estimates being higher in the over\xa018 population are explained in this guidance, as are the reasons for having 22 as the age for stopping treatment. The committee explored alternative approaches but could not find any better alternative to this approach.\n\n## Sapropterin is recommended for pregnant women with PKU for treating HPA that has been shown to respond to sapropterin\n\nThe committee recognised that pregnant women with PKU needed to be considered differently, particularly taking into account the benefits to the unborn child. The committee concluded that the ICER for pregnant women with PKU is likely to be within what NICE considers a cost-effective use of NHS resources. Therefore, sapropterin is recommended for pregnant women with PKU (if treatment is offered during pregnancy, that is, from positive pregnancy test until birth) for treating HPA that has been shown to respond to sapropterin. NICE is aware that a recommendation for use during pregnancy is necessarily only of benefit to people who become pregnant. This is permitted by s.17(6)(a) of the Equality Act 2010.\n\n## Potential future generic products may allow access to sapropterin for all adults with PKU\n\nThe committee was disappointed not to have been able to extend the recommendation at least to all young adults aged up to 25, or indeed all adults. However, it was acutely aware of the lack of evidence in this disease area and the limitations of the model, which does not include several factors. It was also aware that the model has a 1‑year time horizon so the long-term benefits and cost savings for people with PKU are unable to be modelled. However, even when considering these additional potential benefits of sapropterin, the price of the drug was too high to allow the ICERs to be considered an acceptable use of NHS resources. The committee was aware that generic products could be available in the near future and hoped these would be priced to allow access to this drug for all adults with PKU. This possibility has not affected the committee's consideration of sapropterin in this appraisal."}
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https://www.nice.org.uk/guidance/ta729
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Evidence-based recommendations on sapropterin for treating hyperphenylalaninaemia in phenylketonuria.
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0d6a3dcb75dda7e0343d1d5a306b31a922109335
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nice
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Abemaciclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy
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Abemaciclib with fulvestrant for treating hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy
Evidence-based recommendations on abemaciclib (Verzenios) with fulvestrant for hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy in adults.
# Recommendations
Abemaciclib plus fulvestrant is recommended as an option for treating hormone receptor‑positive, human epidermal growth factor receptor 2 (HER2)‑negative, locally advanced or metastatic breast cancer in adults who have had endocrine therapy only if:
exemestane plus everolimus is the most appropriate alternative to a cyclin‑dependent kinase 4 and 6 (CDK 4/6) inhibitor and
the company provides abemaciclib according to the commercial arrangement.
Why the committee made these recommendations
This appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for abemaciclib plus fulvestrant for treating hormone receptor‑positive, HER2‑negative, locally advanced or metastatic breast cancer after endocrine therapy (see NICE's technology appraisal guidance 579). The usual treatment for this is exemestane plus everolimus.
Additional clinical trial evidence was collected while abemaciclib plus fulvestrant was in the Cancer Drugs Fund. Some people in the trial had a higher dose of abemaciclib than would normally be used, so it is uncertain how well the drug will work in clinical practice. But an indirect comparison suggests that people having abemaciclib plus fulvestrant have longer before their disease progresses and live longer than people having exemestane plus everolimus.
The cost‑effectiveness estimates vary. But, even with the uncertainty around the estimates, abemaciclib plus fulvestrant is considered a cost‑effective use of NHS resources. Therefore, abemaciclib plus fulvestrant is recommended.# Information about abemaciclib with fulvestrant
# Marketing authorisation indication
Abemaciclib (Verzenios, Eli Lilly) is indicated 'for the treatment of women with hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2)‑negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine‑based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone‑releasing hormone (LHRH) agonist'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price for abemaciclib is £2,950 per 28 day cycle (excluding VAT; BNF online, accessed January 2021):
for 150 mg tablets: £1,475 per 28 tablet pack or £2,950 per 56 tablet pack
for 100 mg tablets: £1,475 per 28 tablet pack or £2,950 per 56 tablet pack
for 50 mg tablets: £1,475 per 28 tablet pack or £2,950 per 56 tablet pack of 50 mg tablets.
The list price for fulvestrant is £522.41 for two 250 mg/5 ml prefilled syringes of solution for injection (excluding VAT; BNF online, accessed January 2021). This equates to £1,044.82 for the first cycle, and £522.41 for subsequent cycles.
The company has a commercial arrangement. This makes abemaciclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.
# Clinical pathway
## There is a population who could benefit from abemaciclib plus fulvestrant
Advanced breast cancer is an incurable condition and the aim of treatment is to delay progression and extend survival. Most people who do not need urgent treatment with chemotherapy are offered endocrine therapy as initial treatment, in line with NICE's guideline on advanced breast cancer. After initial endocrine therapy, people can have exemestane plus everolimus before progressing to chemotherapy, though adverse events limit the use of everolimus. People who have had endocrine therapy and are eligible for exemestane plus everolimus as their next treatment may instead have a cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor (that is, abemaciclib, palbociclib or ribociclib) with fulvestrant. Ribociclib is recommended for routine use (see NICE's technology appraisal guidance on ribociclib) and palbociclib is available through the Cancer Drugs Fund (see NICE's technology appraisal guidance on palbociclib). In NICE's original technology appraisal guidance on abemaciclib for advanced disease after endocrine therapy, the clinical experts explained that CDK4/6 inhibitors would not be used twice in the treatment pathway. This is because of the potential for tumours becoming resistant. The clinical experts said that the main groups of people who could benefit from abemaciclib plus fulvestrant after previous endocrine treatment for advanced disease are those whose:
disease has progressed on or within 12 months of neoadjuvant or adjuvant endocrine therapy (because they are not eligible for CDK4/6 inhibitors with aromatase inhibitors in the NHS)
advanced disease is progressing slowly on endocrine therapy.They noted that, through the Cancer Drugs Fund, abemaciclib plus fulvestrant could also be offered later in the treatment pathway, after chemotherapy. The patient experts explained that it would be a backwards step if abemaciclib plus fulvestrant was not recommended for routine commissioning. The committee concluded that there is a population who could benefit from abemaciclib plus fulvestrant being routinely available.
## People with advanced breast cancer value the option of a CDK4/6 inhibitor after endocrine therapy
The patient and clinical experts explained that CDK4/6 inhibitors were welcomed by patients because they can delay disease progression and so delay or avoid the need for chemotherapy. This is desirable because chemotherapy side effects can substantially reduce quality of life. Extending survival can give people valuable extra time with family and friends. The patient experts explained that exemestane plus everolimus, the comparator, was poorly tolerated and used for only a small number of people, because it has similar effects to chemotherapy on quality of life. They also noted that although abemaciclib plus fulvestrant can cause debilitating diarrhoea and other side effects, these can usually be managed and are preferable to having chemotherapy. The committee concluded that having a choice of treatments that extend how long people live before their disease progresses and delay chemotherapy is valued by people who have already had endocrine therapy.
## Having multiple CDK4/6 inhibitor options allows side effects to be managed, which is of value to patients
The patient and clinical experts explained that they would prefer having a choice of CDK4/6 inhibitors. This is because they have different side effect profiles so it would give people the option to change to a different treatment if needed. The patient experts stated that managing side effects through having different CDK4/6 inhibitor options is crucial to maintaining quality of life and is of great importance to patients. One clinical expert further noted that ribociclib and palbociclib can cause dose limiting neutropenia. This means that people having treatment need a week off treatment after 3 weeks, and need up-to-date blood counts to continue treatment. Abemaciclib is continuously dosed, is associated with less neutropenia and there is less of a need for up-to-date blood counts. However, it may cause diarrhoea that needs treatment. The clinical expert said that timing of treatment and managing adverse effects are factors to consider when choosing between CDK4/6 inhibitors. The committee concluded that having multiple CDK4/6 inhibitors allows adverse effects to be managed, which is of value to patients.
# Clinical evidence
## Data from the group starting on the licensed dose is the most relevant
MONARCH 2 is a phase 3, multinational, placebo‑controlled, double‑blind trial. It enrolled women with hormone receptor‑positive, human epidermal growth factor receptor 2 (HER2)‑negative locally advanced or metastatic breast cancer whose disease had progressed on neoadjuvant or adjuvant endocrine therapy, either:
months or less from the end of adjuvant endocrine therapy or
while having first‑line endocrine therapy for metastatic disease.Because of adverse events (diarrhoea), a protocol amendment was made after 26.6% of patients were enrolled. This changed the starting dose of abemaciclib from 200 mg to 150 mg, both twice per day. At the time of the protocol amendment anyone still on 200 mg had their dose reduced to 150 mg. In total, 446 patients were enrolled to have abemaciclib plus fulvestrant (pre‑amendment: n=121, postamendment: n=325) and 223 to have placebo plus fulvestrant (pre-amendment: n=57, postamendment: n=166). The company considered it appropriate for the committee to use data from the full trial population in its decision making, rather than from separate pre- and postamendment groups, which the ERG preferred. The overall survival estimate in the full trial population differed from those for the separate pre- and postamendment groups (see more about survival in the trial in section 3.5). The company provided:
the median dose for the pre- and postamendment groups
the median time to dose reduction and
results from an interaction test after adjustments for multiplicity and baseline confounding factors.These were marked confidential and cannot be reported here. The company did not believe that the outcomes in the subgroups could reasonably be attributed to the starting dose used. It stated that starting dose is not a treatment effect modifier. The company further explained that worldwide regulators have used data that included all patients. Also, clinical advice to the company was that it would be inappropriate to analyse the groups separately, or exclude patients recruited before the amendment. The clinical experts said that they would not expect abemaciclib's efficacy to differ between the 150 mg and 200 mg doses, and clinical outcomes with the 2 doses were similar in practice. A larger study of 150 mg abemaciclib plus an aromatase inhibitor, which is now routinely commissioned, showed clear efficacy at that dosage. They also explained that a higher dose for a short time at the start of treatment was not likely to confer a long‑term advantage, because CDK4/6 inhibitors work through long‑term suppression of tumour growth. The ERG noted that the 150 mg starting dose is in the marketing authorisation and will be used in clinical practice. The ERG acknowledged that the sample size calculations for the postamendment population were based on safety outcomes rather than progression‑free survival. However, the ERG maintained that the postamendment population was sufficiently powered to detect differences in clinical outcomes and provided methodologically robust results. The committee did not consider that the company's interaction test was sufficient evidence to support using the full trial population. It also noted that the patient baseline characteristics provided by the company were not likely to account for the difference in efficacy reported, but that not all characteristics were provided. The committee considered that the ERG had made a coherent case that the postamendment group was methodologically robust. It discussed whether there was a genuine dose effect, or whether differences between the groups were because of chance or baseline imbalances. It considered whether the differences might be greater in the placebo arm than in the treatment arm, but this was difficult to determine. The committee understood the challenges of interpreting the MONARCH 2 clinical data given the protocol amendment. It preferred to use the postamendment group data to estimate the clinical effectiveness of abemaciclib plus fulvestrant because:
this group included only people who had the licensed dose of abemaciclib
the trial was redesigned and adequately powered to detect a treatment effect for progression‑free survival in this group.The committee considered that excluding data from the 26.6% of people who were recruited before the amendment was justified. It concluded that data from those recruited after the amendment, who started on the licensed dose, was more relevant than data for the full trial population
# Clinical effectiveness
## Abemaciclib plus fulvestrant improves progression-free survival but the improvement in overall survival is less certain
In the original NICE technology appraisal guidance for abemaciclib plus fulvestrant, abemaciclib plus fulvestrant statistically significantly improved progression‑free survival compared with placebo plus fulvestrant in the full trial population. The effect of abemaciclib plus fulvestrant on overall survival was not statistically significant. It was concluded that more mature data from MONARCH 2 could resolve uncertainty around this outcome. More data from MONARCH 2 has now been collected and was analysed in June 2019. This analysis included an additional 28 months of data compared with the original appraisal:
Median follow up was 47.70 months.
Median progression‑free survival was 16.87 months with abemaciclib plus fulvestrant compared with 9.27 months with placebo plus fulvestrant.
Median overall survival was 46.72 months for abemaciclib plus fulvestrant and 37.25 months for placebo plus fulvestrant.This analysis confirmed the previous progression‑free survival results for the full trial population. The progression‑free survival data for the pre- and postamendment groups was marked academic in confidence and cannot be reported here. The updated data from MONARCH 2 also showed that abemaciclib plus fulvestrant statistically significantly improved overall survival compared with placebo plus fulvestrant (hazard ratio 0.757, 95% confidence interval 0.606 to 0.945). The improvement in overall survival was smaller in the postamendment group than in the pre‑amendment group. The company explained that it was likely that any differences in outcomes seen when comparing subgroups were the result of differences in baseline characteristics between subgroups, and random variation. The committee agreed that the explanation for the different clinical results between the pre- and postamendment groups was uncertain. This was because it could not be determined if the differences were because of a genuine dose effect, or because of chance or baseline imbalances. It concluded that abemaciclib plus fulvestrant improved progression‑free survival compared with placebo plus fulvestrant. But the improvement in overall survival was less certain in the postamendment group data, which the committee preferred (see more about the group data in section 3.4).
## Clinical-effectiveness data from the SACT dataset is less relevant than the updated MONARCH 2 data for decision making
The company presented observational data from the systemic anticancer therapy (SACT) dataset for 876 people who had abemaciclib plus fulvestrant through the Cancer Drugs Fund:
Median follow up was only 4.4 months, because more mature MONARCH 2 data became available, which was suitable for decision making.
Median treatment duration was 10.2 months and the median overall survival was not reached.
Fewer people were alive at 12 months after having abemaciclib plus fulvestrant compared with those who had treatment in MONARCH 2.The SACT data was not included in the company's economic analysis. The company explained that the difference in the number of people alive at 12 months may be because people having treatment through the Cancer Drugs Fund were generally older and frailer than those in MONARCH 2. Also, they may have had treatment later in the pathway or when the disease was more advanced. The company also highlighted that people with visceral disease may be offered abemaciclib plus fulvestrant over other CDK4/6 inhibitors because there is evidence of efficacy for this group. The company noted that the data was immature, and since there was no comparator arm, the relative efficacy was unknown. The ERG agreed with most points and considered that MONARCH 2 was the more robust evidence source. The clinical experts agreed that the relative efficacy from MONARCH 2 was generalisable and provided the most robust clinical evidence for decision making. The committee concluded that the SACT data was too immature and that clinical‑effectiveness data from MONARCH 2 was more appropriate for decision making.
# Indirect treatment comparison
## Data from the postamendment group from MONARCH 2 should be used to estimate the clinical effectiveness of abemaciclib plus fulvestrant
There were no trials directly comparing abemaciclib plus fulvestrant with exemestane plus everolimus. So, the company presented fractional polynomial network meta‑analyses in line with the committee's preferred assumptions. These meta‑analyses incorporated the updated MONARCH 2 data for progression‑free and overall survival for the full trial population. The results were based on the postamendment group at technical engagement, at the ERG's request. The fractional polynomial network meta‑analyses for progression‑free and overall survival showed that abemaciclib plus fulvestrant improved progression‑free and overall survival compared with exemestane plus everolimus for the full trial population. The ERG highlighted that progression‑free and overall survival with abemaciclib plus fulvestrant were shorter in the postamendment group than for the full trial population. Considering the heterogeneity and uncertainty across the network, the size of these benefits was uncertain. The committee recalled its preference to use the postamendment group data to estimate the clinical effectiveness of abemaciclib with fulvestrant (see more about the group data in section 3.4). It concluded that data from the postamendment group from MONARCH 2 should be used to estimate the clinical effectiveness of abemaciclib plus fulvestrant compared with exemestane plus everolimus.
# The company's economic model
## Data from the postamendment group from MONARCH 2 should be used to estimate the cost effectiveness of abemaciclib plus fulvestrant
In its original submission, the company used fractional polynomial network meta‑analysis data that used the full trial population from MONARCH 2 in its economic model for progression‑free and overall survival (see more about the meta-analyses in section 3.7). The ERG was concerned that this may have overestimated the treatment effects compared with clinical practice. It emphasised that this did not fully reflect the licensed dose that would be used in clinical practice. The ERG preferred to use fractional polynomial network meta‑analysis data that used the postamendment group from MONARCH 2 in the economic model. The committee was aware that the results of the model were highly sensitive to the choice of clinical‑effectiveness data for abemaciclib plus fulvestrant. Also, using only the postamendment group data gave a much lower estimate of abemaciclib's clinical effectiveness compared with using the full trial population data. The committee was not persuaded that the company's approach was more appropriate, since the trial was redesigned and powered to detect an effect in progression‑free survival in the postamendment group (see more about the group data in section 3.4). After consultation, the company used the committee's preferred postamendment data in its network meta‑analysis and revised base case to estimate the clinical- and cost effectiveness of abemaciclib plus fulvestrant compared with exemestane plus everolimus. Although the company used the postamendment data in its revised base case, it maintained the view that the full trial population was also relevant when considering the efficacy of abemaciclib plus fulvestrant. The committee concluded that the postamendment group data should be used in the economic model. But it recognised that the cost‑effectiveness results were highly sensitive to the choice of clinical‑effectiveness data for abemaciclib plus fulvestrant. It further concluded that the uncertainty surrounding why the clinical‑effectiveness estimates differed in the postamendment and full trial population should be considered in its decision making.
## The estimates of time to treatment discontinuation for abemaciclib from the MONARCH trial period and over 10 years are plausible
In the original NICE technology appraisal guidance for abemaciclib with fulvestrant there was uncertainty around how long people had treatment with abemaciclib plus fulvestrant (time to treatment discontinuation). Also, the company's model underestimated the treatment duration and therefore the treatment costs of abemaciclib plus fulvestrant. This was because the company used data from the full trial population, including those who were enrolled before the protocol amendment. Also, people on the lower dose stopped treatment less often because they had fewer adverse events. During that appraisal, the committee suggested that discontinuation should be estimated using the postamendment group data. This was because it used the lower licensed dose with fewer side effects, and more data could be collected on this outcome. In the current appraisal, the company used updated discontinuation data from the postamendment group as requested. It calculated a hazard ratio to apply to the progression‑free survival curve for abemaciclib with fulvestrant to extrapolate the time on treatment beyond the available trial data from MONARCH 2. This hazard ratio was estimated by comparing the area under the extrapolated time to treatment discontinuation and progression-free survival curves from MONARCH 2 (a restricted means analysis). It presented hazard ratios estimated at 3 time points: the period covering the trial, 10 years (which it used in its base case) and over a person's lifetime. These hazard ratios are commercial in confidence and cannot be reported here. The ERG preferred the hazard ratio estimated over the trial period but considered the 10‑year estimate was plausible. The committee concluded that both the company's and ERG's preferred hazard ratio estimates were plausible and took these into account in its decision making.
## The time to stopping everolimus is likely to lie between that based on clinical opinion and that based on BOLERO‑2 data in the modelling
In the original NICE technology appraisal guidance for abemaciclib with fulvestrant, the company estimated a hazard ratio for the time to treatment discontinuation for exemestane plus everolimus compared with progression‑free survival. To do this, it used the median progression‑free survival and median time to treatment discontinuation from BOLERO‑2, a phase 3 randomised controlled trial comparing exemestane plus everolimus with exemestane alone. The hazard ratio was applied to the progression‑free survival curve for exemestane plus everolimus generated by the fractional polynomial network meta‑analysis, which was used in the model. The company's original model was not set up to model time to treatment discontinuation for exemestane and everolimus separately. This was a limitation because people tended to stop treatment with everolimus because of adverse events but continued to have exemestane. This affected cost effectiveness because everolimus is considerably more expensive than exemestane. In this appraisal, the ERG preferred to use a different approach. It calculated a hazard ratio and applied it to the fractional polynomial network meta‑analysis progression‑free survival curve to estimate the exemestane plus everolimus time to treatment discontinuation curve in the model. Three approaches to estimate the hazard ratio were presented by the company:
An estimate based on the clinical opinion from the Cancer Drugs Fund review of NICE's technology appraisal guidance on ribociclib with fulvestrant for hormone receptor‑positive, HER2‑negative, advanced breast cancer – this assumed that 20% of people stopped everolimus after 6 months, and 70% of those remaining on treatment had a dose reduction (10 mg to 5 mg) but continued exemestane until disease progression.
An approach using median data from BOLERO‑2, which resulted in a hazard ratio of 1.58: the committee noted that the same approach had also been presented in the Cancer Drugs Fund review of ribociclib plus fulvestrant.
A restricted mean analysis of BOLERO‑2 data to determine the progression‑free survival and time to treatment discontinuation relationship: This assumed that progression‑free survival and time to treatment discontinuation could be fitted on an exponential curve. The hazard ratio is commercial in confidence and cannot be reported here but the company stated that it was between the estimated hazard ratios for the other approaches.The committee noted that the committee for the ribociclib plus fulvestrant appraisal stated its preference for the time to stopping everolimus hazard ratio as likely lying between clinical expert opinion and the BOLERO‑2 scenario. The clinical experts for the current appraisal noted that the change at 6 months seemed implausible because people would be more likely to stop gradually throughout the first 6 months. The committee said that BOLERO‑2 data, even if not based on individual patient data from the trial, was preferable to the opinion of 1 clinician. It also noted, however, that BOLERO‑2 is an old trial in which many had pretreatment with chemotherapy. So, how well this would correlate with treatment times for people having exemestane plus everolimus in current clinical practice is unknown. The committee noted the ERG's concerns that the company's third restricted means approach was flawed because it assumed that the data could be fitted on an exponential curve and could underestimate the hazard ratio. The committee was aware that the results of the economic model were highly sensitive to the assumption used to estimate the time to treatment discontinuation for exemestane plus everolimus. It concluded that time on treatment was likely to be between that estimated by the clinicians and that estimated by median data from BOLERO‑2.
## Fulvestrant administration costs can be reduced in primary care but it is not appropriate to assume this
The company's base case used administration costs for fulvestrant based on costs used in NICE's technology appraisal guidance on ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. The company also did a scenario analysis in which it assumed that fulvestrant injections are administered by community nurse specialists at a lower cost rather than in secondary care. It also excluded the initial loading dose. The clinical experts agreed that this does not happen in clinical practice, and people have fulvestrant in secondary care. The committee concluded that the company's base‑case assumptions on fulvestrant administration cost were appropriate.
# Cost-effectiveness results
## Abemaciclib plus fulvestrant is likely to be cost effective
The cost‑effectiveness estimates included patient access scheme discounts for abemaciclib and everolimus, and the NHS England price for generic fulvestrant. The exact incremental cost‑effectiveness ratio (ICER) cannot be reported here because of the confidential prices. The committee noted that there were a range of ICERs presented, which reflected the range of assumptions about time on treatment with abemaciclib plus fulvestrant and exemestane plus everolimus. It considered these plausible. The range included estimates that were above and below £30,000 quality‑adjusted life years (QALYs) gained. Also, the ICER was primarily driven by assumptions about time on treatment with exemestane plus everolimus. The committee noted:
There were ICERs within the range that NICE considers a cost‑effective use of NHS resources, although there were uncertainties in the cost‑effectiveness estimates.
The patient and clinical expert statements that abemaciclib plus fulvestrant is needed as an alternative to the other available CDK4/6 inhibitors, ribociclib and palbociclib, to allow management of adverse effects.
The scope of the Cancer Drugs Fund review was to compare abemaciclib plus fulvestrant with exemestane plus everolimus in practice. However, since the availability of CDK4/6 inhibitors, the use of exemestane plus everolimus is decreasing, and abemaciclib will be largely used as an alternative to ribociclib and palbociclib. Therefore, the overall cost to the NHS was not expected to increase if abemaciclib were recommended.
The postamendment data was appropriate for decision making. However, there was unresolved uncertainty as to why the estimates of overall survival were lower using postamendment data to those using data from the full trial population from MONARCH 2. If the full trial data had been used to estimate overall survival in the economic model, the ICER would have been expected to be lower.The committee concluded that, taking into account the uncertainty around the ICER estimates, it was plausible that abemaciclib plus fulvestrant could be a cost‑effective use of NHS resources. It also concluded that the treatment met a need for an alternative CDK4/6 inhibitor treatment.
# Other factors
NICE's advice about life‑extending treatments for people with a short life expectancy did not apply.
# Conclusion
## Abemaciclib plus fulvestrant is recommended for routine use
The committee noted that some combinations of plausible assumptions gave ICERs over £30,000 per QALY gained. However, these combinations did not take into account the difference in survival between the whole trial and postamendment populations. Taking into account the whole trial population, survival estimates would have lowered the ICERs. Noting the uncertainty introduced by this issue, the committee concluded that it was likely that abemaciclib plus fulvestrant was a cost‑effective use of NHS resources. It also concluded that it met a need for an alternative CDK4/6 inhibitor treatment. It therefore recommended abemaciclib plus fulvestrant for treating hormone receptor‑positive, HER2‑negative, locally advanced or metastatic breast cancer in adults who have had endocrine therapy, only if exemestane plus everolimus is the most appropriate alternative to a CDK4/6 inhibitor.
|
{'Recommendations': "Abemaciclib plus fulvestrant is recommended as an option for treating hormone receptor‑positive, human epidermal growth factor receptor\xa02 (HER2)‑negative, locally advanced or metastatic breast cancer in adults who have had endocrine therapy only if:\n\nexemestane plus everolimus is the most appropriate alternative to a cyclin‑dependent kinase\xa04 and\xa06 (CDK 4/6) inhibitor and\n\nthe company provides abemaciclib according to the commercial arrangement.\n\nWhy the committee made these recommendations\n\nThis appraisal reviews the additional evidence collected as part of the Cancer Drugs Fund managed access agreement for abemaciclib plus fulvestrant for treating hormone receptor‑positive, HER2‑negative, locally advanced or metastatic breast cancer after endocrine therapy (see NICE's technology appraisal guidance 579). The usual treatment for this is exemestane plus everolimus.\n\nAdditional clinical trial evidence was collected while abemaciclib plus fulvestrant was in the Cancer Drugs Fund. Some people in the trial had a higher dose of abemaciclib than would normally be used, so it is uncertain how well the drug will work in clinical practice. But an indirect comparison suggests that people having abemaciclib plus fulvestrant have longer before their disease progresses and live longer than people having exemestane plus everolimus.\n\nThe cost‑effectiveness estimates vary. But, even with the uncertainty around the estimates, abemaciclib plus fulvestrant is considered a cost‑effective use of NHS resources. Therefore, abemaciclib plus fulvestrant is recommended.", 'Information about abemaciclib with fulvestrant': "# Marketing authorisation indication\n\nAbemaciclib (Verzenios, Eli Lilly) is indicated 'for the treatment of women with hormone receptor (HR) positive, human epidermal growth factor receptor\xa02 (HER2)‑negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine‑based therapy, or in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinising hormone‑releasing hormone (LHRH) agonist'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price for abemaciclib is £2,950 per 28 day cycle (excluding VAT; BNF online, accessed January\xa02021):\n\nfor 150\xa0mg tablets: £1,475 per 28\xa0tablet pack or £2,950 per 56\xa0tablet pack\n\nfor 100\xa0mg tablets: £1,475 per 28\xa0tablet pack or £2,950 per 56\xa0tablet pack\n\nfor 50\xa0mg tablets: £1,475 per 28\xa0tablet pack or £2,950 per 56\xa0tablet pack of 50\xa0mg tablets.\n\nThe list price for fulvestrant is £522.41 for two 250\xa0mg/5\xa0ml prefilled syringes of solution for injection (excluding VAT; BNF online, accessed January\xa02021). This equates to £1,044.82 for the first cycle, and £522.41 for subsequent cycles.\n\nThe company has a commercial arrangement. This makes abemaciclib available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by Eli Lilly, a review of this submission by the evidence review group (ERG) and responses from stakeholders. See the committee papers for full details of the evidence.\n\n# Clinical pathway\n\n## There is a population who could benefit from abemaciclib plus fulvestrant\n\nAdvanced breast cancer is an incurable condition and the aim of treatment is to delay progression and extend survival. Most people who do not need urgent treatment with chemotherapy are offered endocrine therapy as initial treatment, in line with NICE's guideline on advanced breast cancer. After initial endocrine therapy, people can have exemestane plus everolimus before progressing to chemotherapy, though adverse events limit the use of everolimus. People who have had endocrine therapy and are eligible for exemestane plus everolimus as their next treatment may instead have a cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor (that is, abemaciclib, palbociclib or ribociclib) with fulvestrant. Ribociclib is recommended for routine use (see NICE's technology appraisal guidance on ribociclib) and palbociclib is available through the Cancer Drugs Fund (see NICE's technology appraisal guidance on palbociclib). In NICE's original technology appraisal guidance on abemaciclib for advanced disease after endocrine therapy, the clinical experts explained that CDK4/6 inhibitors would not be used twice in the treatment pathway. This is because of the potential for tumours becoming resistant. The clinical experts said that the main groups of people who could benefit from abemaciclib plus fulvestrant after previous endocrine treatment for advanced disease are those whose:\n\ndisease has progressed on or within 12 months of neoadjuvant or adjuvant endocrine therapy (because they are not eligible for CDK4/6 inhibitors with aromatase inhibitors in the NHS)\n\nadvanced disease is progressing slowly on endocrine therapy.They noted that, through the Cancer Drugs Fund, abemaciclib plus fulvestrant could also be offered later in the treatment pathway, after chemotherapy. The patient experts explained that it would be a backwards step if abemaciclib plus fulvestrant was not recommended for routine commissioning. The committee concluded that there is a population who could benefit from abemaciclib plus fulvestrant being routinely available.\n\n## People with advanced breast cancer value the option of a CDK4/6 inhibitor after endocrine therapy\n\nThe patient and clinical experts explained that CDK4/6 inhibitors were welcomed by patients because they can delay disease progression and so delay or avoid the need for chemotherapy. This is desirable because chemotherapy side effects can substantially reduce quality of life. Extending survival can give people valuable extra time with family and friends. The patient experts explained that exemestane plus everolimus, the comparator, was poorly tolerated and used for only a small number of people, because it has similar effects to chemotherapy on quality of life. They also noted that although abemaciclib plus fulvestrant can cause debilitating diarrhoea and other side effects, these can usually be managed and are preferable to having chemotherapy. The committee concluded that having a choice of treatments that extend how long people live before their disease progresses and delay chemotherapy is valued by people who have already had endocrine therapy.\n\n## Having multiple CDK4/6 inhibitor options allows side effects to be managed, which is of value to patients\n\nThe patient and clinical experts explained that they would prefer having a choice of CDK4/6 inhibitors. This is because they have different side effect profiles so it would give people the option to change to a different treatment if needed. The patient experts stated that managing side effects through having different CDK4/6 inhibitor options is crucial to maintaining quality of life and is of great importance to patients. One clinical expert further noted that ribociclib and palbociclib can cause dose limiting neutropenia. This means that people having treatment need a week off treatment after 3 weeks, and need up-to-date blood counts to continue treatment. Abemaciclib is continuously dosed, is associated with less neutropenia and there is less of a need for up-to-date blood counts. However, it may cause diarrhoea that needs treatment. The clinical expert said that timing of treatment and managing adverse effects are factors to consider when choosing between CDK4/6 inhibitors. The committee concluded that having multiple CDK4/6 inhibitors allows adverse effects to be managed, which is of value to patients.\n\n# Clinical evidence\n\n## Data from the group starting on the licensed dose is the most relevant\n\nMONARCH\xa02 is a phase\xa03, multinational, placebo‑controlled, double‑blind trial. It enrolled women with hormone receptor‑positive, human epidermal growth factor receptor\xa02 (HER2)‑negative locally advanced or metastatic breast cancer whose disease had progressed on neoadjuvant or adjuvant endocrine therapy, either:\n\nmonths or less from the end of adjuvant endocrine therapy or\n\nwhile having first‑line endocrine therapy for metastatic disease.Because of adverse events (diarrhoea), a protocol amendment was made after 26.6% of patients were enrolled. This changed the starting dose of abemaciclib from 200\xa0mg to 150\xa0mg, both twice per day. At the time of the protocol amendment anyone still on 200\xa0mg had their dose reduced to 150\xa0mg. In total, 446\xa0patients were enrolled to have abemaciclib plus fulvestrant (pre‑amendment: n=121, postamendment: n=325) and 223 to have placebo plus fulvestrant (pre-amendment: n=57, postamendment: n=166). The company considered it appropriate for the committee to use data from the full trial population in its decision making, rather than from separate pre- and postamendment groups, which the ERG preferred. The overall survival estimate in the full trial population differed from those for the separate pre- and postamendment groups (see more about survival in the trial in section\xa03.5). The company provided:\n\nthe median dose for the pre- and postamendment groups\n\nthe median time to dose reduction and\n\nresults from an interaction test after adjustments for multiplicity and baseline confounding factors.These were marked confidential and cannot be reported here. The company did not believe that the outcomes in the subgroups could reasonably be attributed to the starting dose used. It stated that starting dose is not a treatment effect modifier. The company further explained that worldwide regulators have used data that included all patients. Also, clinical advice to the company was that it would be inappropriate to analyse the groups separately, or exclude patients recruited before the amendment. The clinical experts said that they would not expect abemaciclib's efficacy to differ between the 150\xa0mg and 200\xa0mg doses, and clinical outcomes with the 2\xa0doses were similar in practice. A larger study of 150\xa0mg abemaciclib plus an aromatase inhibitor, which is now routinely commissioned, showed clear efficacy at that dosage. They also explained that a higher dose for a short time at the start of treatment was not likely to confer a long‑term advantage, because CDK4/6 inhibitors work through long‑term suppression of tumour growth. The ERG noted that the 150\xa0mg starting dose is in the marketing authorisation and will be used in clinical practice. The ERG acknowledged that the sample size calculations for the postamendment population were based on safety outcomes rather than progression‑free survival. However, the ERG maintained that the postamendment population was sufficiently powered to detect differences in clinical outcomes and provided methodologically robust results. The committee did not consider that the company's interaction test was sufficient evidence to support using the full trial population. It also noted that the patient baseline characteristics provided by the company were not likely to account for the difference in efficacy reported, but that not all characteristics were provided. The committee considered that the ERG had made a coherent case that the postamendment group was methodologically robust. It discussed whether there was a genuine dose effect, or whether differences between the groups were because of chance or baseline imbalances. It considered whether the differences might be greater in the placebo arm than in the treatment arm, but this was difficult to determine. The committee understood the challenges of interpreting the MONARCH\xa02 clinical data given the protocol amendment. It preferred to use the postamendment group data to estimate the clinical effectiveness of abemaciclib plus fulvestrant because:\n\nthis group included only people who had the licensed dose of abemaciclib\n\nthe trial was redesigned and adequately powered to detect a treatment effect for progression‑free survival in this group.The committee considered that excluding data from the 26.6% of people who were recruited before the amendment was justified. It concluded that data from those recruited after the amendment, who started on the licensed dose, was more relevant than data for the full trial population\n\n# Clinical effectiveness\n\n## Abemaciclib plus fulvestrant improves progression-free survival but the improvement in overall survival is less certain\n\nIn the original NICE technology appraisal guidance for abemaciclib plus fulvestrant, abemaciclib plus fulvestrant statistically significantly improved progression‑free survival compared with placebo plus fulvestrant in the full trial population. The effect of abemaciclib plus fulvestrant on overall survival was not statistically significant. It was concluded that more mature data from MONARCH\xa02 could resolve uncertainty around this outcome. More data from MONARCH\xa02 has now been collected and was analysed in June\xa02019. This analysis included an additional 28\xa0months of data compared with the original appraisal:\n\nMedian follow up was 47.70\xa0months.\n\nMedian progression‑free survival was 16.87\xa0months with abemaciclib plus fulvestrant compared with 9.27\xa0months with placebo plus fulvestrant.\n\nMedian overall survival was 46.72\xa0months for abemaciclib plus fulvestrant and 37.25\xa0months for placebo plus fulvestrant.This analysis confirmed the previous progression‑free survival results for the full trial population. The progression‑free survival data for the pre- and postamendment groups was marked academic in confidence and cannot be reported here. The updated data from MONARCH\xa02 also showed that abemaciclib plus fulvestrant statistically significantly improved overall survival compared with placebo plus fulvestrant (hazard ratio 0.757, 95% confidence interval 0.606 to 0.945). The improvement in overall survival was smaller in the postamendment group than in the pre‑amendment group. The company explained that it was likely that any differences in outcomes seen when comparing subgroups were the result of differences in baseline characteristics between subgroups, and random variation. The committee agreed that the explanation for the different clinical results between the pre- and postamendment groups was uncertain. This was because it could not be determined if the differences were because of a genuine dose effect, or because of chance or baseline imbalances. It concluded that abemaciclib plus fulvestrant improved progression‑free survival compared with placebo plus fulvestrant. But the improvement in overall survival was less certain in the postamendment group data, which the committee preferred (see more about the group data in section\xa03.4).\n\n## Clinical-effectiveness data from the SACT dataset is less relevant than the updated MONARCH\xa02 data for decision making\n\nThe company presented observational data from the systemic anticancer therapy (SACT) dataset for 876\xa0people who had abemaciclib plus fulvestrant through the Cancer Drugs Fund:\n\nMedian follow up was only 4.4\xa0months, because more mature MONARCH\xa02 data became available, which was suitable for decision making.\n\nMedian treatment duration was 10.2\xa0months and the median overall survival was not reached.\n\nFewer people were alive at 12\xa0months after having abemaciclib plus fulvestrant compared with those who had treatment in MONARCH\xa02.The SACT data was not included in the company's economic analysis. The company explained that the difference in the number of people alive at 12\xa0months may be because people having treatment through the Cancer Drugs Fund were generally older and frailer than those in MONARCH\xa02. Also, they may have had treatment later in the pathway or when the disease was more advanced. The company also highlighted that people with visceral disease may be offered abemaciclib plus fulvestrant over other CDK4/6 inhibitors because there is evidence of efficacy for this group. The company noted that the data was immature, and since there was no comparator arm, the relative efficacy was unknown. The ERG agreed with most points and considered that MONARCH\xa02 was the more robust evidence source. The clinical experts agreed that the relative efficacy from MONARCH\xa02 was generalisable and provided the most robust clinical evidence for decision making. The committee concluded that the SACT data was too immature and that clinical‑effectiveness data from MONARCH\xa02 was more appropriate for decision making.\n\n# Indirect treatment comparison\n\n## Data from the postamendment group from MONARCH\xa02 should be used to estimate the clinical effectiveness of abemaciclib plus fulvestrant\n\nThere were no trials directly comparing abemaciclib plus fulvestrant with exemestane plus everolimus. So, the company presented fractional polynomial network meta‑analyses in line with the committee's preferred assumptions. These meta‑analyses incorporated the updated MONARCH\xa02 data for progression‑free and overall survival for the full trial population. The results were based on the postamendment group at technical engagement, at the ERG's request. The fractional polynomial network meta‑analyses for progression‑free and overall survival showed that abemaciclib plus fulvestrant improved progression‑free and overall survival compared with exemestane plus everolimus for the full trial population. The ERG highlighted that progression‑free and overall survival with abemaciclib plus fulvestrant were shorter in the postamendment group than for the full trial population. Considering the heterogeneity and uncertainty across the network, the size of these benefits was uncertain. The committee recalled its preference to use the postamendment group data to estimate the clinical effectiveness of abemaciclib with fulvestrant (see more about the group data in section\xa03.4). It concluded that data from the postamendment group from MONARCH\xa02 should be used to estimate the clinical effectiveness of abemaciclib plus fulvestrant compared with exemestane plus everolimus.\n\n# The company's economic model\n\n## Data from the postamendment group from MONARCH\xa02 should be used to estimate the cost effectiveness of abemaciclib plus fulvestrant\n\nIn its original submission, the company used fractional polynomial network meta‑analysis data that used the full trial population from MONARCH\xa02 in its economic model for progression‑free and overall survival (see more about the meta-analyses in section\xa03.7). The ERG was concerned that this may have overestimated the treatment effects compared with clinical practice. It emphasised that this did not fully reflect the licensed dose that would be used in clinical practice. The ERG preferred to use fractional polynomial network meta‑analysis data that used the postamendment group from MONARCH\xa02 in the economic model. The committee was aware that the results of the model were highly sensitive to the choice of clinical‑effectiveness data for abemaciclib plus fulvestrant. Also, using only the postamendment group data gave a much lower estimate of abemaciclib's clinical effectiveness compared with using the full trial population data. The committee was not persuaded that the company's approach was more appropriate, since the trial was redesigned and powered to detect an effect in progression‑free survival in the postamendment group (see more about the group data in section\xa03.4). After consultation, the company used the committee's preferred postamendment data in its network meta‑analysis and revised base case to estimate the clinical- and cost effectiveness of abemaciclib plus fulvestrant compared with exemestane plus everolimus. Although the company used the postamendment data in its revised base case, it maintained the view that the full trial population was also relevant when considering the efficacy of abemaciclib plus fulvestrant. The committee concluded that the postamendment group data should be used in the economic model. But it recognised that the cost‑effectiveness results were highly sensitive to the choice of clinical‑effectiveness data for abemaciclib plus fulvestrant. It further concluded that the uncertainty surrounding why the clinical‑effectiveness estimates differed in the postamendment and full trial population should be considered in its decision making.\n\n## The estimates of time to treatment discontinuation for abemaciclib from the MONARCH trial period and over 10\xa0years are plausible\n\nIn the original NICE technology appraisal guidance for abemaciclib with fulvestrant there was uncertainty around how long people had treatment with abemaciclib plus fulvestrant (time to treatment discontinuation). Also, the company's model underestimated the treatment duration and therefore the treatment costs of abemaciclib plus fulvestrant. This was because the company used data from the full trial population, including those who were enrolled before the protocol amendment. Also, people on the lower dose stopped treatment less often because they had fewer adverse events. During that appraisal, the committee suggested that discontinuation should be estimated using the postamendment group data. This was because it used the lower licensed dose with fewer side effects, and more data could be collected on this outcome. In the current appraisal, the company used updated discontinuation data from the postamendment group as requested. It calculated a hazard ratio to apply to the progression‑free survival curve for abemaciclib with fulvestrant to extrapolate the time on treatment beyond the available trial data from MONARCH\xa02. This hazard ratio was estimated by comparing the area under the extrapolated time to treatment discontinuation and progression-free survival curves from MONARCH\xa02 (a restricted means analysis). It presented hazard ratios estimated at 3\xa0time points: the period covering the trial, 10\xa0years (which it used in its base case) and over a person's lifetime. These hazard ratios are commercial in confidence and cannot be reported here. The ERG preferred the hazard ratio estimated over the trial period but considered the 10‑year estimate was plausible. The committee concluded that both the company's and ERG's preferred hazard ratio estimates were plausible and took these into account in its decision making.\n\n## The time to stopping everolimus is likely to lie between that based on clinical opinion and that based on BOLERO‑2 data in the modelling\n\nIn the original NICE technology appraisal guidance for abemaciclib with fulvestrant, the company estimated a hazard ratio for the time to treatment discontinuation for exemestane plus everolimus compared with progression‑free survival. To do this, it used the median progression‑free survival and median time to treatment discontinuation from BOLERO‑2, a phase\xa03 randomised controlled trial comparing exemestane plus everolimus with exemestane alone. The hazard ratio was applied to the progression‑free survival curve for exemestane plus everolimus generated by the fractional polynomial network meta‑analysis, which was used in the model. The company's original model was not set up to model time to treatment discontinuation for exemestane and everolimus separately. This was a limitation because people tended to stop treatment with everolimus because of adverse events but continued to have exemestane. This affected cost effectiveness because everolimus is considerably more expensive than exemestane. In this appraisal, the ERG preferred to use a different approach. It calculated a hazard ratio and applied it to the fractional polynomial network meta‑analysis progression‑free survival curve to estimate the exemestane plus everolimus time to treatment discontinuation curve in the model. Three approaches to estimate the hazard ratio were presented by the company:\n\nAn estimate based on the clinical opinion from the Cancer Drugs Fund review of NICE's technology appraisal guidance on ribociclib with fulvestrant for hormone receptor‑positive, HER2‑negative, advanced breast cancer – this assumed that 20% of people stopped everolimus after 6\xa0months, and 70% of those remaining on treatment had a dose reduction (10\xa0mg to 5\xa0mg) but continued exemestane until disease progression.\n\nAn approach using median data from BOLERO‑2, which resulted in a hazard ratio of 1.58: the committee noted that the same approach had also been presented in the Cancer Drugs Fund review of ribociclib plus fulvestrant.\n\nA restricted mean analysis of BOLERO‑2 data to determine the progression‑free survival and time to treatment discontinuation relationship: This assumed that progression‑free survival and time to treatment discontinuation could be fitted on an exponential curve. The hazard ratio is commercial in confidence and cannot be reported here but the company stated that it was between the estimated hazard ratios for the other approaches.The committee noted that the committee for the ribociclib plus fulvestrant appraisal stated its preference for the time to stopping everolimus hazard ratio as likely lying between clinical expert opinion and the BOLERO‑2 scenario. The clinical experts for the current appraisal noted that the change at 6\xa0months seemed implausible because people would be more likely to stop gradually throughout the first 6\xa0months. The committee said that BOLERO‑2 data, even if not based on individual patient data from the trial, was preferable to the opinion of 1\xa0clinician. It also noted, however, that BOLERO‑2 is an old trial in which many had pretreatment with chemotherapy. So, how well this would correlate with treatment times for people having exemestane plus everolimus in current clinical practice is unknown. The committee noted the ERG's concerns that the company's third restricted means approach was flawed because it assumed that the data could be fitted on an exponential curve and could underestimate the hazard ratio. The committee was aware that the results of the economic model were highly sensitive to the assumption used to estimate the time to treatment discontinuation for exemestane plus everolimus. It concluded that time on treatment was likely to be between that estimated by the clinicians and that estimated by median data from BOLERO‑2.\n\n## Fulvestrant administration costs can be reduced in primary care but it is not appropriate to assume this\n\nThe company's base case used administration costs for fulvestrant based on costs used in NICE's technology appraisal guidance on ribociclib with an aromatase inhibitor for previously untreated, hormone receptor-positive, HER2-negative, locally advanced or metastatic breast cancer. The company also did a scenario analysis in which it assumed that fulvestrant injections are administered by community nurse specialists at a lower cost rather than in secondary care. It also excluded the initial loading dose. The clinical experts agreed that this does not happen in clinical practice, and people have fulvestrant in secondary care. The committee concluded that the company's base‑case assumptions on fulvestrant administration cost were appropriate.\n\n# Cost-effectiveness results\n\n## Abemaciclib plus fulvestrant is likely to be cost effective\n\nThe cost‑effectiveness estimates included patient access scheme discounts for abemaciclib and everolimus, and the NHS England price for generic fulvestrant. The exact incremental cost‑effectiveness ratio (ICER) cannot be reported here because of the confidential prices. The committee noted that there were a range of ICERs presented, which reflected the range of assumptions about time on treatment with abemaciclib plus fulvestrant and exemestane plus everolimus. It considered these plausible. The range included estimates that were above and below £30,000 quality‑adjusted life years (QALYs) gained. Also, the ICER was primarily driven by assumptions about time on treatment with exemestane plus everolimus. The committee noted:\n\nThere were ICERs within the range that NICE considers a cost‑effective use of NHS resources, although there were uncertainties in the cost‑effectiveness estimates.\n\nThe patient and clinical expert statements that abemaciclib plus fulvestrant is needed as an alternative to the other available CDK4/6 inhibitors, ribociclib and palbociclib, to allow management of adverse effects.\n\nThe scope of the Cancer Drugs Fund review was to compare abemaciclib plus fulvestrant with exemestane plus everolimus in practice. However, since the availability of CDK4/6 inhibitors, the use of exemestane plus everolimus is decreasing, and abemaciclib will be largely used as an alternative to ribociclib and palbociclib. Therefore, the overall cost to the NHS was not expected to increase if abemaciclib were recommended.\n\nThe postamendment data was appropriate for decision making. However, there was unresolved uncertainty as to why the estimates of overall survival were lower using postamendment data to those using data from the full trial population from MONARCH\xa02. If the full trial data had been used to estimate overall survival in the economic model, the ICER would have been expected to be lower.The committee concluded that, taking into account the uncertainty around the ICER estimates, it was plausible that abemaciclib plus fulvestrant could be a cost‑effective use of NHS resources. It also concluded that the treatment met a need for an alternative CDK4/6 inhibitor treatment.\n\n# Other factors\n\nNICE's advice about life‑extending treatments for people with a short life expectancy did not apply.\n\n# Conclusion\n\n## Abemaciclib plus fulvestrant is recommended for routine use\n\nThe committee noted that some combinations of plausible assumptions gave ICERs over £30,000 per QALY gained. However, these combinations did not take into account the difference in survival between the whole trial and postamendment populations. Taking into account the whole trial population, survival estimates would have lowered the ICERs. Noting the uncertainty introduced by this issue, the committee concluded that it was likely that abemaciclib plus fulvestrant was a cost‑effective use of NHS resources. It also concluded that it met a need for an alternative CDK4/6 inhibitor treatment. It therefore recommended abemaciclib plus fulvestrant for treating hormone receptor‑positive, HER2‑negative, locally advanced or metastatic breast cancer in adults who have had endocrine therapy, only if exemestane plus everolimus is the most appropriate alternative to a CDK4/6 inhibitor."}
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https://www.nice.org.uk/guidance/ta725
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Evidence-based recommendations on abemaciclib (Verzenios) with fulvestrant for hormone receptor-positive, HER2-negative advanced breast cancer after endocrine therapy in adults.
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82d2f41b54eab34cd79a5a06ba6e250ffc4ee8e1
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nice
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Nivolumab with ipilimumab and chemotherapy for untreated metastatic non-small-cell lung cancer
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Nivolumab with ipilimumab and chemotherapy for untreated metastatic non-small-cell lung cancer
Evidence-based recommendations on nivolumab (Opdivo) with ipilimumab (Yervoy) and chemotherapy for untreated metastatic non-small-cell lung cancer.
# Recommendations
Nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy is not recommended, within its marketing authorisation, for untreated metastatic non-small-cell lung cancer (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations.
This recommendation is not intended to affect treatment with nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Standard care for untreated metastatic NSCLC that has no EGFR or ALK mutations is usually immunotherapy plus platinum-doublet chemotherapy. People have different treatments depending on their PD‑L1 tumour proportion score and whether they have squamous or non-squamous NSCLC.
Clinical trial evidence suggests that people who have nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy (nivolumab combination) live longer than those who have platinum-doublet chemotherapy alone. Nivolumab combination has only been compared indirectly with other treatments. The results of these indirect comparisons of nivolumab combination with atezolizumab plus bevacizumab, carboplatin and paclitaxel (atezolizumab combination), pembrolizumab monotherapy, and pembrolizumab plus pemetrexed and platinum chemotherapy are uncertain. It is also uncertain how long the effect of nivolumab combination lasts.
The cost-effectiveness estimates for nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy are higher than what NICE considers an acceptable use of NHS resources. The cost-effectiveness estimates compared with pembrolizumab plus pemetrexed and platinum chemotherapy are uncertain because of problems with the analysis.
There is no additional data that could be collected through the Cancer Drugs Fund or from clinical trials that could resolve the uncertainty. So, nivolumab combination is not recommended for routine use or through the Cancer Drugs Fund.# Information about nivolumab with ipilimumab and chemotherapy
# Marketing authorisation indication
Nivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy, Bristol Myers Squibb) and 2 cycles of platinum-based (platinum-doublet) chemotherapy has a marketing authorisation for 'the first-line treatment of metastatic non-small-cell lung cancer in adults whose tumours have no sensitising epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of nivolumab is £2,633 per 240 mg per 24‑ml vial (excluding VAT; BNF online, accessed May 2021). The list price of ipilimumab is £15,000 per 200 mg per 40‑ml vial (excluding VAT; BNF online, accessed May 2021). The company has commercial arrangements for nivolumab and ipilimumab. These make nivolumab and ipilimumab available to the NHS with discounts, which would have applied to this indication if the technology had been recommended. The size of the discounts is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discounts.# Committee discussion
The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.
The appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:
the populations in the clinical trials generally reflected people who would have treatment in NHS clinical practice (issue 2, see ERG report page 17)
the company's indirect treatment comparisons at technical engagement were acceptable for decision making, despite some differences between the trials in patient characteristics and trial design (issue 3, see ERG report page 18)
the CheckMate‑227 data should be incorporated into the indirect treatment comparisons (issue 4, see ERG report page 19)
nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy (nivolumab combination) was likely to have similar efficacy across subgroups, including people aged 75 and over, people who have never smoked, and people with liver or bone metastases (issue 5, see ERG report page 20)
the duration of treatment for atezolizumab plus bevacizumab, carboplatin and paclitaxel (atezolizumab combination) should be based on the observed data from the IMPower150 trial (issue 11, see ERG report page 27)
docetaxel should be removed as a subsequent therapy for people having first-line platinum-doublet chemotherapy (issue 15, see ERG report page 30).
The committee recognised that there were remaining areas of uncertainty associated with the analyses presented, and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:
whether the decision problem should be split into 3 separate subgroups based on histology (non-squamous or squamous non-small-cell lung cancer ) and PD‑L1 tumour proportion score (TPS; issue 1, see ERG report page 16)
whether different curves should be used to model overall survival and progression-free survival for nivolumab combination in these 3 subgroups (issue 8, see ERG report, page 23)
what composition of platinum-doublet chemotherapy best reflects NHS clinical practice (issues 6 and 7, see ERG report, pages 21 to 23)
whether survival for people having platinum-doublet chemotherapy should be modelled using the CheckMate‑9LA data up to 13 months and the CheckMate‑227 data thereafter, or using the CheckMate‑227 data alone (issue 9, see ERG report, page 25)
how long the effect of treatment with nivolumab combination lasts (issue 10, see ERG report, page 26)
whether the utility values should be based on progression status or time to death (issue 12, see ERG report, page 28)
whether the adjustment for relative dose intensity should be applied to the cost of the drug, or the expected required treatment dose (issue 13, see ERG report, page 29)
what proportion of people have subsequent anticancer therapy after their first-line treatment (issue 14, see ERG report, page 29)
whether nivolumab combination meets the criteria for end of life treatments (issue 16, see ERG report, page 31)
whether nivolumab combination meets the criteria to be considered for use within the Cancer Drugs Fund (issue 17, see ERG report, page 32).
# Clinical need and management
## Nivolumab combination is another option for untreated, metastatic NSCLC
The clinical experts explained that immunotherapy with platinum-doublet chemotherapy (chemo-immunotherapy) is standard care in the NHS for untreated metastatic NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. Most people having chemo-immunotherapy stop treatment before 2 years because their disease progresses or there are tolerability issues, and few survive in the long term. The clinical experts considered that nivolumab combination is likely to have similar efficacy to other first-line chemo-immunotherapy combinations. Limiting the duration of chemotherapy to 2 cycles may reduce renal toxicity and allow platinum-doublet chemotherapy to be offered again as a later-line therapy. The side effects of long-term immunotherapy are usually mild but can sometimes be considerable, needing specialist management. The clinical experts noted that combining 2 immunotherapies is likely to cause more immune-related toxicities than current regimens with only 1 immunotherapy. The committee concluded that nivolumab combination offers another treatment option for untreated metastatic NSCLC with no EGFR or ALK mutations, which may have advantages for some people.
## Treatment and prognosis differ based on histology and PD-L1 status, and subgroups based on these should be considered separately
The clinical experts explained that:
current treatment is based on histology (non-squamous or squamous NSCLC) and PD‑L1 TPS, in line with NICE guidance
prognosis may differ by histology and PD‑L1 TPS, and outcomes tend to be worse for people with squamous NSCLC.The ERG considered that the population with untreated metastatic NSCLC who have no EGFR or ALK tumour mutations should be split into 3 subgroups, according to the treatments currently available:
non-squamous NSCLC, with PD‑L1 TPS below 50%
squamous NSCLC, with PD‑L1 TPS below 50% and
NSCLC of either histology, with PD‑L1 TPS at least 50%.The committee concluded that it was appropriate to consider the 3 subgroups identified by the ERG separately.
## The comparators are appropriate, but pembrolizumab plus pemetrexed and platinum chemotherapy is also relevant for non-squamous NSCLC
The committee heard that, in line with NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for non-squamous NSCLC and pembrolizumab with carboplatin and paclitaxel for squamous NSCLC, these combinations are widely used in NHS clinical practice. When the scope for this appraisal was developed, pembrolizumab plus pemetrexed and platinum chemotherapy was recommended for use within the Cancer Drugs Fund. So, it was not included as a comparator in line with NICE's position statement on handling comparators and treatment sequences in the Cancer Drugs Fund. However, it is now recommended for routine commissioning, and is therefore an appropriate comparator for non-squamous NSCLC. NICE's technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel is being reviewed, but this technology is still recommended for use within the Cancer Drugs Fund while the review is ongoing. It is therefore not an appropriate comparator. The committee understood that, in line with the scope, the following comparators were included in the cost-effectiveness analysis:
platinum-doublet chemotherapy for all 3 subgroups, including optional pemetrexed maintenance for people with non-squamous NSCLC
atezolizumab combination for the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50%
pembrolizumab monotherapy for the subgroup with either histology and PD‑L1 TPS at least 50%.The committee agreed that these comparators were appropriate. However, it concluded that pembrolizumab plus pemetrexed and platinum chemotherapy became a relevant comparator for non-squamous NSCLC. So it should be included in the analysis to reflect established NHS practice (see section 3.7).
# Clinical effectiveness
## CheckMate-9LA does not include all the relevant treatments used in NHS clinical practice
The main clinical effectiveness evidence for nivolumab combination came from CheckMate‑9LA. This is an ongoing open-label phase 3 randomised controlled trial, comparing nivolumab combination with standard platinum-doublet chemotherapy. For people with non-squamous NSCLC, platinum-doublet chemotherapy was pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance therapy. For people with squamous NSCLC, platinum-doublet chemotherapy was paclitaxel plus carboplatin. The committee was aware that CheckMate‑9LA included adults with untreated recurrent or metastatic NSCLC (with no EGFR or ALK mutations) with an Eastern Cooperative Oncology Group performance status of 0 or 1. The trial included people regardless of PD‑L1 status. CheckMate‑9LA did not include these comparators used in NHS clinical practice:
atezolizumab combination and pembrolizumab plus pemetrexed and platinum chemotherapy (for non-squamous NSCLC and PD‑L1 TPS below 50%)
pembrolizumab monotherapy (for NSCLC of any histology and PD‑L1 TPS at least 50%)
pembrolizumab plus pemetrexed and platinum chemotherapy (for non-squamous NSCLC).The committee acknowledged that, because there was no head-to-head evidence with these comparators, indirect treatment comparisons were needed to assess the relative effectiveness of nivolumab combination.
## Nivolumab combination improves overall and progression-free survival compared with standard chemotherapy
An interim analysis of CheckMate‑9LA showed a statistically significant difference in overall and progression-free survival in favour of nivolumab combination compared with standard platinum-doublet chemotherapy. At the most recent data cut (March 2020), median overall survival was 15.6 months for nivolumab combination and 10.9 months for standard chemotherapy (hazard ratio 0.66, 95% confidence interval 0.55 to 0.80). Median progression-free survival was 6.7 months for nivolumab combination and 5.0 months for standard chemotherapy (HR 0.68, 95% CI 0.57 to 0.82). Some people having nivolumab combination in CheckMate‑9LA had either immunotherapy or a therapy targeted against EGFR, ALK or vascular endothelial growth factor as a subsequent therapy. This did not represent NHS clinical practice, because people would not have immunotherapy again or a targeted therapy on disease progression. The clinical experts stated that this was unlikely to have had a large effect on treatment outcomes. But it meant that the survival of people having nivolumab combination may have been overestimated in CheckMate‑9LA. The committee concluded that nivolumab combination was clinically effective compared with standard chemotherapy.
# Indirect treatment comparisons
## Most of the company's indirect treatment comparisons are acceptable for decision making, despite uncertainty
The company did indirect treatment comparisons because there were no head-to-head trials comparing nivolumab combination with pembrolizumab monotherapy and atezolizumab combination. The company considered that the proportional hazards assumption (that is, the relative risk of an event is fixed irrespective of time) was not met. It therefore used fractional polynomial models to estimate time-varying hazard ratios. The committee noted that this approach meant that there was a lot of uncertainty with the indirect treatment comparisons. For the indirect comparison with pembrolizumab monotherapy in the subgroup with PD‑L1 TPS at least 50%, the company used the data from the full intention-to-treat (ITT) population from CheckMate‑9LA. For the comparison with atezolizumab combination for the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50%, the company used the data from the relevant subgroup of CheckMate‑9LA. The results of the indirect comparisons are confidential and cannot be reported here. At technical engagement, it was agreed that the CheckMate‑227 data should also be included in the indirect treatment comparisons. CheckMate‑227 is an ongoing open-label phase 3 randomised controlled trial in a similar population to that in CheckMate‑9LA. It includes a nivolumab plus ipilimumab treatment arm and a platinum-doublet chemotherapy treatment arm, both stratified by PD‑L1 TPS. The most recent data cut from CheckMate‑227 (February 2020) had a minimum follow up of 37.7 months compared with 12.7 months for CheckMate‑9LA. The committee noted that some of the company's indirect treatment comparison results had wide confidence intervals and were uncertain, but concluded that they were acceptable for decision making.
## The indirect treatment comparison with pembrolizumab plus pemetrexed plus platinum chemotherapy is not suitable for decision making
At the first meeting, the committee concluded that pembrolizumab plus pemetrexed and platinum chemotherapy was now widely used in the NHS. It was approved for routine use after the initial scope for this appraisal, and became a relevant comparator for the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50% (see section 3.3). So, the company updated its indirect treatment comparison at consultation. It found that nivolumab combination was more effective than pembrolizumab plus pemetrexed and platinum chemotherapy in this subgroup. The ERG was concerned because:
the updated indirect treatment comparison excluded pembrolizumab monotherapy as a comparator
there was no evidence for pembrolizumab monotherapy compared with pembrolizumab plus pemetrexed and platinum chemotherapy in the subgroup with non-squamous NSCLC and PD‑L1 TPS at least 50%.The ERG explained that the updated analysis included an additional trial for pembrolizumab plus pemetrexed and platinum chemotherapy. This affected both the nivolumab combination arm and the atezolizumab combination arm. It increased the life years gained for nivolumab combination but reduced the life years gained for atezolizumab combination. The additional trial increased the incremental difference in life years gained, which the ERG was unable to validate. The committee discussed the unexpected results of the comparison of nivolumab combination with pembrolizumab plus pemetrexed and platinum chemotherapy; particularly that a shorter duration of treatment resulted in a longer duration of benefit for this pembrolizumab combination. The ERG considered that the modelling for this comparison was not robust enough for decision making. The company explained that KEYNOTE‑598 (a trial of pembrolizumab with either ipilimumab or placebo for people with untreated metastatic NSCLC) had a short follow up (about 12 months), with heavy censoring around that time. But for the nivolumab combination trials, there was separation of the curves around 12 months. However, the committee was aware that KEYNOTE‑598 was stopped because adding ipilimumab to the immunotherapy showed no incremental survival benefit. Also, the company's indirect treatment comparison comparing progression-free and overall survival for nivolumab combination with pembrolizumab for the subgroup with non-squamous and squamous NSCLC with PD‑L1 TPS at least 50% favoured single-agent immunotherapy, as in KEYNOTE‑598. But the difference was not statistically significant. The committee recalled that the clinical experts expected similar outcomes for the nivolumab combination and other first-line chemo-immunotherapy combinations (see section 3.1) in clinical practice. This contradicted the findings in the company's analysis, in which nivolumab combination dominated (was more effective and less expensive) the pembrolizumab combination. The committee had several concerns about the company's comparative efficacy and modelling results, which suggested that overall survival was better with nivolumab combination than with many other options. The committee noted that there was a lot of uncertainty with the fractional polynomial indirect treatment comparison (see section 3.6). It recalled a direct comparison in KEYNOTE‑198 showing that pembrolizumab plus ipilimumab was no better than pembrolizumab alone for non-squamous metastatic NSCLC. It also recalled previous trial evidence (KEYNOTE‑024, CheckMate‑026) which suggested that nivolumab monotherapy was inferior to pembrolizumab monotherapy for untreated NSCLC. So, the committee considered that the modelled outcomes did not seem realistic. The committee concluded that the company's indirect treatment comparison of nivolumab combination with pembrolizumab plus pemetrexed and platinum chemotherapy was not robust enough for decision making.
# Adverse events
## Nivolumab combination is likely to be less well tolerated than other chemo-immunotherapy combinations
The clinical experts explained that immunotherapy is generally well tolerated but is associated with some rare but unpleasant, and potentially serious, adverse events. These were likely to be more common for nivolumab combination (2 different immunotherapies) than current chemo-immunotherapy combinations (only 1 immunotherapy). The company did not agree, so at consultation provided further evidence using data from CheckMate‑227. It explained that:
adverse events from chemotherapy are less frequent with nivolumab combination, which includes only 2 cycles of chemotherapy
adverse events with nivolumab combination tend to occur early in treatment and, if managed effectively, reduce with later cycles.The company provided adverse event results over time from an indirect treatment comparison of nivolumab combination and pembrolizumab plus chemotherapy. This showed no statistically significant differences in the odds of having adverse events leading to discontinuation of any drug in the combination. This was true for grade 3 to 5 and grade 1 to 5 adverse events. However, the ERG could not comment because details of the indirect treatment comparison were not available. The committee considered that it would be helpful to understand which drugs in the combinations are most frequently discontinued. It was unclear how the company's evidence on treatment-related adverse events over time should be interpreted, because some people would stop treatment for other reasons. The committee understood that clinicians are experienced in recognising and managing serious adverse events, and established toxicity management algorithms are in place. It concluded that nivolumab combination was likely to be less well tolerated than other chemo-immunotherapy combinations, so more specialist management would be needed for serious adverse events.
# The company's economic model
## The company's model structure is acceptable for decision making
The company used a 3‑state partitioned survival model to estimate the cost effectiveness of nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy. People were able to move to different health states; from pre-progression to post-progression and death and from post-progression to death. The ERG agreed with the company's model structure, noting that it was consistent with previous appraisals. For people having nivolumab combination and people having standard platinum-doublet chemotherapy, the company used the results from CheckMate‑9LA to model overall and progression-free survival for the first 13 months. The results from CheckMate‑227 were used after this point because longer-term data was available (see section 3.6). Survival curves were modelled for the ITT population and applied for everyone, regardless of histology and PD‑L1 TPS. Relative risks from the indirect comparisons were then applied to the nivolumab combination data to estimate overall and progression-free survival for atezolizumab combination and for pembrolizumab monotherapy. The committee concluded that the company's model structure was acceptable for decision making. But it noted the uncertainty about whether it was appropriate to use the same survival curves for everyone (see section 3.11).
## Including a 2-year stopping rule is acceptable
The company included a 2‑year treatment stopping rule in its model. The maximum possible duration for nivolumab combination in CheckMate‑9LA was 24 months, and this was also stated in the summary of product characteristics. The committee understood that implementing a 2‑year stopping rule was consistent with other NICE technology appraisal guidance on untreated NSCLC. It also reflected how nivolumab combination would be used in clinical practice. The committee concluded that a 2‑year treatment stopping rule, in line with the clinical- and cost-effectiveness evidence, was acceptable.
# Modelling survival
## The company's analyses modelling survival for histology and PD-L1 subgroups separately are appropriate for decision making
The committee considered whether it was appropriate to use the same overall and progression-free survival curves across all 3 subgroups, based on the ITT data from CheckMate‑9LA and CheckMate‑227 (see section 3.9). The company took this approach because it believed there was a consistent efficacy benefit across subgroups in CheckMate‑9LA, including those based on PD‑L1 and histology. However, the ERG noted that the CheckMate‑9LA and CheckMate‑227 results suggested there were differences in the absolute and relative efficacy of nivolumab combination across some of the subgroups. Clinical advice to the ERG was that people whose NSCLC has a higher PD‑L1 TPS generally have greater benefit with anti‑PD‑L1 immunotherapies. The company considered that using the ITT data was more appropriate than the subgroup data, because the subgroups were not prespecified and included smaller numbers of people. The company also noted that the lack of external clinical data available to validate the subgroup curves placed greater reliance on clinical opinion. Also, it considered that by combining 3 different mechanisms of action, nivolumab combination was not expected to have the same efficacy differences by histology or PD‑L1 TPS as other immunotherapies. The committee considered that because it had agreed to separate the population into 3 subgroups (see section 3.2), it was appropriate to reflect this heterogeneity in the data used to generate the survival curves. It also noted that applying separate survival curves based on the subgroup data had a considerable impact on the cost-effectiveness results. The committee agreed that there was uncertainty about the validity of applying survival curves derived from the ITT data across all the subgroups. It concluded that survival curves should be modelled separately for each subgroup. So, in its updated base case after consultation, the company modelled the survival curves separately for each subgroup, based on the 1‑year data cut for CheckMate‑9LA and 3‑year data cut for CheckMate‑227. The company highlighted that CheckMate‑9LA not was not stratified or powered for analyses of combined histology and PD‑L1 subgroups. The committee concluded that the company's analyses modelling overall survival data for histology and PD‑L1 subgroups separately were appropriate for decision making.
## Survival for people having platinum-doublet chemotherapy should be modelled using the CheckMate-227 data alone
The ERG noted that median overall survival for people having platinum-doublet chemotherapy was longer in CheckMate‑227 than in CheckMate‑9LA. This could have been because fewer people had subsequent therapy in CheckMate‑9LA than in CheckMate‑227. The ERG considered that the proportion of people having subsequent therapy after platinum-doublet chemotherapy in CheckMate‑9LA was lower than in NHS clinical practice. It was therefore concerned that using the CheckMate‑9LA data to estimate survival for the first 13 months (see section 3.9) may have underestimated survival for people having platinum-doublet chemotherapy. The ERG did a scenario analysis in which survival for people having platinum-doublet chemotherapy was modelled using the CheckMate‑227 data alone. In this, the relative efficacy of nivolumab combination was taken from the indirect treatment comparison. However, the ERG preferred to retain the company's original approach of using the CheckMate‑9LA data followed by the CheckMate‑227 data for its base case. This was because it used the same data sources for people having nivolumab combination and people having platinum-doublet chemotherapy. The committee noted that in NICE's technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for squamous NSCLC, it was estimated that around 50% of people having first-line chemotherapy have immunotherapy after disease progression. The clinical experts noted that this may be an underestimate based on the proportion of people switching from chemotherapy to pembrolizumab in the KEYNOTE‑024 trial. KEYNOTE‑024 was an open-label phase 3 randomised controlled trial, comparing pembrolizumab with chemotherapy for untreated metastatic NSCLC. At consultation, the company said that it preferred its original approach, in line with the nivolumab combination arm (CheckMate‑9LA data used up to 13 months, then conditional survival from CheckMate‑227 applied). Because CheckMate‑9LA was the registration trial, the company felt it was the most appropriate to estimate survival for people having platinum-doublet chemotherapy. It would preserve the benefits of comparing between arms of the randomised controlled trial. The ERG found that the model predicted 5‑year survival of 10.5% for platinum-doublet chemotherapy using CheckMate‑227 alone, and 9% in the approach using CheckMate‑9LA and CheckMate‑227. This was consistent with previous appraisals. The committee understood that around 28% of people had subsequent immunotherapy after first-line chemotherapy in CheckMate‑9LA, compared with around 41% in CheckMate‑227. It considered that the rate of subsequent immunotherapy in CheckMate‑227 was likely closer to that in NHS clinical practice. The committee concluded that survival for people having platinum-doublet chemotherapy should be modelled using the CheckMate‑227 data alone.
## A treatment effect lasting 3 to 5 years after starting treatment is appropriate and consistent with previous appraisals
The company's base case included a lifetime treatment effect with nivolumab combination. The company justified this using pooled data from 4 clinical trials of nivolumab for previously treated NSCLC, which showed that nivolumab had a long-term survival advantage over docetaxel. The ERG noted that a lifetime treatment effect was inconsistent with previous technology appraisals for NSCLC. For those, a treatment effect lasting from 3 to 5 years after starting treatment had been accepted. The ERG also considered the pooled data used by the company to be of limited relevance. This was because the data was from trials of nivolumab as a monotherapy in a population who had previous treatment, and survival outcomes were only reported to 4 years. The ERG preferred a scenario with a treatment effect lasting 5 years after stopping treatment. This was modelled by setting the mortality rate as equal to that of platinum-doublet chemotherapy from this timepoint onwards. The committee understood that the assumption around the duration of treatment effect had a considerable impact on the cost-effectiveness results. It agreed that, although it was biologically plausible for the treatment effect to continue after stopping treatment with nivolumab combination, its duration was uncertain. The clinical experts explained that there was insufficient evidence to suggest the treatment effect of nivolumab combination lasted longer than for other immunotherapies. The committee concluded that a treatment effect lasting 3 to 5 years after starting treatment was appropriate for decision making, for consistency with previous immunotherapy appraisals in NSCLC.
## There is no evidence to support a treatment effect duration of longer than 3 to 5 years
At consultation, the company's updated base case used a 5‑year treatment effect after stopping treatment. This was more optimistic than what the committee preferred at the first meeting, which was a treatment effect lasting 3 to 5 years after starting treatment (see section 3.13). The company acknowledged the misunderstanding, but explained that a treatment effect of 5 years after stopping would be a conservative assumption. It explained that the new CheckMate‑227 data would support an additional benefit over other chemo-immunotherapy combinations, particularly the number of people whose disease maintained a response at 3 years. However, this new data did not arrive in time to be incorporated into its analyses. The committee recalled the plausible treatment effect duration for single-agent immunotherapy plus platinum-doublet chemotherapy and noted that strong evidence would be needed to accept a longer duration. It considered that there was no evidence that nivolumab combination had a longer treatment effect duration than pembrolizumab plus platinum-doublet chemotherapy. So, a more favourable assumption could not be made for nivolumab combination. The committee concluded that its preferred assumption for nivolumab combination was still a treatment effect lasting 3 to 5 years after starting treatment.
# Health-related quality of life
## The ERG's approach of using progression-based utility values is preferred
The ERG explained that the company's time-to-death approach for including utility values was not appropriate. This was because in previous technology appraisals in which this approach had been accepted, health-related quality-of-life data had only been collected for up to 30 days after stopping treatment. This meant that the utility value for the post-progression state may have been overestimated, because the full effects of progression may not yet have been evident. However, in CheckMate‑9LA, health-related quality-of-life data was collected until death, and there were many observations (1,004) contributing to the post-progression health state. In contrast, there were only 114 observations contributing to the utility value for 4 weeks or less to death in the company's approach. The ERG also had concerns with using time to death to determine health-related quality of life. A time-to-death approach meant that people entering the model had a different health-related quality of life depending on the treatment arm they were assigned to. The ERG preferred a progression-based approach, using utility values derived from the EQ‑5D data collected in CheckMate‑9LA. The clinical experts explained that quality of life may not immediately decline after disease progression. The committee was also aware that progression-based utility values may be overestimated because there were fewer observations in people with more severe disease. However, it agreed with the ERG that utility values based on disease progression were more appropriate for decision making, given the large amount of data captured after progression. At consultation, the company maintained that the time-to-death approach was an appropriate way to include utility values. But it accepted the use of health state utility values in line with the committee's preferred assumption.
# Composition of platinum-doublet chemotherapy
## Separate chemotherapy regimen distributions should be used for each subgroup to reflect differences in clinical practice
To calculate the costs associated with platinum-doublet chemotherapy, the company based the distribution of chemotherapy regimens on the CheckMate‑9LA data. It applied the same assumption for everyone having platinum-doublet chemotherapy, regardless of histology or PD‑L1 TPS. The ERG considered that the distribution of chemotherapy regimens in CheckMate‑9LA may not reflect NHS clinical practice. For example, some people with squamous NSCLC were modelled as having pemetrexed, which they would not have in practice. It noted that there were differences in drug and administration costs between chemotherapy regimens, which meant that the costs calculated from the company's distribution may not have been representative. The ERG preferred to apply a specific distribution of chemotherapy agents for each subgroup (see section 3.2), including different proportions of people having pemetrexed maintenance therapy. It took these distributions from reported UK market share information in:
NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for non-squamous NSCLC (TA557) and
NICE's technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for squamous NSCLC (TA600).At technical engagement and with clinical input, the company revised the proportion of people having each chemotherapy regimen but continued to apply a single weighted distribution for everyone. The clinical experts explained that the most widely used chemotherapy regimens in clinical practice differed by histology. Carboplatin plus either gemcitabine or vinorelbine were the most common combinations for people with squamous NSCLC, but pemetrexed was preferred for people with non-squamous NSCLC. The committee considered that these differences should be reflected in the composition of platinum-doublet chemotherapy in the economic model. It concluded that the ERG's approach of applying separate distributions of chemotherapy regimens for each subgroup was more appropriate for decision making.
# Subsequent therapy
## The proportion of people having subsequent therapy should be based on the CheckMate-227 data
In the company's model, 31% of people having nivolumab combination as their first-line treatment had subsequent therapy, based on the CheckMate‑9LA data. The same assumption was used for people having pembrolizumab monotherapy and atezolizumab combination. In the model, 40% of people having platinum-doublet chemotherapy as their first-line treatment had subsequent therapy. The ERG noted that the data on the rates of subsequent therapy from CheckMate‑9LA was immature, and likely an underestimate. The rates from CheckMate‑227 were higher (45% for people having nivolumab combination as first-line treatment, and 61% for people having platinum-doublet chemotherapy). The ERG considered that the CheckMate‑227 rates were more in line with those seen in NHS clinical practice. They were also based on more mature data. Also, using the CheckMate‑227 data was consistent with the approach used for modelling long-term survival. At technical engagement, the company accepted that the rates of subsequent therapy in CheckMate‑9LA may be lower than expected in a clinical trial, but considered that they reflected NHS clinical practice. The committee recalled its earlier conclusion that the proportion of people having subsequent therapy in the clinical trials was likely lower than in NHS clinical practice (see section 3.12). Therefore, it concluded that the higher rates from CheckMate‑227 better reflected clinical practice and should be used in the model.
# Relative dose intensity
## The difference between the company and the ERG's relative dose intensity adjustments has minimal impact on the cost-effectiveness results
Relative dose intensity is the percentage of the prescribed dose of a treatment that people take. The company applied the relative dose intensities to the cost of the drug, after this had been estimated from the number of vials needed based on the treatment dose in the marketing authorisation. The ERG considered it more appropriate to apply the relative dose intensities to the expected treatment dose, and then calculate the number of vials and associated drug costs from these adjusted numbers. Because this may not necessarily reduce the number of vials, the ERG was concerned that the company may have underestimated the drug costs. The committee concluded that the relative dose intensity likely lay between the company's and the ERG's assumptions. However, it noted that this had minimal impact on the cost-effectiveness results.
# End of life
## Nivolumab combination is likely to meet the end of life criteria for squamous NSCLC with PD-L1 TPS below 50%
The committee considered the advice about life-extending treatment for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It understood that, at the first meeting, the company and the ERG agreed that nivolumab combination did not meet the criteria for end of life treatments for:
non-squamous NSCLC and PD‑L1 TPS below 50% or
NSCLC of either histology and PD‑L1 TPS at least 50%.For the subgroup with squamous NSCLC and PD‑L1 TPS below 50%, both the company's and the ERG's base cases predicted a mean overall survival of around 24 months for people having platinum-doublet chemotherapy. The clinical experts stated that the life expectancy for this subgroup was likely to be less than 2 years, even with immunotherapy. The company and the ERG estimated that the mean life extension for nivolumab combination in this subgroup was more than 3 months compared with platinum-doublet chemotherapy. The committee was satisfied that nivolumab combination was likely to meet the criteria for end of life treatments in the subgroup with squamous NSCLC and PD‑L1 TPS below 50%.
## The end of life criteria are not met for all other populations covered by this appraisal
At consultation, the company presented evidence to support that the end of life criteria should apply across all the populations in this appraisal. This included a retrospective study using data from the Flatiron database, for people with stage 3B or stage 4 NSCLC who had chemo-immunotherapy (over 98% had pembrolizumab plus chemotherapy). The reported median overall survival for people with squamous and non-squamous NSCLC was shorter than in the KEYNOTE‑407 and KEYNOTE‑189 trials. However, the ERG considered it uncertain whether the Flatiron evidence reflected the population who would have nivolumab combination for untreated, metastatic NSCLC in the NHS. This was because people in the Flatiron dataset had poorer performance status, were older, and were more likely to have unstable brain metastases. Also, they had treatment in the US, which has different treatment patterns to the UK. The company contrasted the real-world Flatiron evidence with real-world evidence for nivolumab as second-line treatment for NSCLC. It explained that outcomes in clinical practice (from the Systemic Anti-Cancer Therapy Dataset) were similar to those seen in the randomised controlled trials. The committee recalled that in NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for non-squamous NSCLC, the committee did not accept that the end of life criteria were met. The ERG noted that there was little long-term observational evidence on whether having nivolumab first line would extend survival by 3 months in clinical practice. It considered that efficacy might decline in practice (similar to the clinical trial) when people with more severe disease have nivolumab. Also, survival may not be extended by 3 months for people with severe disease. But the ERG noted that this was uncertain and not supported by evidence. The Cancer Drugs Fund clinical lead explained that real-world outcomes for chemo-immunotherapy seem to reflect what is seen in trials. This is because people must be well enough to have chemo-immunotherapy, which has additional selection considerations for clinicians, compared with immunotherapy alone. The committee considered that the evidence presented by the company only showed that the end of life criteria could plausibly be met for the subgroup with squamous NSCLC and PD‑L1 TPS below 50%. It recalled that mean survival was preferable to median survival for decision making around end of life criteria for chemo-immunotherapy. The committee concluded that the criteria were not met for all other populations covered by this appraisal.
# Cost-effectiveness results
## Nivolumab combination is not cost effective in any subgroup
The committee recalled that its preferred assumptions were:
considering 3 separate subgroups based on histology and PD‑L1 TPS (see section 3.2)
applying separate survival curves for each subgroup (see section 3.11)
modelling survival for people having platinum-doublet chemotherapy using the CheckMate‑227 data alone (see section 3.12)
a treatment effect lasting 3 to 5 years after starting treatment (see section 3.13 and section 3.14)
utility values based on disease progression rather than time to death (see section 3.15)
applying separate platinum-doublet chemotherapy distributions for each subgroup, using UK market share data from TA557 and TA600 (see section 3.16)
subsequent treatment rates based on the CheckMate‑227 data (see section 3.17).The cost-effectiveness results are commercial in confidence because they included the discounts from commercial access agreements and patient access schemes for atezolizumab, pembrolizumab, bevacizumab and pemetrexed maintenance.
For the subgroup with squamous NSCLC and PD‑L1 TPS below 50%, the incremental cost-effectiveness ratios (ICERs) for nivolumab combination compared with platinum‑doublet chemotherapy were above what is normally considered a cost‑effective use of NHS resources for end of life treatments (£50,000 per quality-adjusted life year gained).
For the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50%, the ICERs for nivolumab combination compared with both atezolizumab combination and platinum-doublet chemotherapy were above the upper end of the range normally considered a cost-effective use of NHS resources (£30,000 per QALY gained). Although nivolumab combination dominated (was more effective and less expensive) pembrolizumab plus pemetrexed and platinum-doublet chemotherapy, the analysis was not considered robust enough for decision making and the modelled outcomes did not seem realistic.
For the subgroup with NSCLC of either histology and PD‑L1 TPS at least 50%, nivolumab combination was more costly and less effective than pembrolizumab monotherapy (that is, it was dominated by pembrolizumab). Compared with platinum-doublet chemotherapy, the ICERs were above £30,000 per QALY gained.The committee concluded that the cost-effectiveness estimates for nivolumab combination were mostly higher than what NICE normally considers a cost-effective use of NHS resources.
# Other factors
No relevant equalities issues were identified.
The company stated that nivolumab combination was innovative because it was the first dual immunotherapy licensed for NSCLC. However, the clinical experts explained that they did not consider the treatment to be innovative because the important step change had already been made by the earlier immunotherapies. The committee concluded that there were no additional benefits associated with nivolumab combination that had not been captured in the economic analysis.
# Conclusion
## Nivolumab combination is not recommended for routine use in the NHS
Nivolumab combination is more clinically effective than standard chemotherapy, and is likely to have similar efficacy to other chemo-immunotherapies. The committee agreed that the most plausible ICERs for nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy were mostly higher than what NICE normally considers a cost-effective use of NHS resources. The results comparing nivolumab combination with pembrolizumab plus pemetrexed and platinum chemotherapy did not seem realistic, and that analysis was not considered robust enough for decision making. Therefore, it concluded that nivolumab combination could not be recommended for routine use as an option for untreated metastatic NSCLC with no EGFR or ALK mutations.
## Nivolumab combination is not recommended for use in the Cancer Drugs Fund
Having concluded that nivolumab combination could not be recommended for routine use, the committee then considered if it could be recommended within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund technology appraisal process and methods guide (addendum). The company had expressed an interest in the treatment being considered for funding through the Cancer Drugs Fund. At consultation, the company provided the most up-to-date overall survival results for CheckMate‑9LA compared with CheckMate‑227, for subgroups with:
non-squamous NSCLC and PD‑L1 TPS below 50%
all types of non-squamous NSCLC
squamous NSCLC with PD‑L1 TPS below 50%
all types of squamous NSCLC.The company considered this data to be commercially sensitive so it cannot be shown here. The company explained that additional data for both these trials would reduce uncertainty, increase confidence in the analyses, and allow long-term outcomes across currently approved chemo-immunotherapy regimens to be compared. The ERG considered that, because the new data was not included in the new indirect treatment comparisons, the long-term efficacy of nivolumab combination compared with other chemo-immunotherapy combinations was uncertain. Also, any long-term outcomes data collected in the Cancer Drugs Fund would be affected by subsequent treatments that people had in CheckMate‑9LA, which are not used in UK practice. The ERG emphasised that even if data for nivolumab combination was collected in the Cancer Drugs Fund, the maximum duration of treatment benefit that could be seen would be 5 years from the start of treatment. This would be in line with the upper limit of the committee's preference. At the first meeting, the key uncertainty around lifelong duration of benefit (that is, cure in some people) was thought to be unresolvable with up to 2 years of further data collection. The committee understood that CheckMate‑9LA and CheckMate‑227 were ongoing, and further data would become available. However, the committee agreed that this would likely be insufficient to reduce the uncertainty affecting the cost-effectiveness results, particularly the duration of the treatment effect. The committee concluded that nivolumab combination did not meet the criteria to be considered for inclusion in the Cancer Drugs Fund.
|
{'Recommendations': 'Nivolumab plus ipilimumab and 2\xa0cycles of platinum-doublet chemotherapy is not recommended, within its marketing authorisation, for untreated metastatic non-small-cell lung cancer (NSCLC) in adults whose tumours have no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations.\n\nThis recommendation is not intended to affect treatment with nivolumab plus ipilimumab and 2\xa0cycles of platinum-doublet chemotherapy that was started in the NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nStandard care for untreated metastatic NSCLC that has no EGFR or ALK mutations is usually immunotherapy plus platinum-doublet chemotherapy. People have different treatments depending on their PD‑L1 tumour proportion score and whether they have squamous or non-squamous NSCLC.\n\nClinical trial evidence suggests that people who have nivolumab plus ipilimumab and 2\xa0cycles of platinum-doublet chemotherapy (nivolumab combination) live longer than those who have platinum-doublet chemotherapy alone. Nivolumab combination has only been compared indirectly with other treatments. The results of these indirect comparisons of nivolumab combination with atezolizumab plus bevacizumab, carboplatin and paclitaxel (atezolizumab combination), pembrolizumab monotherapy, and pembrolizumab plus pemetrexed and platinum chemotherapy are uncertain. It is also uncertain how long the effect of nivolumab combination lasts.\n\nThe cost-effectiveness estimates for nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy are higher than what NICE considers an acceptable use of NHS resources. The cost-effectiveness estimates compared with pembrolizumab plus pemetrexed and platinum chemotherapy are uncertain because of problems with the analysis.\n\nThere is no additional data that could be collected through the Cancer Drugs Fund or from clinical trials that could resolve the uncertainty. So, nivolumab combination is not recommended for routine use or through the Cancer Drugs Fund.', 'Information about nivolumab with ipilimumab and chemotherapy': "# Marketing authorisation indication\n\nNivolumab (Opdivo, Bristol Myers Squibb) plus ipilimumab (Yervoy, Bristol Myers Squibb) and 2\xa0cycles of platinum-based (platinum-doublet) chemotherapy has a marketing authorisation for 'the first-line treatment of metastatic non-small-cell lung cancer in adults whose tumours have no sensitising epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of nivolumab is £2,633 per 240\xa0mg per 24‑ml vial (excluding VAT; BNF online, accessed May 2021). The list price of ipilimumab is £15,000 per 200\xa0mg per 40‑ml vial (excluding VAT; BNF online, accessed May 2021). The company has commercial arrangements for nivolumab and ipilimumab. These make nivolumab and ipilimumab available to the NHS with discounts, which would have applied to this indication if the technology had been recommended. The size of the discounts is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discounts.", 'Committee discussion': "The appraisal committee considered evidence submitted by Bristol Myers Squibb, a review of this submission by the evidence review group (ERG), and responses from stakeholders. See the committee papers for full details of the evidence.\n\nThe appraisal committee was aware that several issues were resolved during the technical engagement stage, and agreed that:\n\nthe populations in the clinical trials generally reflected people who would have treatment in NHS clinical practice (issue\xa02, see ERG report page\xa017)\n\nthe company's indirect treatment comparisons at technical engagement were acceptable for decision making, despite some differences between the trials in patient characteristics and trial design (issue\xa03, see ERG report page\xa018)\n\nthe CheckMate‑227 data should be incorporated into the indirect treatment comparisons (issue\xa04, see ERG report page\xa019)\n\nnivolumab plus ipilimumab and 2\xa0cycles of platinum-doublet chemotherapy (nivolumab combination) was likely to have similar efficacy across subgroups, including people aged\xa075 and over, people who have never smoked, and people with liver or bone metastases (issue\xa05, see ERG report page\xa020)\n\nthe duration of treatment for atezolizumab plus bevacizumab, carboplatin and paclitaxel (atezolizumab combination) should be based on the observed data from the IMPower150\xa0trial (issue\xa011, see ERG report page\xa027)\n\ndocetaxel should be removed as a subsequent therapy for people having first-line platinum-doublet chemotherapy (issue\xa015, see ERG report page\xa030).\n\nThe committee recognised that there were remaining areas of uncertainty associated with the analyses presented, and took these into account in its decision making. It discussed the following issues, which were outstanding after the technical engagement stage:\n\nwhether the decision problem should be split into 3\xa0separate subgroups based on histology (non-squamous or squamous non-small-cell lung cancer [NSCLC]) and PD‑L1 tumour proportion score (TPS; issue 1, see ERG report page\xa016)\n\nwhether different curves should be used to model overall survival and progression-free survival for nivolumab combination in these 3\xa0subgroups (issue\xa08, see ERG report, page\xa023)\n\nwhat composition of platinum-doublet chemotherapy best reflects NHS clinical practice (issues\xa06 and 7, see ERG report, pages 21\xa0to\xa023)\n\nwhether survival for people having platinum-doublet chemotherapy should be modelled using the CheckMate‑9LA data up to 13\xa0months and the CheckMate‑227 data thereafter, or using the CheckMate‑227 data alone (issue\xa09, see ERG report, page\xa025)\n\nhow long the effect of treatment with nivolumab combination lasts (issue\xa010, see ERG report, page\xa026)\n\nwhether the utility values should be based on progression status or time to death (issue\xa012, see ERG report, page\xa028)\n\nwhether the adjustment for relative dose intensity should be applied to the cost of the drug, or the expected required treatment dose (issue\xa013, see ERG report, page\xa029)\n\nwhat proportion of people have subsequent anticancer therapy after their first-line treatment (issue\xa014, see ERG report, page\xa029)\n\nwhether nivolumab combination meets the criteria for end of life treatments (issue\xa016, see ERG report, page\xa031)\n\nwhether nivolumab combination meets the criteria to be considered for use within the Cancer Drugs Fund (issue\xa017, see ERG report, page\xa032).\n\n# Clinical need and management\n\n## Nivolumab combination is another option for untreated, metastatic NSCLC\n\nThe clinical experts explained that immunotherapy with platinum-doublet chemotherapy (chemo-immunotherapy) is standard care in the NHS for untreated metastatic NSCLC with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. Most people having chemo-immunotherapy stop treatment before 2\xa0years because their disease progresses or there are tolerability issues, and few survive in the long term. The clinical experts considered that nivolumab combination is likely to have similar efficacy to other first-line chemo-immunotherapy combinations. Limiting the duration of chemotherapy to 2\xa0cycles may reduce renal toxicity and allow platinum-doublet chemotherapy to be offered again as a later-line therapy. The side effects of long-term immunotherapy are usually mild but can sometimes be considerable, needing specialist management. The clinical experts noted that combining 2\xa0immunotherapies is likely to cause more immune-related toxicities than current regimens with only 1\xa0immunotherapy. The committee concluded that nivolumab combination offers another treatment option for untreated metastatic NSCLC with no EGFR or ALK mutations, which may have advantages for some people.\n\n## Treatment and prognosis differ based on histology and PD-L1 status, and subgroups based on these should be considered separately\n\nThe clinical experts explained that:\n\ncurrent treatment is based on histology (non-squamous or squamous NSCLC) and PD‑L1 TPS, in line with NICE guidance\n\nprognosis may differ by histology and PD‑L1 TPS, and outcomes tend to be worse for people with squamous NSCLC.The ERG considered that the population with untreated metastatic NSCLC who have no EGFR or ALK tumour mutations should be split into 3\xa0subgroups, according to the treatments currently available:\n\nnon-squamous NSCLC, with PD‑L1 TPS below 50%\n\nsquamous NSCLC, with PD‑L1 TPS below 50% and\n\nNSCLC of either histology, with PD‑L1 TPS at least 50%.The committee concluded that it was appropriate to consider the 3\xa0subgroups identified by the ERG separately.\n\n## The comparators are appropriate, but pembrolizumab plus pemetrexed and platinum chemotherapy is also relevant for non-squamous NSCLC\n\nThe committee heard that, in line with NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for non-squamous NSCLC and pembrolizumab with carboplatin and paclitaxel for squamous NSCLC, these combinations are widely used in NHS clinical practice. When the scope for this appraisal was developed, pembrolizumab plus pemetrexed and platinum chemotherapy was recommended for use within the Cancer Drugs Fund. So, it was not included as a comparator in line with NICE's position statement on handling comparators and treatment sequences in the Cancer Drugs Fund. However, it is now recommended for routine commissioning, and is therefore an appropriate comparator for non-squamous NSCLC. NICE's technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel is being reviewed, but this technology is still recommended for use within the Cancer Drugs Fund while the review is ongoing. It is therefore not an appropriate comparator. The committee understood that, in line with the scope, the following comparators were included in the cost-effectiveness analysis:\n\nplatinum-doublet chemotherapy for all 3\xa0subgroups, including optional pemetrexed maintenance for people with non-squamous NSCLC\n\natezolizumab combination for the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50%\n\npembrolizumab monotherapy for the subgroup with either histology and PD‑L1 TPS at least 50%.The committee agreed that these comparators were appropriate. However, it concluded that pembrolizumab plus pemetrexed and platinum chemotherapy became a relevant comparator for non-squamous NSCLC. So it should be included in the analysis to reflect established NHS practice (see section\xa03.7).\n\n# Clinical effectiveness\n\n## CheckMate-9LA does not include all the relevant treatments used in NHS clinical practice\n\nThe main clinical effectiveness evidence for nivolumab combination came from CheckMate‑9LA. This is an ongoing open-label phase\xa03 randomised controlled trial, comparing nivolumab combination with standard platinum-doublet chemotherapy. For people with non-squamous NSCLC, platinum-doublet chemotherapy was pemetrexed plus either cisplatin or carboplatin, with optional pemetrexed maintenance therapy. For people with squamous NSCLC, platinum-doublet chemotherapy was paclitaxel plus carboplatin. The committee was aware that CheckMate‑9LA included adults with untreated recurrent or metastatic NSCLC (with no EGFR or ALK mutations) with an Eastern Cooperative Oncology Group performance status of 0 or 1. The trial included people regardless of PD‑L1 status. CheckMate‑9LA did not include these comparators used in NHS clinical practice:\n\natezolizumab combination and pembrolizumab plus pemetrexed and platinum chemotherapy (for non-squamous NSCLC and PD‑L1 TPS below 50%)\n\npembrolizumab monotherapy (for NSCLC of any histology and PD‑L1 TPS at least 50%)\n\npembrolizumab plus pemetrexed and platinum chemotherapy (for non-squamous NSCLC).The committee acknowledged that, because there was no head-to-head evidence with these comparators, indirect treatment comparisons were needed to assess the relative effectiveness of nivolumab combination.\n\n## Nivolumab combination improves overall and progression-free survival compared with standard chemotherapy\n\nAn interim analysis of CheckMate‑9LA showed a statistically significant difference in overall and progression-free survival in favour of nivolumab combination compared with standard platinum-doublet chemotherapy. At the most recent data cut (March 2020), median overall survival was 15.6\xa0months for nivolumab combination and 10.9\xa0months for standard chemotherapy (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.55 to 0.80). Median progression-free survival was 6.7\xa0months for nivolumab combination and 5.0\xa0months for standard chemotherapy (HR\xa00.68, 95%\xa0CI 0.57 to 0.82). Some people having nivolumab combination in CheckMate‑9LA had either immunotherapy or a therapy targeted against EGFR, ALK or vascular endothelial growth factor as a subsequent therapy. This did not represent NHS clinical practice, because people would not have immunotherapy again or a targeted therapy on disease progression. The clinical experts stated that this was unlikely to have had a large effect on treatment outcomes. But it meant that the survival of people having nivolumab combination may have been overestimated in CheckMate‑9LA. The committee concluded that nivolumab combination was clinically effective compared with standard chemotherapy.\n\n# Indirect treatment comparisons\n\n## Most of the company's indirect treatment comparisons are acceptable for decision making, despite uncertainty\n\nThe company did indirect treatment comparisons because there were no head-to-head trials comparing nivolumab combination with pembrolizumab monotherapy and atezolizumab combination. The company considered that the proportional hazards assumption (that is, the relative risk of an event is fixed irrespective of time) was not met. It therefore used fractional polynomial models to estimate time-varying hazard ratios. The committee noted that this approach meant that there was a lot of uncertainty with the indirect treatment comparisons. For the indirect comparison with pembrolizumab monotherapy in the subgroup with PD‑L1 TPS at least 50%, the company used the data from the full intention-to-treat (ITT) population from CheckMate‑9LA. For the comparison with atezolizumab combination for the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50%, the company used the data from the relevant subgroup of CheckMate‑9LA. The results of the indirect comparisons are confidential and cannot be reported here. At technical engagement, it was agreed that the CheckMate‑227 data should also be included in the indirect treatment comparisons. CheckMate‑227 is an ongoing open-label phase\xa03 randomised controlled trial in a similar population to that in CheckMate‑9LA. It includes a nivolumab plus ipilimumab treatment arm and a platinum-doublet chemotherapy treatment arm, both stratified by PD‑L1 TPS. The most recent data cut from CheckMate‑227 (February 2020) had a minimum follow up of 37.7\xa0months compared with 12.7\xa0months for CheckMate‑9LA. The committee noted that some of the company's indirect treatment comparison results had wide confidence intervals and were uncertain, but concluded that they were acceptable for decision making.\n\n## The indirect treatment comparison with pembrolizumab plus pemetrexed plus platinum chemotherapy is not suitable for decision making\n\nAt the first meeting, the committee concluded that pembrolizumab plus pemetrexed and platinum chemotherapy was now widely used in the NHS. It was approved for routine use after the initial scope for this appraisal, and became a relevant comparator for the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50% (see section\xa03.3). So, the company updated its indirect treatment comparison at consultation. It found that nivolumab combination was more effective than pembrolizumab plus pemetrexed and platinum chemotherapy in this subgroup. The ERG was concerned because:\n\nthe updated indirect treatment comparison excluded pembrolizumab monotherapy as a comparator\n\nthere was no evidence for pembrolizumab monotherapy compared with pembrolizumab plus pemetrexed and platinum chemotherapy in the subgroup with non-squamous NSCLC and PD‑L1 TPS at least 50%.The ERG explained that the updated analysis included an additional trial for pembrolizumab plus pemetrexed and platinum chemotherapy. This affected both the nivolumab combination arm and the atezolizumab combination arm. It increased the life years gained for nivolumab combination but reduced the life years gained for atezolizumab combination. The additional trial increased the incremental difference in life years gained, which the ERG was unable to validate. The committee discussed the unexpected results of the comparison of nivolumab combination with pembrolizumab plus pemetrexed and platinum chemotherapy; particularly that a shorter duration of treatment resulted in a longer duration of benefit for this pembrolizumab combination. The ERG considered that the modelling for this comparison was not robust enough for decision making. The company explained that KEYNOTE‑598 (a trial of pembrolizumab with either ipilimumab or placebo for people with untreated metastatic NSCLC) had a short follow up (about 12\xa0months), with heavy censoring around that time. But for the nivolumab combination trials, there was separation of the curves around 12\xa0months. However, the committee was aware that KEYNOTE‑598 was stopped because adding ipilimumab to the immunotherapy showed no incremental survival benefit. Also, the company's indirect treatment comparison comparing progression-free and overall survival for nivolumab combination with pembrolizumab for the subgroup with non-squamous and squamous NSCLC with PD‑L1 TPS at least 50% favoured single-agent immunotherapy, as in KEYNOTE‑598. But the difference was not statistically significant. The committee recalled that the clinical experts expected similar outcomes for the nivolumab combination and other first-line chemo-immunotherapy combinations (see section\xa03.1) in clinical practice. This contradicted the findings in the company's analysis, in which nivolumab combination dominated (was more effective and less expensive) the pembrolizumab combination. The committee had several concerns about the company's comparative efficacy and modelling results, which suggested that overall survival was better with nivolumab combination than with many other options. The committee noted that there was a lot of uncertainty with the fractional polynomial indirect treatment comparison (see section\xa03.6). It recalled a direct comparison in KEYNOTE‑198 showing that pembrolizumab plus ipilimumab was no better than pembrolizumab alone for non-squamous metastatic NSCLC. It also recalled previous trial evidence (KEYNOTE‑024, CheckMate‑026) which suggested that nivolumab monotherapy was inferior to pembrolizumab monotherapy for untreated NSCLC. So, the committee considered that the modelled outcomes did not seem realistic. The committee concluded that the company's indirect treatment comparison of nivolumab combination with pembrolizumab plus pemetrexed and platinum chemotherapy was not robust enough for decision making.\n\n# Adverse events\n\n## Nivolumab combination is likely to be less well tolerated than other chemo-immunotherapy combinations\n\nThe clinical experts explained that immunotherapy is generally well tolerated but is associated with some rare but unpleasant, and potentially serious, adverse events. These were likely to be more common for nivolumab combination (2\xa0different immunotherapies) than current chemo-immunotherapy combinations (only 1\xa0immunotherapy). The company did not agree, so at consultation provided further evidence using data from CheckMate‑227. It explained that:\n\nadverse events from chemotherapy are less frequent with nivolumab combination, which includes only 2\xa0cycles of chemotherapy\n\nadverse events with nivolumab combination tend to occur early in treatment and, if managed effectively, reduce with later cycles.The company provided adverse event results over time from an indirect treatment comparison of nivolumab combination and pembrolizumab plus chemotherapy. This showed no statistically significant differences in the odds of having adverse events leading to discontinuation of any drug in the combination. This was true for grade\xa03 to 5 and grade\xa01 to 5 adverse events. However, the ERG could not comment because details of the indirect treatment comparison were not available. The committee considered that it would be helpful to understand which drugs in the combinations are most frequently discontinued. It was unclear how the company's evidence on treatment-related adverse events over time should be interpreted, because some people would stop treatment for other reasons. The committee understood that clinicians are experienced in recognising and managing serious adverse events, and established toxicity management algorithms are in place. It concluded that nivolumab combination was likely to be less well tolerated than other chemo-immunotherapy combinations, so more specialist management would be needed for serious adverse events.\n\n# The company's economic model\n\n## The company's model structure is acceptable for decision making\n\nThe company used a 3‑state partitioned survival model to estimate the cost effectiveness of nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy. People were able to move to different health states; from pre-progression to post-progression and death and from post-progression to death. The ERG agreed with the company's model structure, noting that it was consistent with previous appraisals. For people having nivolumab combination and people having standard platinum-doublet chemotherapy, the company used the results from CheckMate‑9LA to model overall and progression-free survival for the first 13\xa0months. The results from CheckMate‑227 were used after this point because longer-term data was available (see section\xa03.6). Survival curves were modelled for the ITT population and applied for everyone, regardless of histology and PD‑L1 TPS. Relative risks from the indirect comparisons were then applied to the nivolumab combination data to estimate overall and progression-free survival for atezolizumab combination and for pembrolizumab monotherapy. The committee concluded that the company's model structure was acceptable for decision making. But it noted the uncertainty about whether it was appropriate to use the same survival curves for everyone (see section\xa03.11).\n\n## Including a 2-year stopping rule is acceptable\n\nThe company included a 2‑year treatment stopping rule in its model. The maximum possible duration for nivolumab combination in CheckMate‑9LA was 24\xa0months, and this was also stated in the summary of product characteristics. The committee understood that implementing a 2‑year stopping rule was consistent with other NICE technology appraisal guidance on untreated NSCLC. It also reflected how nivolumab combination would be used in clinical practice. The committee concluded that a 2‑year treatment stopping rule, in line with the clinical- and cost-effectiveness evidence, was acceptable.\n\n# Modelling survival\n\n## The company's analyses modelling survival for histology and PD-L1 subgroups separately are appropriate for decision making\n\nThe committee considered whether it was appropriate to use the same overall and progression-free survival curves across all 3\xa0subgroups, based on the ITT data from CheckMate‑9LA and CheckMate‑227 (see section\xa03.9). The company took this approach because it believed there was a consistent efficacy benefit across subgroups in CheckMate‑9LA, including those based on PD‑L1 and histology. However, the ERG noted that the CheckMate‑9LA and CheckMate‑227 results suggested there were differences in the absolute and relative efficacy of nivolumab combination across some of the subgroups. Clinical advice to the ERG was that people whose NSCLC has a higher PD‑L1 TPS generally have greater benefit with anti‑PD‑L1 immunotherapies. The company considered that using the ITT data was more appropriate than the subgroup data, because the subgroups were not prespecified and included smaller numbers of people. The company also noted that the lack of external clinical data available to validate the subgroup curves placed greater reliance on clinical opinion. Also, it considered that by combining 3\xa0different mechanisms of action, nivolumab combination was not expected to have the same efficacy differences by histology or PD‑L1 TPS as other immunotherapies. The committee considered that because it had agreed to separate the population into 3\xa0subgroups (see section\xa03.2), it was appropriate to reflect this heterogeneity in the data used to generate the survival curves. It also noted that applying separate survival curves based on the subgroup data had a considerable impact on the cost-effectiveness results. The committee agreed that there was uncertainty about the validity of applying survival curves derived from the ITT data across all the subgroups. It concluded that survival curves should be modelled separately for each subgroup. So, in its updated base case after consultation, the company modelled the survival curves separately for each subgroup, based on the 1‑year data cut for CheckMate‑9LA and 3‑year data cut for CheckMate‑227. The company highlighted that CheckMate‑9LA not was not stratified or powered for analyses of combined histology and PD‑L1 subgroups. The committee concluded that the company's analyses modelling overall survival data for histology and PD‑L1 subgroups separately were appropriate for decision making.\n\n## Survival for people having platinum-doublet chemotherapy should be modelled using the CheckMate-227 data alone\n\nThe ERG noted that median overall survival for people having platinum-doublet chemotherapy was longer in CheckMate‑227 than in CheckMate‑9LA. This could have been because fewer people had subsequent therapy in CheckMate‑9LA than in CheckMate‑227. The ERG considered that the proportion of people having subsequent therapy after platinum-doublet chemotherapy in CheckMate‑9LA was lower than in NHS clinical practice. It was therefore concerned that using the CheckMate‑9LA data to estimate survival for the first 13\xa0months (see section\xa03.9) may have underestimated survival for people having platinum-doublet chemotherapy. The ERG did a scenario analysis in which survival for people having platinum-doublet chemotherapy was modelled using the CheckMate‑227 data alone. In this, the relative efficacy of nivolumab combination was taken from the indirect treatment comparison. However, the ERG preferred to retain the company's original approach of using the CheckMate‑9LA data followed by the CheckMate‑227 data for its base case. This was because it used the same data sources for people having nivolumab combination and people having platinum-doublet chemotherapy. The committee noted that in NICE's technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for squamous NSCLC, it was estimated that around 50% of people having first-line chemotherapy have immunotherapy after disease progression. The clinical experts noted that this may be an underestimate based on the proportion of people switching from chemotherapy to pembrolizumab in the KEYNOTE‑024 trial. KEYNOTE‑024 was an open-label phase\xa03 randomised controlled trial, comparing pembrolizumab with chemotherapy for untreated metastatic NSCLC. At consultation, the company said that it preferred its original approach, in line with the nivolumab combination arm (CheckMate‑9LA data used up to 13\xa0months, then conditional survival from CheckMate‑227 applied). Because CheckMate‑9LA was the registration trial, the company felt it was the most appropriate to estimate survival for people having platinum-doublet chemotherapy. It would preserve the benefits of comparing between arms of the randomised controlled trial. The ERG found that the model predicted 5‑year survival of 10.5% for platinum-doublet chemotherapy using CheckMate‑227 alone, and 9% in the approach using CheckMate‑9LA and CheckMate‑227. This was consistent with previous appraisals. The committee understood that around 28% of people had subsequent immunotherapy after first-line chemotherapy in CheckMate‑9LA, compared with around 41% in CheckMate‑227. It considered that the rate of subsequent immunotherapy in CheckMate‑227 was likely closer to that in NHS clinical practice. The committee concluded that survival for people having platinum-doublet chemotherapy should be modelled using the CheckMate‑227 data alone.\n\n## A treatment effect lasting 3 to 5\xa0years after starting treatment is appropriate and consistent with previous appraisals\n\nThe company's base case included a lifetime treatment effect with nivolumab combination. The company justified this using pooled data from 4\xa0clinical trials of nivolumab for previously treated NSCLC, which showed that nivolumab had a long-term survival advantage over docetaxel. The ERG noted that a lifetime treatment effect was inconsistent with previous technology appraisals for NSCLC. For those, a treatment effect lasting from 3 to 5\xa0years after starting treatment had been accepted. The ERG also considered the pooled data used by the company to be of limited relevance. This was because the data was from trials of nivolumab as a monotherapy in a population who had previous treatment, and survival outcomes were only reported to 4\xa0years. The ERG preferred a scenario with a treatment effect lasting 5\xa0years after stopping treatment. This was modelled by setting the mortality rate as equal to that of platinum-doublet chemotherapy from this timepoint onwards. The committee understood that the assumption around the duration of treatment effect had a considerable impact on the cost-effectiveness results. It agreed that, although it was biologically plausible for the treatment effect to continue after stopping treatment with nivolumab combination, its duration was uncertain. The clinical experts explained that there was insufficient evidence to suggest the treatment effect of nivolumab combination lasted longer than for other immunotherapies. The committee concluded that a treatment effect lasting 3 to 5\xa0years after starting treatment was appropriate for decision making, for consistency with previous immunotherapy appraisals in NSCLC.\n\n## There is no evidence to support a treatment effect duration of longer than 3 to 5\xa0years\n\nAt consultation, the company's updated base case used a 5‑year treatment effect after stopping treatment. This was more optimistic than what the committee preferred at the first meeting, which was a treatment effect lasting 3 to 5\xa0years after starting treatment (see section\xa03.13). The company acknowledged the misunderstanding, but explained that a treatment effect of 5\xa0years after stopping would be a conservative assumption. It explained that the new CheckMate‑227 data would support an additional benefit over other chemo-immunotherapy combinations, particularly the number of people whose disease maintained a response at 3\xa0years. However, this new data did not arrive in time to be incorporated into its analyses. The committee recalled the plausible treatment effect duration for single-agent immunotherapy plus platinum-doublet chemotherapy and noted that strong evidence would be needed to accept a longer duration. It considered that there was no evidence that nivolumab combination had a longer treatment effect duration than pembrolizumab plus platinum-doublet chemotherapy. So, a more favourable assumption could not be made for nivolumab combination. The committee concluded that its preferred assumption for nivolumab combination was still a treatment effect lasting 3 to 5\xa0years after starting treatment.\n\n# Health-related quality of life\n\n## The ERG's approach of using progression-based utility values is preferred\n\nThe ERG explained that the company's time-to-death approach for including utility values was not appropriate. This was because in previous technology appraisals in which this approach had been accepted, health-related quality-of-life data had only been collected for up to 30\xa0days after stopping treatment. This meant that the utility value for the post-progression state may have been overestimated, because the full effects of progression may not yet have been evident. However, in CheckMate‑9LA, health-related quality-of-life data was collected until death, and there were many observations (1,004) contributing to the post-progression health state. In contrast, there were only 114\xa0observations contributing to the utility value for 4\xa0weeks or less to death in the company's approach. The ERG also had concerns with using time to death to determine health-related quality of life. A time-to-death approach meant that people entering the model had a different health-related quality of life depending on the treatment arm they were assigned to. The ERG preferred a progression-based approach, using utility values derived from the EQ‑5D data collected in CheckMate‑9LA. The clinical experts explained that quality of life may not immediately decline after disease progression. The committee was also aware that progression-based utility values may be overestimated because there were fewer observations in people with more severe disease. However, it agreed with the ERG that utility values based on disease progression were more appropriate for decision making, given the large amount of data captured after progression. At consultation, the company maintained that the time-to-death approach was an appropriate way to include utility values. But it accepted the use of health state utility values in line with the committee's preferred assumption.\n\n# Composition of platinum-doublet chemotherapy\n\n## Separate chemotherapy regimen distributions should be used for each subgroup to reflect differences in clinical practice\n\nTo calculate the costs associated with platinum-doublet chemotherapy, the company based the distribution of chemotherapy regimens on the CheckMate‑9LA data. It applied the same assumption for everyone having platinum-doublet chemotherapy, regardless of histology or PD‑L1 TPS. The ERG considered that the distribution of chemotherapy regimens in CheckMate‑9LA may not reflect NHS clinical practice. For example, some people with squamous NSCLC were modelled as having pemetrexed, which they would not have in practice. It noted that there were differences in drug and administration costs between chemotherapy regimens, which meant that the costs calculated from the company's distribution may not have been representative. The ERG preferred to apply a specific distribution of chemotherapy agents for each subgroup (see section\xa03.2), including different proportions of people having pemetrexed maintenance therapy. It took these distributions from reported UK market share information in:\n\nNICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for non-squamous NSCLC (TA557) and\n\nNICE's technology appraisal guidance on pembrolizumab with carboplatin and paclitaxel for squamous NSCLC (TA600).At technical engagement and with clinical input, the company revised the proportion of people having each chemotherapy regimen but continued to apply a single weighted distribution for everyone. The clinical experts explained that the most widely used chemotherapy regimens in clinical practice differed by histology. Carboplatin plus either gemcitabine or vinorelbine were the most common combinations for people with squamous NSCLC, but pemetrexed was preferred for people with non-squamous NSCLC. The committee considered that these differences should be reflected in the composition of platinum-doublet chemotherapy in the economic model. It concluded that the ERG's approach of applying separate distributions of chemotherapy regimens for each subgroup was more appropriate for decision making.\n\n# Subsequent therapy\n\n## The proportion of people having subsequent therapy should be based on the CheckMate-227 data\n\nIn the company's model, 31% of people having nivolumab combination as their first-line treatment had subsequent therapy, based on the CheckMate‑9LA data. The same assumption was used for people having pembrolizumab monotherapy and atezolizumab combination. In the model, 40% of people having platinum-doublet chemotherapy as their first-line treatment had subsequent therapy. The ERG noted that the data on the rates of subsequent therapy from CheckMate‑9LA was immature, and likely an underestimate. The rates from CheckMate‑227 were higher (45% for people having nivolumab combination as first-line treatment, and 61% for people having platinum-doublet chemotherapy). The ERG considered that the CheckMate‑227 rates were more in line with those seen in NHS clinical practice. They were also based on more mature data. Also, using the CheckMate‑227 data was consistent with the approach used for modelling long-term survival. At technical engagement, the company accepted that the rates of subsequent therapy in CheckMate‑9LA may be lower than expected in a clinical trial, but considered that they reflected NHS clinical practice. The committee recalled its earlier conclusion that the proportion of people having subsequent therapy in the clinical trials was likely lower than in NHS clinical practice (see section\xa03.12). Therefore, it concluded that the higher rates from CheckMate‑227 better reflected clinical practice and should be used in the model.\n\n# Relative dose intensity\n\n## The difference between the company and the ERG's relative dose intensity adjustments has minimal impact on the cost-effectiveness results\n\nRelative dose intensity is the percentage of the prescribed dose of a treatment that people take. The company applied the relative dose intensities to the cost of the drug, after this had been estimated from the number of vials needed based on the treatment dose in the marketing authorisation. The ERG considered it more appropriate to apply the relative dose intensities to the expected treatment dose, and then calculate the number of vials and associated drug costs from these adjusted numbers. Because this may not necessarily reduce the number of vials, the ERG was concerned that the company may have underestimated the drug costs. The committee concluded that the relative dose intensity likely lay between the company's and the ERG's assumptions. However, it noted that this had minimal impact on the cost-effectiveness results.\n\n# End of life\n\n## Nivolumab combination is likely to meet the end of life criteria for squamous NSCLC with PD-L1 TPS below 50%\n\nThe committee considered the advice about life-extending treatment for people with a short life expectancy in NICE's guide to the methods of technology appraisal. It understood that, at the first meeting, the company and the ERG agreed that nivolumab combination did not meet the criteria for end of life treatments for:\n\nnon-squamous NSCLC and PD‑L1 TPS below 50% or\n\nNSCLC of either histology and PD‑L1 TPS at least 50%.For the subgroup with squamous NSCLC and PD‑L1 TPS below 50%, both the company's and the ERG's base cases predicted a mean overall survival of around 24\xa0months for people having platinum-doublet chemotherapy. The clinical experts stated that the life expectancy for this subgroup was likely to be less than 2\xa0years, even with immunotherapy. The company and the ERG estimated that the mean life extension for nivolumab combination in this subgroup was more than 3\xa0months compared with platinum-doublet chemotherapy. The committee was satisfied that nivolumab combination was likely to meet the criteria for end of life treatments in the subgroup with squamous NSCLC and PD‑L1 TPS below 50%.\n\n## The end of life criteria are not met for all other populations covered by this appraisal\n\nAt consultation, the company presented evidence to support that the end of life criteria should apply across all the populations in this appraisal. This included a retrospective study using data from the Flatiron database, for people with stage\xa03B or stage\xa04 NSCLC who had chemo-immunotherapy (over 98% had pembrolizumab plus chemotherapy). The reported median overall survival for people with squamous and non-squamous NSCLC was shorter than in the KEYNOTE‑407 and KEYNOTE‑189 trials. However, the ERG considered it uncertain whether the Flatiron evidence reflected the population who would have nivolumab combination for untreated, metastatic NSCLC in the NHS. This was because people in the Flatiron dataset had poorer performance status, were older, and were more likely to have unstable brain metastases. Also, they had treatment in the US, which has different treatment patterns to the UK. The company contrasted the real-world Flatiron evidence with real-world evidence for nivolumab as second-line treatment for NSCLC. It explained that outcomes in clinical practice (from the Systemic Anti-Cancer Therapy Dataset) were similar to those seen in the randomised controlled trials. The committee recalled that in NICE's technology appraisal guidance on pembrolizumab with pemetrexed and platinum chemotherapy for non-squamous NSCLC, the committee did not accept that the end of life criteria were met. The ERG noted that there was little long-term observational evidence on whether having nivolumab first line would extend survival by 3\xa0months in clinical practice. It considered that efficacy might decline in practice (similar to the clinical trial) when people with more severe disease have nivolumab. Also, survival may not be extended by 3\xa0months for people with severe disease. But the ERG noted that this was uncertain and not supported by evidence. The Cancer Drugs Fund clinical lead explained that real-world outcomes for chemo-immunotherapy seem to reflect what is seen in trials. This is because people must be well enough to have chemo-immunotherapy, which has additional selection considerations for clinicians, compared with immunotherapy alone. The committee considered that the evidence presented by the company only showed that the end of life criteria could plausibly be met for the subgroup with squamous NSCLC and PD‑L1 TPS below 50%. It recalled that mean survival was preferable to median survival for decision making around end of life criteria for chemo-immunotherapy. The committee concluded that the criteria were not met for all other populations covered by this appraisal.\n\n# Cost-effectiveness results\n\n## Nivolumab combination is not cost effective in any subgroup\n\nThe committee recalled that its preferred assumptions were:\n\nconsidering 3\xa0separate subgroups based on histology and PD‑L1 TPS (see section\xa03.2)\n\napplying separate survival curves for each subgroup (see section\xa03.11)\n\nmodelling survival for people having platinum-doublet chemotherapy using the CheckMate‑227 data alone (see section\xa03.12)\n\na treatment effect lasting 3 to 5\xa0years after starting treatment (see section\xa03.13 and\xa0section 3.14)\n\nutility values based on disease progression rather than time to death (see section\xa03.15)\n\napplying separate platinum-doublet chemotherapy distributions for each subgroup, using UK market share data from TA557 and TA600 (see section\xa03.16)\n\nsubsequent treatment rates based on the CheckMate‑227 data (see section\xa03.17).The cost-effectiveness results are commercial in confidence because they included the discounts from commercial access agreements and patient access schemes for atezolizumab, pembrolizumab, bevacizumab and pemetrexed maintenance.\n\nFor the subgroup with squamous NSCLC and PD‑L1 TPS below 50%, the incremental cost-effectiveness ratios (ICERs) for nivolumab combination compared with platinum‑doublet chemotherapy were above what is normally considered a cost‑effective use of NHS resources for end of life treatments (£50,000 per quality-adjusted life year [QALY] gained).\n\nFor the subgroup with non-squamous NSCLC and PD‑L1 TPS below 50%, the ICERs for nivolumab combination compared with both atezolizumab combination and platinum-doublet chemotherapy were above the upper end of the range normally considered a cost-effective use of NHS resources (£30,000 per QALY gained). Although nivolumab combination dominated (was more effective and less expensive) pembrolizumab plus pemetrexed and platinum-doublet chemotherapy, the analysis was not considered robust enough for decision making and the modelled outcomes did not seem realistic.\n\nFor the subgroup with NSCLC of either histology and PD‑L1 TPS at least 50%, nivolumab combination was more costly and less effective than pembrolizumab monotherapy (that is, it was dominated by pembrolizumab). Compared with platinum-doublet chemotherapy, the ICERs were above £30,000 per QALY gained.The committee concluded that the cost-effectiveness estimates for nivolumab combination were mostly higher than what NICE normally considers a cost-effective use of NHS resources.\n\n# Other factors\n\nNo relevant equalities issues were identified.\n\nThe company stated that nivolumab combination was innovative because it was the first dual immunotherapy licensed for NSCLC. However, the clinical experts explained that they did not consider the treatment to be innovative because the important step change had already been made by the earlier immunotherapies. The committee concluded that there were no additional benefits associated with nivolumab combination that had not been captured in the economic analysis.\n\n# Conclusion\n\n## Nivolumab combination is not recommended for routine use in the NHS\n\nNivolumab combination is more clinically effective than standard chemotherapy, and is likely to have similar efficacy to other chemo-immunotherapies. The committee agreed that the most plausible ICERs for nivolumab combination compared with platinum-doublet chemotherapy, atezolizumab combination and pembrolizumab monotherapy were mostly higher than what NICE normally considers a cost-effective use of NHS resources. The results comparing nivolumab combination with pembrolizumab plus pemetrexed and platinum chemotherapy did not seem realistic, and that analysis was not considered robust enough for decision making. Therefore, it concluded that nivolumab combination could not be recommended for routine use as an option for untreated metastatic NSCLC with no EGFR or ALK mutations.\n\n## Nivolumab combination is not recommended for use in the Cancer Drugs Fund\n\nHaving concluded that nivolumab combination could not be recommended for routine use, the committee then considered if it could be recommended within the Cancer Drugs Fund. The committee discussed the arrangements for the Cancer Drugs Fund agreed by NICE and NHS England in 2016, noting NICE's Cancer Drugs Fund technology appraisal process and methods guide (addendum). The company had expressed an interest in the treatment being considered for funding through the Cancer Drugs Fund. At consultation, the company provided the most up-to-date overall survival results for CheckMate‑9LA compared with CheckMate‑227, for subgroups with:\n\nnon-squamous NSCLC and PD‑L1 TPS below 50%\n\nall types of non-squamous NSCLC\n\nsquamous NSCLC with PD‑L1 TPS below 50%\n\nall types of squamous NSCLC.The company considered this data to be commercially sensitive so it cannot be shown here. The company explained that additional data for both these trials would reduce uncertainty, increase confidence in the analyses, and allow long-term outcomes across currently approved chemo-immunotherapy regimens to be compared. The ERG considered that, because the new data was not included in the new indirect treatment comparisons, the long-term efficacy of nivolumab combination compared with other chemo-immunotherapy combinations was uncertain. Also, any long-term outcomes data collected in the Cancer Drugs Fund would be affected by subsequent treatments that people had in CheckMate‑9LA, which are not used in UK practice. The ERG emphasised that even if data for nivolumab combination was collected in the Cancer Drugs Fund, the maximum duration of treatment benefit that could be seen would be 5\xa0years from the start of treatment. This would be in line with the upper limit of the committee's preference. At the first meeting, the key uncertainty around lifelong duration of benefit (that is, cure in some people) was thought to be unresolvable with up to 2\xa0years of further data collection. The committee understood that CheckMate‑9LA and CheckMate‑227 were ongoing, and further data would become available. However, the committee agreed that this would likely be insufficient to reduce the uncertainty affecting the cost-effectiveness results, particularly the duration of the treatment effect. The committee concluded that nivolumab combination did not meet the criteria to be considered for inclusion in the Cancer Drugs Fund."}
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https://www.nice.org.uk/guidance/ta724
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Evidence-based recommendations on nivolumab (Opdivo) with ipilimumab (Yervoy) and chemotherapy for untreated metastatic non-small-cell lung cancer.
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fe62c382cd7b2655d8a8f2b99763b30eacc43c87
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nice
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Bimekizumab for treating moderate to severe plaque psoriasis
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Bimekizumab for treating moderate to severe plaque psoriasis
Evidence-based recommendations on bimekizumab (Bimzelx) for treating moderate to severe plaque psoriasis in adults.
# Recommendations
Bimekizumab is recommended as an option for treating plaque psoriasis in adults, only if:
the disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of 10 or more and a Dermatology Life Quality Index (DLQI) of more than 10 and
the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
the company provides the drug according to the commercial arrangement.
Stop bimekizumab treatment at 16 weeks if the psoriasis has not responded adequately. An adequate response is defined as:
a 75% reduction in the PASI score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in DLQI from when treatment started.
Choose the least expensive treatment if patients and their clinicians consider bimekizumab to be one of a range of suitable treatments (taking into account availability of biosimilar products, administration costs, dosage, price per dose and commercial arrangements).
Take into account how skin colour could affect the PASI score and make any appropriate clinical adjustments.
Take into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any appropriate adjustments.
These recommendations are not intended to affect treatment with bimekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.
Why the committee made these recommendations
Bimekizumab is an alternative to other biological treatments already recommended by NICE for treating severe plaque psoriasis in adults. Evidence from clinical trials shows that bimekizumab is more effective than adalimumab, secukinumab and ustekinumab. Indirect comparisons suggest that bimekizumab is similarly or more effective than other biological treatments.
For the cost comparison, it is appropriate to compare bimekizumab with brodalumab, risankizumab and ixekizumab because they work in a similar way and would likely be used as an alternative to those treatments. The total costs associated with bimekizumab are similar to or lower than those associated with brodalumab, risankizumab and ixekizumab. Therefore, bimekizumab is recommended as an option for severe plaque psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.# Information about bimekizumab
# Marketing authorisation indication
Bimekizumab (Bimzelx, UCB Pharma) has a marketing authorisation 'for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.
# Dosage in the marketing authorisation
The dosage schedule is available in the summary of product characteristics.
# Price
The list price of bimekizumab is £2,443 per 320 mg dose (two 160 mg prefilled syringes or prefilled pens; excluding VAT; price as quoted in company's submission).
The company has a commercial arrangement. This makes bimekizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.# Committee discussion
The appraisal committee considered evidence submitted by UCB Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.
# Decision problem
## The company's proposed population is consistent with previous NICE recommendations for biological treatments for psoriasis
The company's proposed population was narrower than bimekizumab's marketing authorisation because it excluded people who had not had systemic non-biological therapy or phototherapy. It considered that bimekizumab would be used in adults as an alternative to other biological therapies for psoriasis, that is in those whose disease has not responded adequately to non-biological systemic treatment or phototherapy, or if these treatments are contraindicated or not tolerated. The committee concluded that the proposed population was consistent with previous NICE recommendations for biological treatments for psoriasis, and in line with its expected use in clinical practice.
## Brodalumab, risankizumab and ixekizumab are relevant comparators
The company presented a comparison with 3 NICE-recommended biological treatments (NICE's technology appraisals on brodalumab, risankizumab and ixekizumab for treating moderate to severe plaque psoriasis). The committee noted in a recent guideline from the British Association of Dermatologists (2020) that all of the currently licensed biological therapies are now equally recommended options after non-biological systemic therapy. The committee was aware that adalimumab biosimilars have been available to the NHS since 2019 and are available at considerable discount (exact prices are confidential and cannot be reported here). But it was told that in clinical practice a TNF inhibitor such as adalimumab was frequently used first, followed by an interleukin (IL) inhibitor. Brodalumab and ixekizumab work in a similar way to bimekizumab because they are all IL‑17 inhibitors. Risankizumab, an IL‑23 inhibitor, is the most recent biological treatment for psoriasis to be recommended by NICE. The committee noted that if bimekizumab was recommended it would likely displace other IL inhibitors. It was aware that cost comparison recommendations include a statement to note that if patients and their clinicians consider the intervention to be 1 of a range of suitable treatments, the least expensive should be chosen. The committee agreed that this was consistent with the criteria for a cost-comparison appraisal. It concluded that brodalumab, risankizumab and ixekizumab are relevant comparators, and that they adequately represent the NICE-recommended biological treatments for plaque psoriasis overall.
## Definition of response is consistent with other NICE technology appraisal guidance
The committee recalled that NICE's technology appraisal guidance on risankizumab for treating moderate to severe plaque psoriasis and other biological treatments recommends that treatment should stop if there is an inadequate disease response after an initial treatment period, usually between 12 and 16 weeks. An adequate response is defined as:
a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75) from when treatment started or
a 50% reduction in the PASI score (PASI 50) and a 5‑point reduction in Dermatology Life Quality Index (DLQI) from when treatment started.The committee noted that the definition of response to bimekizumab proposed by the company is in line with these criteria. However, it noted that response to bimekizumab should be assessed after 16 weeks, which is the same as timing for risankizumab, whereas disease response to brodalumab and ixekizumab should be assessed after 12 weeks. The committee concluded that definition of response is consistent with other NICE technology appraisal guidance, although timing of this assessment varies slightly between different biological treatments.
# Clinical effectiveness
## Bimekizumab is more effective than adalimumab, secukinumab and ustekinumab
Bimekizumab has been studied in 4 randomised controlled trials including a total of about 2,200 adults with plaque psoriasis. It was directly compared in clinical trials with placebo (BE READY), with placebo and ustekinumab (BE VIVID), with adalimumab (BE SURE) and with secukinumab (BE RADIANT). In these trials, bimekizumab showed higher response rates compared with placebo, ustekinumab, adalimumab and secukinumab for both PASI 90 (90% reduction in PASI score) and PASI 100 (100% reduction in PASI score) at week 16. The committee accepted that the results of these trials showed that bimekizumab was more effective than adalimumab, secukinumab and ustekinumab.
## The company's network meta-analyses are suitable for decision making
The company did a series of network meta-analyses on PASI response rates (50, 75, 90 and 100) and safety outcomes. These compared bimekizumab with all other NICE-recommended biological agents and systemic non-biological treatments. The ERG noted that studies included in network meta-analyses varied considerably in the proportion of patients who had had previous biological therapies. It noted that disease response to subsequent biological treatments may be lower than the level of response achieved by the initial biological therapy. However, it explained that because the proportion of people who had previous biological therapy in bimekizumab trials was at the higher end of the range for the network as a whole, this is unlikely to bias the results in favour of bimekizumab. The ERG also noted that the company had not included DLQI as an outcome in the network meta-analysis. However, it was satisfied that the company's approach was appropriate. The committee accepted the ERG's view, concluding that the network meta-analyses provided by the company was suitable for decision making.
## Bimekizumab provides similar or better PASI response rates than other biologicals
The committee acknowledged that in previous psoriasis appraisals, PASI 75 is the key outcome when deciding whether to continue treatment. It noted that the results of the network meta-analysis suggested that bimekizumab was similarly effective compared with brodalumab, risankizumab and ixekizumab in terms of PASI 75 response. The committee appreciated that PASI 90 and 100 were increasingly becoming important outcomes to patients and were collected in newer clinical trials. It noted that bimekizumab was more effective compared with brodalumab, risankizumab and ixekizumab in terms of PASI 90 and 100 response. It noted the safety and tolerability outcomes in the company's network meta-analysis and considered that bimekizumab had a similar safety profile to other biologicals for psoriasis. The committee concluded that bimekizumab provides similar or greater benefits than other biological agents including brodalumab, risankizumab and ixekizumab.
## More frequent dosing of bimekizumab will be rarely used
The committee noted that summary of product characteristics states that some patients with body weight 120 kg or more who did not have complete skin clearance at week 16 (PASI100) may improve further if they increase their dosage (320 mg every 4 weeks rather than every 8 weeks). The company explained that only a small proportion of patients in bimekizumab trials had a body weight 120 kg or more, and had not had a PASI 100 response. Also, it explained that this dosing option will not be mandated in label, nor is it anticipated to be standard dosing regimen for patients. The committee recalled that PASI 90 and 100 are important outcomes for patients but PASI 75 was a key outcome when deciding whether to continue treatment. It further noted that between 85% and 90% of people having bimekizumab in the clinical trials had a PASI 90 response and up to 95% of people had a PASI 75 response. It noted people whose disease reached at least a PASI 75 response may not be willing to have their dose increased to achieve PASI 100 because of an increased risk of side effects, or the inconvenience of more frequent dosing. The committee concluded that only a very small number of patients might be eligible for an increased dosage, and only a small proportion of them would be willing to have it.
# Cost comparison
## The total costs associated with bimekizumab are similar to or lower than those associated with brodalumab, risankizumab and ixekizumab
The company presented a cost-comparison analysis that modelled the total costs of bimekizumab and the comparators brodalumab, risankizumab and ixekizumab over 10 years. It took into account stopping treatment based on PASI 75 response rates, which was consistent with the stopping rules specified in previous NICE's technology appraisal guidance. The base-case analysis used the same PASI 75 response rates and applied the same rate of long-term stopping of treatment during maintenance therapy for all treatments. The base-case analysis assumed similar monitoring, safety profile, treatment administration and subsequent therapies for bimekizumab and the comparators, and therefore excluded these costs. That is, the base-case analysis considered only the acquisition costs of bimekizumab and the comparators. The committee accepted the company's base-case model. The committee was aware that there was the possibility for some patients to have more frequent dosing but recalled that this would only happen in very rare circumstances (see section 3.7). Assuming that 10% of patients who are eligible would want to have more frequent dosing had a minimal effect on the cost-comparison results (the results are confidential and cannot be reported here). Considering the confidential patient access schemes for bimekizumab and the comparators, the committee concluded that the total costs associated with bimekizumab were similar to or lower than those associated with brodalumab, risankizumab and ixekizumab (the exact results cannot be reported here because the discounts are confidential).
## Bimekizumab is recommended as an option for treating severe plaque psoriasis in adults
The committee concluded that the criteria for a positive cost comparison were met because:
bimekizumab provided similar or greater overall health benefits than brodalumab, risankizumab and ixekizumab, and
the total costs associated with bimekizumab were similar to or lower than the total costs associated with brodalumab, risankizumab and ixekizumab.The committee therefore recommended bimekizumab as an option for treating plaque psoriasis in adults. It concluded that the recommendations for bimekizumab should be consistent with the company's proposal and NICE's recommendations for other biological therapies, that is:
if the disease is severe (that is, a PASI of 10 or more and a DLQI of more than 10) and
when the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and
when treatment is stopped at 16 weeks if the psoriasis has not responded adequately.If patients and their clinicians consider bimekizumab to be one of a range of suitable treatments, for example brodalumab, risankizumab and ixekizumab, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).
## The PASI and DLQI may not be appropriate for all people with psoriasis
The committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:
the PASI might underestimate disease severity in people with darker skin
the DLQI has limited validity in some people and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any adjustments they consider appropriate.
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{'Recommendations': 'Bimekizumab is recommended as an option for treating plaque psoriasis in adults, only if:\n\nthe disease is severe, as defined by a total Psoriasis Area and Severity Index (PASI) of\xa010 or more and a Dermatology Life Quality Index (DLQI) of more than\xa010 and\n\nthe disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nthe company provides the drug according to the commercial arrangement.\n\nStop bimekizumab treatment at 16\xa0weeks if the psoriasis has not responded adequately. An adequate response is defined as:\n\na 75% reduction in the PASI score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in DLQI from when treatment started.\n\nChoose the least expensive treatment if patients and their clinicians consider bimekizumab to be one of a range of suitable treatments (taking into account availability of biosimilar products, administration costs, dosage, price per dose and commercial arrangements).\n\nTake into account how skin colour could affect the PASI score and make any appropriate clinical adjustments.\n\nTake into account any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI and make any appropriate adjustments.\n\nThese recommendations are not intended to affect treatment with bimekizumab that was started in the NHS before this guidance was published. People having treatment outside these recommendations may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.\n\nWhy the committee made these recommendations\n\nBimekizumab is an alternative to other biological treatments already recommended by NICE for treating severe plaque psoriasis in adults. Evidence from clinical trials shows that bimekizumab is more effective than adalimumab, secukinumab and ustekinumab. Indirect comparisons suggest that bimekizumab is similarly or more effective than other biological treatments.\n\nFor the cost comparison, it is appropriate to compare bimekizumab with brodalumab, risankizumab and ixekizumab because they work in a similar way and would likely be used as an alternative to those treatments. The total costs associated with bimekizumab are similar to or lower than those associated with brodalumab, risankizumab and ixekizumab. Therefore, bimekizumab is recommended as an option for severe plaque psoriasis that has not responded to systemic non-biological treatments, or if these are contraindicated or not tolerated.', 'Information about bimekizumab': "# Marketing authorisation indication\n\nBimekizumab (Bimzelx, UCB Pharma) has a marketing authorisation 'for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy'.\n\n# Dosage in the marketing authorisation\n\nThe dosage schedule is available in the summary of product characteristics.\n\n# Price\n\nThe list price of bimekizumab is £2,443 per 320\xa0mg dose (two 160\xa0mg prefilled syringes or prefilled pens; excluding VAT; price as quoted in company's submission).\n\nThe company has a commercial arrangement. This makes bimekizumab available to the NHS with a discount. The size of the discount is commercial in confidence. It is the company's responsibility to let relevant NHS organisations know details of the discount.", 'Committee discussion': "The appraisal committee considered evidence submitted by UCB Pharma and a review of this submission by the evidence review group (ERG). See the committee papers for full details of the evidence.\n\n# Decision problem\n\n## The company's proposed population is consistent with previous NICE recommendations for biological treatments for psoriasis\n\nThe company's proposed population was narrower than bimekizumab's marketing authorisation because it excluded people who had not had systemic non-biological therapy or phototherapy. It considered that bimekizumab would be used in adults as an alternative to other biological therapies for psoriasis, that is in those whose disease has not responded adequately to non-biological systemic treatment or phototherapy, or if these treatments are contraindicated or not tolerated. The committee concluded that the proposed population was consistent with previous NICE recommendations for biological treatments for psoriasis, and in line with its expected use in clinical practice.\n\n## Brodalumab, risankizumab and ixekizumab are relevant comparators\n\nThe company presented a comparison with 3\xa0NICE-recommended biological treatments (NICE's technology appraisals on brodalumab, risankizumab and ixekizumab for treating moderate to severe plaque psoriasis). The committee noted in a recent guideline from the British Association of Dermatologists (2020) that all of the currently licensed biological therapies are now equally recommended options after non-biological systemic therapy. The committee was aware that adalimumab biosimilars have been available to the NHS since 2019 and are available at considerable discount (exact prices are confidential and cannot be reported here). But it was told that in clinical practice a TNF inhibitor such as adalimumab was frequently used first, followed by an interleukin (IL) inhibitor. Brodalumab and ixekizumab work in a similar way to bimekizumab because they are all IL‑17 inhibitors. Risankizumab, an IL‑23 inhibitor, is the most recent biological treatment for psoriasis to be recommended by NICE. The committee noted that if bimekizumab was recommended it would likely displace other IL inhibitors. It was aware that cost comparison recommendations include a statement to note that if patients and their clinicians consider the intervention to be 1 of a range of suitable treatments, the least expensive should be chosen. The committee agreed that this was consistent with the criteria for a cost-comparison appraisal. It concluded that brodalumab, risankizumab and ixekizumab are relevant comparators, and that they adequately represent the NICE-recommended biological treatments for plaque psoriasis overall.\n\n## Definition of response is consistent with other NICE technology appraisal guidance\n\nThe committee recalled that NICE's technology appraisal guidance on risankizumab for treating moderate to severe plaque psoriasis and other biological treatments recommends that treatment should stop if there is an inadequate disease response after an initial treatment period, usually between 12\xa0and 16\xa0weeks. An adequate response is defined as:\n\na 75% reduction in the Psoriasis Area and Severity Index score (PASI\xa075) from when treatment started or\n\na 50% reduction in the PASI score (PASI\xa050) and a 5‑point reduction in Dermatology Life Quality Index (DLQI) from when treatment started.The committee noted that the definition of response to bimekizumab proposed by the company is in line with these criteria. However, it noted that response to bimekizumab should be assessed after 16\xa0weeks, which is the same as timing for risankizumab, whereas disease response to brodalumab and ixekizumab should be assessed after 12\xa0weeks. The committee concluded that definition of response is consistent with other NICE technology appraisal guidance, although timing of this assessment varies slightly between different biological treatments.\n\n# Clinical effectiveness\n\n## Bimekizumab is more effective than adalimumab, secukinumab and ustekinumab\n\nBimekizumab has been studied in 4\xa0randomised controlled trials including a total of about 2,200\xa0adults with plaque psoriasis. It was directly compared in clinical trials with placebo (BE READY), with placebo and ustekinumab (BE VIVID), with adalimumab (BE SURE) and with secukinumab (BE RADIANT). In these trials, bimekizumab showed higher response rates compared with placebo, ustekinumab, adalimumab and secukinumab for both PASI\xa090 (90% reduction in PASI score) and PASI\xa0100 (100% reduction in PASI score) at week\xa016. The committee accepted that the results of these trials showed that bimekizumab was more effective than adalimumab, secukinumab and ustekinumab.\n\n## The company's network meta-analyses are suitable for decision making\n\nThe company did a series of network meta-analyses on PASI response rates (50, 75, 90 and 100) and safety outcomes. These compared bimekizumab with all other NICE-recommended biological agents and systemic non-biological treatments. The ERG noted that studies included in network meta-analyses varied considerably in the proportion of patients who had had previous biological therapies. It noted that disease response to subsequent biological treatments may be lower than the level of response achieved by the initial biological therapy. However, it explained that because the proportion of people who had previous biological therapy in bimekizumab trials was at the higher end of the range for the network as a whole, this is unlikely to bias the results in favour of bimekizumab. The ERG also noted that the company had not included DLQI as an outcome in the network meta-analysis. However, it was satisfied that the company's approach was appropriate. The committee accepted the ERG's view, concluding that the network meta-analyses provided by the company was suitable for decision making.\n\n## Bimekizumab provides similar or better PASI response rates than other biologicals\n\nThe committee acknowledged that in previous psoriasis appraisals, PASI\xa075 is the key outcome when deciding whether to continue treatment. It noted that the results of the network meta-analysis suggested that bimekizumab was similarly effective compared with brodalumab, risankizumab and ixekizumab in terms of PASI\xa075 response. The committee appreciated that PASI\xa090 and\xa0100 were increasingly becoming important outcomes to patients and were collected in newer clinical trials. It noted that bimekizumab was more effective compared with brodalumab, risankizumab and ixekizumab in terms of PASI\xa090 and\xa0100 response. It noted the safety and tolerability outcomes in the company's network meta-analysis and considered that bimekizumab had a similar safety profile to other biologicals for psoriasis. The committee concluded that bimekizumab provides similar or greater benefits than other biological agents including brodalumab, risankizumab and ixekizumab.\n\n## More frequent dosing of bimekizumab will be rarely used\n\nThe committee noted that summary of product characteristics states that some patients with body weight 120\xa0kg or more who did not have complete skin clearance at week\xa016 (PASI100) may improve further if they increase their dosage (320\xa0mg every 4\xa0weeks rather than every 8\xa0weeks). The company explained that only a small proportion of patients in bimekizumab trials had a body weight 120\xa0kg or more, and had not had a PASI\xa0100 response. Also, it explained that this dosing option will not be mandated in label, nor is it anticipated to be standard dosing regimen for patients. The committee recalled that PASI\xa090 and\xa0100 are important outcomes for patients but PASI\xa075 was a key outcome when deciding whether to continue treatment. It further noted that between 85% and 90% of people having bimekizumab in the clinical trials had a PASI\xa090 response and up to 95% of people had a PASI\xa075 response. It noted people whose disease reached at least a PASI\xa075 response may not be willing to have their dose increased to achieve PASI\xa0100 because of an increased risk of side effects, or the inconvenience of more frequent dosing. The committee concluded that only a very small number of patients might be eligible for an increased dosage, and only a small proportion of them would be willing to have it.\n\n# Cost comparison\n\n## The total costs associated with bimekizumab are similar to or lower than those associated with brodalumab, risankizumab and ixekizumab\n\nThe company presented a cost-comparison analysis that modelled the total costs of bimekizumab and the comparators brodalumab, risankizumab and ixekizumab over 10\xa0years. It took into account stopping treatment based on PASI\xa075 response rates, which was consistent with the stopping rules specified in previous NICE's technology appraisal guidance. The base-case analysis used the same PASI\xa075 response rates and applied the same rate of long-term stopping of treatment during maintenance therapy for all treatments. The base-case analysis assumed similar monitoring, safety profile, treatment administration and subsequent therapies for bimekizumab and the comparators, and therefore excluded these costs. That is, the base-case analysis considered only the acquisition costs of bimekizumab and the comparators. The committee accepted the company's base-case model. The committee was aware that there was the possibility for some patients to have more frequent dosing but recalled that this would only happen in very rare circumstances (see section\xa03.7). Assuming that 10% of patients who are eligible would want to have more frequent dosing had a minimal effect on the cost-comparison results (the results are confidential and cannot be reported here). Considering the confidential patient access schemes for bimekizumab and the comparators, the committee concluded that the total costs associated with bimekizumab were similar to or lower than those associated with brodalumab, risankizumab and ixekizumab (the exact results cannot be reported here because the discounts are confidential).\n\n## Bimekizumab is recommended as an option for treating severe plaque psoriasis in adults\n\nThe committee concluded that the criteria for a positive cost comparison were met because:\n\nbimekizumab provided similar or greater overall health benefits than brodalumab, risankizumab and ixekizumab, and\n\nthe total costs associated with bimekizumab were similar to or lower than the total costs associated with brodalumab, risankizumab and ixekizumab.The committee therefore recommended bimekizumab as an option for treating plaque psoriasis in adults. It concluded that the recommendations for bimekizumab should be consistent with the company's proposal and NICE's recommendations for other biological therapies, that is:\n\nif the disease is severe (that is, a PASI of 10\xa0or more and a DLQI of more than\xa010) and\n\nwhen the disease has not responded to other systemic treatments, including ciclosporin, methotrexate and phototherapy, or these options are contraindicated or not tolerated and\n\nwhen treatment is stopped at 16\xa0weeks if the psoriasis has not responded adequately.If patients and their clinicians consider bimekizumab to be one of a range of suitable treatments, for example brodalumab, risankizumab and ixekizumab, the least expensive should be chosen (taking into account administration costs, dosage, price per dose and commercial arrangements).\n\n## The PASI and DLQI may not be appropriate for all people with psoriasis\n\nThe committee noted, as in previous NICE technology appraisals on psoriasis, potential equality issues:\n\nthe PASI might underestimate disease severity in people with darker skin\n\nthe DLQI has limited validity in some people and may miss anxiety and depression.The committee concluded that, when using the PASI, healthcare professionals should take into account skin colour and how this could affect the PASI score and make the clinical adjustments they consider appropriate. Also, it concluded that, when using the DLQI, healthcare professionals should consider any physical, psychological, sensory or learning disabilities, or communication difficulties that could affect the responses to the DLQI, and make any adjustments they consider appropriate."}
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https://www.nice.org.uk/guidance/ta723
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Evidence-based recommendations on bimekizumab (Bimzelx) for treating moderate to severe plaque psoriasis in adults.
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